Carmine1983.pdf

Drug Eval uations

Drugs 25: 223-289 (1983) 0012-6667/83/0003-0223/$33.50/0 ©ADlS Press Australasia Ply Ltd. All rights reserved.

Cefotaxime A review of its Antibacterial Activity, Pharmacological Properties and Therapeutic Use A.A. Carmine, R.N. Brogden, R.C. Heel, T.M. Speight and G.S. Avery ADIS Drug Information Services, Auckland

Various sections of the manuscript reviewed by: J.P. Fillastre, Faculty of Medicine, Boisguillaume Hospital, Boisguillaume, France; R. Fujii, Department of Paediatrics, Teikyo University School of Medicine, Tokyo, Japan; D.A. Kafetzis, Department of Pediatrics, University of Athens, Greece; S.D.R. Lang, Department of Microbiology, Middlemore Hospital, Auckland, New Zealand; S. Masuy08hi, Department of Microbiology, School of Medicine, Gunma University, Gunma, Japan; P.J. McDonald, Department of Clinical Microbiology, Flinders Medical Centre, Adelaide, Australia; H.C. Neu, Division of Infectious Diseases, College of Physicians and Surgeons of Columbia University, New York, USA; M. Richmond, University of Manchester, England; P.M. Shah, Centre for Internal Medicine, J.W. Goethe University, Frankfurt, Germany; R.C.B. Slack, Department of Microbiology, University Hospital, Queen's Medical Centre, Nottingham, England; C.R. Smith, Department of Medicine, The Johns Hopkins University School of Medicine and The John Hopkins Hospital, Baltimore, Maryland, USA; A.J. Weinstein, Department of Infectious Disease, Cleveland Clinic, Cleveland, Ohio, USA; D.H. Wittman, Surgery Department, Altona General Hospital, Hamburg, Germany.

Contents Summary .................................................................................................................................... 1. Antibacterial Activity ............................................................................................................ l.l In Vitro Inhibitory Activity against Aerobic Bacteria ................................................ 1.1.1 Gram-positive Bacteria.......................................................................................... 1.1.2 Gram-negative Bacteria ........................................................................................ 1.2 In Vitro Inhibitory Activity against Anaerobic Bacteria ............................................ 1.3 Activity of Desacetyl-cefotaxime .................................................................................. 1.4 fJ-Lactamase Resistance ................................................................................................. 1.5 Bactericidal Activity ...................................................................................................... 1.6 Effect on Activity of Inoculum, Media, pH and Serum ............................................ 1.7 Antibiotic Synergy .......................................................................................................... 1.8 Activity In Vivo ............................................................................................................. 2. Renal Tolerance .................................................................................................................... 3. Toxicity Studies .................................................................................................................... 3.1 Acute Toxicity ...............................................................................................................•

224 228 228 229 230 236 237 237 238 239 240 241 242 243 243

224

Cefotaxime: A Review

3.2 Subacute and Chronic Toxicity ...................................................................................... 3.3 Reproduction Studies ...................................................................................................... 4. Pharmacokinetic Studies ........................................................................................................ 4.1 Absorption and Serum Concentration ........................................................................... 4.2 Distribution ...................................................................................................................... 4.2.1 Protein Binding ....................................................................................................... 4.3 Elimination ....................................................................................................................... 4.3.1 Metabolism and Excretion ..................................................................................... 4.3.2 Half-life .................................................................................................................... 4.4 Influence of Age on Pharmacokinetics .......................................................................... 4.5 Influence of Disease on Pharmacokinetics .................................................................... 5. Therapeutic Trials .................................................................................................................. 5.1 Treatment of Established Infections ............................................................................... 5.1.1 Urinary Tract Infections ......................................................................................... 5.1.2 Lower Respiratory Tract Infections ...................................................................... 5.1.3 Bacteraemia/Septicaemia and Endocarditis .......................................................... 5.1.4 Gonorrhoea .............................................................................................................. 5.1.5 Obstetric and Gynaecological Infections ............................................................... 5.1.6 Intra-abdominal Infections ..................................................................................... 5.1.7 Skin, Soft-tissue, Bone and Joint Infections ......................................................... 5.1.8 Infections in Immunologically Compromised Patients ....................................... 5.1. 9 Infections caused by Multiresistant Bacteria and Pseudomonas species ............ 5.1.10 Meningitis in Children and Adults ...................................................................... 5.1.11 Other Paediatric Infections .................................................................................. 5.2 Prevention of Infection in Surgery ................................................................................. 6. Side Effects .............................................................................................................................. 6.1 Local Reactions ................................................................................................................ 6.2 Haematological and Hepatic Effects ............................................................................... 6.3 Renal Effects .................................................................................................................... 6.4 Other Adverse Reactions ................................................................................................. 6.5 Adverse Bacteriological Effects ....................................................................................... 7. Dosage and Administration ................................................................................................... 8. The Place of Cefotaxime in Therapy ....................................................................................

Summary

243 243 244 244 245 249 249 249 251 251 252 253 253 253 257 261 262 263 264 265 266 266 267 269 270 271 271 271 272 273 273 274 275

Synopsis: Cefotaxime l is a new 'third generation' semisynthetic cephalosporin administered intravenously or intramuscularly. It has a broad spectrum of activity against Grampositive and Gram-negative aerobic and anaerobic bacteria, and is generally more active against Gram-negative bacteria than the 'first' and 'second generation' cephalosporins. Although cejotaxime has some activity against Pseudomonas aeruginosa, on the basis ofpresent evidence it cannot be recommended as sole antibiotic therapy for pseudomonal infections. However, cejotaxime has been effective in treating infections due to other 'difficult' organisms, such as multidrug-resistant Enterobacteriaceae. Like other cephalosporins, cefotaxime is effective in treating patients with complicated urinary tract and lower respiratory tract infections, particularly pneumonia caused by Gram-negative bacilli. High response rates have also been achieved in patients with Gram-negative bacteraemia. Although favourable clinical results have been obtained in patients with infections caused by mixed aerobic/anaerobic organisms (such as peritonitis or soft tissue infections), the relatively low in vitro activity of cejotaxime against Bacteroides fragilis may restrict its usage in situations where this organism is the suspected or proven pathogen. In preliminary studies, males and I 'Claforan' (Hoechst, Roussel).

Cefotaxime: A Review

225

females treated with a single intramuscular dose of cefotaxime for uncomplicated gonorrhoea caused by penicillinase-producing strains of Neisseria gonorrhoeae responded very favourably. Encouraging results have also been reported in open studies in children, including neonates, treated with cefotaxime for meningitis and various other serious infections. In some situations, cefotaxime has been given in combination with another antibiotic such as an aminoglycoside, but the merits of such a combination have not been clearly established. Whether cefotaxime alone is appropriate therapy for conditions previously treated with aminoglycosides (other than pseudomonal infections) also needs additional clarification, but if established as equally effective in such conditions cefotaxime offers potentially important clinical and practical advantages in its apparent lack of serious adverse effects and freedom from the need to undertake drug plasma concentration monitoring. Antibacterial Activity: Cefotaxime has a broad spectrum of activity in vitro which includes Gram-positive and Gram-negative aerobic and anaerobic bacteria. Cefotaxime is as active as benzyl penicillin against Streptococcus pneumoniae and pyogenes, but is also very active against penicillin-resistant and multiple drug-resistant strains of Streptococcus pneumoniae. Like other cephalosporins, cefotaxime has poor activity against enterococci (including Streptococcus faecalis). Penicillin-sensitive and -resistant strains of Staphylococcus aureus are inhibited by low concentrations of cefotaxime, but cephalothin and cefamandole are more active against this species. When compared with other 'third generation' cephalosporins, cefotaxime tends to be similar in activity to cefoperazone against S. aureus, but more active than cefoperazone against streptococci in general, and more active than moxalactam against all Gram-positive bacteria. Cefotaxime exhibits both a wider spectrum and greater activity against Gram-negative aerobic bacteria than 'first generation' or 'second generation' cephalosporins, is generally more active than cefoperazone except against Pseudomonas aeruginosa, and similar in activity to moxalactam. A multicentre study in the USA found that over 91% of 6000 clinical isolates of Enterobacteriaceae were inhibited by 0.5 /Lgfml or less of cefotaxime. This antibiotic is active against many cephalothin-resistant and gentamicin-resistant Enterobacteriaceae and against some strains which show multiple drug resistance. Cefotaxime is also active at very low concentrations (MIC90 :E: 0.06 /Lgfml) against fj-lactamase-producing and non-producing strains of Haemophilus influenzae and Neisseria gonorrhoeae. Although cefotaxime tends to be less active than cefoxitin against Bacteroides fragilis, it inhibits most other anaerobic bacteria at low concentrations. Like cefuroxime, cefotaxime is highly stable to degradation by fj-lactamases produced by S. aureus and various Gram-negative bacteria, but not to that produced by B. fragilis. Although desacetyl-cefotaxime, the principal metabolite of cefotaxime, is less active in vitro than the parent compound, it appears to be more active than cefoxitin and cefuroxime against some Gram-negative bacilli. A combination of cefotaxime and gentamicin was found to be synergistic for over onehalf of the strains of P. aeruginosa tested, including gentamicin-resistant strains but not carbenicillin-resistant strains. Similar results were obtained with cefotaxime plus tobramycin against tobramycin-sensitive strains of P. aeruginosa. However, the synergistic activity of cefotaxime and amikacin varied widely between studies. In general, there was usually little difference between minimum bactericidal (MBC) and minimum inhibitory concentrations (MIC) of cefotaxime for most Gram-negative organisms studied. Although results tended to vary from study to study, larger differences have been reported for some species such as Enterobacter, indole-positive Proteus and Pseudomonas aeruginosa. Little information is available on the MBC to MIC relationship for Gram-positive organisms. Renal Tolerance: In studies to date, cefotaxime appeared to be free of adverse effects on renal function. Thus, a renal tolerance study in rabbits found that subcutaneous cefo-

Cefotaxime: A Review

226

taxime (750 or 1500 mg,/kg/day for 7 days), like moxalactam (same dose), but unlike cephaloridine (100 or 200 mg,/kg/day) did not significantly increase plasma creatinine or excretion of the lysosomal enzyme N-acetylglucosaminidase. A study in healthy volunteers which measured urinary excretion of alanine aminopeptidase (an early sensitive indicator of renal tubular damage) found that cefotaxime 6 g,/ day alone or given with frusemide 20 mg,/day did not affect proximal renal tubule function. Similar results were reported in small groups of patients with serious infections (and normal renal function) treated with cefotaxime 6 g,/day alone or combined with azlocillin 15 gJday. Results from this small study also found that cefotaxime given in combination with tobramycin 3 mg,/kg/day did not increase the risk of tobramycin nephrotoxicity. Some patients with impaired renal function have also been treated with cefotaxime, usually without any deterioration in renal function. However, there is relatively little detailed information available on such patients.

Pharmacokinetics: After a lOOOmg intravenous bolus, mean peak plasma concentrations of cefotaxime usually range between 81 and 102 ILgJml. Doses of 500mg and 2000mg produce plasma concentrations of 38 and 200 lLg,/ml, respectively. There is no accumulation following administration of lOOOmg intravenously or 500mg intramuscularly for 10 or 14 days. The apparent volume of distribution at steady-state of cefotaxime is 21.6 L/1.73m2 after 19 intravenous 3D-minute infusions. Concentrations of cefotaxime (usually determined by non-selective assay) have been studied in a wide range of human body tissues and fluids. Cerebrospinal fluid concentrations are low when the meninges are not inflamed, but are between 3 and 30 lLg,/ml in children with meningitis. Concentrations (0.2-5.4 1Lg,/ ml) inhibitory for most Gram-negative bacteria, are attained in purulent sputum, bronchial secretions and pleural fluid after doses of 1 or 2g. Concentrations likely to be effective against most sensitive organisms are similarly attained in female reproductive organs, otitis media effusions, prostatic tissue, interstitial fluid, renal tissue, peritoneal fluid and gallbladder wall, after usual therapeutic doses. High concentrations of cefotaxime and desacetyl-cefotaxime are attained in bile. Cefotaxime is partially metabolised prior to excretion. The principal metabolite is the microbiologically active product, desacetyl-cefotaxime. Most of a dose of cefotaxime is excreted in the urine, about 60% as unchanged drug and a further 24% as desacetyl-cefotaxime. Plasma clearance is reported to be between 260 and 390 ml/minute and renal clearance 145 to 217 ml/minute. After intravenous administration of cefotaxime to healthy adults, the elimination halflife of the parent compound is 0.9 to 1.14 hours and that of the deSacetyl metabolite, about 1.3 hours. In neonates the pharmacokinetics are influenced by gestational and chronological age, the half-life being prolonged in premature and low birth weight babies relative to that in term and average birth weight neonates of the same age. In severe renal dysfunction the elimination half-life of cefotaxime itself is increased minimally to about 2.5 hours, whereas that of desacetyl-cefotaxime is increased to about 10 hours. Total urinary recovery of cefotaxime and its principal metabolite decreases with reduction in renal function. Therapeutic Trials: Published studies on several thousand patients have documented the efficacy of cefotaxime (usual dosage, 2 to 6 gJdayat 6-, 8- or 12-hourly intervals) in a wide range of infections caused by Gram-positive and Gram-negative aerobic bacteria and, occasionally, anaerobic bacteria. Cefotaxime has been used successfully in patients who had failed to respond to other antibiotics, and in infections caused by organisms resistant to usual therapy, such as: Enterobacteriaceae resistant to other cephalosporins, gentamicin and/or carbenicillin; Serratia marcescens and Klebsiella pneumoniae resistant

Cefotaxime: A Review

227

to all commercially available antibiotics; ampicillin-resistant Haemophilus influenzae; and penicillin-resistant Neisseria gonorrhoeae. Although cefotaxime alone was effective in some patients with pseudomonal infections, on the basis of present evidence it cannot be recommended as the sole antibiotic for suspected or confirmed pseudomonal infections. A large number of patients with urinary tract infections, many of which were complicated by underlying urological abnormalities, have been treated successfully with cefotaxime in open or controlled studies. About 70 to 90% of infecting strains of cefotaximesensitive Gram-negative organisms were eradicated from patients with complicated and uncomplicated urinary tract infections immediately following treatment with cefotaxime 2 gfday. In general, E. coli. Klebsiella species, indole-positive and -negative Proteus. Enterobacter and Citrobacter species were eradicated more successfully than Pseudomonas and Serratia species. Although large studies in patients with complicated urinary tract infections have shown intravenous cefotaxime in a dose of 2 gfday to be significantly (p < 0.01) superior to cefazolin 4 gfday, ceftezole 4 gfday and sulbenicillin 10 gfday, caution must be exercised in interpreting these results because of the manner in which response was assessed. Results from smaller comparative studies suggested that better bacteriological responses were obtained with cefotaxime 2 gfday, than with cefazolin 2 gfday, cefuroxime 2.25 gfday, cefoxitin 3 gfday, or gentamicin 160 mgfday in various types of urinary tract infections. However, these results require confirmation in well-controlled studies. Cefotaxime has been studied in many hospitalised patients with lower respiratory tract infections, frequently caused by Streptococcus pneumoniae. Haemophilus influenzae. Klebsiella species, E. coli and Proteus mirabilis. 75 to 100% of patients with pneumonia showed complete resolution or improvement in clinical signs and symptoms and chest radiographs. In a large comparative study in patients with mild to moderate pneumonia complicated by underlying respiratory disease, or in patients with other lower respiratory tract infections, cefotaxime 4 gfday was as effective clinically, but more effective bacteriologically, than intravenous cefazolin 4 gfday. However, only 35% of 218 patients in this study were bacteriologically assessable. In the treatment of patients with septicaemia/bacteraemia, cefotaxime-sensitive Gramnegative bacteria such as E. coli. Klebsiella and Proteus species were isolated most frequently and over 90% of these organisms were eradicated from blood. Bacteraemia caused by Serratia marcescens. Pseudomonas species and Gram-positive bacteria was also treated successfully with cefotaxime alone. Intra-abdominal infections such as peritonitis, and to a lesser extent hepatic and biliary infections, have also been treated with cefotaxime, often as an adjunct to surgery. Cefotaxime 80 mgfkgJday was as effective as a combination of gentamicin 3 mgfkgJday and a rather lower than usual dose of clindamycin (20 mgfkgJday) in treating patients with peritonitis (85% vs 82% cured, respectively) and similar polymicrobial soft-tissue surgical sepsis, despite in vitro susceptibility results suggesting superior activity of the combination therapy. Satisfactory clinical responses occurred in over 86% of patients treated with cefotaxime (often in conjunction with surgical procedures) for skin and soft tissue infections (average dose 4 gfday) or osteomyelitis (average dose 9 g,lday) caused by Gram,positive aerobes (such as S. aureus), Gram-negative aerobes and by anaerobes. In general, over 90% of women with a variety of obstetric and gynaecological infections have responded to cefotaxime, sometimes in conjunction with surgery. Similar response rates of 96 to 100% have been reported in patients (usually male) treated with a single intramuscular injection of cefotaxime for uncomplicated gonorrhoea caused by penicillinase-producing or non-penicillinase-producing strains of Neisseria gonorrhoeae. Encouraging results have been obtained with cefotaxime used alone or in combination with another antibiotic in the treatment of patients (mainly neonates and infants) with meningitis caused by the major meningeal pathogens, H. influenzae. S. pneumoniae and N. meningitidis, and also by Gram-negative bacilli (e.g. E. coli and Klebsiella species),

Cefotaxime: A Review

228

including strains resistant to traditional therapy. To date, published clinical experience in other difficult therapeutic areas such as endocarditis, or suspected or proven infections in granulocytopenic and/or cancer patients is rather limited. Several hundred children with various other types of serious infections have also been treated in open studies with cefotaxime alone or in combination with another antibiotic such as an aminoglycoside or penicillin. In general, clinical response rates varied from about 90% for children with septicaemia, gastrointestinal or multiple infections, to 100% for infections of the respiratory and urinary tracts treated with cefotaxime alone. Several studies in children with bacteriologically confirmed infections found that over 90% of the pathogens (predominantly cefotaxime-sensitive Gram-negative bacteria) were eradicated with cefotaxime alone. Dosages usually ranged between 50 and 100 mgjkgjday, given at 6-, 8-, or l2-hourly intervals. In some countries cefotaxime is approved for perioperative use to reduce the incidence of postoperative infections in patients undergoing contaminated or potentially contaminated surgery, and in women undergoing caesarean section. Favourable results after prophylactic perioperative treatment with cefotaxime have been reported in several branches of surgery, such as genitourinary, abdominal, gynaecological and obstetric surgery.

Side effects: Cefotaxime has generally been well tolerated by adults and children following intravenous or intramuscular injection. The most commonly reported adverse clinical effects were reactions at the injection site such as pain on intramuscular injection (similar in intensity and incidence to that occurring with procaine penicillin G), and phlebitis (5%). Rash (2%), diarrhoea (1 %) and variations in laboratory test results including transient elevations of renal and liver function tests have occurred with cefotaxime, but symptomatic drug-related nephrotoxicity or hepatotoxicity have not been reported. Superinfection (1.2%) and colonisation (1.6%) caused by cefotaxime-resistant Pseudomonas species or other Gramnegative bacilli, group D streptococci or Candida have occurred in patients treated with cefotaxime, particularly those who were seriously ill. Dosage: Cefotaxime can be administered intravenously or intramuscularly. For adults with uncomplicated infections the usual dosage is Ig 12-hourly, while for those with moderate to severe infections 1 to 2g may be given 6- or 8-hourly, up to a maximum of 12 gj day. The recommended dose in neonates, infants and children usually varies between 50 and 150 mgjkgjday given 6- to 12-hourly, up to a maximum of 200 mgjkgjday in serious infections.

1. Antibacterial Activity

1.1 In Vitro Inhibitory Activity against Aerobic Bacteria

Cefotaxime (fig. 1) is a 'third generation'· cephalosporin administered by intravenous or intramuscular injection. It has a broad spectrum of activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria, and is generally more active against Gram-negative bacteria than the 'first generation' and 'second generation' cephalosporins.

The antibacterial activity of cefotaxime has been studied extensively in various parts of the world, particularly the USA, UK, Europe and Japan. Wellreported studies in which a relatively large number of strains (usually clinical isolates) were tested, using an inoculum of 104 to 106 colony-forming units (cfu), are reviewed here. In the following discus-

• Although structurally cefoxitin is a cephamycin-derivative and moxalactam (also known as lamoxactam and latamoxef) is an oxa-j3-lactam, these antibiotics are referred to in this review

as 'second generation' and 'third generation' cephalosporins, respectively, as is common practice because of their spectra of antibacterial activity.

229

Cefotaxime: A Review

sion, the concentration at which 'most' organisms were inhibited, generally refers to the concentration which inhibited 90% of the organisms (MIC90), and the concentration which inhibited 'many' organisms usually refers to inhibition of 50% of the organisms (MIC so ). Concentrations of cefotaxime said to be indicative of 'sensitivity' or 'resistance' to the drug in vitro have varied from place to place and as experience with the drug has increased. For example, bacterial isolates are now considered to be sensitive in vitro if the MIC is not more than 16 ~gjml, while an MIC of 64 ~gjml or greater is generally considered to indicate resistance.

1.1.1 Gram-positive Bacteria Cefotaxime usually inhibits 90% of strains of Staphylococcus aureus at a concentration of 2 to 4

COON a N..... OCH 30~

) CH,OCOCH 3 N:-.;::

I'i

II

N --rC-CONH---r--t-..

H,N

JlJ

H S

H

S

Cefotaxime

6¥

OH

r\ H,C,-N

H

0

CH 3

N:)CH'SIl~'N

N-CONH--C--CONH--~I'~ I t---f.-. s

'-./ II \\

o

COONa

O~

H

N1

1I

N

H

Cefoperazone

COONa

0""" HO--{5\

CH 3 I

N~CH'SlIN'N

CHCONH-A ) CH 30 H 0 COONa

~I

N-~

Moxalactam

Fig. 1. Structural formulae of cefotaxime sodium, cefoperazone sodium and moxalactam disodium.

~gjml (Braveny et aI., 1979; Fuchs et aI., .1980; Hamilton-Miller et aI., 1978; Masuyoshi et aI., 1980; Neu et aI., 1979a; Sosna et aI., 1978; Wise et aI., 1980a), and is equally active against penicillin-sensitive and penicillin-resistant strains (Barry et aI., 1980; Hall et aI., 1980a; King et aI., 1980; Knothe, 1980; Shah et aI., 1978). However, like cefazolin and cefoxitin, cefotaxime has poor activity against methicillin-resistant strains of S. aureus, with MIC90 values generally 32 ~gjml or greater (Barry et aI., 1980; Cherubin et aI., 1981; Kayser 1980a), although in 1 study (Hall et aI., 1980a) all 38 such isolates were inhibited by 4 ~gjmI. When the activity of various cephalosporins against S. aureus was compared, cefotaxime was found to be less active than cephalothin (Barry et aI., 1980; Braveny et aI., 1979; Hall et aI., 1980a; Sosna et aI., 1978) and cefamandole (Barry et aI., 1980; Counts and Turck, 1979; Kayser, 1980b; Neu et aI., 1979a), more active than moxalactam (Barry et aI., 1980; Wasilauskas, 1981; Wise et aI., 1980a), and generally comparable with cefoperazone (Hall et aI., 1980; Katsu et aI., 1982; Kayser, 1980b; Trager et aI., 1981). Staphylococcus epidermidis tends to be less sensitive to cefotaxime than S. aureus, with most strains usually being inhibited by 8 ~gjml (Fuchs et aI., 1980; Hall et aI., 1980a; Sosna et aI., 1978; Wasilauskas, 1981), although a high concentration (64 ~g/ml) was required to inhibit 90% ofthe penicillinase-producing strains studied by Hall et aI. (l980a). As occurs with S. aureus, cefotaxime is usually more active than moxalactam (Hall et aI., 1980a; Neu et aI., 1979b; Verbist and Verhaegen, 1981), but less active than cephalothin (Fuchs et aI., 1980; Neu et aI., 1979b; Sosna et aI., 1978) against S. epidermidis. Streptococcus pneumoniae and Streptococcus pyogenes (group A) are very sensitive to cefotaxime, with most isolates being inhibited by 0.1 and 0.25 ~gjml or less, respectively (Barry et aI., 1980; Hall et aI., 1980a; Neu et aI., 1979a; Verbist and Verhaegen, 1980). Concentrations as low as 0.02 ~gjml frequently inhibit these organisms (Hall et

Cefotaxime: A Review

aI., 1980a; Masuyoshi et aI., 1980; Verbist and Verhaegen, 1980). Cefotaxime also inhibits penicillinresistant and multidrug-resistant strains of S. pneumoniae at low concentrations (e.g. ~ 2 p,gjml; Cherubin et aI., 1981; Goldstein et aI., 1982; Hansman, 1981; Landesman et aI., 1981c). Against penicillin-susceptible strains of S. pneumoniae and S. pyogenes, cefotaxime is as active as benzyl penicillin, slightly more active than cefoperazone and more active than moxalactam (Hall et aI., 1980a; Landesman et aI., 1981c). Cefotaxime is also active against other streptococcal species such as S. agalactiae and viridans streptococci. 90% of strains of S. agalactiae (group B streptococci) were inhibited at very low concentrations (e.g. 0.1 p,gjml) [Hamilton-Miller et ai., 1978; Landesman et ai., 1981a; Neu et ai., 1979a; Verbist and Verhaegen, 1980], while the concentration required to inhibit 90% of the few strains tested of viridans streptococci varied from 0.125 p,g/ml (Cherubin et ai., 1981) to 3.1 p,g/ml (Fu and Neu, 1980). In general, cefotaxime is more active in vitro than cefoperazone and moxalactam against streptococci (Hall et ai., 1980a; Kayser, 1980b; landesman et aI., 1981c; Neu et ai., 1979b,c). However, like other cephalosporins, very high concentrations of cefotaxime (MIC 5o ~ 64 p,gjml) are required to inhibit enterococci (including S. faecalis) in vitro (Braveny et ai., 1979; Fuchs et ai., 1980; Hall et aI., 1980a; Neu et ai., 1979b; Sosna et ai., 1978; Verbist and Verhaegen, 1981; Wasilauskas, 1981).

1.1.2 Gram-negative Bacteria As a 'third generation' cephalosporin, cefotaxime exhibits a wider spectrum of activity and greater potency against Gram-negative organisms than the 'first generation' and 'second generation' cephalosporins. Indeed, over 91 % of 6083 clinical isolates of the Enterobacteriaceae (studied in 6 laboratories in the USA) were inhibited by ~ 0.5 p,gj ml of cefotaxime (the minimum concentration used). Hence, cefotaxime was 8 to 64 times more active than cephalothin (Fuchs et ai., 1980). Nu-

230

merous in vitro studies (see below) have shown that E. coli, Klebsiella species, P. mirabilis, Salmonella and Shigella species, H. injIuenzae, N. gonorrhoeae, N. meningitidis and Citrobacter diversus are very susceptible to inhibition by cefotaxime (MIC9o values of 1 p,gjml or less). Providencia species are also susceptible to cefotaxime, but activity against indole-positive Proteus species and Morganella morganii can vary widely from high to moderate activity (MIC 9o values of 0.2 to 8 p,gjml). Although the concentrations of cefotaxime required to inhibit most strains (90%) of Serratia (1 to 16 p,gjml) and Enterobacter species (~ 8 p,g/ml or > 32 p,gjml) also varied widely, many of these organisms (about one-half the strains tested in each study) were frequently inhibited by 0.5 p,g/ml or less. In general, many Pseudomonas aeruginosa isolates are moderately sensitive to cefotaxime, but a proportion are resistant and thus concentrations of 64 p,gjml or more were usually required to inhibit 90% of the strains tested. Cefotaxime appears to be more active against Acinetobacter calcoaceticus subspecies lwoffi than against the anitratus subspecies of Acinetobacter calcoaceticus. The in vitro activity of cefotaxime against various Gram-negative organisms is compared with that of moxalactam, cefoperazone and cefamandole in table I, and with gentamicin, tobramycin, amikacin, cefoxitin and ticarcillin in table II.

Escherichia coli E. coli is very susceptible to cefotaxime, with most strains usually being inhibited by concentrations of 0.12 to 0.5 p,gjml (Braveny et ai., 1979; Fuchs et ai., 1980; Hall et ai., 1980a; Masuyoshi et ai., 1980; Neu et ai., 1979c; Shah et ai., 1978; Sosna et ai., 1978; Verbist, 1981a). In studies which used very low concentrations of the drug, 0.06 p,gjml or less often inhibited 50% of isolates tested (Hall et ai., 1980a; Lang et ai., 1980; Wise et aI., 1980a; Verbist, 1981a). Cefotaxime was active against most cephalothin-resistant strains of E. coli, but higher concentrations than

Table I. Antibacterial activity in vitro of cefotaxime, moxalactam, cefoperazone and cefamandole against Gram-negative aerobes. Inoculum size was 10s cOlonyforming units (after Hall et aI., 1980a,b)

Organism (no. of isolates)

0'

Antibiotic MIG (ltg/ml)

6i x

cefotaxime range

moxalactam MIGso

(') CD

MIGgo

range

cefoperazone MIGso

MIGgo

range

3'

cefamandole MIGso

MIGgo

range

!'!

MIG so

MIGgo

»

:II

<0.03-64

<0.03

0.12

0.03->128

0.06

<0.03-16

0.03

0.12

0.12-128

0.25

<0.03-0.06

<0.03

<0.03

0.06-1

0.12

<0.03-<0.03

<0.03

<0.03

<0.03-0.25

<0.03-4

<0.03

0.06

M. morganii (27)

<0.03->128

<0.03

P. rettgeri

<0.03-4

<0.03

<0.03-8

0.12

S. marcescens' (61)

0.12-16

0.25

E. cloacae

<0.3-128

0.12

<0.03-64

0.06

8->128

C. diversus (18)

E. coli

0.25

<0.03-32

0.12

0.25-64

0.5

2

0.06->128

4

0.25->128

8

128

0.25

<0.03-8

0.5

0.12-32

0.5

4

0.06

0.12

<0.03-1

0.12

0.25

0.12-4

0.5

2

0.12->128

0.25

0.5

0.06-8

0.12

0.25

0.5->128

8

8

8

<0.03->128

0.12

0.25

0.12-32

0.5

16

0.5-128

2

32

0.06

<0.03-0.25

<0.03

0.25

<0.03-16

0.25

4

<0.03-16

0.12

4

0.06-8

0.12

0.5

0.12-32

2

4

0.12-32

2

8

0.12->128

0.5

4

0.5-128

8

16

4->128

128

>128

0.06-32

0.12

<0.03->128

0.12

32

0.5->128

2

128

4

0.12-8

0.25

0.06->128

0.25

8

0.5->128

2

32

16

128

2->128

16

64

0.5-64

4

16

>128

>128

>128

<0.03-1

0.06

0.25

0.06-1

0.06

0.25

<0.03-16

0.25

2

0.5-32

8

C. freundii (30)

<0.03-32

0.12

8

0.12->128

0.12

2

0.06-64

0.5

16

0.5->128

32

N. gonorrhoeae 2

<0.001-0.03

<0.001

0.01

<0.001-0.025 0.03

0.06

<0.001-0.12

0.01

0.06

(114) K. pneumoniae'

CD

<

(ii'

::e 128

(62) K.oxytoca

(21) P. mirabilis

(30) P. vulgaris

(29)

(29) P. stuartii

(27) 4

(26) E. aerogenes

(20) P. aeruginosa'

(63)

... 3

. .. 3

(27)

1 2 3

Includes gentamicin-sensitive (MIG ~ 4 Itg/ml) and gentamicin-resistant (MIG", 8 Itg/ml) strains, for which the MIGs of cefotaxime were very similar. Includes penicillinase-producing and non-penicillinase-producing strains, for which the MICs of cefotaxime were very similar. No data for cefamandole, but for penicillin G, range = <0.001->128; MIC so = 0.25 and MIC go = 128.

I\)

~

Cefotaxime: A Review

those required for cephalothin-sensitive strains were usually needed (Sosna et al., 1978; Verbist; 1981 b). Similarly, Knothe et al. (1980) reported higher MICs of cefotaxime for t1-lactamase-positive strains of E. coli than for t1-lactarnase-negative strains (MIC 9o of 1.0 and 0.125 #LgJml, respectively). Cefotaxime was also very active against a small number of gentamicin-resistant strains of E. coli (MIC9Q = 0.125 #LgJml) [Jorgensen et al., 1980b]. When compared with other antibiotics, cefotaxime was usually slightly more active (a 2-fold difference in MICs) than moxalactam (Braveny et al., 1982; Delgado et al., 1979; Hall et al., 1980a) against E. coli, several-fold more active than cefoperazone (Braveny et al., 1982; Hall et al., 1980a; Kurtz et al., 1980), and markedly more active than cefamandole (Neu et al., 1979c), cefoxitin and cefuroxime (Braveny et al., 1979; Wise et al., 1980a), cefazolin (Braveny et al., 1979; Shah et al., 1978), cephalothin (Shah et al., 1978; Verbist, 1981a), and the aminoglycosides (Delgado et al., 1979).

Klebsiella species Cefotaxime is very active against Klebsiella species, with most isolates of this genus (Fuchs et al., 1980; Knothe, 1980; Lang et al., 1980) and of K. pneumoniae in particular (Delgado et al., 1979; Masuyoshi et al., 1980; Shah et al., 1978; Sosna et al., 1978; Verbist, 1981a) usually inhibited by 0.12 to 0.5 #LgJml. Like E. coli, many isolates (50%) of K. pneumoniae were inhibited at a very low concentration of 0.06 #Lg/ml or less (Fu and Neu, 1980; Masuyoshi et al., 1980; Verbist, 1981a). Cefotaxime is active against cephalothin-resistant strains of Klebsiella species, usually at concentrations only slightly higher than those required for cephalothin-sensitive isolates (Sosna et al., 1978; Verbist, 1981 b). Many gentamicin-resistant strains are also inhibited by low concentrations (e.g. 0.125 #LgJml) of cefotaxime (Braveny and Dickert, 1979; Hall et al., 1980a; Machka et al., 1980; Stephens et al., 1979), although some such strains may require higher concentrations (e.g. 8 to 32 ~ml) for inhibition (Drasar et al., 1978; Hall et al., 1980a; Le-

232

gakis et al., 1980). Compared with other antibiotics, cefotaxime was generally slightly more active (2- to 4-fold) against K. pneumoniae than moxalactam (Delgado et al., 1979; Verbist, 1981a; Verbist and Verhaegen, 1981), several-fold more active than cefoperazone (Kurtz et al., 1980), tobramycin and gentamicin (Delgado et al., 1979), and markedly more active than cefamandole and cefoxitin (Fu and Neu, 1980; Masuyoshi et al., 1980; Wise et al., 1980a).

Proteus and Providencia species Proteus mirabilis is so susceptible to cefotaxime that 90% of isolates were frequently inhibited at the lowest concentration used for in vitro testing, whether it was 0.5 #LgJml (Fuchs et al., 1980), 0.2 #Lgfml (Sosna et al., 1978), 0.125 #Lgfml (Braveny et al., 1979), or even 0.03 #Lgfml (Hall et al., 1980a; Lang et al., 1980). However, Proteus vulgaris, Morganella morganii (Barry et al., 1980; Hall et al., 1980a; Knothe, 1980; Masuyoshi et al., 1980) and indole-positive Proteus species in general (Braveny et al., 1979; Delgado et al., 1979; Fuchs et al., 1980; Kurtz et al., 1980; Trager et al., 1981), were less sensitive to cefotaxime compared with P. mirabilis. MIC90 values for these organisms varied widely between studies; for example, from less than 0.12 to 8 #Lgfml. However, in most studies 50% of the strains tested were inhibited by 0.5 #Lgfml or less. 90% of strains of Providencia stuartii (inconstans) and P. rettgeri were usually inhibited by 0.4 to 4 #Lgfml (Hall et al., 1980a; Knothe, 1980; Masuyoshi et al., 1980; Neu et al., 1979c; Verbist, 1981a). Moxalactam is also extremely active against P. mirabilis (Hall et al., 1980a; Verbist, 1981a; Wise et al., 1980a), while cefoperazone is slightly less active than cefotaxime (Hall et al., 1980a; Lang et al., 1980). Cefotaxime is more active than the second generation cephalosporins (Braveny et al., 1979) and the aminoglycosides against P. mirabilis (Delgado et al., 1979). The activity of cefotaxime against indole-positive Proteus species is generally comparable with that of moxalactam (Trager et al., 1981) - although moxalactarn appears to be more

233

Cefotaxime: A Review

active against M. morganii (Barry et aI., 1980; Hall et aI., 1980a) - and greater than that of cefoperazone (Neu et aI., 1979c; Trager et al., 1981). Cefotaxime aIso has slightly greater activity than cefoperazone, and similar activity to moxalactam, against Providencia species (Hall et al., 1980a). These organisms, and indole-positive Proteus species, are less sensitive to cefoxitin, and tend to be less susceptible to the aminoglycosides, than to cefotaxime (Barry et aI., 1980). Indeed, cefotaxime is often reasonably active against gentamicin-resistant strains of Proteus mirabilis (Legakis et aI., 1980) and Providencia species (Drasar et aI., 1978; Stephens et aI., 1979), and moderately active against indole-positive Proteus species resistant to gentamicin (Legakis et aI., 1980). Cefotaxime is very active against cephalothin-resistant isolates of P. mirabilis (Legakis et aI., 1980; Verbist, 1981b) and Proteus species in general (Sosna et aI., 1978).

Serratia species Although there was wide vanatton between studies in the concentration of cefotaxime required to inhibit 90% of isolates of Serratia species and S. marcescens (e.g. from 1 to 16 "Wml), in most studies 50% of strains tested were inhibited by 0.5 "g/ml or less (Barry et aI., 1980; Delgado et aI., 1979; Fuchs et aI., 1980; Knothe, 1980; Masuyoshi et al., 1980; Verbist, 1981a). When gentamicin-resistant strains of S. marcescens were studied, about one-haIf the strains tested in each study were inhibited by low concentrations (e.g. < 2 "g/ml) of cefotaxime (HaIl et al., 1980a; Markowitz and Sibilla, 1980), but relatively high concentrations (e.g. 16 and 25 "wml) were usually required to inhibit 90% of such isolates (Jorgensen et aI., 1980b; Markowitz and Sibilla, 1980). Cefotaxime showed similar activity against gentamicinresistant and gentamicin-sensitive strains of S. marcescens in the study by HaIl et al. (1980a), but other authors (Markowitz and Sibilla, 1980; Trager et aI., 1981) reported about a 4-fold increase in MICs for gentamicin-resistant strains. Fu and Neu (1980) studied strains of S. marcescens which

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234

Cefotaxime: A Review

showed multiple resistance to aminoglycosides and other (j-Iactam antibiotics and found that the majority of these were also resistant to cefotaxime (MIC 5o of 25 ~gjml). When compared with other antibiotics used in the treatment of Serratia infections, cefotaxime seems to have similar in vitro activity to gentamicin against gentamicin-sensitive strains of Serratia species (Trager et aI., 1981; Wasilauskas, 1981), but is considerably more active than cefoxitin (Delgado et aI., 1979). Cefotaxime is also more active than cefoperazone (Hall et aI., 1980a), and generally comparable to moxalactam (Barry et aI., 1980; Delgado et aI., 1979; Hall et aI., 1980a).

Enterobacter species While many authors found that most of their isolates of Enterobacter species were inhibited by 8 ~g/ml or less of cefotaxime (Delgado et aI., 1979; Fuchs et aI., 1980; Hall et aI., 1980a), some reported MIC 90 values of at least 32 ~g/ml (Braveny et aI., 1979; Masuyoshi et aI., 1980; Wasilauskas, 1981). Nevertheless, 50% of isolates tested were frequently inhibited by 0.5 ~gjml or less (Braveny et aI., 1979; Hall et aI., 1980a; Sosna et aI., 1978). In general, there was little difference in the susceptibility of E. cloacae and E. aerogenes to cefotaxime (Barry et aI., 1980; Delgado et aI., 1979; Neu et aI., 1979c). When compared with cefotaxime, cefoperazone showed similar activity against E. aerogenes, but was much less active against E. cloacae (Hall et aI., 1980a; Neu et aI., 1979c). Moxalactam was at least as active as cefotaxime, or more so, against Enterobacter species (Barry et aI., 1980; Gentry et aI., 1980; Hall et aI., 1980a; Verbist, 1981a). Cefotaxime is more active than cefamandole (Delgado et aI., 1979; Hall et aI., 1980a) but usually less active than gentamicin against Enterobacter species (Barry et aI., 1980; Wasilauskas, 1981). However, the strains tested by Delgado et ai. (1979) [most of which were gentamicin-sensitive] were less suceptible to gentamicin than to cefotaxime (see table II). In general, most strains of

Enterobacter species which are gentamicin-resistant, are also resistant to cefotaxime (Legakis et aI., 1980; Machka et aI., 1980), although this was not the case in the study by Drasar et ai. (1978) which used a low inoculum (10 3 cfu) of gentamicinresistant E. cloacae. Pseudomonas species Unlike previously available cephalosporins, the third generation of this class of antibiotics has some activity against P. aeruginosa. Although cefotaxime is active against some strains of this organism, the extent of the drug's activity in vitro has varied widely among laboratories; for instance, Kurtz et ai. (1980) found that only 5% of their 150 isolates were inhibited by a concentration of 32 ~g/ml, but elsewhere in the USA Sosna et ai. (1978) reported that 86% of 155 isolates were inhibited at 12.5 ~g/mi.

In numerous studies, at least 50% of P. aeruginosa isolates tested were moderately sensitive to cefotaxime (MIC ~ 16 ~g/ml) [Barry et aI., 1980; Braveny et aI., 1979; Delgado et aI., 1979; Fuchs et aI., 1980; Lang et aI., 1980; Masuyoshi et aI., 1980; Shah et aI., 1978; Yourassowsky et aI., 1980], while in other studies, higher concentrations (~ 32 ~g/ml) were required for inhibition of one-half the isolates tested (Knothe, 1980; Kurtz et aI., 1980; Verbist, 1981a). In general, at least 64 ~gjml of cefotaxime is required to inhibit 90% of P. aeruginosa isolates (Braveny et aI., 1979; Fuchs et aI., 1980; Hanslo et aI., 1981; Neu et aI., 1979a). When compared with other drugs used to treat infections due to P. aeruginosa, cefotaxime was usually less active than tobramycin and gentamicin (Delgado et aI., 1979; Kurtz et aI., 1980; Neu et aI., 1979a); it tended to be more active than carbenicillin (Neu et aI., 1979a; Shah et aI., 1978), showed similar activity to ticarcillin and was less active than piperacillin (Barry et aI., 1980; Delgado et at., 1979). Strains of P. aeruginosa which were resistant to gentamicin also tended to be resistant to cefotaxime, as shown in the studies by Hall et ai. (1980a), Machka et ai. (1980), Trager et ai. (1981) and

235

Cefotaxime: A Review

Woolfrey et al. (1981 in which at least half of the gentamicin-resistant isolates required 25 p.g/ml of cefotaxime or more for inhibition. An even higher degree of cross-resistance to cefotaxime was observed with carbenicillin-resistant, and ticarcillinresistant isolates of P. aeruginosa (Woolfrey et aI., 1981; Yourassowsky et aI., 1980). Although the minimum inhibitory concentrations of cefotaxime and moxalactam are usually several-fold higher than those of cefoperazone for P. aeruginosa (Fu and Neu, 1980; Hall et aI., 1980a; Kurtz et aI., 1980; Lang et aI., 1980; Woolfrey et aI., 1981), the relative in vitro activity of these antibiotics can depend on whether activity is assessed by MIC titration, turbidimetric studies, or the organism's morphological response (Greenwood and Eley, 1982). In general, cefotaxime appears to have rather greater activity against some pseudomonal species, such as P. cepacia, but less activity against others such as P. maltophilia than it has against P. aeruginosa (Applebaum et aI., 1982; Hanslo et aI., 1981; Jorgensen et aI., 1980b; Masuyoshi et aI., 1980).

Haemophilus species Haemophilus species are extremely susceptible to cefotaxime, with most strains of H. influenzae and H. parainjluenzae being inhibited by 0.06 p.g/ ml or less (Baker et aI., 1980; Braveny et aI., 1980; Howard et aI., 1979; Khan et aI., 1980; King et aI., 1980; Masuyoshi et aI., 1980; Wise et aI., 1980a), although higher concentrations (e.g. 0.8 p.g/ml) are required occasionally (Neu et aI., 1979c). In addition to being more active than ampicillin against tl-lactamase-negative strains of Haemophilus (Baker et aI., 1980; Braveny et aI., 1980), cefotaxime has the additional advantage of also being highly active against tl-Iactamase-producing strains (Baker et aI., 1980; Howard et aI., 1979; Khan et aI., 1980), and against multiresistant strains of Haemophilus species (Braveny and Machka, 1980). Cefotaxime is considerably more active than cefamandole and cefuroxime (Braveny et aI., 1980; Howard et aI., 1979; Khan et aI., 1980), slightly

more active than cefoperazone (Baker et aI., 1980), and at least as active as moxalactam against Haemophilus species in general, but possibly slightly more active against tl-Iactamase-producing strains (Braveny and Machka, 1980; Jorgensen et aI., 198Oc; Khan et aI., 1980; Wise et aI., I 980a).

Neisseria species Both tl-Iactamase-producing and non-producing strains of Neisseria gonorrhoeae are highly susceptible to cefotaxime, with most isolates being inhibited by 0.06 p.g/ml or less (Baker et aI., 1980; Hall et aI., 1980a; Khan et aI., 1981; Piot et aI., 1979; 1980; Sng et al., 1981). Hence, like moxalactam and cefoperazone, cefotaxime is more active than penicillin, cefuroxime, cefamandole and cefoxitin against tl-Iactamase-producing and non-producing strains of N. gonorrhoeae (Baker et aI., 1980; Hall et al., 1980a; Ng et al., 1981; Piot et aI., 1979; 1980). Cefotaxime is also extremely active against N. meningitidis. In 1 non-comparative study 96.5% of 150 strains were inhibited by a concentration of 0.004 p.g/ml, and all isolates were inhibited by ~ 0.016 p.g/ml (Brown and Fallon, 1979). In comparing the susceptibility of 30 clinical isolates of N. meningitidis to various tl-lactam antibiotics, Scribner et al. (l982b) reported MIC90 values of 0.001 p.g/ml for cefotaxime, 0.008 p.g/ml for moxalactam, 0.016 p.g/ml for cefoperazone and 0.12 p.g/ml for ampicillin and penicillin. Other Gram-negative Organisms Many strains of Citrobacter diversus and Citrobacter freundii are highly susceptible to cefotaxime (MIC 5o ~ 0.25 p.g/ml), but the concentration required to inhibit 90% of strains is usually considerably higher for C. freundii (MIC9o ~ 8 p.g/ml) than for C. diversus (MIC90 ~ 0.25 p.g/ml). Nevertheless, cefotaxime is markedly more active than cefoxitin and cefamandole against both these species (Barry et aI., 1980; Hall et aI., 1980a). Salmonella species are highly susceptible to cefotaxime, with most isolates being inhibited by 0.25 p.g/ml or less (Masuyoshi et aI., 1980; Verbist, 198Ia), a concentration considerably lower than

Cefotaxime: A Review

inhibitory concentrations of ampicillin and cefazolin (Barry et al., 1980). Shigella species are also inhibited at very low concentrations (~ 0.8 "gfml) ofcefotaxime (Fu and Neu, 1980; Verbist, 1981a). High concentrations of cefotaxime (MIC so = 8 "g/ml; MIC90 = 32 "g/ml) are required to inhibit most isolates of Acinetobacter calcoaceticus subspecies anitratus (Daschner and Nopper, 1980; Fuchs et al., 1980; Wasilauskas, 1981). However, it appears from a limited number of isolates that cefotaxime is more active against lwoffi and other subspecies of Acinetobacter calcoaceticus (Appelbaum et al., 1982; Jorgensen et al., 1980b). Infrequent Pathogens Cefotaxime is also active in vitro against a number of less commonly encountered Gram-positive and -negative organisms (table III).

236

Table III. Antibacterial activity in vitro of cefotaxime against 10 or more strains of various less commonly encountered pathogens. Inoculum sizes were between 1Q4 and 1()8 cfu MIC50

MICgg

Refer-

(}tg/ml)

IJt9/ml)

ence'

Bordetella pertussis

0.2

0.4

g

Campylobacter fetus subspecies jejuni

3-10

6-40

h, j

Eikenella corrodens

0.12

0.5

b

Listeria monocytogenes

8-25

16-100

a, e

Nocardia asteroides

2

64

c

Yersinia enteroco/itica

'::;0.12

.::;0.25

b, d, i, f

Organism

1 Key to references: a = Ahonkhai et al. (1982); b = Goldstein et al. (1982); c = Gombert (1982); d= Martinez-Beltran et al. (1980); e = Neu et al. (1979c); f = Scribner et al. (1982a); g = Shishido et al. (1980); h = Van hoof et al. (1980); i = Verbist (1981a); j = Walder (1979).

1.2 In Vitro Inhibitory Activity against Anaerobic Bacteria The activity of cefotaxime against Bacteroides jragilis varied widely among studies, which used a variety of culture media (Borobio et aI., 1980; Hamilton-Miller et al., 1978; Jacobus et al., 1980; Jorgensen et al., 1980a; Neu et al., 1979a; Niederau et al., 1980a; Phillips et al., 1981; Soussy et al., 1981; Wise et al., 1980a), and .also within a study comparing agar and broth dilution methods (Werner et aI., 1980). However, an MIC of at least 4 "g/ml was usually required to inhibit 50% of the strains tested, and MIC90 values usually exceeded 16 "g/ml. Hence, in most studies cefotaxime tended to be less active than cefoxitin and was less active than moxalactam against B. jragilis (Borobio et al., 1980; Cuchural et al., 1981;Jacobus et al., 1980; Jenkins et al., 1982; Neu et al., 1979a; Niederau et al., 1980a; Wise et al., 1980a). In addition, 11 cefoxitin-resistant strains of B. jragilis were also resistant to cefotaxime (Dornbusch et al., 1980). However, compared with B. jragilis, other species of Bacteroides were usually more sensitive to

cefotaxime, cefoxitin and moxalactam (Jacobus et al., 1980; Niederau et al., 1980b; Phillips et al., 1981), although again there was a wide variation in results among these studies (MIC90 of 1 to 25 "g/ml), and within the study by Werner et al. (1980) which compared the agar and broth dilution methods. Most of a few strains of Clostridium perjringens were inhibited by cefotaxime 4 "g/ml or less (Jorgensen et aI., 1980a; Soussy et al., 1981), but many strains of C. difficile were resistant (MIC90 ~ 64 "g/ml) to the drug (Henry et al., 1980; Greenfield et al., 1982). Fusobacteria (Jacobus et aI., 1980; Niederau et aI., 1980a; Phillips et aI., 1981) and anaerobic Gram-positive cocci (Borobio et al., 1980; Jorgensen et al., 1980a; Phillips et al., 1981) are usually susceptible to cefotaxime, with MIC90 values of ~ 2 "g/ml, and ~ 4 "g/ml, respectively. Cefotaxime was very active (MIC90 < 1 "gfml) against propionibacteria (Jorgensen et al., 1980a; Homer et al., 1980) and Veillonella species (Phillips et al., 1981). For a comparison of the activity

237

Cefotaxime: A Review

of cefotaxime, moxalactam, and several other cephalosporins against anaerobic bacteria (table IV).

1.3 Activity of Desacetyl-cefotaxime

Cefotaxime is partly metabolized to desacetylcefotaxime (see section 4.3.1), which also has some antibacterial activity. Although not as active as the parent compound against most species, desacetylcefotaxime inhibited 90% of strains of E. coli, K. pneumoniae, P. mirabilis, C. diversus, P. rettgeri, Salmonella and Shigella species, H. influenzae, N. meningitidis and Streptococcus species other than S. jaecalis at low concentrations « 1 ~gfml), but higher concentrations (> 12.5 ~gfml) were generally required to inhibit 90% of isolates of S. mar-

cescens, M. morganii, P. vulgaris, P. stuartii, Enterobacter species, P. aeruginosa, B. jragilis and S. aureus (Jones et aI., 1982; Limbert et aI., 1982; Neu, et aI., 1982; Wise et aI., 198Oc). Desacetylcefotaxime was also shown to be bactericidal, with the minimum bactericidal concentration usually the same or within 1 dilution of the minimum inhibitory concentration (Jones et al., 1982). Comparative studies with a limited number of isolates (about 10 per species) showed that desacetyl-cefotaxime was less active than cefazolin against staphylococci but more active than cefazolin against all the Enterobacteriaceae (Limbert et aI., 1982; Wise et aI., 198Oc), and more active than cefuroxime and cefoxitin against E. coli, P. mirabilis and Klebsiella species (Wise et aI., 1980c). However, cefoxitin was consistently more active than this metabolite against Bacteroides fragilis (Wise et aI., 198Oc). Cefotaxime and desacetyl-cefotaxime exhibited complete or partial synergy against about 20% and 55%, respectively, of a wide variety of clinical isolates (Jones et aI., 1982; Neu, 1982). This activity may in part result from the very high (j-Iactamase stability of the desacetyl metabolite (Limbert et aI., 1982). Antagonism also occurred (against 4% of isolates), predominantly with M. morganii and oc-

casionally with P. vulgaris (Jones et aI., 1982; Neu, 1982). However, in the former study the 8 strains of M. morganii affected in this way were still susceptible to cefotaxime (MICs ~ 2 ~gfml) despite the addition of up to 256~g of desacetyl-cefotaxime per mi.

1.4 (j-Lactamase Resistance Cefotaxime is highly stable against degradation by penicillinase-producing strains of S. aureus (O'Callaghan et aI., 1980; Richmond, 1980), and against most of the chromosomal- or plasmid-mediated (j-Iactamases [such as Richmond types I, III (TEM), IV and V] which are produced by a variety of Gram-negative species (Fu and Neu, 1978, 1979; King et aI., 1980; Labia et aI., 1980; Mouton et aI., 1979; O'Callaghan et aI., 1980; Richmond, 1980). In general, the (j-Iactamase stability pattern of cefotaxime is similar to that of cefuroxime, both being hydrolysed by fewer (j-Iactamases than cefamandole, cephalothin and cephaloridine (King et aI., 1980; Mouton et aI., 1979). However, cefotaxime has been shown to be more susceptible than cefoxitin to a number of (j-lactamases (Mouton et aI., 1979; see below). When hydrolysis occurred, it was usually at a slower rate for cefotaxime than for cefuroxime (Mouton et aI., 1979) but more rapid for cefotaxime than for cefoxitin. Unlike cefoxitin, cefotaxime was hydrolysed by (j-Iactamase isolated from several strains of B. fragilis (Dornbusch et aI., 1980; King et aI., 1980; Richmond, 1980; Sato et aI., 1980), but less rapidly than was cefuroxime (King et aI., 1980; Richmond, 1980; Sato et aI., 1980). In general, (j-lactamase extracted from P. vulgaris also hydrolysed cefotaxime and cefuroxime (cefuroxime usually more rapidly than cefotaxime), but not cefoxitin (King et aI., 1980; Matsubara et aI., 1981; Mouton et aI., 1979). In some studies, cefotaxime and cefoxitin were shown to be competitive inhibitors of purified cephalosporinases extracted from E. coli (Minami et aI., 1980a), P. rettgeri (Matsuura et aI., 1980), and

238

Cefotaxime: A Review

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In general, there has been little difference (i.e. less than or equal to a 2-fold difference) between minimum bactericidal and inhibitory concentrations of cefotaxime for most Gram-negative organisms studied (Barry et aI., 1980; Bartmann and Tarbuc, 1980; King et aI., 1980; Martinez-Beltran et aI., 1980; Sosna et aI., 1978; Verbist, 1981a). However, larger differences were occasionally reported for some species, such as Enterobacter (Barry et aI., 1980; Sosna et aI., 1978), indole-positive Proteus (Barry et aI., 1980), Pseudomonas aeruginosa (Barry et aI., 1980; Corrado et aI., 1980; Neu et aI., 1979a), Serratia marcescens (Verbist, 1981a) and S. aureus (Sosna et aI., 1978), although results tended to vary from study to study despite the use of similar inoculum sizes (104 or 105 cfu). Unfortunately, few authors have specifically mentioned the relationship between the MBC and MIC of cefotaxime for Gram-positive organisms. When the bactericidal activity of cefotaxime was compared with that of other antibiotics by means of killing-curve studies, cefotaxime killed E. coli at a rate similar to that of moxalactam, cefuroxime and cefoxitin; Klebsiella species at the same rate as moxalactam; P. aeruginosa at least as rapidly as carbenicillin and piperacillin, and S. aureus at a rate comparable to that of cephalothin and cefamandole (Neu et aI., 1979a,b). Using the membrane filtration method, Shah et ai. (1978, 1979b) also determined the rate and ex-

Cefotaxime: A Review

tent of the bactericidal activity of cefotaxime against various Gram-negative bacilli, and showed that as with penicillin, increasing concentrations of cefotaxime did not lead to higher kill rates. Another group of investigators has measured (by bioassay) the serum bactericidal activity of cefotaxime in healthy volunteers (Bernard et aI., 1980; Klastersky et al., 1980; Lagast et aI., 1981; Zinner et ai., 1981). Against E. coli and Klebsiella species this activity was relatively high at 1 and 6 hours following infusion of cefotaxime 15 mg/kg compared with the activity against P. aeruginosa or S. aureus, and was not enhanced significantly by combination with amikacin. Although serum bactericidal activity against P. aeruginosa was inadequate 1 hour after administration of cefotaxime alone, significant improvement occurred when cefotaxime and amikacin were given in combination, but not when cefotaxime and tobramycin were combined. The negligible serum bactericidal activity of cefotaxime against S. aureus improved considerably with the addition of either amikacin or tobramycin, but this improved activity appeared to be due chiefly to the latter (2) drugs.

1.6 Effect on Activity of Inoculum, Media, pH and Serum When the size of the inoculum was increased 100-fold (usually) or 1000-fold to 105 or 106 colony-forming units (cfu) this usually had little effect on the in vitro activity of cefotaxime (i.e. no more than a 2-fold increase in MIC) for most strains of the various Gram-negative and -positive organisms tested (Barry et ai., 1980; Corrado et aI., 1980; Hamilton-Miller et ai., 1978; Lang et ai., 1980; Markowitz and Sibilla, 1980; Neu et aI., 1979a; Wise et aI., 1978; 1980a). However, when B. fragilis (Wise et aI., 1978) and some strains of Gramnegative bacilli showing multiple drug resistance (Hall et aI., 1980a) were tested, an inoculum effect occurred. Similarly, increasing the inoculum size to 10 7 or 108 cfu usually resulted in a marked de-

239

crease in the inhibitory activity of cefotaxime on most Gram-negative species (to the extent that many organisms highly susceptible at low inocula appearred resistant when over 106 cfu were used), but activity against Gram-positive organisms was rarely affected in this way (Barry et aI., 1980; Corrado et aI., 1980; Neu et aI., 1979a). In contrast to these studies, no important inoculum effect was seen by Shah et aI. (1978), but this may arise from the use of a different culture media in this study (Diagnostic Sensitest Agar) compared with most others (Mueller Hinton broth). Interestingly, Counts and Turck (1979) found that a greater inoculum effect occurred when cefotaxime MICs were determined in Mueller Hinton broth compared with Mueller Hinton agar. From limited data on the effect of inoculum size on the minimum bactericidal concentration (MBC) of cefotaxime it appears that, as with MICs, larger increases in MBCs usually occur when inocula of Gram-negative organisms are increased above 105 cfu than with increases up to 105 cfu (Corrado et ai., 1980; King et aI., 1980; Kropp et aI., 1980; Verbist and Verhaegen, 1980). Conflicting comments have been made regarding the effect on cefotaxime's inhibitory activity of various culture media (Counts and Turck, 1979; Neu et aI., 1979a), the form of the media (e.g. Mueller Hinton broth vs Mueller Hinton agar) [Counts and Turck, 1979; Marklein and Mattias, 1980; Neu et aI., 1979a; Verbist and Verhaegen, 1981], variations in media calcium and magnesium ion content (Neu et ai., 1979a; Yu et al., 1980) and media pH (Neu et aI., 1979a; Trager et ai., 1981 ). It appears that increasing the sodium chloride content of Mueller-Hinton broth to 4% decreases MICs of cefotaxime for some genera, particularly E. coli, Enterobacter and Serratia species, but not for P. aeruginosa (Trager et al., 1981). In general, addition of 50% inactivated human serum to Mueller Hinton broth has little effect on the MIC and MBC of cefotaxime (Lang et aI., 1980; Neu et ai., 1979a; Trager et aI., 1981).

Cefotaxime: A Review

1.7 Antibiotic Synergy The synergistic activity of cefotaxime in combination with various antibiotics, particularly aminoglycosides, has been studied using the classic in vitro checkerboard method. Synergy was usually defined on the basis of the antibiotics' minimum inhibitory concentrations (decreased 4-fold) or the fractional inhibitory concentration index (less than 1). In such studies with P. aeruginosa, cefotaxime in combination with gentamicin was synergistic for about 60% of strains tested (Murray, 1980; Neu et al., 1979a; Perea et aI., 1980), including gentamicin-resistant strains (Murray, 1980). Synergism between cefotaxime and gentamicin occurred more frequently with carbenicillin-sensitive strains of P. aeruginosa than with strains resistant to carbenicillin (88% vs 48%) in the study by Perea et al. (1980). Synergy between cefotaxime and tobramycin occurred against 34 to 63% of P. aeruginosa isolates (Mintz and Drew, 1981; Murray, 1980; Perea et aI., 1980); the lower percentage occurred in a study in which two-thirds ofthe strains tested were tobramycin-resistant (Murray, 1980), while the higher percentage resulted from the testing of predominantly tobramycin-sensitive strains (Mintz and Drew, 1981). Results from studies in which cefotaxime and amikacin were combined varied widely, with synergy being demonstrated with about 10 to 60% of P. aeruginosa isolates (Jorgensen et al., 1980b; Kurtz et aI., 1980; Murray, 1980; Perea et al., 1980; Zinner et al., 1981). Antagonism between an aminoglycoside and cefotaxime occurred very rarely when testing P. aeruginosa (Perea et al., 1980; Regamey and Lavanchy, 1980; Zinner et aI., 1981). In addition to reporting the extent of synergy, it is also important to consider the actual MICs obtained when antibiotics are tested in combination. In one such study (Murray, 1980) using 50 isolates of P. aeruginosa which were selected for

240

resistance to at least 1 aminoglycoside, the MICs of both drugs in a synergistic combination were reduced to clinically achievable concentrations (MIC ~ 8"g of gentamicin or tobramycin per ml, and ~ 16"g ofamikacin or cefotaxime per ml) for 18% of the strains using combinations of gentamicin and cefotaxime or amikacin and cefotaxime, and for 10% of the strains using a combination of tobramycin and cefotaxime. Clinically relevant synergism occurred mainly with strains moderately reo sistant to the aminoglycoside (MIC ~ 64 "g/ml), and only very rarely with highly resistant strains of P. aeruginosa. When 22 strains of Serratia marcescens (all of which were resistant to gentamicin and cephalothin but not to cefotaxime) were studied by the checkerboard method, 3 criteria for synergy were met for only 9% of isolates when cefotaxime was combined with gentamicin or tobramycin and for about 20% of isolates when combined with amikacin or netilmicin. However, antagonism occurred with 18 to 27% of isolates in each cefotaxime-aminoglycoside combination, except gentamicin plus cefotaxime (Markowitz and Sibilla, 1980). In contrast, when 1 criterion was considered indicative of synergy,S of 10 S. marcescens isolates (which were also resistant to gentamicin, but susceptible to amikacin) were inhibited synergistically by amikacin plus cefotaxime, with MIC90 values of2 and 0.25 "g/ml, respectively. No antagonism was observed in this study (Kurtz et al., 1981). In a study which tested about 100 strains of Enterobacteriaceae, synergy between amikacin and cefotaxime was demonstrated for a high proportion (72 to 85%) of E. coli, Klebsiella species and P. mirabilis isolates, and to a lesser extent (44%) for strains of S. aureus (Klastersky et al., 1980; Zinner et al., 1981). These authors also evaluated synergy between cefotaxime and aminoglycosides by studying infected neutropenic mice, and serum bactericidal activity in human volunteers (see sections 1.8 and 1.5, respectively).

Cefotaxime: A Review

1.8 Activity In Vivo Cefotaxime was shown to be effective in treating systemic infections in mice inoculated intraperitoneally with a wide variety of organisms and subsequently given I to 3 doses of the drug subcutaneously. In general, the median effective dose (ED so) of cefotaxime calculated from survival rates on days 4 or 5 was below 1.5 mg/kg for infections due to most Enterobacteriaceae (including many fJlactamase-producing strains), and slightly higher (2 to 5 mg/kg) for the limited number of S. aureus strains tested (Angehrn et aI., 1980; Kamimura et aI., 1979; O'Callaghan et aI., 1980; Tsuchiya et aI., 1981 ). When single doses of cefotaxime or cefuroxime were given at the time of bacterial inoculation, the ED so determined for cefotaxime was considerably lower (around 30 times) than that for cefuroxime for infections with strains of Enterobacteriaceae sensitive (MIC ~ 4 J,Lg/ml) to both drugs (Tsuchiya et aI., 1981). However, cefotaxime (administered twice) was less effective than gentamicin against systemic infections in mice caused by 4 strains of P. aeruginosa; the EDso values ranged from 33 to over 200 mg/kg for cefotaxime and from 2.6 to 6.3 mg/kg for gentamicin. The MIC of cefotaxime for each strain was 16 J,Lg/ml, and for gentamicin it was between 2 and 8 J,Lg/ml, using a rather high inoculum of 107 cfu (O'Callaghan et aI., 1980). The effect of cefotaxime on the bacterial content of particular tissues or fluids has been studied in various experimental models of infection. In mice with pneumonia caused by K. pneumoniae, the 50% clearance dose (CDso) of subcutaneously administered cefotaxime was 24 mg/kg, while the 50% survival dose was 20 mg/kg (Tsuchiya et aI., 1981). These authors also treated urinary tract infection in mice with subcutaneous cefotaxime given 4 times daily for 5 days, starting 3 days after injecting P. mirabilis into the ascending route. This resulted in a 50% clearance dose (8 days after infection) of 0.53 mg/kg for the bladder wall and 0.84 mg/kg for the kidney. In chronic oestrogen-in-

241

duced pyelonephritis in rats subsequently infected with fJ-lactamase-producing and non-producing strains of E. coli, treatment with cefotaxime or cefoxitin 150 mg/kg twice daily for a week (probably intramuscularly) considerably reduced bacterial counts in the kidneys, compared with untreated controls (Marre and Sack, 1979). In an animal model of intra-abdominal sepsis designed to simulate sepsis following colonic perforation, optimal results were obtained with cefotaxime and other antibiotics active against coliform and anaerobic bacteria. The incidences of mortality (3%) and intra-abdominal abscesses (4%) following 10 days' treatment with intramuscular cefotaxime 60 mg/day were similar to those occurring with the same dosages of moxalactam or cefoxitin or with a combination of clindamycin 48 mg/day plus gentamicin 6 mg/day (0 to 7% mortality, 5 to 7% abscess formation). However, mortality (37%) and abscess formation (100%) were significantly higher in untreated rats (Bartlett et aI., 1981 ). In rabbits with experimental meningitis caused by E. coli and treated with continuous antibiotic infusions of 25 mg/kg per hour for 9 hours, either cefotaxime or moxalactam significantly (p < 0.05) reduced bacteria in the CSF, compared with netilmicin 2 mg/kg per hour which had no significant effect. However, when experimental meningitis was caused by group B Streptococcus type III, moxalactam was significantly (p < 0.01) less effective than cefotaxime, ampicillin and cefoperazone in reducing bacterial counts in CSF; moxalactam was also much less active against this organism than the other antibiotics when tested in vitro (Schaad et aI., 1981). Combined antibiotic therapy was studied using neutropenic mice injected intraperitoneally with either E. coli, K. pneumoniae or S. marcescens (Zinner et aI., 1981). When subeffective doses of each antibiotic were administered subcutaneously about I and 4 hours later, significantly enhanced survival occurred with cefotaxime plus amikacin compared with either drug alone (p < 0.05).

Cefotaxime: A Review

The nonspecific influence of cefotaxime on the immune system has been studied by Gillissen (1981, 1982). Cefotaxime enhanced antibody formation in mice and also significantly prolonged (p < 0.05) survival time of immunocompromised mice infected with Candida albicans, although this fungus is highly resistant to cefotaxime. Thus, cefotaxime did not have a negative effect on immune response in vivo.

2. Renal Tolerance In studies to date cefotaxime appeared to be free of adverse effects on renal function. Thus, in comparing the effects of single daily subcutaneous injections of cefotaxime (750 or 1500 mg/kg), moxalactam (750 or 1500 mg/kg), cephaloridine (100 or 200 mg/kg) or saline on rabbit kidneys, which provide a sensitive model of cephalosporin nephrotoxicity, excretion of the lysosomal enzyme N-acetylglucosaminidase, and the concentration of creatinine in plasma were not significantly increased with either dose of cefotaxime or moxalactam given for 7 days. Minor morphological changes to the glomerular ultrastructure with the higher dose of these antibiotics were detected by electron microscopy, but not by light microscopy. However, cephaloridine caused significant functional and morphological damage to the rabbit kidney (Luft et ai., 1982). In rats (Marre and Sack, 1979; Sack et ai., 1978), very high doses (i.e. 5000 mg/kg/day) of cefotaxime and cefuroxime were required to increase urinary excretion of renal tubular epithelial cells, compared with cephalothin or cefamandole (3000 mg/ kg/day), cefazolin or cefoxitin (2000 mg/kg/day), and cephaloridine (500 mg/kg/day). [See also section 3.2 for renal effects detected during toxicological studies.] The effect of cefotaxime on renal tolerance has been assessed in healthy subjects by measuring urinary excretion of alanine aminopeptidase (AAP), an enzyme in the brush border membrane of proxi-

242

mal renal tubules which is considered to be an early indicator of renal tubular damage. AAP excretion in urine was not significantly altered during and after intravenous cefotaxime 3g twice daily for 3 days, or when cefotaxime 6g daily was combined with frusemide 20mg daily (Mondorf et ai., 1980). In another study in healthy volunteers (Luthy et ai., 1979), but using a high rate of infusion of cefotaxime (2, 5, or 8g in 3.25 hours), a marked transient increase in alanine aminopeptidase activity occurred during infusion (only) of each dose. However, the activity of alanine aminopeptidase remained within the normal range at all times. Evidence from a study by Kuhlmann et ai. (1982a,b) suggests that cefotaxime can be combined with the aminoglycoside tobramycin without increasing the risk of nephrotoxicity compared with that with the aminoglycoside alone. Thus, urinary excretion of alanine aminopeptidase was measured in 44 patients with normal renal function and serious infections treated with cefotaxime 6 g/day, tobramycin 3 mg/kg/day, cefotaxime plus tobramycin (at the same dosages), cefotaxime plus azlocillin 15 g/day, or azlocillin plus tobramycin. All antibiotics were given intravenously at 8-hourly intervals for at least 7 days. None of the patients treated with cefotaxime alone or in combination with azlocillin showed an appreciable rise in AAP excretion or in serum creatinine, or a reduction in creatinine clearance. However, patients treated with tobramycin alone, tobramycin plus cefotaxime or tobramycin plus azlocillin, showed significant (p < 0.05) increases in AAP excretion during therapy compared with pre-therapy levels. The magnitude of increases seen with these antibiotic combinations was similar to that with tobramycin alone. In addition, a similar proportion of patients in each of the 3 treatment groups receiving tobramycin alone or in combination showed pathological changes in serum creatinine and/or creatinine clearance. Changes in renal function were reversible in all cases.

243

Cefotaxime: A Review

3. Toxicity Studies 3.1 Acute Toxicity The median lethal dose (LDso) of cefotaxime for mice is 9.1 g/kg, or> 10.4 g/kg when the drug is administered intravenously to females and males, respectively; 12 g/kg when given intraperitoneally to females, and 18.7 g/kg when given subcutaneously to both sexes. In rats the intravenous LDso of cefotaxime is 9.9 (female) or 10.7 g/kg (male), while the intramuscular LDso is > 7 g/kg for both sexes. When administered intravenously to male and female dogs the LDso of cefotaxime is > 1. 5 g/kg (Doerr et aI., 1980).

3.2 Subacute and Chronic Toxicity When repeated doses of cefotaxime were administered for 30 days, no pathological changes occurred in rats given up to 238 mg/kg subcutaneously or 300 mg/kg intravenously, in dogs given up to 179 mg/kg intramuscularly or 300 mg/kg intravenously, and in puppies receiving up to 1500 mg/kg subcutaneously, apart from local reactions (Doerr et aI., 1980; data on file, Roussel). The highest daily dose (3000 mg/kg) of cefotaxime administered subcutaneously to rats for 30 days, resulted in haemorrhage at the injection site, dilation of the caecum, increases in spleen and kidney weights and histopathological changes to renal tubules (Morioka et aI., 1980). Following 90 days' administration of cefotaxime 500, 1000 or 1500 mg/kg/day intravenously to dogs, some animals (especially in the high dose group) showed slight necrotic lesions of doubtful significance in the proximal tubules of the kidney. No lesions were found in any organs of rats given up to 1600 mg/kg/day subcutaneously over the same period (Doerr et aI., 1980; data on file, Roussel). Chronic toxicity studies conducted for 6 months with daily cefotaxime doses of up to 250 mg/kg

administered subcutaneously and intramuscularly to rats and dogs respectively, occasionally resulted in dose-dependent local reactions (Doerr et aI., 1980; data on file, Roussel). Subcutaneous administration of cefotaxime 1000 mg/kg/day to rats for 6 months resulted in similar changes to those which occurred in rats given 3000 mg/kg/day for 90 days by the same route (see above; Morioka et aI., 1981b). Potential toxicological effects on the kidney of cefotaxime alone and in combination with gentamicin or frusemide have been studied. A single intravenous dose of cefotaxime 1 g/kg resulted in a slight, transient reduction in para-amino hippuric acid clearance in dogs, but creatinine clearance and urine output were not affected (data on file, Roussel). When a lower dose (220 mg/kg/day intramuscularly) was administered to rabbits for 7 days no drug-related renal changes occurred (data on file, Roussel). A longer term study (Morioka et aI., 1981a) in female rats treated for 28 days with cefotaxime 1000 mg/kg/day intravenously, or gentamicin 30 mg/kg/day intramuscularly or frusemide 100 mg/kg/day orally, found no signs of renal toxicity based on urinalysis, excretion of urinary enzymes and plasma chemical tests. In addition, cefotaxime given together with gentamicin or frusemide did not enhance the incidence or extent of histopathological changes to renal tubules seen when each drug was given alone. In a study in rabbits (Doerr et aI., 1980), additive histopathological effects on renal tubules occurred when very high single doses of cefotaxime (5 g/kg) and gentamicin (100 mg/kg) were given intravenously in combination.

3.3 Reproduction Studies A summary of numerous reproductive studies conducted in rats and rabbits indicates that cefotaxime does not inflence fertility, or fetal and postnatal development (Doerr et aI., 1980). Similar conclusions were reached by Sugisaki et al. (1981 b)

244

Cefotaxime: A Review

in studying mice given up to 2000 mg/kg/day intravenously or 6000 mg/kg/day subcutaneously. The only notable abnormalities (e.g. slight dilation of the caecum and gallbladder, and haemorrhage at the site of subcutaneous injection) occurred in parental mice given doses of 1500 mg/kg/day or higher. Administration of intravenous cefotaxime 6.25 mg/kg/day to rabbits from days 6 to 18 of gestation did not affect the dams or offspring. However, with higher doses (12.5, 25 and 50 mg/ kg/day), a few animals in each group had anorexia and loose stools, followed by abortion of the fetus or death of the dam. Reproduction in the remaining dams was similar to that in controls, except for the number ofresorptions and/or dead fetuses. No drug-related dysmorphogenic effects occurred in the live fetuses (Sugisaki et al., 1981 a).

ant to desacetyl-cefotaxime. Whilst either bioassay or HPLC may be adequately specific for determining serum concentrations in healthy subjects (00luisio, 1982; Ings et aI., 1982), it is important that a selective assay be used in patients with renal dysfunction (Doluisio, 1982). In this review, only those studies which have used HPLC or an indicator organism stated to be specific for cefotaxime, or much more susceptible to cefotaxime than to desacetyl-cefotaxime, will be discussed, except for distribution data, as the vast majority of body tissue or fluid concentrations were determined by nonspecific assays. The one situation in which the use of a nonselective reference strain is of value, however, is where the infecting organism is used as the reference strain; here, the antibacterial activity in plasma is relevant to the therapeutic activity of cefotaxime in the individual patient.

4. Pharmacokinetic Studies Pharmacokinetic studies of cephalosporins are usually performed by microbiological determination of the drug concentration in plasma and urine. The lack of specificity of the microbiological assay often does not permit the determination of unchanged drug in the presence of its metabolites. Antimicrobially active biotransformation products are produced from cefotaxime, the princIpal one being desacetyl-cefotaxime (section 4.3.1). In healthy subjects, this metabolite accounts for about 5 and 14% of the peak plasma drug concentration after intravenous and intramuscular administration (15 mg/kg), respectively (Ings et aI., 1982). Since cefotaxime and its metabolites differ in antibacterial activity (section 1.3) and in pharmacokinetic properties (sections 4.3.2 and 4.5), it is desirable that the assay method used to study the pharmacokinetics of cefotaxime can distinguish between the antimicrobially active products. Differentiation between cefotaxime and desacetyl-cefotaxime can be achieved by using high performance liquid chromatography (HPLC) or an indicator strain of a micro-organism that is resist-

4.1 Absorption and Serum Concentration After an intravenous bolus of 1000mg, mean peak plasma concentrations of cefotaxime have usually ranged between 81 and 102 ~g/ml (Ho et aI., 1980; Luthy et aI., 1981a,b; McKendrick et aI., 1980a). Mean peak plasma concentrations were 174 to 214 ~g/ml after a 2g intravenous bolus dose (Ho et aI., 1980; Luthy et aI., 1981a,b; Neu et aI., 1980;) [table V). At 4 and 6 hours, after a 1000mg dose mean plasma concentrations were 1.9 and 0.4 ~g/ ml, respectively (Ho et aI., 1980; Luthy et aI., 1981a). A 1000mg dose administered by intravenous infusion over a period of 30 minutes resulted in a mean peak plasma concentration of 41 ~g/ml at the end of the infusion (Fu et aI., 1979). A cross-over comparison of equal doses of cefotaxime, moxalactam and ceftazidime resulted in lower plasma concentrations of cefotaxime than of the other two drugs (Luthy et aI., 1981a), although such data should be interpreted alongside data on the relative antibacterial activity of the drugs being compared. A comparison of some of

245

Cefotaxime: A Review

Table V. Mean plasma concentrations of cefotaxime after intravenous or intramuscular administration of 0.5 to 2.0g doses to healthy subjects. All studies used assay methods able to differentiate between cefotaxime and desacetyl-cefotaxime Reference

Fu et al. (1979)

No. of subjects

13 10

Ho et al. (1980)

11

Ings et al. (1982)

6

Luthy et al. (1981a,b)

6

Dose (mg)

Route of administration

500 1000 1000

1M 1M IV (30-min infusion)

500 1000 2000

IV (bolus) IV (bolus) IV (bolus)

15 mg/kg'

1M

Peak cone.

Cone. at 4 hours

Cone. at 8 hours

(ltg/ml)

(ltg/ml)

(ltg/ml)

11.7 20.5 41

38 102 214

AUC (ltg/mi. h)

1.4 3.36 1.5

23.2 45.7 44.3

1.0 1.9 3.3

30.6 70.4 134

25.5

500 1000 2000

IV (bolus) IV (bolus) IV (bolus)

38 81 174

<0.1 <0.1 0.5

1000 + probenecid

IV

109

0.6

Bodyweight was 54 to 72 kg.

the important pharmacokinetic values of cefotaxime, cefoperazone, moxalactam, cefuroxime and cefoxitin, is summarised in table VI. Bax et ai. (1980) reported a linear increase in plasma cefotaxime concentrations and in the area under the plasma concentration-time curve (AVC) after bolus injections of 0.5, 1.0 and 2.0g. However, a non-linear increment in AVC was noted by Luthy et ai. (198Ia,b) and Ho et ai. (1980), who reported a greater than 4-fold increase in AVC when the dose was increased from 0.5 to 2.0g. Concomitant administration of probenecid increases and sustains the plasma concentrations of cefotaxime (Bax et aI., 1980, Luthy et aI., 1981a,b). In this respect, cefotaxime is similar to cefuroxime (Foord, 1976), but unlike cefoperazone (Shimizu, 1980), moxalactam (Luthy et aI., 1981a,b) or ceftazidime (Luthy et aI., 1981a,b). There was no evidence of cefotaxime accumulation when 1.0g every 6 hours was administered by intravenous infusion for 14 days. The AVC was 57 Ilg/ml • hand 69 Ilg/ml • h on days 1 and 15

respectively (Ho et aI., 1980). Similarly, intramuscular administration of O.5g 6-hourly for II days did not result in any drug accumulation (Ho et aI., 1980). Mean peak plasma cefotaxime concentrations after intramuscular injection of 500 or 1000mg are about one-quarter to one-third those after intravenous administration of the same dose (Fu et aI., 1979; Ho et aI., 1980; Ings et aI., 1982; Ohkawa and Kuroda, 1981). Lignocaine (lidocaine) 1%, which may be included with intramuscular cefotaxime to minimize discomfort at the injection site, has little or no effect on the absorption kinetics of cefotaxime (Bax et aI., 1980).

4.2 Distribution The apparent volume of distribution at steadystate (Vd •• ) of cefotaxime was 21.6 L/1.73m 2 after Ig intravenous 30-minute infusions. In single-dose studies with Ig doses of cefotaxime, the apparent

Table VI. Summary of some pharmacokinetic values of cefotaxime. cefoperazone. moxalactam. cefuroxime and cefoxitin

Drug

Dose (Iv)a

Mean peak serum concentration (ltg/ml)

Half-life (hours) normal

severe renal failure

Urinary recovery (% in 24h)

Protein binding

Reference"

() CD

§;

'"3' )(

(%)

!'!

> :D

CD

19

81-102

2g

174-214

Cefoperazone

19 2g

140-200 250-375

Moxalactam

19

Cefuroxime Cefoxitin

Cefotaxime

0.9-1.14 b 1.4-1.9c

2.3-2.6b 8-12C

50-65

37-38

8. 13. 18. 19. 20. 21. 33

1.6-2.05

2.3-4.2

19-36

87-93

2. 3. 5. 17. 25. 30

95-147d

1.9-2.7

13.3-20

61-96

52

1.16.17.22.23.29.32

19

90-144

1.1-1.4

14.8-15.2

92-96

33

4. 6. 11. 12. 14. 27

19

110-125

0.9

13

77-99

65-80

7. 9. 10. 15. 24. 25. 26. 28. 31

a Intravenous bolus. b Half-life of unchanged cefotaxime. c Half-life of desacetyl-cefotaxime. d Higher value is after a dose of15 mg/kg to 5 subjects with a mean bodyweight of 71.7kg. e 1 = Aronoff et al. (1981); 2 = Bundtzen et al. (1980); 3 = Craig (1980); 4 = Daikos et al. (1977); 5 = Dayer et al. (1980); 6 = Foord (1976); 7 = Fillastre et al. (1978); 8 = Fu et al. (1979); 9 = Gillett and Wise (1978); 10 = Goodwin et al. (1974); 11 = Gower and Dash (1977); 12 = Gower et al. (1977); 13 = Ho et al. (1980); 14 = Kosmidis et al. (1977); 15 = Leroy et al. (1978); 16 = Leroy et al. (1981); 17 = Lode et al. (1980c); 18 = Luthy et al. (1981b); 19 = Murakawa et al. (1980); 20 = Neu et al. (1979a); 21 = Ohkama and Kuroda (1981); 22 = Parsons et al. (1980); 23 = Peterson et al. (1981); 24 = Reeves et al. (1978); 25 = Reeves et al. (1980a); 26 = Schwartz et al. (1976); 27 = Simon and Malerezyk (1977); 28 = Sonneville et al. (1976); 29 = Srinivasin et al. (1980); 30 = Swarz et al. (1981); 31 = Trollfors et al. (1978); 32 = Wise et al. (1980b); 33 = Wise et al. (1981).

< CD'

=:

I\) ~

a>

Cefotaxime: A Review

volume of distribution during the tl-phase (Vdarea) was 37.2 L/1. 73m2 after intramuscular injection and 33.3 L/1.73m 2 after a 30-minute intravenous infusion (Fu et aI., 1979; Ho et al., 1980; Neu et al., 1980). In 6 healthy volunteers with a mean bodyweight of 69kg, the apparent volume of distribution was 0.29,0.24 and 0.21 Lfkg after single intravenous bolus doses of 0.5, 1.0 and 2.0g, respectively (Luthy et aI., 1981a,b). Concentrations of cefotaxime (usually determined by non-selective assay) ha ve been determined in a wide range of human body tissues and fluids. In the cerebrospinal fluid of infants, children and adults, cefotaxime concentrations are low when the meninges are not inflamed, but are considerably higher in patients with meningitis (table VII). Cerebrospinal fluid cefotaxime concentrations in meningitis appear to be higher in patients with impaired renal function (plasma creatinine 720-780 ~mol/L) than in patients with normal renal function (Bruckner et aI., 1982). Cherubin et ai. (1982) mentioned that mean cerebrospinal fluid concentrations (measured by HPLC) of the parent drug and desacetyl-cefotaxime were 5.2 and 5.9 ~g/ml, respectively, 1 hour after repeated bolus injections of cefotaxime (dosage not given) to 11 patients. These concentrations represented about 10 and 55% of the average serum concentration of the parent compound and desacetyl-cefotaxime, respectively. Concentrations (0.2 to 5.4 ~g/ml) inhibitory for most Gram-negative bacteria are attained in purulent sputum, bronchial secretions and pleural fluid in adults given 1 or 2g of cefotaxime parenterally (table VII). A parenteral dose of 25 mg/kg in children produces maximum concentrations of about 3 to 11 ~g/ml in empyema fluid (Kafetzis, 1980). Concentrations of cefotaxime likely to be effective against most sensitive organisms are attained in the uterus and adnexa after intravenous administration of 1 or 2g (table VIII). Concentrations of antimicrobially active drug in amniotic fluid have varied between studies but are higher after repeated doses than after a single dose (Kafetzis et

247

al., 1980). Drug concentrations in human milk are low, reaching a maximum of 0.32 jLg/ml (mean) after a Ig intravenous dose (Kafetzis et al., 1980). Renal tissue concentrations were 1.9 to 7.0 (inner cortex), 1.9 to 10.8 (outer medulla) and 2.3 to 14 ~g/g (inner medulla) after a Ig intramuscular injection (Grabe et al., 1981). 1.5 hours after a 2g intravenous bolus, prostatic adenoma contained 22.9 ~g/g, testes 5.4 ~g/g and ureter 9.2 jLg/g (Schalkhauser and Adam, 1980). A Img intramusdar dose produced prostatic tissue concentrations of 2.6 ~g/g in the deep layer and 3.9 ~g/g in superficial tissue (Grabe et al., 1981). Peritoneal fluid contained a mean peak concentration of 28.6 ~g/ml after a 2g intravenous dose (Wittmann et aI., 1980b) and non-infected ascitic fluid contained 3.8 to 17.6 ~g/ml 2 hours after a Ig dose (Moreau et aI., 1980). High concentrations of cefotaxime and desacetyl-cefotaxime are attained in both common duct bile (Kees et aI., 1981; McKendrick et al., 1980a; Pelz et al., 1980; White et aI., 1980), and gallbladder bile (McKendrick et aI., 1980a; Soussy et al., 1980). In patients receiving repeated Ig doses, common duct bile concentrations of cefotaxime and desacetyl-cefotaxime were 36 and 243 lLg/ml, respectively, 1.3 hours after injection. The corresponding serum concentration of cefotaxime was 19.2 ~g/ml (McKendrick et al., 1980a). Concentrations in gallbladder wall are about one-fifth to onetenth those in bile at the same time (Pelz et al., 1980). Peak drug concentrations of 32 ~g/g in pericardium and of 22 ~g/g in myocardium occurred 15 minutes after intravenous cefotaxime 50 mg/kg. After 2 hours, the average concentrations were 10.7 and 3.8 jLg/g in pericardium and myocardium, respectively. The corresponding serum concentrations were 237 and 33 ~g/ml at 15 minutes and 2 hours (Adam and Struck, 1982). Cefotaxime concentrations in bone are between 3 and 15 ~g/g after a single 2g intravenous dose or repeated intramuscular 2g doses (table IX). Concentrations in interstitial fluid vary according to

Cefotaxime: A Review

248

Table VII. Antimicrobial activity (cefotaxime plus active metabolites) in cerebrospinal fluid (CSF), sputum and pulmonary fluids after single or repeated doses of cefotaxime

Population (number)

Tissue specimen

Time after drug (h)

Drug dose

Drug cone. !ltg/ml)

Specimen cone. rati0 1

Reference7

Infants/children (34)

CSF (meningitis)

1-2

50 mg/kg

3-30

0.27-0.62

b, g, i

CSF (not inflamed)

2-6

Adults (37)

100-300 mg/kg/ 24 hours 19 IV,3 2g IV, 0.5-1g 1M

0-0.45

c, h, j, m

0-1

c

30 mg/kg IV Adults (6) (7)

CSF (slightly inflamed) CSF meningitis

2-4

2g IV

1-4

2g IV

1.1-7.14 8.9-17.6;

Adults (64)

(4) (6) Adults (> 13) (79)

Children (6)

Sputum (purulent)

Sputum Pleural fluid

2-4

19lV 19 inhalation 19lV

3

Bronchial secretions

2-4

0.06-0.16 0.04

19lV 2g IV

1.58-2.46 2.96 1.66 5.1

25 mg/kg 1M 25 mg/kg IV

2.9-3.8 2.25-11.2

c c e n e k, I 0 I

" 150 7.2

19lM 2g IV

Bronchial tissue

Empyema fluid

1.3 1.8 2.91-5.4 0.22-0.70

19lM 2g 1M 2g IV

0.1-1.0 0.14-0.18

d, e e a a

0.03

0.38-1.6 1-5.6

1 Ratio of specimen/serum concentration at same time. 2 Data from Kafetzis et al. (1982) only. 3 Abbreviations: IV = intravenous; 1M = Intramuscular. 4 Values in patients with normal renal function. 5 Values in patients with impaired renal function. 6 Concentration in ltg/g. 7 Key to references: a Blind et al. (1982); b Borderon et al. (1981b); c Bruckner et al. (1982); d Fraschini et al. (1981); e Gialdroni et al. (1980); f Kafetzis (1980); 9 Kafetzis et al. (1982); h Karimi et al. (1980); i Kobayashi et al. (1981a,b); Kosmidis et al. (1980); k Lode at al. (1980a); I Lode et al. (1980b); m McKendrick et al. (1980); n Maesen et al. j (1980); 0 = Newsom et al. (1980).

= =

=

= =

= =

=

the method used (table IX), but are above 7 ",glml after a Ig intravenous or intramuscular dose. The mean extravasal cefotaxime concentration in skin was 9.9 ",gig 60 minutes after a 2g intravenous injection in 8 patients (Gninder et al., 1980). Otitis media effusions from children with acute otitis media who were treated with 50 mg/kg of intravenous cefotaxime, contained a drug concen-

= =

=

=

=

=

tration of 2.1 to 3.3 ",glml 1 hour after injection (Danon, 1980). Intramuscular injections of 50 mgl kg and 1()(} mg/kg resulted in a mean effusion concentration of 1.2 ",glml in 3 patients and 17.5 ",gI ml in 2 patients, respectively. Non-infected aqueous humour contained low concentrations (0 to 2.3 ",gI ml) I hour after a single 2g intravenous injection (Busse et aI., 1980).

Cefotaxime: A Review

249

Table VIII. Antimicrobial activity (cefotaxime plus active metabolites) in female reproductive organs, milk, amniotic fluid, cord blood and fetal tissue after parEjnteral cefotaxime

Specimen (no. of patients)

Time after drug

Drug dose

Drug concentration 1

(h)

Specimen/serum concentration ratio

References

Ovary, oviduct, cervix uteri, corpus uteri, endometrium (25)

0.5-2

19lV

0.5-2.9 p.g/g

a, b, e, f

Portio vaginalis (17)

0.5-1

19 IV

3.3-3.4 p.g/g

a, b

Ovary, oviduct, endometrium, myometrium (17)

:s; 0.75

2g IV

3.5-4.8 p.g/g

Cervix uteri, portio vaginalis (17)

:s; 0.75

2g IV

5.3-5.8 p.g/g

Ovary, oviduct, uterus

2-4

2g IV

0.26-5.6 p.g/g

e, g

Ovary, uterus, fallopian tubes (29)

0.3-1.15

2g IV

1.3-6.4 p.g/g

d

Cord blood (19)

1.0

19lM

3.8p.g/ml

0.23,20.57, 1.0 at 1, 2, 3 hours

h

Amniotic fluid (19)

1-4

19lM

3.6p.g/ml

0.09, 0.3, 0.8 at 1, 2, 3 hours

h

1-4

19 IV 19lV

0.47-13 1.8-3.3

Milk (12)

2

19 IV

0.32

Fetal tissue kidney; lung; serum (10)

1-4

19 IV

1.8-5

19lV

1.0-6.3; 0.5-6.3; 0.9-6.53 1.1-3.5; 0.8-1.5; 0.8-6.74

kidney; lung; serum (4)

c

0.09

c

c c

1 2 3 4

Concentration of cefotaxime and its active metabolites in nearly all instances. Cord blood/maternal plasma concentration ratio. Single dose. Repeated doses. 5 Key to references: a = Ikeuchi et al. (1981); b = Ishii et al. (1981); c = Kafetzis et al. (1980); d = Kleinstein and Neubiiser (1980); e = Ludwig et al. (1980); f = Miyamoto et al. (1981); g = Motomura et al. (1981); h = Pierre et al. (1981); i = Saito et al. (1981).

4.2.1 Protein Binding When determined by ultracentrifugation and dialysis, protein binding of cefotaxime at therapeutic concentrations is about 38% (Murakawa et al., 1980; Neu et aI., 1979a). A value of 27% was reported when agar diffusion was used to determine binding (Neu et aI., 1979a).

4.3 Elimination

4.3.1 Metabolism and Excretion Cefotaxime is partially metabolized prior to excretion. The principal metabolite is the microbiologically active product, desacetyl-cefotaxime (Bax et aI., 1980; Chamberlain et aI., 1980; Reeves et

Cefotaxime: A Review

250

al., 1980b, White et al., 1980). Two other (inactive) metabolites, M2 and M3 (isomers of desacetylcefotaxime lactone in which the ,B-lactam ring has been opened) [Coombes, 1982] are generally undetectable in serum of healthy subjects, but are found in higher concentrations in patients with renal failure (Reeves et al., 1980b). These metabolites are present in significant concentrations in the urine of healthy subjects (Chamberlain et al., 1980; Coombes, 1982; Ings et al., 1982; Reeves et

al., 1980b). At 15 minutes after an intravenous injection of a single 800mg dose of 14C-cefotaxime, 81 % of plasma radioactivity represented unchanged drug and 6%, desacetyl-cefotaxime. One hour after injection, 42% of plasma radioactivity was present as cefotaxime and 28% as desacetylcefotaxime (Chamberlain et al., 1980). Most of a dose of cefotaxime is excreted in the urine. About 50 to 60% of an intravenous dose of I or 2g is excreted as unchanged cefotaxime over

Table IX. Antimicrobial activity (cefotaxime plus active metabolites) in uninfected bone and interstitial (extravascular) fluid in humans after single or repeated doses of cefotaxime

Time after drug (h)

Drug dose1

Drug concentration

Reference

0.5-1 1-2 2-4

2g 2g 19 2g

IV (bolus) IV (bolus) x 41M x 31M

5.41'9/g 4.41'9/g

Wittmann et al. (198Oc) Wittman et al. (l98Oc) Papathanassiou et al. (1980)

Cortical bone

0.5-1 1-2

2g IV (bolus) 2g IV (bolus)

5.4 "gIg 2.1 "gIg

Wittmann et al. (1980c) Wittmann et al. (198Oc)

Cortical and spongy

0.5-3

2g IV

7.64 "g/ml3

Wittmann (1980a)

Specimen

Bone Spongy bone

< 0.5-1.8 "gIg 3.3-15.4 "gIg

Compact bone

2g IV

'" 3

Interstitial fluid (obtained by indicated method) Suction blister 1 2 4

19lM 19lV

25 "g/ml4 4 "g/ml 5 1.6 "g/ml6

Skin window

19lM

9 "g/ml

Frongilla et al. (1980)

Skin chamber

19lM

11 "g/ml

Frongillo et al. (1980)

Subcutaneously implanted cotton threads

2g IV (infusion)

16.8 "g/ml

Blister fluid

19 IV (bolus)

7.2 "g/ml

2g IV (bolus)

20.8 "g/ml

Tissue fluid secreted in postsurgical wounds 1 2 3 4 5 6

3

2-3

19 x 4 indicates that 19 was administered 4 times daily. Absolute value. Geometric mean. All values for extravascular fluid are peak concentrations. Concentration of cefotaxime itself at peak (determined by HPLC). Concentration of desacetyl-cefotaxime at peak (determined by HPLC).

"9/9 2

Rosin and Uphaus (1980)

Frongillo et al. (1981) Bergan et al. (1982a) Bergan et al. (1982a)

Wise et al. (1980b) Wittmann et al. (1980b)

251

Cefotaxime: A Review

a 24-hour period (Bax et al., 1980; Ho et at, 1980; Luthy et at, 1981a,b; Neu et al., 1980). In addition, about 24% of a dose is excreted in the urine as desacetyl-cefotaxime. Most of the drug recovered in the urine is excreted in the first 2 hours after drug administration. Total plasma clearance is reported to be between 260 and 390 ml/minute after intravenous or intramuscular injection, and renal clearance between 145 and 217 ml/minute (Bax et at, 1980; Luthy et at, 1981a,b). Renal clearance values related to body area varied from 104 to 122 ml/minj 1. 73m 2 after intramuscular administration of 500 or 1000mg (Fu et at, 1979), and from 130 to 154 ml/minjl. 73m 2 after intravenous administration of 1000mg (Fu et at, 1979; Ho et at, 1980; Neu et at, 1980). A significant decrease in total plasma and renal clearance was noted by Luthy et at (1981a,b) as the dose was increased from 500mg to 2000mg, but this was not reported by Ho et at (1980). The plasma clearance after the first dose of intravenous cefotaxime was not significantly different from that after 14 days' treatment with Ig 6-hourly (Ho et at, 1980), but a significantly decreased fractional serum and renal clearance occurred after 10 days' treatment with an intramuscular dose of 500mg 8-hourly (Neu et at, 1980). Renal clearance is significantly decreased by the concomitant administration of oral probenecid, with a consequent increase in AVC (Bax et at, 1980; Luthy et at, 1981a,b). 4.3.2 Half-life The mean elimination half-life of cefotaxime is 0.9 to 1.14 hours after intravenous administration of single doses of 500 to 2000mg to healthy adults (Bax et at, 1980; Fu et at, 1979; Ho et at, 1980; Ings et at, 1982; Luthy et at, 1981a,b) and is not altered after repeated doses (Ho et at, 1980). The mean half-life is 1.2 and 1.34 hours following single intramuscular doses of 500 and 1000mg, respectively (Fu et at, 1979). Following administration of cefotaxime, the elimination half-life of desacetyl-cefotaxime in healthy subjects is reported to

be about 1.3 hours after bolus injection of 15 mgj kg or 2000mg (Ings et al., 1982; Luthy et al., 1981 b). However, after intravenous administration of the metabolite itself, the half-life is less than 1 hour (data on file, Hoechst). The half-life of desacetylcefotaxime is markedly increased in patients with severe renal dysfunction (section 4.5).

4.4 Influence of Age on Pharmacokinetics The pharmacokinetics of cefotaxime have been studied in neonates, infants and children and to a limited extent, in elderly patients. In neonates, the pharmacokinetics of cefotaxime are significantly influenced by gestational and chronological age (Hashira et at, 1982; Hattingberg et at, 1980; Heimann et at, 1980; Helwig, 1980a; Kafetzis et at, 1982; Kobayashi et at, 1982) as well as by birth weight (McCracken et at, 1982). In preterm and low birth weight neonates, the elimination half-life is prolonged relative to that of full term (Hashira et at, 1982; Kafetzis et at, 1982) or average birth weight neonates of the same age (table X). The plasma clearance is decreased in preterm and low birth weight neonates compared with full term and average birth weight babies and infants, and children (Heimann et at, 1980; Helwig, 1980a; Kafetzis et at, 1982). High performance liquid chromatography studies indicate that the plasma concentration of desacetyl-cefotaxime varies considerably between subjects, but in some instances is equal to or exceeds that of cefotaxime 2 to 4 hours after intravenous injection (Kobayashi et at, 1982; Nishimura et at, 1982). The elimination of the metabolite is somewhat slower than that of the parent drug (Kobayashi et at, 1982). The volume of distribution of cefotaxime under steady-state conditions, is higher in the newborn (0.31 to 0.35 Ljkg) than in adults (Luthy et at, 1981b). In elderly patients (72 to 95 years) given 2g cefotaxime by intravenous and intramuscular injection, the elimination half-life of 2 to 2.5 hours

252

Cefotaxime: A Review

Table X. Pharmacokinetics of cefotaxime in neonates according to gestational age and birthweight after intravenous administration of 25 to 50 mg/kg (data from Kafetzis et al.. 1982; McCracken et al.. 1982) Population

Preterm

< 1 week

1-4 weeks Full term < 1 week 1-4 weeks low birthweight (1103 ± 216g)

< 1 week

Average birthweight (2561 ± S07g)

< 1 week

Elimination half-life (h)

Volume of distribution

Plasma clearance

5.7 3.5 3.4 2.0

0.61l 0.53l 0.S8l 0.S9l

1.37 1.79 2.30 4.45

4.S

0.51 l/kg

23 ml/min/1.73m 2

3.3

0.44 l/kg

43.9 ml/min/1.73m 2

was longer than in younger adults (section 4.3.2). The plasma clearance was 114 to 161 ml/minute after intravenous injection (Miihlberg and Platt, 1982; Naber and Adam, 1980) and 148 ml/minute after an equal intramuscular dose (Naber and Adam, 1980). The mean plasma creatinine concentration in these patients was 140 ~mol/L.

4.5 Influence of Disease on Pharmacokinetics The pharmacokinetics of cefotaxime have been studied in patients with varying degrees of renal dysfunction, in patients with severe renal dysfunction and coexisting acute illness and in patients with hepatic dysfunction. As the pharmacokinetics of cefotaxime and its principal metabolite desacetyl-cefotaxime differ to a greater extent in patients with renal dysfunction than in those with normal renal function, it is particularly important that pharmacokinetic studies in patients with renal dysfunction employ assay methods that provide data on both cefotaxime and desacetyl-cefotaxime. Thus, only studies which have used HPLC are discussed in this section. In patients with severe renal dysfunction (creatinine clearance < 10 ml/minute), the total plasma clearance, renal clearance, and the urinary recovery of unchanged cefotaxime is decreased. The

ml/min ml/min ml/min ml/min

maximum plasma concentration is slightly or moderately increased and the half-life increased to about 2.5 hours (Ings et aI., 1982; Ohkawa and Kuroda, 1981; Usuda et aI., 1980, 1981; Wise et aI., 1981). The extent of the increase in the half-life of unchanged cefotaxime is slight compared with that of cephalosporins such as cefuroxime, which is not metabolised (Foord, 1976). The volume of distribution of cefotaxime is not significantly altered in severe renal dysfunction (Bergan et aI., 1982b; Fillastre et aI., 1981; Ings et aI., 1982; Ohkawa and Kuroda, 1981; Wise et aI., 1981). Changes in the pharmacokinetics of desacetylcefotaxime are more marked (table XI), with the elimination half-life increasing to about 10 to 15 hours (Fillastre et aI., 1981; Ings et aI., 1982; Wise et aI., 1981). A more marked increase in the elimination half-life of both cefotaxime and desacetylcefotaxime occurs in patients who have acute illness (e.g. heart failure, pulmonary oedema and septicaemia) in addition to severe renal dysfunction (table 'XI) [Wise et aI., 1981]. Total urinary recovery of cefotaxime and desacetyl-cefotaxime decreases with reduction in renal function. However, the ratio of urinary recovery of desacetyl-cefotaxime to that of cefotaxime increases with declining renal function. Thus, the percentage of a dose recovered in the urine as the metabolite exceeds that excreted unchanged in patients whose creatinine clearance is below about

253

Cefotaxime: A Review

10 mljminute (Ohkawa and Kuroda, 1981; Usuda et aI., 1980, 1981). The elimination of cefotaxime in severe renal dysfunction is improved by haemodialysis, the halflife decreasing from 2.5-3.4 to about 1.5 hours (Ings et aI., 1982; Ohkawa and Kuroda, 1981; Usuda et aI., 1980, 1981). The decrease in the half-life of desacetyl-cefotaxime (from 14 hours to 3 hours) is more marked, however (Ings et aI., 1982). Although cefotaxime is absorbed into serum when given by the peritoneal route to patients undergoing peritoneal dialysis (Shurig, 1981), this is of little value in increasing the elimination of the drug (Wise et aI., 1981; Wright and Wise, 1980). There is slight accumulation of cefotaxime following intravenous administration of Ig twice daily to patients with creatinine clearances below lOmlj minute (Wise et aI., 1981). However, desacetylcefotaxime, M2 and M3 accumulated to a greater extent than the unchanged drug (Ings et aI., 1982; Wise et aI., 1981). Thus, the frequency of administration should probably be reduced in patients with severe renal impairment. The half-life of unchanged cefotaxime is not appreciably influenced by the presence of liver damage (Wise et aI., 1981). However, desacetyl-cefotaxime formation is markedly decreased in severe liver damage (Wright and Wise, 1980).

5. Therapeutic Trials Published studies on several thousand patients worldwide have documented the efficacy of cefotaxime in treating a wide range of infections caused by Gram-positive and Gram-negative aerobic bacteria, and occasionally anaerobic bacteria. Cefotaxime has been used in the treatment of urinary tract infections, lower respiratory tract infections, bacteraemia/septicaemia, intra-abdominal, obstetric and gynaecological infections, and in uncomplicated gonorrhoea, and in soft tissue infections. Open studies have also been conducted in a smaller number of adults with bone and joint infections,

endocarditis, meningitis, and in immunologically compromised patients with suspected or proven infection. Neonates, infants and children with various bacteriologically confirmed infections - including septicaemia, urinary tract, respiratory tract and gastrointestinal infections, peritonitis and meningitis - were treated with cefotaxime alone or in combination with another antibiotic. In published studies in adults, cefotaxime has been compared with other cephalosporins, gentamicin and sulbenicillin in treating urinary tract infections, with cefazolin and cefoperazone in lower respiratory tract infections, and with a combination of gentamicin plus clindamycin in peritonitis and other similar soft-tissue infections. In addition, a single intramuscular dose of cefotaxime alone or with oral probenecid has been compared with procaine penicillin G plus probenecid in males and females with uncomplicated gonorrhoea caused by penicillinase-producing and non-producing strains of Neisseria gonorrhoeae. In controlled studies of perioperative prophylactic use of cefotaxime to reduce the incidence of infection in patients undergoing various types of surgery, cefotaxime was compared with untreated controls and with cefazolin. The usual total daily doses of cefotaxime studied in the treatment of established infections were 2 to 6g in adults and 50 to 100 mg/ kg in children. The drug was given by intravenous or intramuscular injection at 6-, 8-, or 12-hourly intervals.

5.1 Treatment of Established Infections

5.1.1 Urinary Tract Infections A large number of patients with urinary tract infections, many of which were complicated by underlying urological abnormalities, have been treated with cefotaxime in open or controlled studies. Response rates varied widely between studies, as did the types of infection, presence of predisposing factors, definition of response, and time of assessment. Hence, it is difficult to establish a 'usual'

Cefotaxime: A Review

254

Table XI. Mean half-lives of cefotaxime and desacetyl-cefotaxime in patients with varying degrees of renal dysfunction following single intravenous bolus injection of 19 or 0.5g of cefotaxime (after Wise et aI., 1981; Wright and Wise, 1980) Renal function (creatinine clearance; ml/min)

No. of patients

Cefotaxime serum half-life (h)

No. of patients

4

Desacetyl-cefotaxime half-life (h)

> 100 30-100 10-30 3-10

1.0 (0.72-1.3) 1.3 (1.27-1.34) 1.9 (1.26-2.4) 2.6 (1.4-3.6)

3

1.5 (1.1-1.8)

3 6 9

2 6

6.6 (2-9.9) 10 (8.2-11.8)

Severe impairment

7

5.6 (2.2-11.5)

4

30 (19.2-56.8)

« 5) plus acute illness

response rate, even in patients with specific bacterial infections. Patients were usually treated with between 1.5 and 6 gJday of cefotaxime alone, the most common dosage being 19 l2-hourly for 5 to 10 days. Studies in a relatively small number of patients with uncomplicated urinary tract infections gave bacteriological response rates of 87 to 100% after treatment with cefotaxime 2 gJday (Graninger et al., 1981; Ludwig and Knebel, 1980). Not unexpectedly, in patients with complicated urinary tract infections the bacteriological response to cefotaxime varied according to when patients were assessed. On the last day of treatment urine cultures were negative in 93 to 100% of73 patients treated for 5 to 10 days with either 1.5 or 3 gJday of intramuscular cefotaxime. One week later, sterile urine was observed in about 60 to 70% of patients; the original organism was re-isolated in 14 to 29%, and/or a different organism in 4 to 21 % of cases (Madsen and Iversen, 1981). In this study, complicated urinary tract infections were usually due to a single pathogen, and a relatively high proportion (28%) were Gram-positive. In another study (Casellas et al., 1980), in which about half of the patients had renal or ureteric obstruction, urine from 97% of 30 patients was sterile 7 days following the end of treatment (2 gJday for 5 days). Four weeks later 59% of patients had no bacteriuria and 90% remained asymptomatic. Overall, 70 to 90% of infecting strains of cefotaxime-sensitive Gram-negative organisms were

eradicated from patients with complicated or uncomplicated urinary tract infections at the end of treatment (Homer and Piper, 1981; Kawada et al., 1980; Ludwig and Knebel, 1980) [tables XII and XIV]. In general, E. coli, Klebsiella species, indolepositive and -negative Proteus, Enterobacter and Citrobacter species were eradicated more successfully than Pseudomonas and Serratia species (table XII). Interestingly, in the study by Kawada et al. (1980) in patients with complicated infections, eradication rates were similar for bacteria (both Gram-positive and -negative) with cefotaxime MICs less than or equal to 25 ~gJml (76% eradicated) and those bacteria resistant to cefotaxime (MIC > 25 ~gJml) on in vitro testing (68%). Notably, 12 of 14 (86%) 'resistant' strains of Streptococcus faecalis were eradicated by the end of 5 days' treatment with cefotaxime. These responses presumably result from the high urinary excretion of cefotaxime. Although cefotaxime is active in vitro against fJlactamase-producing strains of Gram-negative organisms, little information is available on the drug's clinical activity against these strains. However, in one small study (Portier et al., 1981), 8 of 10 patients with urinary tract infections caused by fJ-lactamase-producing strains of Klebsiella species (4), Proteus mirabilis (4), or E. coli (3), and who also had underlying diseases, were successfully treated with up to 50 mgJkgJday of intramuscular cefotaxime.

Cefotaxime: A Review

In a few studies which specifically reported patients' clinical response to cefotaxime, about 90 to 97% of those treated with cefotaxime alone for complicated or uncomplicated infections became asymptomatic (Cassellas et aI., 1980; Ludwig and Knebel, 1980) and/or showed improvement (Cox and Simmons, 1982). Similar results (84 to 95% of patients clinically cured) were reported in several large reviews of data collated by the manufacturers from studies conducted in Europe (including the UK) and Latin America (Bax and Young, 1981; Connelly, 1982; Young et aI., 1980). However, a small proportion of these patients probably received other antibiotics as well as cefotaxime. The response of specific types of urinary tract infection to cefotaxime has been reported in small open studies. Paradisi et ai. (1982) used cefotaxime to treat 30 hospitalised patients with urinary tract infections which had not responded to prior antibiotics. Some patients also had underlying urinary tract abnormalities. Those 'cured' clinically and bacteriologically 2 weeks after the end of treatment included 11 of 12 patients with acute cystitis, 4 of 5 with chronic or recurrent cystitis, all 9 with acute pyelonephritis, but none of 3 patients with chronic pyelonephritis. Daily doses of cefotaxime ranged between 2 and 6g given 6- or 8-hourly, usually intramuscularly, for 7 to 11 days. Ofthe 6 patients with infections caused by cefotaxime-sensitive Pseudomonas aeruginosa, 3 were cured, 1 relapsed and 2 failed. The strains of P. aeruginosa isolated from post-therapy specimens from the 2 failures were apparently the same as the pre-therapy strains, but were shown to be resistant to cefotaxime (by the disc diffusion method). Guibert et ai. (1981) reported negative followup cultures 4 weeks after the end of treatment in 10 of23 patients (44%) with chronic pyelonephritis and underlying urological pathology, in 8 of 12 cases (67%) with uncomplicated cystitis and 11 of 18 cases (61 %) with cystitis associated with urological abnormalities. Doses administered were 1.5 or 2 g/ day (range, 1 to 4 g/day) given intramuscularly. The duration of treatment was longer than usual, rang-

255

ing from 7 to 28 days with a median of 18 days. It is well known that catheterised patients with urinary tract infections are more difficult to treat than those without catheters, and this was also shown to be the case with cefotaxime (Kawada et aI., 1980; Ohkawa and Kuroda, 1980). Although urinary catheters were used in some patients in several other studies, rarely was the extent of such usage and the response of these patients specifically reported (Mogabgab et aI., 1982). Some studies in urinary tract infection included patients with impaired renal function, but response to cefotaxime in this subgroup of patients was rarely reported. However, Daikos et ai. (1980) reported eradication of urinary pathogens (many of which were multidrug-resistant) from 5 of 6 patients with 'renal failure' (not defined), 6 of 7 with kidney stones, and from 3 patients requiring haemodialysis. No side effects or toxicity were reported in these patients, most of whom received 0.5g of cefotaxime 8-hourly (range 0.5 to 3 g/day). Controlled Studies Cefotaxime has been compared with various other antibiotics used to treat urinary tract infections, in blinded and non-blinded studies. In 3 large Japanese trials in complicated urinary tract infection (summarised in table XIII), response was based on the assessment of bacteriuria and pyuria, probably at the end of treatment. Elimination of both signs was classed as 'excellent', but a 'moderate' response was very broadly defined (see footnotes to table XIII). Significantly (p < 0.01) more patients given intravenous cefotaxime 2 g/day, usually for 5 days, had excellent plus moderate responses compared with those on cefazolin 4 g/day, ceftezole 4 g/day or sulbenicillin 10 g/day (table XIII). However, in patients assigned at random to treatment with sulbenicillin, 55% of urinary organisms were resistant to the drug (MIC > 200 ~gfml) and, not unexpectedly, these organisms were less frequently eradicated than were sulbenicillin-sensitive organisms (Kawada et aI., 1980). Unfortunately, the sensitivity (or resistance) of organisms

256

Cefotaxime: A Review

Table XII. Frequency of eradication of bacteria during treatment of complicated urinary tract infections with cefotaxime

Bacteria

No. of bacteria eradicated/ no. isolated (% eradicated) in studies by Kumazawa et al. (1981)'

Kawada et al.

(1980)2

Gram-positive Staphylococcus epidermidis Streptococcus faecalis /

4/4 3/5

enterococcus Streptococcus pyogenes

Other Gram-positive cocci

3/3 5/6

6/6

Gram-negative

Acinetobacter species

17/17 2/2 4/4 6/7 6/8 13/21 9/10 10/17 4/6 2/3

Total Gram-negatives

73/95 (77)

Escherichia coli Klebsiella species Proteus mirabilis

Indole-positive Proteus Enterobacter species Serratia species Citrobacter species Pseudomonas aeruginosa

Other Pseudomonas

28/34 12/14

} 11/12 4/4 7/15 3/4 4/11

69/94 (73)

1 Patients had chronic complicated urinary tract infections and were treated with cefotaxime 2 g/day intravenously for 5 or more days. Response was assessed on day 5. Sensitivity of organisms to cefotaxime unknown. 2 Patients had complicated urinary tract infections, were treated with cefotaxime 2 g/day intravenously for 5 days, and assessed 'after treatment'. Results are presented for organisms (isolated from midstream or catheter specimens) with cefotaxime MICs .. 25 ltg/mi.

to the antibiotics used in the other 2 studies (Kumazawa et aI., 1981; Ohkawa and Kuroda, 1980) was not reported. Hence, in view of this, and the manner in which response was assessed, results of these studies should be interpreted with caution. Cefotaxime has also been compared with cefazolin (Madsen and Iversen, 1981), cefuroxime (Homer and Piper, 1981), cefoxitin and gentamicin (Ludwig and Knebel, 1980). Bacteriological response rates in these studies in various types of

urinary tract infection are summarised in table XIV. Although the study by Madsen and Iversen (1981) did not show a statistically significant difference between cefotaxime and cefazolin in the treatment of complicated urinary tract infections, this could well be due to the small number of patients studied. Unpublished reports of small single- or doubleblind studies mainly in hospitalised patients with acute cystitis or pyelonephritis indicated that cefotaxime 2 to 4 gjday was more effective bacteriologically than the same dose of cefazolin, although pathogens were sensitive in vitro to each drug (Drennan, 1982; Mogabgab et aI., 1982). Similar results from large groups of patients were reviewed by Madsen (1982), but unfortunately insufficient information was provided to permit meaningful assessment of these results (e.g. dosage of cefazolin, types of urinary tract infection treated and comparability of treatment groups were not specified). Thus, although such studies suggest that cefotaxime may be more effective than cefazolin in the treatment of urinary tract infections, this needs confirming in a large well-designed and well-reported study using appropriate dosages. In the study by Homer and Piper (1981), the initial pathogen was eradicated from bladder puncture specimens in significantly more (p = 0.05) patients treated with cefotaxime 2 g/day (83%) for 3 days than with cefuroxime 2.25 g/day (56.5%). However, a change in pathogen occurred during therapy in 2 patients in each group thus resulting in 74% of cefotaxime patients and 48% of cefuroxime patients having sterile urine at the end of therapy. The statistical significance of this difference was not reported. Regrettably, there was no late follow-up in this study, nor in the studies by Ludwig and Knebel (1980). These latter authors consider the bacteriological response of urinary pathogens to cefotaxime 2 g/ day superior to that achieved with a relatively low dose of gentamicin (160 mgjday) in acute recurrent and acute on chronic urinary tract infections, and superior to that with cefoxitin 3 g/day in uncom-

Cefotaxime: A Review

257

Table XIII. Summary of controlled studies conducted in Japan in patients with complicated urinary tract infections treated with intravenous cefotaxime (cefot). sulbenicillin (sulb). ceftezole (ceftz). or cefazolin (cefaz) Study design' (duration in days)

Drug and daily dose (g)

No. of patients assessed 2

Kawada et al. (1980)

Db. r. mc (5)

Cefot 2 Sulb 10

Kumazawa et al. (1981)

Mc

(~5)

Reference

Ohkawa and Kuroda (1980)

Db. r. mc (5)

Response3 (% of patients) excellent

moderate

poor

128 133

24 20

41 24

35 56

Cefot 2 Ceftz 4

85 87

14 13

53

33

27

60

Cefot 2 Cefaz 4

131 133

27 16

40 26

33 58

Db = double-blind; r = randomised; mc = multicentre. 2 Presumably assessed on day 5 in all studies. 3 Response based on the assessment of bacteriuria and pyuria. Excellent = elimination of both signs; moderate = bacteriuria eliminated and pyuria decreased or unchanged. or bacteriuria decreased and pyuria cleared. decreased or unchanged. or bacteriuria replaced and pyuria cleared or decreased.

plicated, symptomatic urinary tract infections. However, there was no information concerning comparability of treatment groups in these 2 singleblind, randomised studies and the results were not analysed statistically.

5.1.2 Lower Respiratory Tract Infections Cefotaxime has been studied in a considerable number of patients with lower respiratory tract infections, particularly pneumonia. Many patients also had other conditions, some were elderly, and some seriously ill. While most studies were conducted in hospitalised patients, few indicated whether respiratory infection was hospital- or community-acquired. Usually a daily dose between 2 and 6g of cefotaxime (alone) was given intramuscularly or intravenously in 2 to 4 divided doses for 7 to 14 days. In open and comparative studies, 75 to 100% of patients with pnemonia showed complete resolution or improvement in clinical signs and symptoms and chest radiographs at the end of therapy (see below). In open studies in 'difficult' patients (e.g. those with underlying diseases such as chronic lung disease, alcoholism, ischaemic heart disease, or in the elderly), some of whom were seriously ill, response

rates of 85 to 100% have been reported (Hanninen et aI., 1980; Mullaney and John, 1982; Schleupner and Engle, 1982). Most of such patients received a dose of 4 to 6g daily given intramuscularly or intravenously for about 7 to 10 days. S. pneumoniae, H. injluenzae and K. pneumoniae were isolated most frequently from appropriate specimens (e.g. transtracheal aspirates) and were readily eradicated (Mullaney and John, 1982), but pulmonary superinfection due to Pseudomonas species occurred in 4 patients who were being mechanically ventilated, 3 of whom died (Schleupner and Engle, 1982). A few patients with empyema (Dolmann et al., 1981; Goullon, 1980; Kemmerich, and Lode, 1981; Mullaney and John, 1982) or a lung abscess (Dolmann et aI., 1981; Kemmerich and Lode, 1981; Mullaney and John, 1982; Newsom et aI., 1981) have been treated with cefotaxime in daily doses of 3 to 8g. Most showed clinical improvement or resolution. In summarising results from studies conducted in Europe and LatinAmerica, Younget al. (980) reported that 81 % of 410 patients with various respiratory tract infections were cured clinically, 5% relapsed and 14% failed. Over 80% of patients were treated with 2 to 4 gfday of cefotaxime, but some

Table XIV. Summary of some controlled studies in patients with various types of urinary tract infections (UTI). Also see text (section 5.1.1) for discussion of additional controlled studies

Reference

Type of infection' (no. of patients)

Study design2 (duration in days)

Response assessed (days posttherapy)

Urine specimen

Drug,3 usual daily dose (g), and route

No. of bacteria isolated

Bacteriological response (% of bacteria) eradicated'

relapsed (original pathogen)

persisted reinfected (different pathogen)

()

i3' x

!1!

> :Il

'"ar< ~

Hoffler and Piper (1981)

UTI5 (18) + R uncomp. pyelon (25) + (3) compo pyelon (3)

Ludwig and Knebel (1980)

Acute recurrent or acute on chronic UTI (58) Uncomp., symptomatic UTI (69)

Madsen and Iversen (1981)

1 2 3 4 5 6 7 8 9 10

Compo UTI (43)

Bladder puncture

Cefot 2 Cefur 2.25

23 23

74 48

Sb, r (10)

Midstream or catheter

Cefot 21M Gent 0.16 1M

36 40

81 55

5.5 12.5

5.5 17.5

Sb, r (... )'

Not stated

Cefot 2 1M Cefox 3 IV

47 43

87 72

6.5 14

6.5 14

Midstream

Cefot 1.5 1M Cefaz 3.0 1M

28 15

71 60

25'0 13'0

R8 (5 to 7)

79

Compo = complicated; uncomp. = uncomplicated; pyelon = pyelonephritis. R = randomised; SB = single-blind (observer unaware of antibiotic used). Cefot = cefotaxime, cefur = cefuroxime, gent = gentamicin, cefox = cefoxitin, cefaz = cefazolin. Original organism(s) eradicated and urine remained sterile until post treatment assessment. No renal parenchymal involvement. Response assessed 'after treatment'; no other details given. Not given. Patients randomised to cefotaxime or cefazolin group in a ratio of 2 : 1. Patients also assessed on the last day of treatment (urine sterile in 100% of cefotaxime and 93% of cefazolin patients). Combined results for relapse and persistence of infection.

17 43

9 9

'0 '0

8 15

4 27

I\)

C11 0>

Cefotaxime: A Review

may have also received other antibiotics. Similarly, in 2 multicentre studies in the UK, 82% of 103 patients (Bax and Young, 1981) and 90% of 103 patients (Connelly, 1982) with lower respiratory tract infections were cured with cefotaxime alone or in combination with other unspecified antibiotics. Understandably, bacteriological response by organism was reported only occasionally in patients with respiratory tract infections. In the largest single report (Perkins, 1982) which contained this information (for 328 organisms), a satisfactory bacteriological response (organism eradicated or specimen unobtainable) occurred with over 95% of S. pneumoniae and H. injluenzae isolates, about 90% of S. aureus and E. coli and 70 to 80% of P. mirabilis, Enterobacter and Klebsiella species. Similar results were reported by Young et ai. (1980). Although Pseudomonas species have been isolated from a few patients with respiratory tract infections treated with cefotaxime (e.g. Dolmann et ai., 1981; KrUger et ai., 1980; Maesen et ai., 1980; McKendrick et ai., 1981; Miki and Shiota, 1980; Mullaney and John, 1982; Okubadejo and Bax, 1982; Schleupner and Engle, 1982), there are insufficient data on which to base conclusions, particularly regarding bacteriological response rates of pseudomonal infections. Perkins (1982) reported satisfactory bacteriological and clinical responses in 5 and 9 patients, respectively, of 13 patients treated with cefotaxime for lower respiratory tract infections involving P. aeruginosa. Many, but not all of these isolates were sensitive in vitro (MIC range 0.08 to 200 ~g/ml, MIC 50 10 ~gfml). In a brief report, Newsom et al. (1981) commented that 4 patients with severe chronic bronchitis/bronchopneumonia due to ampicillin-resistant (MIC ~ 16 ~g/ml) H. injluenzae were treated successfully with intravenous cefotaxime Ig thrice daily for at least 7 days. Controlled Studies Cefotaxime has been compared with cefazolin (Jenkinson et ai., 1980; Miki and Shiota, 1980; Per-

259

kins, 1982) and cefoperazone (Kemmerich and Lode, 1981) in lower respiratory tract infections. In randomised controlled multicentre trials (Perkins, 1982) in hospitalised patients with bacteriologically confirmed lower respiratory tract infections, clinical response rates (by patient) with cefotaxime (95%) and cefazolin (92.5%) were similar in a 79-patient observer-blind study, but differed significantly (99% vs 92%, respectively; p = 0.03) in a single-blind study in about 200 patients, two-thirds of whom received cefotaxime. Bacteriological response rates were similar with each antibiotic in both studies (bacteria eradicated in about 96% of patients or sputum production resolved). The specific types of infection treated in these studies were not clearly specified. A summary of dosage data from these patients plus 210 patients treated with cefotaxime in an open study was provided and showed the mean dosage of cefotaxime ranged from 4 to 6 gfday depending on the patient's initial condition, and of cefazolin from 3 to 4 g/ day. The route of administration differed between treatment groups in the single-blind triai. In another comparative study, clinical response with intravenous cefotaxime 4 g/day was similar to that with the same intravenous dose of cefazolin in 128 patients with mild to moderate pneumonia complicated by underlying respiratory disease, and in 90 patients with other respiratory tract infections such as infected bronchiectasis, 'infected lung cancer', lung abscess, and infection associated with chronic obstructive pulmonary diseases (fig. 2). Bacteria (mainly Gram-negative bacilli) were isolated from sputum in only 92 (42%) of all 218 patients in this multicentre randomised, nonblinded, Japanese study (Miki and Shiota, 1980); the bacteriological response was assessable in just 76 patients. At the end of treatment the putative pathogen was eradicated from significantly more patients in the cefotaxime group than in the cefazolin group (65% vs 39%). Results from a small non-blinded study in patients with uncomplicated pneumococcal pneumonia suggested cefotaxime 2 g/day intramuscu-

260

Cefotaxime: A Review

larly was as effective clinically as cefazolin 1 gjday intramuscularly; bacteriological response was not assessed (Jenkinson et aI., 1980, 1982). In a non-blinded, non-randomised study, intravenous cefotaxime 6 gjday appeared comparable to intravenous cefoperazone 4 to 8 gjday (mean, 5 gjday) in patients with serious bronchopulmonary and pleural infections such as pneumonia, acute exacerbations of chronic bronchitis, and pleural empyema. Complete resolution or clinical improvement occurred in 14 of 19 (74%) patients treated with cefotaxime for an average of 12 days, and in 16 of22 (73%) cefoperazone patients treated for a similar period. Although most pre-treatment bacterial isolates were Gram-negative bacilli, organisms differed between the 2 groups: K. pneu-

moniae and E. coli predominated in cefotaximetreated patients, while P. aeruginosa, H. injluenzae and Gram-positive cocci were isolated more frequently from cefoperazone patients. Unfortunately, bacteriological assessment was not reported (Kemmerich and Lode, 1981; Lode et aI., 1980b). Cefotaxime has been used successfully in treating acute purulent exacerbations of chronic bronchitis. In an inpatient study by Maesen et ai. (1980), cefotaxime-sensitive H. injluenzae (43%) and S. pneumoniae (22%) were the most common isolates from sputum. Clinical and bacteriological response in 27 patients treated with intramuscular cefotaxime 19 twice daily was excellent (78%) or good (22%) at the end of 10 days' treatment; however, 22% of patients were reinfected 7 days later. In

•

= excellent (rapid and complete remission)

oo

good (complete remIssion)

= faIr (partial remiSsion)

= poor (no improvement)

Cefotaxime Pneumonia (28 patients)

Cefazohn

Cefotaxime

Cefazolin

Other respiratClrf tract infectJ()(ls (90 patients)

Fig. 2. Clinical response to intravenously administered cefotaxime 4 g/day or cefazolin 4 g/day by patients with pneumonia or other lower respiratory tract infections (after Miki and Shiota, 1980).

Cefotaxime: A Review

similar groups of patients previously treated by these investigators, clinical response rates (with orally administered drugs) were lower with ampicillin 3 gjday, and similar with amoxycillin 2.25 gj day and bacampicillin 2.4 gjday, while recurrence rates were higher with ampicillin and amoxycillin and similar with bacampicillin to results achieved with cefotaxime 2 gjday. Excellent results, with no reinfections within 10 days, occurred in all 10 patients treated with 4 gjday of cefotaxime.

5.1.3 Bacteraemia/Septicaemia and Endocarditis Published reports on several hundred patients indicate that cefotaxime has been used successfully in the treatment of bacteraemia/septicaemia over a wide dosage range (2 to 12 gjday). However, in patients with normal renal function, the usual dose was 3 or 6g daily for about 8 to 17 days. Many patients had concomitant disease in addition to septicaemia, which usually originated from the urinary, respiratory or gastrointestinal tracts. Blood samples from most patients grew a single species of a cefotaxime-sensitive Gram-negative organism. Cefotaxime was used alone in the treatment of most patients, although a few also received another antibiotic, mainly on aminoglycoside, and such patients usually responded favourably (Armengaud et aI., 1980; Bastin et aI., 1981; Goulon et al., 1981; Lepeu et aI., 1981; Portier et al., 1981). Occasionally, patients who had not responded to other antibiotics were treated successfully with cefotaxime (Bastin et al., 1981; Bruch and Blomer, 1980; GouIon et aI., 1981; Motin et aI., 1981), as were a few patients with bacteraemia caused by organisms resistant to other ~-lactam antibiotics (Neu and Francke, 1982). Reviews of data from bacteraemic/septicaemic patients treated with cefotaxime alone in the USA (Meyers, 1982; Neu, 1981), or the UK and Ireland (Bax, 1982) reported very similar results. In patients assessed according to strict criteria, Neu (1981) reported that 91 % of 79 pathogens were eradicated with cefotaxime (mean dose, 6 gjday), including 47

261

of 54 (87%) Gram-negative aerobes, all 16 Grampositive aerobes and the 2 anaerobic isolates. Singlepathogen bacteraemias were eradicated in 94% of 65 assessable patients and multiple pathogen bacteraemias in 5 of 7 patients (79%). Bax (1982) reported an overall bacteriological eradication rate of 83%, comprised of 51 of 58 (88%) Gram-negative aerobes, 6 of 8 Gram-positive aerobes and 1 of 2 anaerobes. The response of those organisms isolated most often from patients in these 2 reports are presented in table XV. Bax (1982) also reported that 85% of 78 assessable patients were cured clinically, 4% relapsed and 11% failed. However, some of the 7 patients classified as 'unassessab1e' by the individual investigators could also have been considered to be 'failures'. The commonest dosage used was 19 8-hourly, although some severely ill patients required double that dose. In small individual studies in which patients with bacteraemia were treated with cefotaxime alone, bacteriological response rates between 80 and 100% were reported (McKendrick et aI., 1980b, 1981, 1982; Motin et al., 1981). Clinical response rates in these studies tended to be lower than bacteriological response rates. For instance, 71 % of 17 patients in intensive care with severe Gram-negative infections (and other conditions) were clinically cured with 2 to 6 gjday of cefotaxime (Motin et aI., 1981), as were 60% of 25 patients treated with 3 or 4 gjday of cefotaxime (in most cases) [McKendrick et aI., 1980b). In the latter study, the clinical response in patients infected with Gramnegative organisms (e.g. E. coli, Klebsiella aerogenes, P. mirabi/is) was better than in those infected with staphylococcal and streptococcal species, although all organisms were eradicated from the blood. It should be noted, however, that this study included patients with endocarditis (4), typhoid fever (2), osteomyelitis (1), and agranulocytosis (1), who did not respond as well as those in whom the primary diagnosis was intra-abdominal sepsis (12) or renal tract infection (5). The 4 patients with endocarditis in the above study were treated with 1.5 to 3g daily of cefotax-

262

Cefotaxime: A Review

ime alone. Blood cultures became sterile soon after starting therapy in all patients; one (infected with /1-haemolytic streptococci, Group G) was cured clinically, one (with S. aureus) improved, and 2 (with E. coli or /1-haemolytic streptococci, Group C) required urgent cardiac surgery. In other studies, a few patients with endocarditis due to E. coli, P. aeruginosa, Branhamella catarrhalis (Neisseria catarrhalis), S. aureus, Streptococcus durans (Armengaud et aI., 1980), viridans streptococci (Daikos et aI., 1980; Niebel and Rinke, 1980), Serratia liquefaciens (Bastin et aI., 1981), Serratia marcescens (Hyams et aI., 1981), Proteus mirabilis (Aznar et aI., 1981), or Actinobacillis actinomycetemcomitans (Shah et aI., 1980) have been treated with 4 to 8 g/day or cefotaxime for prolonged periods, often in conjunction with an aminoglycoside. Most patients were cured clinically and/or bacteriologically.

5.1.4 Gonorrhoea The excellent in vitro activity of cefotaxime against penicillinase-producing and non-producing strains of Neisseria gonorrhoeae has been corroborated clinically in patients with uncomplicated gonorrhoea. Although clinical efficacy against penicillinase-producing strains is of greater interest with a drug such as cefotaxime, most of the data available, particularly concerning comparative efficacy and in the treatment of non-genital gonorrhoea, pertain to non-penicillinase-producing strains. Non-penicillinase-producing

Neisseria gonorrhoeae A single intramuscular injection of cefotaxime (0.5 to Ig) given to patients (most of whom were male) infected with non-penicillinase-producing strains usually yielded cure rates of 96 to 100% (Backhaus and Myer-Rohn, 1980; Belli et aI., 1980; Handsfield, 1982; Hard et aI., 1980; Hubrechts et aI., 1980b; Lee and Ngeow, 1982; Panikabutra et aI., 1982; Rajan et aI., 1980; Simpson et aI., 1981). The most frequently used dosage was a single intramuscular injection of Ig, but some patients re-

Table XV. Bacteriological response of the more common organisms causing bacteraemia in patients treated with cefotaxi me (data after Bax, 1982; Neu, 1981)

Pathogen

No. eradicated/ no. isolated (%)

Staphylococcus aureus

7/8 (88) 5/5 (100) 9/10 (90) 48/52 (92) 20/21 (95) 12/13 (92)

Streptococcus pneumoniae

Other streptOCOCCi Escherichia coli Klebsiella species Proteus species

(indole-positive and -negative) Serratia marcescens Pseudomonas species

8/9 (89) 8/10 (80)

ceived a smaller dose plus probenecid Ig (Backhaus and Meyer-Rohn, 1980; Panikabutra et aI., 1982; Rajan et aI., 1980). A single Ig dose of cefotaxime was as effective as aqueous procaine penicillin G 4.8 million units given in 2 intramuscular injections plus probenecid (1g orally) in treating patients with genital or rectal infections caused by /1-lactamase-negative N. gonorrhoeae (Handsfield, 1982; Handsfield and Holmes, 1981; Lutz et aI., 1982; Simpson et aI., 1981). In a non-blinded multicentre study conducted in the USA (Handsfield, 1982), cefotaxime and penicillin plus probenecid each cured 98% of 287 urethral or endocervical infections, and 96% or 94%, respectively, of 41 rectal infections. Although cefotaxime cured 8 of 11 (73%) pharyngeal infections while penicillin plus probenecid cured all 4 such infections, further studies are needed to determine clearly the relative efficacy of cefotaxime in pharyngeal gonococcal infection. In most centres, cefotaxime and aqueous procaine penicillin G caused similar degrees of pain following injection, but as only 1 dose of cefotaxime was required, this drug appeared to be better accepted by patients and easier to administer. Similar efficacy and tolerance data were reported from individual centres in the USA (Handsfield and Holmes, 1981; Simpson et aI., 1981).

263

Cefotaxime: A Review

In one of the few studies which determined the incidence of post-gonococcal urethritis following cefotaxime therapy, Handsfield and Holmes (1981) diagnosed this condition in 10 (43%) of23 men reexamined 11 to 30 days following treatment; in 5 of these patients Chlamydia trachomatis was isolated from the urethra. When seen within a week of treatment, 2 of 50 patients given cefotaxime in the study by Simpson et ai. (1981) had postgonococcal urethritis. Penicillinase-producing Neisseria gonorrhoeae Since other effective oral and parenteral antibiotics are available for the treatment of gonorrhoea caused by non-penicillinase-producing strains of N. gonorrhoeae, the use of cefotaxime in treating penicillinase-producing strains is of greater potential importance. From published data available so far on a relatively small number of patients (about 150 in total), a single dose of cefotaxime (0.5 to Ig) appears to be highly effective (98 to 100% response) in the treatment of uncomplicated genital gonorrhoea due to penicillinase-producing gonococci (Boakes et aI., 1981; Egere et aI., 1982; Hard et aI., 1980; Handsfield, 1982; Lancaster et aI., 1980, 1982; Lee and Ngeow, 1982; Panikabutra et aI., 1982; Slack et aI., 1980). A 98% cure rate was achieved by Rajan et ai. (1980) in treating 13 males and 42 females (mainly prostitutes in Singapore) who had genital or rectal gonorrhoea, with a single 0.5g intramuscular dose of cefotaxime plus Ig of probenecid orally. The only failure was a female prostitute; the MIC of cefotaxime for her original infecting strain of N. gonorrhoeae was ~ 0.016 ~g/mi. In a Nigerian study, all 19 males with gonococcal urethritis caused by penicillinase-producing strains were cured with a single Ig dose of cefotaxime (Egere et aI., 1982). Similarly, a brief communication from the UK indicated that all 33 patients treated with a single 0.5g dose of cefotaxime were cured, including 2 with oropharyngeal as well as genital infections and one patient who had not responded to treatment with spectinomycin

despite in vitro sensitivity of the strain to spectinomycin (Boakes et aI., 1981). Two studies compared the efficacy of cefotaxime, in a dose of Ig (Lancaster et aI., 1980) or 0.5g plus oral probenecid (Panikabutra et aI., 1982), with that of aqueous procaine penicillin G 4.8 million units and probenecid Ig in the treatment of gonococcal urethritis in males. Because a mixture of patients infected with penicillinase-producing and non-producing strains of N. gonorrhoeae participated in these studies, cefotaxime was markedly more effective than penicillin (overall response rates of 94 to 100% vs 40 to 62%). All 41 patients (in both studies) with penicillinase-positive strains were cured with cefotaxime, compared with about 22% of 60 who were treated with penicillin.

5.1.5 Obstetric and Gynaecological Infections In several studies in the treatment of obstetric and gynaecological infections, cefotaxime 2 to 6 g/ day has been used successfully, with response rates generally greater than 90% (Hemsell and Cunningham, 1981; Hemsell et aI., 1982; Soutoul et aI., 1980; Takase, 1981). In a summary of results from 172 evaluable cases studied at 31 institutions in Japan, Takase (1981) reported clinical resolution in 98% of 43 uterine infections, 94% of 51 cases of adnexitis, 93% of 14 infections on external genitalia, 91 % of 57 pelvic infections and in all cases of mastitis (4) and panperitonitis (3) treated with cefotaxime (no data on dosage and duration given). Patients who also underwent surgery (as part of therapy) were included in these results, but no details were provided. 158 organisms were isolated from 98 (57%) of the patients studied, and consisted of Gram-negative (42%) and Gram-positive (28%) aerobes or anaerobes (30%). A retrospective analysis of 7 different antimicrobial regimens studied in various protocols by the same group of investigators in more than 600 women with serious pelvic infections suggests that cefotaxime 3 or 6g daily given intravenously is more effective than parenterally administered penicillin

Cefotaxime: A Review

G plus an aminoglycoside, and that cefotaxime 6g daily is as effective as intravenously administered clindamycin 2400mg daily plus gentamicin 3 mgf kg/day in women with endomyometritis following caesarean section (Hemsell and Cunningham, 1981; Hemsell et ai., 1982). However, such findings have not been confirmed in well-controlled studies. In a small study in women with bacteriologically confirmed pelvic inflammatory disease, N. gonorrhoeae was isolated from the cervix of 5 patients (2 of whom also had E. coli in culdocentesis aspirates). Non-gonococcal aerobic and anaerobic bacteria were isolated from culdocentesis aspirates taken from 11 others. Signs and symptoms completely resolved with 5 days of intravenous cefotaxime therapy (3 or 6 gfday) in all 5 patients with gonococcal pelvic inflammatory disease and in 7 (64%) of those with non-gonococcal pelvic infection. Two of the remaining patients improved with cefotaxime 6 gfday, but were changed after 5 days of therapy to another antibiotic. Despite a daily dose of 6g, 1 patient developed tuboovarian abscesses following the end of therapy, and the fourth remained febrile throughout the course. The identity and sensitivity of organisms isolated from these patients with partial or unsatisfactory responses were similar to those treated successfully, as were serum concentrations 1 hour after the first dose. Unfortunately, cultures were not done for Chlamydia, which can playa role in pelvic inflammatory disease (Monson et ai., 1981).

5.1.6 Intra-Abdominal Injections Cefotaxime has been used alone in the treatment of patients with peritonitis and, to a lesser extent, in treating biliary and hepatic infections. Most patients with peritonitis, treated in a large comparative study (Stone et ai., 1981) or in small open studies (Berndt et ai., 1980; Goullan, 1980; Wittmann et ai., 1980a), were cured clinically with cefotaxime given intravenously in total daily doses of about 4 to 6g. In many cases this was accomplished in conjunction with surgical treatment. A non-blinded comparative study by Stone et

264

ai. (1981) demonstrated that cefotaxime 80 mg/kgf day (i.e. usually about 6g daily) was as effective as gentamicin (3 mgjkgfday) given in combination with a relatively low dose of clindamycin (20 mg/ kg/day) to patients with peritonitis. Of 77 assessable patients given cefotaxime for 5 to 10 days, 85% were cured clinically, infection recurred in 10% and in 5% treatment failed. Corresponding results in 76 patients treated with gentamicin plus clindamycin were 82% cured, 14% recurred and 4% failed. In addition to receiving antimicrobial therapy, about 80% of all patients studied also underwent an operative procedure. On analysing clinical response by operative procedure, the authors postulated that late or inadequate surgery, rather than inferior antibiotic therapy, probably contributed to many of the treatment failures. This study also included another 75 patients with polymicrobial soft-tissue surgical sepsis (see section 5.1.7). The overall incidence and severity of adverse reactions other than nephrotoxicity (see section 6.3) was similar for both treatment groups. The difference in mortality rates between treatment groups was not statistically significant: 4 (3%) cefotaxime-treated patients died (2 from uncontrolled sepsis) compared with 9 (7%) control patients (including 3 from uncontrolled sepsis and 2 from superinfection). In a review of chemotherapeutic principles of the treatment of peritonitis, Wittmann (1980b) commented that cefotaxime should be combined with another antibiotic such as metronidazole, clindamycin or piperacillin, in view of the relatively few isolates of Bacteroides species inhibited by achievable intraperitoneal drug concentrations. Interestingly, in vitro sensitivity data from the study by Stone et ai., (1981) suggested the antibiotic combination of gentamicin and clindamycin was more active than. cefotaxime alone, but both regimens were equally effective clinically, as described above. Although cefotaxime has been used in a small number of patients with biliary, hepatic or pancreatic infections (Kasai et ai., 1981; McKendrick et ai., 1981; Paris et ai., 1981; Wittmann et ai.,

Cefotaxime: A Review

1980a), further data are required in order to assess clearly the efficacy of the drug in treating these conditions. Interestingly, Paris et al. (1981) reported that cefotaxime 2 to 3g daily was tolerated well, without adversely affecting liver function tests in 8 patients with cirrhosis. Results from a few patients treated with cefotaxime for typhoid fever (McKendrick et al., 1980b, 1981; Papadatos et aI., 1980; Shah et aI., 1980), enteric fever (Rimmer, 1981) and enterocolitis (Kalager et al., 1982), suggest that this drug is usually not effective in treating these infections caused by Salmonella species, despite its good in vitro activity in general against this genera. It has been postulated that this situation, which has occurred with other antibiotics, may be due to inadequate intracellular penetration of the drug.

5.1.7 Skin, Soft-Tissue, Bone and Joint Infections Favourable results have been reported following the use of cefotaxime in large (LeFrock and McOoskey, 1982; McCloskey et al., 1982) and small groups (Aznar et aI., 1981; Chandler et aI., 1982; Clumeck et aI., 1981, 1982; Daikos et al., 1980; Kalager et al., 1982; Karakusis et aI., 1982; Keaney et al., 1982; Wittmann et al., 1980a) of patients with infections of skin and subcutaneous tissues, and in comparison with a· combination of gentamicin and clindamycin (Stone et aI., 1981). A satisfactory clinical response (cure and improvement) occurred in 86 to 100% of those patients, many of whom also underwent surgical procedures. In summarising manufacturer's data on up to 260 hospitalised patients treated in the USA with cefotaxime for bacteriologically confirmed wound infections of the skin and subcutaneous tissue such as cellulitis, abscess or necrotising ulcers, McCloskey et al. (1982) found the mean daily dose used was 4g (range 1.4 to 12g). Cefotaxime was usually given by intravenous infusion 3 or 4 times daily for a minimum of 5 days and surgical procedures (mainly debridement and drainage) were performed whenever indicated. Infection in 94% of

265

260 clinically evaluable patients improved or completely cleared, while treatment was successful bacteriologically (pathogen eradicated or wound/lesion healed with no follow-up cultures possible) in 84% of 225 evaluable patients. Bacteriological success rates for the more frequently reported pathogens (single and mUltiple combined) were about 70% for P. aeruginosa and enterococci, about 85% for Enterobacter species and indole-positive Proteus species and over 90% for S. aureus, S. epidermidis, Groups A and B' streptococci, E. coli, P. mirabilis, Klebsiella and Bacteroides species. Clinical success rates by organism tended to be higher. A comparative study by Stone et al.(1981) included 75 patients with polymicrobial soft tissue surgical sepsis in addition to a large group of patients with peritonitis (previously discussed in section 5.1.6). Similar clinical response rates were achieved with intravenous cefotaxime 20 mg/kg 6hourly and with a combination of gentamicin 1 mgf kg 8-hourly and a relatively low dose of clindamycin (5 mgfkg 6-hourly) in 45 patients with deep soft-tissue sepsis (86% vs 83% cured), and in 30 patients with perirectal abscess (100% vs 89% cured). Interestingly, each of the 4 'failures' had sites of infection that had only been drained or debrided, whereas radical excision (when possible) consistently provided either a permanent cure or a more easily controlled recurrent sepsis. Clinical experience with cefotaxime in the treatment of 55 patients with serious bone and joint infections such as osteomyelitis, septic arthritis and bursitis has been summarised from manufacturer's data by LeFrock and Carr (1982). Additionally, a number of individual reports on studies with cefotaxime have included a few patients with postoperative or post-traumatic bone and joint infections (Berndt et al., 1980; Dutoy and Wauters, 1980), or osteomyelitis caused by Enterobacteriaceae (Clumeck et aI., 1982; Daikos et al., 1980; Fabricus and Riegel, 1980; Francke and Neu, 1981; Harle, 1980; KrUger et aI., 1980; McKendrick et aI., 1981; Wittmann et aI., 1980a), Pseudomonas aeruginosa (Ka-

266

Cefotaxime: A Review

rakusis et aI., 1982; McKendrick et aI., 1981), or Gram-positive aerobes (Fabricus and Riegel, 1980; Wittmann et aI., 1980a). However, in view of the limited data often available for such patients in these studies, results reported by Mader et ai. (1982) are of particular interest. Their open study in 43 evaluable patients with osteomyelitis found that high doses of cefotaxime plus aggressive debridement surgery yielded favourable results. Osteomyelitis was arrested (according to clinical criteria) on completion of therapy and on follow-up examination about 6 months later (range 0 to 17 months) in 15 of 16 patients (94%) with acute infection and in 24 of27 patients (89%) with chronic infection unsuccessfully treated with other antibiotics. Similar clinical response rates were achieved in patients with chronic osteomyelitis from whom 1 aerobic species was isolated (9 of 10 arrested), more than 1 aerobic species was isolated (8 of 9 arrested) or mixed aerobic and anaerobic pathogens were isolated (7 of 8 arrested), usually by bone biopsy. Acute or chronic osteomyelitis was arrested in 20 of 22 (91 %) of patients infected with the predominant pathogen, S. aureus, 12 of 13 (92%) infected with other Gram-positive bacteria, all 15 with Enterobacteriaceae, 6 of 7 with Pseudomonas species (MICs of 0.1 to 25 ~g/ml) and all 13 infected with anaerobes. The usual dose of intravenous cefotaxime was 2g given 4- or 6hourly (average dose, 9 g/day) for about 5 weeks (range, 3 to 8 weeks). Most patients with chronic osteomyelitis subsequently took oral antibiotics for 1 to 3 months. Some patients also received hyperbaric oxygen therapy.

5.1.8 Infections in Immunologically Compromised Patients Cefotaxime has been used to treat suspected or proven infections in granulocytopenic patients (Bint et aI., 1980; Guy et aI., 1981; Karakusis et aI., 1982; Preiss, 1980) and in cancer patients whose haematological profile was not reported (Cone et aI., 1.981). In the latter study, 28 of 40 patients (70%) with pneumonia (16), fever of unknown origin (8),

bacteraemia (7), urinary tract infections (6), or softtissue infections (3), were cured with cefotaxime given alone in 1 to 2g doses every 4 to 6 hours. Treatment was successful in 8 of 10 patients infected with Gram-positive cocci, 10 of 16 with Gram-negative bacilli and 10 of 13 from whom no pathogen was isolated. A slightly higher response rate (80%) was obtained in 30 acute leukaemic patients with therapeutically induced bone marrow aplasia who were treated with cefotaxime 240 mg/kg/day plus amikacin 15 mg/kg/day (given 6-hourly by intravenous infusion) for fever of unknown origin (13), septicaemia (11), perianal abscesses (4) or lung disease (2). The predominant pathogens were S. epidermidis (4), s. aureus (2), E. cloacae (4) and P. aeruginosa (2), most of which were eradicated. However, 9 (37.5%) of 24 patients treated successfully developed new infections during treatment with cefotaxime for a mean period of 14 days. Group D streptococci (7) and P. aeruginosa (2) were isolated from stool specimens of such patients and B. fragilis (1) from a perianal fistula (Guy et aI., 1981).

5.1.9 Infections Caused by Multiresistant Bacteria and Pseudomonas species Cefotaxime has been used successfully in the treatment of serious infections due to multiresistant Gram-negative organisms (Oumeck et al., 1981, 1982; Daikos et al., 1980; Dureux et aI., 1981; Francke and Neu, 1981; Shah et aI., 1979c, 1980; Van Laethem et aI., 1981). A few patients with infections (usually bacteraemia or urinary tract infections) caused by Klebsiella species (Daikos et aI., 1980; Dureux et aI., 1981; Francke and Neu, 1981), E. coli (Daikos et aI., 1980), Serratia (Dureux et aI., 1981), Enterobacter and Proteus species (Daikos et aI., 1980), Francke and Neu, 1981) resistant to one or more of cephalothin, cefuroxime, gentamicin or carbenicillin, were usually cured with cefotaxime (alone) in dosages of 1.5 to 6 g/day. Of particular importance, Karakusis et ai. (1982) reported that 10 of 13 patients infected with strains of Serratia marcescens resistant to all commer-

Cefotaxime: A Review

cially available antibiotics, including amikacin, responded favourably to high doses (8 to 12 g/day) of cefotaxime. Because cefotaxime has shown some in vitro activity against P. aeruginosa (see section 1.1.2), its clinical efficacy against this pathogen is of particular interest. However, from published data it is difficult to determine clearly the effect of adequate doses of cefotaxime, given alone or in combination with other antibiotics, on patients infected with this organism. Results from a small number of patients treated with cefotaxime alone for various infections caused by P. aeruginosa (Aguirre et ai., 1981; Karakusis et ai., 1982; McKendrick et ai., 1981; Wittmann et ai., 1980a,b) or Pseudomonas species (Francke and Neu, 1981; Lepeu et ai., 1981) tend to suggest that treatment was effective clinically and bacteriologically in only about half of these patients. However, many received daily doses less than the 6g minimum recommended for cefotaxime-sensitive Pseudomonas species. In addition, some organisms were not sensitive on in vitro testing, while for others sensitivity data was not provided. Interestingly, higher response rates (70% bacteriological success, 87% clinical success) were reported following treatment with cefotaxime (dosage not specified) in 23 patients with infections of skin or subcutaneous tissue attributed to P. aeruginosa alone or in combination with other organisms (McCloskey et ai., 1982). In a review by the manufacturer of a large number of patients, 52% of 147 isolates of Pseudomonas species were eliminated. However, these results included 'a small number of patients' who were receiving other antibiotics in addition to cefotaxime (Young et ai., 1980). Hence, the efficacy of cefotaxime for the treatment of pseudomonal infections has not been clearly established, and thus at this stage cetofaxime could not be recommended as the sole therapy for such infections.

5.1.10 Meningitis in Children and Adults Cefotaxime can be considered for the treatment of meningitis because in addition to entering cere-

267

brospinal fluid of adults and children with inflamed meninges (see section 4.2), low concentrations of this antibiotic are bactericidal for most organisms which cause this condition, such as H. influenzae, N. meningitidis, S. pneumoniae, group B streptococci, E. coli and Klebsiella species. Hence, patients of all ages have been treated with cefotaxime for meningitis, although most experience to date has been in neonates and infants up to 2 years old. Several papers have summarised clinical experience in children with meningitis (Belohradsky et ai., 1980; Roos et ai., 1980), and in patients of all ages, particularly those with Gram-negative bacillary meningitis (Cherubin et ai., 1982; Landesman et ai., 1981 b). Results from the largest group of patients reported to date (l00 children and 27 adults) indicated that cefotaxime alone or in combination with other unspecified antibiotics was highly successful in the treatment of meningitis caused by the 3 major meningeal pathogens, N. meningitidis, H. injluenzae and S. pneumoniae (98% of 55 patients cured), and by E. coli and Klebsiella species (96% of 37 patients cured). Although one-quarter of these patients (mainly those who entered early in the study) received concomitant antibiotics, their response rates are said not to have differed from those receiving cefotaxime alone. Neonatal meningitis, caused predominantly by Enterobacteriaceae, was usually treated successfully with cefotaxime alone (Borderon et ai., 1981 a; Kobayashi et ai., 1981b) or in combination with other antibiotics such as amikacin (Belohradsky et ai., 1980; Kafetzis et ai., 1982). The dosage of cefotaxime used in this relatively small group of patients varied widely from 70 to 300 mg/kg/day given at 4-,6-, or 8-hourly intervals. Borderon et ai. (l981a) reported curing 4 cases of neonatal meningitis, due to cefotaxime-sensitive E. coli, P. mirabilis, Enterobacter cloacae and S. marcescens, with cefotaxime 200 mg/kg/day given 6 hourly for 3 weeks. Drainage was also used in 2 of these patients, who had ventriculitis and either hydrocephalus or cerebral abscesses.

268

Cefotaxime: A Review

Table XVI. Summary of results of treating meningitis in children (including neonates and infants), according to the causative organism, with cefotaxime alone (monotherapy) or combined with another antibiotic such as an aminoglycoside, chloramphenicol or ampicillin (data after Belohradskey et aI., 1980; Borderon et al., 1981 a; Kobayashi et al., 1981 b)

Pathogen

Monotherapy

Combination therapy

no. successful/no. treated

no. successful/no. treated

Gram-positive Streptococcus pneumoniae

1/2

Group B streptococcus a-Haemolytic streptococcus

0/1

Staphylococcus epidermidis

2/3

1/1

Gram-negative Haemophilus influenzae Haemophilus parainfluenzae

10/10

Enterobacter species

1/1 5/5 1/1 1/1

Proteus mirabilis

1/1

Serratia marcescens

1/1

Salmonella panama

1/1 0/1

Escherichia coli Klebsiella species

Pseudomonas aeruginosa Neisseria meningitidis

In another study (Kafetzis et aI., 1982), 5 of 7 cases of neonatal meningitis (2 E. coli, I S. marcescens, I P. aeruginosa, I group B streptococci) treated with cefotaxime 80 to 200 mg/kg/day plus amikacin or penicillin were cured. Treatment with cefotaxime and gentamicin failed in I neonate with meningitis and ventriculitis due to P. mirabilis. Another neonate with ventriculitis improved clinically with cefotaxime alone, and Klebsiella species was eradicated. All 7 of these neonates had been treated unsuccessfully with gentamicin plus ampicillin or penicillin. A small number of infants and children with bacteriologically confirmed meningitis have also been treated successfully with cefotaxime alone (Belohradsky et aI., 1980; Borderon et aI., 1981a; Helwig and Daschner, 1982; Kobayashi et aI., 1981b) or in combination with an aminoglycoside, ampicillin, penicillin or chloramphenicol (Belohradsky et aI., 1980; Papadatos et aI., 1980). Dosages used were similar to those in neonates. Haemo-

2/2 1/1

1/2 0/1

1/1 1/1

philus influenzae, the predominant pathogen, was successfully eradicated from cerebrospinal fluid with cefotaxime alone in all of 10 patients studied by Borderon et ai. (198Ia) and Kobayashi et ai. (198Ib), including 1 infant infected with an ampiciiIin-resistant strain. Treatment was also effective against various other pathogens (table XVI) [Roos et aI., 1980]. Although some children with meningitis plus complicating factors such as the presence of shunts or ventriculitis and hydrocephalus did not respond to treatment with cefotaxime, alone or in combination, others made a complete recovery (Borderon et aI., 1981 a; Kafetzis et aI., 1982; Kobayashi et aI., 1981 b; Ludwig and Wille, 1980). If sequelae occurred following treatment, these tended to be in patients with underlying conditions or in some of those in whom the use of effective treatment was delayed, e.g. through the use of other antibiotics (Belohradsky et aI., 1980; Borderon et aI., 1981a; Kobayashi et aI., 198Ia,b). Indeed, many of the

Cefotaxime: A Review

children successfully treated with cefotaxime plus another antibiotic had failed to respond to prior treatment with 2 or more antibiotics (Belohradsky et al., 1980; Kafetzis et al., 1982). In addition, a few organisms (such as H. influenzae and Staphylococcus epidermidis) shown to be resistant to other antimicrobial agents were successfully treated with cefotaxime (Belohradsky et aI., 1980; Borderon et al., 1981a). Treatment of a few adults with bacterial meningitis has nearly always been successful using cefotaxime alone or combined with various other antibiotics (Bruckner et al., 1982; Dureux et al., 1981; Fernandez-Guerrero et al., 1982; Francke and Neu, 1981; Landesman et aI., 1981b; Motin et al., 1981; Shah et aI., 1980), although an occasional relapse has been described (Bradsher, 1982; Iannini and Kunkel, 1982). The drug has sometimes been used to treat pneumococcal meningitis, e.g. in penicillin-allergic patients (Bruckner et al., 1982; Shah et al., 1980), but in most cases adults treated with cefotaxime had cerebrospinal fluid infected with Gram-negative enteric bacilli, particularly Klebsiella species. Some of the adults treated with cefotaxime had meningitis due to drug-resistant organisms. For instance, Francke and Neu (1981) reported curing 2 adults with meningitis caused by multiresistant Klebsiella pneumoniae using cefotaxime alone in an initial daily dose of9 or 12g, given 4-hourly for 21 or 28 days. A case of postoperative meningitis due to carbenicillin-resistant P. aeruginosa plus a multiresistant strain of K. pneumoniae was successfully treated with a combination of cefotaxime, azlocillin and gentamicin (Shah et al., 1979a; 1980). Dureux et ai. (1981) also reported curing a patient with meningitis and septicaemia caused by a multiresistant strain of Klebsiella species, using cefotaxime plus tobramycin.

5.1.11 Other Paediatric Infections Cefotaxime is very active in vitro against most bacteria which commonly cause infections in children, such as the Enterobacteriaceae, H. influ-

269

enzae (ampicillin-sensitive and -resistant strains), S. pneumoniae and group B streptococci. Hence, this drug has been used in open studies to treat a variety of infections in several hundred children (including infants and neonates), but no controlled studies have been reported to date. Most patients suffered from serious infections, many of which had not responded to prior antibiotic treatment (Bruch and Blomer, 1980; Kafetzis et al., 1981, 1982). The dosage of cefotaxime was usually between 50 and 100 mg/kgJday, although occasionally total daily doses of 150 to 300 mg/kg have been administered without untoward clinical or biochemical effects (Gamier and Giraud, 1981; Gekle et al., 1980; Kafetzis et aI., 1982; Ramirez et al., 1982). The frequency of administration varied from 1 to 4 times daily. Following analysis of case reports on 129 children treated with cefotaxime alone in trials in European and Latin American countries, Young et ai. (1980) reported that 95% were cured clinically, 1% had a relapse and 4% were considered to be failures. Response rates varied from about 90% for those with septicaemia (26 assessable cases), gastrointestinal (29) or multiple (15) infections, to 100% for infections of the respiratory (26) and urinary (13) tracts, or other sites (20). Similar results from smaller groups of patients were reported in more detail by Aufrant et ai. (1981), Kafetzis et ai. (1981, 1982) plus co-worker Papadatos et al. (1980). All but 1 patient treated in these studies had bacteriologically confirmed infections caused by organisms sensitive to cefotaxime, predominantly Gram-negative bacilli. Thus, Kafetzis et al. (1981) administered cefotaxime 25 mg/kg 6-hourly, usually by intravenous injection, to 33 seriously ill infants and children (aged 5 months to 12 years) with peritonitis (11), pneumonia (5), urinary tract infection (4), septicaemia (2), osteomyelitis (2), infected bums (2), liver abscess (2), infected hydatid cyst (3) and other infections (2), usually due to Gram-negative bacilli. Although most patients (70%) had been treated unsuccessfully with other antibiotics, 85% were

270

Cefotaxime: A Review

cured clinically with cefotaxime alone and 12% improved. Bacteria were eradicated from all but 2 of the patients (94%), both of whom were infected with P. aeruginosa and Proteus species. Kafetzis et al. (1982) also treated 32 neonates (l8 of whom were preterm) with cefotaxime alone (75 to 100 mg/kg/day), or in combination with an aminoglycoside or penicillin, and followed them up for at least 1 month. 16 of 18 patients (89%) treated with cefotaxime alone for septicaemia (10), urinary tract infection (2), pneumonia with cystic fibrosis (1), omphalitis (2) or cellulitis (1) were cured; the other 2 patients improved (I with meningitis plus ventriculitis due to Klebsiella species and 1 with septicaemia). All pathogens were eradicated, most of which were Gram-negative bacilli (e.g. E. coli, Klebsiella species, P. aeruginosa and S. marcescens). Prior to receiving cefotaxime many of these neonates had been treated unsuccessfully with a combination of antibiotics such as gentamicin and ampicillin. In another study in infants and children with severe Gram-negative infections and associated conditions (Aufrant et al., 1981), treatment with cefotaxime 50 to 100 mg/kgfday given 8-hourly was effective clinically and bacteriologically in 4 infants with respiratory tract infection who were being ventilated, 2 with otitis media plus renal failure and 3 children with severe urinary tract infections. In this study the predominant pathogen, H. influenzae, was isolated by tracheal aspiration or lung puncture. Cefotaxime combined with an aminoglycoside has also been used to treat a small number of paediatric infections in several other studies (Aufrant et al., 1981; Blomer et al., 1981; Kafetzis et al., 1982; Marget et al., 1978), some of which included children with leukaemia (LOpez et al., 1980; Peters et al., 1980). Such treatment has usually been well tolerated, as was cefotaxime used alone in paediatric patients. Similar response rates to those above (i.e. over 85% of patients clinically cured) have been achieved in studies in which many infections in children,

particularly those of the respiratory tract, were not confirmed bacteriologically (Gamier and Giraud, 1981; Gekle et al., 1980; Helwig, 1980a,b).

5.2 Prevention of Infection in Surgery In some countries cefotaxime is approved for perioperative use to reduce the incidence of postoperative infections in patients undergoing contaminated or potentially contaminated surgical procedures (e.g. vaginal and abdominal hysterectomy, gastrointestinal and genitourinary surgery), and in women undergoing caesarean section (when the drug is administered after the umbilical cord is clamped). Studies in cardiac surgery (Adam and Struck, 1982; Regensburger and Podszus, 1982) and controlled studies comparing the prophylactic efficacy of cefotaxime with untreated controls in genitourinary (Hargreave et al., 1982; Schalkhauser and Fegg, 1981) and colonic surgery (Germann and Hottenrott, 1982; J ostamdt et al., 1981), with cefoxitin in colonic surgery (Anders et al., 1982) and with cefazolin in genitourinary surgery (Childs et al., 1981, 1982; Iversen and Madsen, 1982), colonic or rectal surgery (Jagelman et al., 1982), surgery for penetrating abdominal trauma (Fabian et al., 1982), vaginal or abdominal hysterectomy (Roy and Wilkins, 1982; Wideman and Matthijssen, 1982) or emergency caesarean section (Louie et al., 1982) have been reported. Cefotaxime was usually administered in Ig doses perioperatively (e.g. within 90 minutes before surgery, 2-hourly during surgery and once immediately following surgery), or perioperatively (as above) and for 24 hours postoperatively (lg 6- or 8-hourly). Used in this way, cefotaxime was reported to have a favourable effect on postoperative infection rates following various types of surgery (Fabian et al., 1982; Iverson and Madsen, 1982; Jagelman et al., 1982; Wideman and Matthijssen, 1982). One study, in patients undergoing prostatectomy by transurethral resection (Hargreave et al.,

271

Cefotaxime: A Review

1982), reported a significant reduction in postoperative sepsis and other complications with cefotaxime (four 0.5g doses within a 48-hour period) compared with untreated controls. As might be expected considering the small treatment groups studied (usually about 30 patients per regimen), none of the studies which compared cefotaxime given perioperatively and/or for 24 hours postoperatively with an equal dose of cefazolin given periand postoperatively showed a statistically significant difference in postoperative infection rates. Results of the study by Anders et ai. (1982) which compared cefotaxime with cefoxitin in patients undergoing colonic surgery were not analysed statistically.

6. Side Effects Cefotaxime has generally been well tolerated by adults and children (including neonates and infants) following intravenous or intramuscular administration. The drug's side effect profile, which closely resembles that of other cephalosporins (Smith, 1981, 1982), includes in particular, local reactions at the injection site, rash and diarrhoea. Occasional variations in laboratory test results have occurred with cefotaxime but significant deterioration in renal function directly attributable to cefotaxime has not been reported. As with other broad spectrum antibiotics, superinfection has occurred, particularly in seriously ill patients. Reviews of the safety and efficacy of cefotaxime, sometimes in combination with other antibiotics, in large groups of patients (from 300 to 4000) have been reported (Bax and Young, 1981; Bruch and Blomer 1980; Childs and Kosola; Connelly, 1982; Smith, 1982; Yakabow and Wood, 1982; Young et aI., 1980). The overall incidence of adverse effects in over 2000 patients was 10% (Childs and Kosola; Yakabow and Wood, 1982), while the incidence of side effects considered to be drug-related was stated as 5 to 8% in other series of patients (Connelly, 1982; Young et al., 1980).

Cefotaxime was discontinued in 1 to 2% of patients (Childs and Kosola; Connelly, 1982; Smith, 1982; Yakabow and Wood, 1982).

6.1 Local Reactions Thrombophlebitis has occurred in about 5% of patients treated with intravenous cefotaxime (Bax and Young, 1981; Smith, 1982; Wittmann et aI., 1980a,b). Although this is a relatively low incidence for a cephalosporin, there is some evidence to suggest that it may be higher than that which occurs with cefazolin (Smith, 1982). However, cefotaxime was rarely discontinued for this reason (e.g. in less than 0.1% of patients) [Smith, 1982]. The incidence and severity of pain on intramuscular injection of cefotaxime was mild in 27%, moderate in 4.5% and severe in 0.4% of889 patients (Smith, 1982). In controlled studies, pain with intramuscular cefotaxime 1.0g was similar in intensity and incidence to that occurring after intramuscular procaine penicillin G (4.8 million units) [Handsfield and Holmes, 1981; Simpson, et aI., 1981] but worse than with intramuscular gentamicin 80mg (Ludwig and Knebel, 1980). Pain is minimised when cefotaxime is diluted with 0.5% or 1% lignocaine (lidocaine) solution instead of sterile water (Hanninen et aI., 1980; Hubrechts et aI., 1980a,b; Ludwig and Knebel, 1980).

6.2 Haematological and Hepatic Effects Haematological effects of cefotaxime noted in reviewing a large number of patient reports included a positive Coombs' reaction (6.4%), thrombocytopenia (3.8%), eosinophilia (1.3%), leucopenia (0.5%), and a single case of reversible agranulocystosis (Smith, 1982). Few studies have included serial determinations of prothrombin time, but the review by Smith (1982) reported that none of 26 patients developed a prolongation of prothrombin time. In a study of coagulation disorders

Cefotaxime: A Review

272

ors did not mention that the gentamicin dosage was adjusted for age, sex or renal function, or that gentamicin serum concentrations were obtained. Thus, it is difficult to determine the clinical relevance of their results. Patients with impaired renal function have been treated with cefotaxime (Bax, 1980; Bax and Young, 1981; Connelly, 1982; Daikos et al., 1980; Motin et aI., 1981; Schulz, 1980; Young et al., 1980), although wide experience in this patient group has not been reported in detail. While the dose in such patients was often said to be 'reduced', little information is available on the actual dosages used. Nevertheless, renal function did not worsen in most cases, and in many it improved as the infection resolved. In· particular, Ninane (1979) and Clumeck et al. (1979, 1982) found no evidence of direct tubular toxicity by measuring urinary excretion of alanine aminopeptidase, ~-N-acetyl­ 6.3 Renal EtTects glucosamidase or serum creatinine in a few patients Cefotaxime did not adversely affect renal func- with impaired renal function who were treated with tion in the majority of patients studied, including cefotaxime 0.5 to 4 g/day. Published summaries of the seriously ill. Changes in blood urea or creatin- data collated by the manufacturer from multiine concentrations which occurred occasionally in centre studies (Bax, 1980; Bax and Young, 1981; patients with normal renal function were usually Connelly, 1982; Young et al., 1980) reported a furtransient and were not reported to be of signifi- ther deterioration in renal function in a few cases. cance in managing the patient (Connelly, 1982; This was usually attributed to the patient's worsFrancke and Neu, 1981; Graninger et aI., 1981; ening clinical condition, leaving only a minimal Keaney et al., 1982; Kumazawa et al., 1981; Miki number of cases of uncertain aetiology. Unfortuand Shiota, 1980). Smith (1982) reported a 1.4% nately, in some studies it was unclear whether these incidence of glomerulotubular dysfunction in 1250 particular patients were receiving cefotaxime alone. In numerous patients, particularly those sutTerpatients receiving cefotaxime who had normal ing from septicaemia, cefotaxime has been given baseline values. In a comparative study by Stone et al. (1981), together with an aminoglycoside, usually without none of the 125 patients treated with cefotaxime . major adverse etTects on the kidney. Results from (80 mg/kgJday) for peritonitis or soft-tissue sepsis a study by Kuhlmannet al. (1982a,b) in about 30 developed signs of nephrotoxicity (serum creatin- patients suggested that cefotaxime in combination ine increased by more than 1.5 mg/l00m1 over pre- with tobramycin did not increase the risk of tobratreatment levels) compared with 8 of 124 patients mycin nephrotoxicity in patients with serious in(7%) receiving a combination of gentamicin (3 mg/ fections and normal renal function (see section 2). kg/day) and clindamycin (20 mg/kgJday). Patients In a review, by the manufacturer, of 22 adults and were assigned at random to the treatment groups 48 children, some of whom had impaired renal but no details were given on the comparability of function before being treated with cefotaxime and pretreatment renal function. In addition, the auth- an aminoglycoside, blood urea and creatinine conin intensive care patients treated with cefotaxime, moxalactam or cefoperazone for bronchopulmonary infections, marked changes in prothrombin time occurred with cefoperazone and moxalactam in patients receiving parenteral nutrition. Although changes also occurred with cefotaxime, prothrombin time remained within the normal range (Schwigon and Barckow, 1982). Transient increases in liver enzymes have been reported occasionally (Bax and Young, 1981; Connelly, 1982; Smith, 1982; Yakabow and Wood, 1982). The incidence of elevated transaminase and alkaline phosphatase concentrations with cefotaxime was similar to that occurring with cefazolin (Miki and Shiota, 1980; Ohkawa and Kuroda, 1980).

273

Cefotaxime: A Review

centrations remained unchanged or abnormal levels improved in 94% of patients. The deterioration in renal function of the remaining 4 patients was attributed to their severe progressive fatal diseases (Blomer et aI., 1981). There was a suggestion of renal impairment occurring in another 5 patients treated in other studies with cefotaxime and gentamicin, but the role of cefotaxime in these findings is unclear (Bastin et aI., 1981; Keaney et aI., 1982; Portier et aI., 1981). Definitive data from a welldesigned and well-controlled study on the safety of cefotaxime in combination with an aminoglycoside would clarify this matter.

6.4 Other Adverse Reactions Hypersensitivity in the form of rash or pruritus occurred in about 2% of patients and was the most common reason for discontinuing cefotaxime (Bax and Young, 1981; Smith, 1982; Young et aI., 1980). Most rashes (95%) were maculopapular. Rashes ha ve developed in some of the patients with a past history of penicillin allergy who were treated with cefotaxime (Jenkinson et aI., 1980; Shah et aI., 1980). Drug fever has also been observed in cefotaxime-treated patients (0.4%), but anaphylaxis has not (Smith, 1982). Gastrointestinal effects such as diarrhoea, colitis, nausea and vomiting have occurred in 1.7% of patients treated with cefotaxime (Yakabow and Wood, 1982). Diarrhoea, which was the most frequently reported gastrointestinal reaction, developed in 0.4 to 1.2% of patients but rarely resulted in cessation of treatment (Connelly, 1982; Smith, 1982; Young et aI., 1980). On rare occasions, pseudomembranous colitis has occurred in patients receiving cefotaxime (Cone et aI., 1981; Gineston and Henry, 1982; Karakusis et aI., 1982; Mader et aI., 1982; Wittmann et aI., 1980b; Yakabow and Wood, 1982). Central nervous system reactions (including hallucinations, vertigo or disorientation have occurred in about 0.3% of patients (Smith, 1982).

Because cefotaxime possesses the cephalosporanic acid nucleus it may interfere with oxidation reduction methods for determining the presence of urine glucose, thus producing a false-positive result (Kennedy and Lauffer, 1982; Kowalsky and Wishnoff, 1982). It appears that desacetyl-cefotaxime present in serum can affect the bioassay of gentamicin unless specifically inactivated by an appropriate i3-lactamase preparation (Johnston and Griffiths, 1982). However, neither cefotaxime nor desacetyl-cefotaxime interfere with creatinine assays of serum and urine by the Jaffe (alkaline picrate) reaction (McKendrick and Legg, 1981). A disulfiram-like reaction, which has occurred in patients drinking alcohol while being treated with cefoperazone, cefamandole or moxalactam (which have a common side chain) has not occurred during clinical studies with cefotaxime, or in a special study in healthy volunteers (Smith, 1982).

6.5 Adverse Bacteriological Effects Colonisation and superinfection, which occur with other broad spectrum antibiotics, have also been reported in patients treated with cefotaxime, particularly those who were seriously ill. On reviewing results from 1650 patients treated with cefotaxime, Smith (1981) reported the incidence of colonisation (defined as isolation of a new organism during therapy without signs of infection) as 1.6%, and of superinfection (isolation of a new organism plus signs or symptoms of infection) as 1.2%. Usually cefotaxime-resistant Pseudomonas species or group D streptococci were isolated, but occasionally other resistant Gram-negative bacilli, or Candida, were involved (Clumeck et aI., 1981, 1982; Guy et aI., 1981; Keaney et aI., 1982; McKendrick et aI., 1980b; Motin et aI., 1981; Schleupner and Engle, 1982; Smith, 1981). Development of resistance to cefotaxime during treatment has been very rarely documented. In 1 such case (Karakusis et aI., 1982), the MIC of cefotaxime for a strain of Pseudomonas aeruginosa iso-

274

Cefotaxime: A Review

Table XVII. Examples of some dosage schedules (dose x frequency) recommended by the manufacturer for cefotaxime given intramuscularly or intravenously. Maximum dose in adults is 12 g/day and in children 200 mg/kg/day Type of infection/patient

USA

Uncomplicated

19 12-hourly

Moderate

UK

Germany

France

19 12-hourly

19 12-hourly

19 12-hourly

Moderate to severe

1-2g 6- or 8-hourly

Severe/serious

2g 6- or 8-hourly

Life-threatening

2g 4-hourly

2g 12-hourly up to 2g 6- or 8-hourly

2g 12-hourly

19 6- or 8-hourly

2-3g 6- or 8-hourly

2g 4-hourly

Gonorrhoea

19 stat

19 stat

Neonates

100-150 mg/kg/day'

50 mg/kg/dayb

50-100 mg/kg/dayb

50-100 mg/kg/dayb

Infants + children usual dose very severe infections

50-180 mg/kg/day<' 180 mg/kg/day<'

100-150 mg/kg/dayb 200 mg/kg/dayb

50-100 mg/kg/dayb

50-100 mg/kg/dayb

a Administered 8- to 12-hourly. b Administered 6- to 12-hourly. c Administered 4- to 6-hourly.

lated from bone biopsies was 25 ~gjml before therapy and greater than 100 ~gjml during therapy (no dosage data given). Selection of resistant bacteria (e.g. P. aeruginosa) [Livermore et aI., 1982] may also be possible with cefotaxime.

7. Dosage and Administration In many countries, cefotaxime is now approved by regulatory agencies for the treatment of bacteraemia/septicaemia, lower respiratory, genitourinary (including gonorrhoea), obstetric, gynaecological, intra-abdominal, soft-tissue, bone and joint infections presumed or shown to be caused by susceptible organisms. Cefotaxime is also approved in some countries for the treatment of meningitis, ventriculitis or endocarditis and for use perioperatively to reduce the incidence of postoperative infections in patients undergoing contaminated or potentially contaminated procedures (e.g. vaginal hysterectomy, genitourinary surgery) or caesarean section. Approval has also been given in some

countries for the treatment of neonatal and paediatric infections with cefotaxime. Examples of some recommended dosage schedules for cefotaxime are shown in table XVII. Obviously, the dosage, route and frequency of administration are determined by the severity of the infection, sensitivity of causative organisms and condition of the patient. The maximum daily dose should not exceed 12g in adults and 200 mg/kg in children. The manufacturer also states that for infections caused by sensitive Pseudomonas species, doses of more than 6 g/day are required. However, on the basis of in vitro data and clinical experience reported to date, it would appear that cefotaxime alone may not be a suitable choice for treatment of suspected or proven pseudomonal infections. In severe infections caused by Pseudomonas the concurrent use of cefotaxime and an aminoglycoside may be appropriate. Although there is no clinical evidence supporting the necessity of changing the dosage of cefotaxime in patients with even severe renal dysfunction, a significant portion of a dose of cefotaxime

Cefotaxime: A Review

is excreted in the urine, either unchanged or as an active metabolite. Hence, until further data are obtained the dose of cefotaxime should be reduced by 50% in patients with severe renal impairment. As with antibiotic therapy in general, administration of cefotaxime should usually be continued for a minimum of 48 to 72 hours after fever abates or after evidence of bacterial eradication has been obtained. When cefotaxime is being used to prevent postoperative infection in contaminated or potentially contaminated surgery, Ig should be administered intravenously or intramuscularly 30 to 90 minutes before the start of surgery and again 30 to 120 minutes later. Another 19 dose should also be administered within 2 hours following surgery. In women undergoing caesarean section the first dose of Ig is administered intravenously as soon as the umbilical cord is clamped; the second and third doses of 19 each should be given 6 and 12 hours later. Although cefotaxime is contraindicated in patients with a known allergy to cefotaxime or other cephalosporins, the drug may be given with caution to patients who are hypersensitive to penicillins. However, special care is indicated in patients who ha ve had an anaphylactic response to penicillin.

8. The Place of Cefotaxime in Therapy The specific infections for which an injectable antibiotic of this type would normally be considered as 'appropriate therapy' vary widely according to local medical custom, decisions of regulatory agencies, and geographical patterns of bacteriological susceptibilities. The wide in vitro antibacterial activity of cefotaxime has been reflected in good clinical efficacy in a variety of infections. Its efficacy has been demonstrated in adults with complicated urinary tract infections, lower respiratory tract infections, such as pneumonia caused by Gram-negative bacilli, and in the treatment of Gram-negative bacteraemia. Less extensive studies in adults with uncomplicated gonorrhoea caused

275

by penicillinase-producing gonococci, and in children with meningitis or other serious infections, indicate potential usefulness of cefotaxime in such patients. Unfortunately, only limited controlled studies with this drug have been published, making it difficult to determine clearly its relative efficacy compared with drugs such as the aminoglycosides and other cephalosporins. The comparative studies which have been conducted suggest cefotaxime is at least as effective as several 'first generation' and 'second generation' cephalosporins in treating patients with urinary tract infections, and as clinically effective as cefazolin in the treatment of lower respiratory tract infections. Cefotaxime appears to be as effective as a combination of gentamicin plus a lower than usual dose of clindamycin in the medical management of peritonitis. However, the relatively low in vitro activity of cefotaxime against Bacteriodes jragilis may temper its usage in situations where this organism is the suspected or proven pathogen. It has been suggested that cefotaxime may sometimes be used instead of an aminoglycoside. On the basis of in vitro activity studies and existing clinical data, this would seem to be a reasonable supposition and may be particularly relevant in Gram-negative bacilliary meningitis. If equivalent efficacy of cefotaxime and aminoglycoside antibiotics is clearly established, cefotaxime may offer potentially important clinical and practical advantages since it appears to be relatively free of adverse effects and it does not require drug plasma concentration monitoring. However, unlike the aminoglycosides, the efficacy of cefotaxime in infections due to Pseudomonas species has not been convincingly demonstrated. In summary, the particular situations in which use of cefotaxime is worthy of consideration are in the initial treatment of seriously ill patients with infections of undetermined aetiology, especially when Gram-negative aerobes (other than Pseudomonas species) are the suspected pathogens, when resistance of Gram-negative organisms to usual

Cefotaxime: A Review

therapy is suspected or has been demonstrated, and when patients are not responding as expected to other antibiotics. However, the most appropriate 'niche' in therapy for cefotaxime, compared with other antibiotics such as the aminoglycosides or other 'third generation' cephalosporins with a similar spectrum of activity, has yet to be clearly established.

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Cefotaxime: A Review

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Cefotaxime: A Review

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Cefotaxime: A Review

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Cefotaxime: A Review

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Cefotaxime: A Review

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Cefotaxime: A Review

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Author's address: Anne Carmine, ADIS Drug Information Services, P.O. Box 34-030, Birkenhead, Auckland 10 (New Zealand).