Pharma - 4th Asessment - Penicillin & Cephalosporins - 2007

Dr. Constantin Cojocel Department of Pharmacology & Toxicology Faculty of Medicine, Kuwait University Room 133/134 Phone 6342

Antimicrobials

Recommended Reading 1. Rang, H.P, Dale, M.M. & Ritter, G.M. Pharmacology, 4th Eddition, 1999 Churchill Livingstone, London, New York 2. Katzung, B.G. Basic and Clinical Pharmacology, 8th Eddition, 2001 McGraw-Hill New York, London

Antimicrobials Clasification of Drugs  BASED ON DEGREE OF TOXICITY TO THE MICROBE  Bacteriostatic  Bactericidal

The Difference Between the Bacteriostatic and Bactericidal Antibiotics  Bacteriostatic anti-infective agents reversibly inhibit the growth and reproduction of bacteria.  Bacteriostatic anti-infective agents can be beneficial since they provide time for the normal defences of the host to kill and remove the bacteria from the body. (Ex. Sulphonamides,Tetracyclines, chloramphenicol)

 Bactericidal anti-infective agents irreversibly destroy (kill) the pathogenic bacteria exposed to them.  Clinically relevant bactericidal action occurs when in the first 4-8 hours at least 99% of bacteria are killed. (Ex. Penicillins, cephalosporins, fluoroquinolones)

 The distinction between bacteriostatic and bactericidal action is a relative one.  At high enough concentration, most bacteriostatic anti-infective agents become bactericidal (concentration dependent killing).  Some anti-infective agents are only bactericidal if an organism is exposed to them for prolonged periods of time (time-dependent killing).

Bacteriostatic vs Bacteriocidal action

Lipopolysaccharide phospholipid ß-lactamase enzymes

Gram-negative

Porin Outer membrane Periplasmic space Penicillin-binding proteins Cytoplasmic membrane

Peptidoglycan strands ß-lactamase enzyme Penicillin-binding proteins

ß-lactamase enzymes Peptidoglycan strands

Gram-positive Penicillin-binding proteins Cytoplasmic membrane Peptidoglycan strands ß-lactamase enzyme Penicillin-binding proteins

Antimicrobials Classification of Drugs  BASED ON SITES AND MECHANISMS OF ACTION  Cell wall synthesis  Cell membrane  Folic acid synthesis  Protein synthesis  DNA synthesis and structure

Beta-Lactam Antibiotics Inhibitors of Cell Wall Synthesis ß-lactam S ring C NH HC HC O

R

O

C

N

C

CH3

CH3 CH COOH

 PENICILLINS  CEPHLOSPORINS

Beta-Lactamase Activity Amdase O H R1

C

S A

N B

Penicillin Nucleus

COOH

N

O

CH3 CH3

Beta-lactamase O H R1

C

S A

N B O

N

Beta-lactamase

Cephalosporin Nucleus CH2 R2

COOH

Beta-Lactam Resistant to Beta-Lactamases O H R1

C

HO

CH3

N

H3C

B N

CH

S

B N

SO3H

O Monobactam nucleus (β-lactamase resistant)

COOH Carbapenem nucleus (high resistance to β-lactamases) O

B N

CH CH2OH COOH Clavulanic acid (inhibits many β-lactamases) O

R1

Beta-Lactamases  The major limit to efficacy of the beta-lactam antibacterials is destruction by a family of enzymes called beta-lactamases.  Efficacy of these enzymes in hydrolyzing the lactam ring, which is necessary for activity, varies widely.

Beta-Lactamases (cont’d) Combinations of beta-lactams and beta-lactamase Inhibitors Clavulinic acid + Amoxicillin Clavulinic acid + Ticarcillin Sulbactam + Ampicillin Tazobactam + Pipreacillin Tazobacta + Ceftriaxon Tazobactam + Cafoperazone Clavulanic acid contains a beta-lactam ring and it does NOT have antibacterial activity

Penicillins - Penicillin G (Benzylpenicillin) Chemical structure and routs of administration

 Penicillin G is a naturally derived antibiotic for parenteral use.

Penicillins - Penicillin G (Benzylpenicillin) (Cont’d)  Penicillin G potassium is susceptible to destruction by gastric acid. Therefore, when oral penicillin therapy is required, penicillin V or amoxicillin, which have higher oral bioavailability, are used.

Penicillin G - Indications  For the treatment of serious infections caused by susceptible organisms including pericarditis, listeriosis , skin infections, anthrax, bacteremia or septicemia, and intraabdominal infections  For the treatment of anaerobic lower respiratory tract infections (e.g. pneumonia, lung abscess)  For the treatment of endocarditis  For the treatment of meningitis  For the treatment of disseminated gonorrhea  For the treatment of late latent syphilis (drug of choice)

Penicillin G Mechanism of Action  Penicillin G is a beta-lactam antibiotic. It is mainly bactericidal in action.  Penicillin inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall.

 The intrinisic activity of penicillin G, as well as the other penicillins, against a particular organism depends on its ability to gain access to and bind with the necessary PBP.  Like all beta-lactam antibiotics, penicillin G's ability to interfere with PBP-mediated cell wall synthesis ultimately leads to cell lysis. Lysis is mediated by bacterial cell wall autolytic enzymes (i.e., autolysins).  It is possible that penicillin G interferes with an autolysin inhibitor.

Pharmacokinetics - Penicillin G  Peak concentrations occur within 15—30 minutes following an IM dose. Approximately 45—68% of the circulating drug is protein-bound, mainly to albumin.  It is distributed into most body tissues and fluids. (e.g. urine, peritoneal, pleural, and synovial fluids).  It penetrates inflamed meninges and reaches therapeutic levels within the CSF.

Pharmacokinetics - Penicillin G (Cont’d)  Penicillin crosses the placenta and is distributed in breast milk.  Between 15—30% of an IM penicillin G dose is metabolized to inactive derivatives.  The drug is excreted into the urine primarily via tubular secretion. A small percentage is excreted in feces, bile, and breast milk.

Pharmacokinetics - Penicillin G (Cont’d)  In patients with normal renal function, the elimination half-life of penicillin G is 20—30 minutes.  The elimination half-life of penicillin increases as renal function declines. Dosages should be adjusted accordingly

Interactions - Penicillin G  Probenecid inhibits renal tubular secretion of penicillin G, causing higher, prolonged serum levels of the drug.  Concomitant use of penicillin G with aminoglycosides provides synergistic activity against enterococci. The drugs should not be mixed together.  Concomitant use of penicillin with clavulanic acid provides synergistic activity against some penicillinase-producing bacteria.

Adverse reactions/ Contraindications Penicillin G  Hypersensitivity reactions are among the most frequent adverse reactions to the penicillins, occurring in 1—10% of patients. These effects range from a benign rash to anaphylaxis.  Interstitial nephritis, a hypersensitivity reaction, with renal tubular necrosis and nephrotic syndrome has been reported.  Nausea/vomiting and diarrhea are commonly reported gastrointestinal side effects of penicillin G therapy.

Adverse reactions/ Contraindications Penicillin G (Cont’d)  Penicillin G should be used with caution in patients with renal disease or renal impairment since the drug is eliminated via renal mechanisms.  Use large doses of parenteral penicillin G potassium or penicillin G sodium with caution in those patients with electrolyte imbalance.  Penicillin should be used cautiously in patients with cephalosporin hypersensitivity or imipenem hypersensitivity.

Penicillins -Adverse reactions Hypersensitivity (allergy) reactions  skin rush (hives), sneezing, pruritus (itching)  anaphylactic shock ( severe hypotension, loss of conciousness, acute respiratory distress, can be fatal)  cross-sensitivity or cross alergenicity (allergy to other penicillins or cephalosporins)

Classes of Penicillins Natural penicillins  Penicillin G (same as Benzylpenicillin) - Parenteral  Penicillin V (same as Phenoxymethylpenicillin) - Oral

Classes of Penicillins Extended spectrum Aminopenicillins - beta-lactamase sensitive  Ampicillin , Amoxicillin Amoxicillin + clavulanic acid or ampicillin + sulbactam

Antipseudomonal penicillins Carbenicillin, Mezlocillin  Piperacillin or Piperacillin +Tazobactam  Ticarcillin or Ticarcillin + Clavulanic acid

Beta-lactamase resistant penicillins (Antistaphylococcal penicillins)  Methicillin (prototype)

Beta-Lactams - Cephalosporins Cephem Nucleus = beta lactam ring + 6-membered dihydrothiazine ring Side chain modifications to the cephem nucleus confers: • Improved spectrum of antibacterial activity • Pharmacokinetic advantages • Additional side effects Based on their spectrum of activity cephalosporins (selection) are categorized in four generations.

Cephalosporins – Cefotaxime Chemical structure and antibacterial activity

Cefotaxime is a parenteral third-generation cephalosporin.

 Cefotaxime is more active and has a broader spectrum against gram-negative species than earlier generations of cephalosporins.  Although it is less active against gram-positive bacteria than first-generation agents, cefotaxime is often an effective agent for the treatment of infections due to methicillin-sensitive S. aureus and susceptible strains of nonenterococcal streptococci.  The spectrum of activity of cefotaxime is similar to that of ceftizoxime and ceftriaxone

Cephalosporins – Cefotaxime Indications  Treatment of lower respiratory tract infections (e.g. pneumonia)  Intraabdominal infections (e.g. peritonitis)  Urinary tract infection (UTI)  Gynecologic infections  Meningitis  For the treatment of gonorrhea  For surgical prophylaxis

Cephalosporins – Cefotaxime Mechanism of Action  Cefotaxime, like other beta-lactam antibiotics, is mainly bactericidal.  It inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) that are located inside the bacterial cell wall. Penicillin-binding proteins are responsible for several steps in the synthesis of the cell wall

Cephalosporins – Cefotaxime Mechanism of Action  The intrinsic activity of cefotaxime as well as other cephalosporins and penicillins against a particular organism depends on its ability to gain access to and bind with the necessary PBP. Like all beta-lactam antibiotics, cefotaxime's ability to interfere with PBP-mediated cell wall synthesis ultimately leads to cell lysis. Lysis is mediated by bacterial cell wall autolytic enzymes (i.e., autolysins).

Cephalosporins – Cefotaxime Pharmacokinetics  Cefotaxime is administered parenterally.  Peak serum levels of cefotaxime occur within 30 minutes following an IM dose.  Approximately 13—38% of the circulating drug is protein-bound. It is distributed into most body tissues and fluids.  It penetrates inflamed meninges and reaches therapeutic levels within the CSF.  It crosses the placenta.

Cephalosporins – Cefotaxime Pharmacokinetics  Cefotaxime is metabolized to desacetylcefotaxime, an active metabolite that displays 10% of the parent drug's antibacterial activity.  Cefotaxime and its metabolites are excreted into the urine primarily via tubular secretion. A small percentage is excreted in breast milk.

Cephalosporins – Cefotaxime Pharmacokinetics  In patients with normal renal function, the elimination half-lives of cefotaxime and desacetylcefotaxime are 1—1.5 hours and 1.5—2 hours, respectively.  The elimination half-life increases to up to 11.5 hours for cefotaxime and 56 hours for desacetylcefotaxime in patients with end-stage renal disease. Dosages should be adjusted accordingly.

Cephalosporins – Cefotaxime Interactions  Probenecid competitively inhibits renal tubular secretion of cefotaxime, thereby causing higher, prolonged serum levels of the drug.  Concominant use of some cephalosporins with nephrotoxic drugs, such as vancomycin, polymyxin B, loop diuretics, and aminoglycosides, increases the risk of developing nephrotoxicity.  Cefotaxime generally is not considered a nephrotoxic drug.

Cephalosporins – Cefotaxime Interactions  Concomitant use of cefotaxime with the aminoglycosides provides synergistic activity against some strains of bacteria.  It is advised not to use bacteriostatic and bactericidal antibiotics together.

Cephalosporins – Cefotaxime Interactions  Many mixed bacterial infections are treated safely and efficaciously with the concomitant administration of cephalosporins and macrolides (e.g., azithromycin, clarithromycin, erythromycin).  As with other cephalosporins, cefotaxime may have additive or synergistic activity with aztreonam, carbapenems, and the penicillins in its bactericidal effects.

Cephalosporins – Cefotaxime Adverse Reactions/Contraindications  Nausea/vomiting and diarrhea are common side effects of cefotaxime.  Cefotaxime should be used cautiously in patients with hypersensitivity to penicillin. Cross-reactivity can occur is approximately 3—7% of patients with a documented history to penicillin.  Cefotaxime should be used with caution in patients with cephalosporin hypersensitivity or cephamycin hypersensitivity.

Cephalosporins – Cefotaxime Adverse Reactions/Contraindications  Cephalosporins should be used with caution in patients with a history of GI disease, especially colitis, because the adverse GI effects associated with cephalosporin therapy can exacerbate the condition.  Cephalosporins which contain the NMTT side chain (e.g., cefoperazone, cefamandole, cefotetan) have an increased risk for bleeding. Caution in elderly patients and patients with a preexisting coagulopathy (e.g., vitamin K deficiency).

Hypersensitivity (allergy) reactions More serious hypersensitivity reactions:

 Stevens-Johnson syndrome (fever cough, muscular aches and pains, headache, lesions of skin, mucous membranes, eyes)  Aplastic anemia (deficient red blood cell production)  Cross-sensitivity or cross allergenicity (allergy to other cephalosporins or penicilins)

USES FOR ß-LACTAM ANTIBIOTICS PENICILLINS  Stretococcus – pneumonia, meningitis, pharyngitis, endocarditis, rheumatic fever  Staphylococcus – wound and skin infections  Gonococcus - gonorrhea  Hemophilus inluenzae – otitis media, others

CEPHALOSPORINS  Hospital-acquired Gram (-) infections  Sepsis (initial treatment)