Chap 118 -- Treatment & Prophylaxis Of Bacterial Infection

Chapter 118: Infection

Treatment & Prophylaxis of Bacterial

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The development of vaccine and antimicrobial agent that prevent and cure bacterial infections was one of the twentieth century’s major contributions to human longevidity and quality of life. Antimicrobial agent are among the most commonly prescribed drugs, however their indiscriminate use drives up the cost of health care, leads to a plethora of side effect & drug interactions, and fosters the emergence of bacterial resistance. Rational Use of antibacterial agent (depends on mechanism of action, pharmacokinetics, pharmacodynamics, toxicities, interactions, bacterial strategies for resistance and bacterial susceptibility in vitro plus the patient-associated parameter: site of infection, immune & excretory status of the host and appropriate therapeutic condition. I. Mechanism of Action (MOA) – directed against unique targets not present in mammalian cells Goal: limit toxicity to the host & maximize chemotherapeutic activity affecting invading microbes only. Bactericidal drug – kill bacteria within it’s spectrum of activity Bacteriostatic drug – inhibit bacterial growth (Refer Basic Antibacterial Mechanism of Action Table 118-1, page 790 depicted on Figure 118-1, page 791, or review pharmacology handouts of Dra. Villar) A. Inhibition of Cell Wall Synthesis Cell wall – unique to bacteria which protect it from osmotic rupture. Peptidoglycan – structure conferring cell-wall rigidity & resistance to osmotic pressure to both gram + (thick layer) & (thin layer) bacteria which composed of: backbone of 2 alternating sugars, Nacetylglucosamine (NAGA) & N-acetylmuramic acid (NAMA)

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a chain of 4 amino acid that extend down from the backbone (stem peptides) peptide bridge that cross-link the peptide chain Chemotherapeutic agent directed at any stage of the synthesis, export, assembly, or cross-linking of peptidoglycan lead to inhibition of bacterial cell growth. Bacitracin – a cyclic peptide antibiotic, which inhibits the conversion of the active form of the lipid carrier that moves the water soluble cytoplasmic peptidoglycan subunitthrough the cell membrane to the exterior. Glycopeptides (vancomycin & teicoplanin – high molecular weight antibiotic that bind to the terminal Dalanine-D-alanine component of stem peptide while the subunits are external to the cell membrane but still linked to the lipid layer causing sterical inhibition of the addition of subunit to the peptidoglycan backbone B-lactam Antibiotics (penicillins, cephalosporins, carbapenem & monobactam) – a four-membered Blactam ring which prevent the cross-linking reaction called transpeptidation by binding to transpeptidases and enzymes invoveld in cross-linking (Penicillin binding proteins[PBP])

B. Inhibition of Protein Synthesis – interacts with bacterial ribosomes. • Aminoglycosides (gentamycin, kanamycin, tobramycin, streptomycin, netilmycin, neomycin & amikacin) – group of structurally related compounds containing 3 linked hexose sugars that exert it’s bactericidal effect by binding irreversibly to the 30S subunit of the bacterial ribosome and blocking the initiation of protein synthesis.

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Macrolide Antibiotics (erythromycin, clarithromycin & azithromycin) – consist of large lactone ring to which sugars are attached which bind specifically to the 50S portion of the bacterial ribosomal subunit inhibiting it to join t the 30S component to form to the 70S subunit complex responsible for further protein chain elongation (so walang protein chain elongation). Although, structurally unrelated to macrolides: lincosamides (clindamycin & lincomycin) bind also to the site of 50S similar to macrolides. Chloramphenicol – consist of a single aromatic ring & a short side chain which bind irreversibly to the 50S portion of the bacterial ribosome at the site close but not identical with the binding site ofmacrolides & linconamides. Linezolid – (first new synthetic class of antibiotics ex. Oxazolidones) – also binds to the 50S ribosomal subunit. Tetracyclines – (tetracycline, doxycycline, minocycline) – consist of 4 aromatic rings with various substituent groups which interact reversibly with the bacterial 30S ribosomal subunit, blocking the binding of aminoacyl tRNA to the mRNA-ribosome complex. Mupirocin (pseudomonic acid) – produced by bacterium Pseudomonas flourescens. It inhibits isoleucine tRNA synthetase by its binding site on the enzyme depleting the cellular store of isoleucin-charged tRNA leading to cessation of protein synthesis.

C. Inhibition of Bacterial Metabolism (Antimetabolite – synthetic compound that interfere with bacterial synthesis of folic acid which lead to the cessation of bacterial cell growth and to bacterial cell death).

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Sulfonamides – are structural analogues of paminobenzoic acid (PABA), one of the three structural component of folic acid (the two are pteridine & glutamate), which competes with PABA for the enzyme dihydropteroic acid synthetase which is responsible for the first step of folic acid synthesis. Trimethoprim – is a diaminopyrimidine, a structural analogue of the pteridine moiety of folic acid, which serve as a competitive inhibitor of dihydrofolate reductase, an enzyme responsible for the reduction of dihydrofolic acid to tetrafolic acid – the essential final component of folic acid synthesis.

D. Inhibition of Nucleic Acid Synthesis or Activity – cause disparate effect to nucleic acid • Quinolones (including Nalidixic acid & its fluorinated derivatives [ciprofloxacin, levofloxacin, gatifloxacin & moxifloxacin]) – synthetic compounds that inhibit the activity of the A subunit of the bacterial enzyme DNA gyrase & topoisomerase IV, an enzyme responsible for negative supercoiling of the DNA – an essential conformation for DNA replication in the intact cell (so walang DNA replication). • Novobiocin – also interfere with the activity of DNA gyrase, but it interferes with the B subunit. • Rifampicin – used primarily in M. tuberculosis. It binds tightly to the B subunit of bacterial DNA-dependent RNA polymerase, thus inhibiting transcription of DNA to RNA. • Nitrofurantoin – synthetic compound containing a single five-membered ring & it is reduced by bacterial enzyme to highly reactive, short lived intermediates that are thought to cause DNA strand breakage. • Metronidazole –a synthetic imidazole which is active against a wide range of anaerobic bacteria & protozoa, . Its activity is totally dependent on its anaerobic electrontransport system for energy production, wherein the nitro group of metronidazole is reduced to series of transiently

produced, reactive intermediates that are thought to cause DNA damage (maybe mutagenic & radiosensitizer of hypoxic mammalian cell). E. Alteration of Cell-Membrane Permeability

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Polymixins (Polymixin B & colistin, or Polymixin E) – are cyclic, basic polypeptide that behave as cationic, surfaceactive compound that disrupt the permeability of both the outer & the cytoplasmic membrane of gram-negative bacteria. Gramicidin A – a polypeptide of 15 amino acids that act as an ionophore, forming pores or channels in lipid bilayers

II. Mechanism of Resistance

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Intrinsic Resistance (resistant na noon pa, ex. Gramnegative bacteria resistant to vancomycin) Acquired Resistance – bacteria which is ordinarily susceptible to antimicrobial agents acquire resistance due to mutation of resident gene or by acquisition of new genes.

Major Mechanisms used by bacteria to resist the action of antimicrobial agent: • Inactivation of the compound • Alteration or overproduction of the antibacterial target through mutation of the target protein gene • Acquisition of new gene that encodes a drug insensitive target

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Decrease permeability of the cell wall envelope to the agent Active efflux of the compound from the periplasm or interior of the cell

A. Beta-lactam Resistance • Destruction of drug by B-lactamase of gram-negative bacteria, which is confined in its periplasm , between the inner & outer membranes, while in gram-positive bacteria secrete their B-lactamase into the surrounding medium.  Strategy: combine B-lactam with an inhibitor (clvulanic acid, sulbactam & tazobactam) that avidly binds the inactivating enzyme , preventing the attack on the antibiotics. • Alteration of PBP targets so that the PBP’s have a markedly reduced affinity to the drug.

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Coupling, in gram-negative bacteria, of a decrease in outer-membrane permeability with rapid efflux of the antibiotic from the periplasm to the cell exterior there is a mutation of gene encoding outer-membrane protein channels called porins which decrease the entry of Blactam into the cell, while additional protein form channels that actively pump B-lactams out of the cell.

B. Vancomycin Resistance – the gene encoding resistance are carried on plasmids that can transfer themselves from cell to cell and from transposons that could jump from plasmid to chromosomes. Resistance is mediated by enzymes that substitute D-lactate for D-alanine on the peptidoglycan stem peptide so that there are no longer an appropriate target for vancomycin binding. C.

Aminoglycoside Resistance

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Inactivation of the antibiotics by aminoglycoside modifying enzyme Decrease antibiotic uptake is some clinical isolate of P. aeruginosa presumably due to alterations in the bacterial outer membrane

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D. Macrolides, Ketolides, Lincosamides & Streptogrammins • Resistance of gram-positive bacteria due to the production of enzyme – most commonly plasmid encoded – that methylates ribosomal RNA, interfering with binding of the antibiotics to their target • Resistance to streptogrammin B convert quinupristin/dalfopristin from bactericidal to bacteriostatic

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Streptococci can actively cause the efflux of macrolides, while Staphylococci can cause the efflux of clindamycin Staphylococci can inactivate streptogrammin by acetylation & hydrolysis Mutation of 23S ribosomal RNA alter macrolides binding to their targets have been found in Streptococci & Staphylococci

E. Chloramphenicol Resistance – due to plasmid encoded enzyme, chloramphenicol acetyltransferase, that inactivates the compound by acetylation. F. Tetracycline Resistance – due to plasmid encoded activeefflux pump that is inserted into the cytoplasmic membrane & extrude antibiotic from the cell. G. Topical Mupirocin Resistance – due to mutation of the target isoleucine tRNA synthetase so that it is no longer inhibited by antibiotic or plasmid-encoded production of a form of the target enzyme that bind to mupirocin poorly. H. Trimethoprim & Sulfonamides Resistance -due to the acquisition of plasmid encoded genes to produce a new, druginsensitive target – insensitive dihydrofolate reductase for trimethoprim & an altered dihydropteroate synthetase for sulfonamide. I. Quinolones Resistance – due to the development of one or more mutations in target DNA gyrases and topoisomerasesIV that prevent antibacterial agent from interfering with the activity of the enzyme. J. Rifampin Resistance– due to developing mutation in the B subunit of RNA polymerase that render the enzyme unable to bind the antibiotic. K. Linezolid Resistance – due to mutation of the 23S rRNA binding site L. Multiple Antibiotic Resistance • Acquisition of the multiple unrelated resistance genes • Development of the mutations in a single gene or gene complex that mediates resistance to a series of unrelated compounds III. Pharmacokinetics of Antibiotics – refers to concentrations in serum & tissue versus time & reflects the process of absorption, distribution, metabolism & excretion. Key terms: Peak & through serum concentration, half-life, clearance & distribution volume (alam nyo nay un from pharma) Pharmacodynamic Profile of Antibiotic – refers to the relationship between serum & tissue concentrations of the antibiotic & its Minimal inhibitory concentration (MICs) for bacteria A. Absorption – refer to the rate & extent of a drug’s systemic bioavailability after oral, IM & IV administration, 1. Oral administration – it is usually used for patient with relatively mild infections in whom absorption is not thought to be compromised by the preceeding conditions with varying bioavailability and has the advantage of low cost, fewer adverse effect & greater acceptance to patient, however therapeutic efficacy may be compromised when absorption is

reduced as a result of physiologic or pathologicconditions, drug interactions or noncompliance. 2. Intramuscular Administration – although route of administration result in 100%bioavailability, it is not widely use due to pain of injection & the relative ease of IV access. 3. Intravenous Administration – appropriate whenoral antibacterial agents are not effective against a particular pathogen, when bioavailability is uncertain,or when larger doses are required than are feasible with the oral route. B. Distribution – antibacterial agent must exceed the pathogen MICs & must distribute to the site of infection to be effective. Hard to distribute areas are in the CSF, the eye, the prostate & infected cardiac vegetationwhich require either high dose or local aministration for prolonged periods. C. Metabolism & Elimination – by hepatic elimination & renal excretionof the unchanged or metabolized form, or by a combination of the two processes. Adustment of dosage of drug should be done when elimination capability is impaired as to prevent toxicity. IV. Principles of Antibacterial Chemotheraphy • When appropriate, material containing the infecting organism(s) should be obtained before the start of treatment so that presumptive identification can be made by microscopic exam, culture & susceptibility testing • Once the organism is identified & its susceptibility to antibacterial agents is determined, the regimen with the narrowest effective spectrum should be chosen. • The choice of antibiotic is guided by the pharmacokinetic & adverse reaction profile of active compounds, the site of infection, the immune status of the host & evidence of efficacy from well performed clinical trials. A. Susceptibility of Bacteria to Antimicrobial Drugs In Vitro – essential first step in devising a chemotherapeutic agent (ito yung Kirby-bauer na ginawa natin noon sa micro wherein we list the drug na pwede mag-inhibit ng growth & from dun ibabase yung drug of choice) B. Pharmacodynamics: relationship of Pharmacokinetics & In Vitro Susceptibility to Clinical Response – the breakpoint is the concentration of the antibiotics that separates susceptible from resistant bacteria.

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Phamacodynamic profile of Antibiotic – the quantitative relationships between the time course of antibiotic concentrations in serum & tissue, in vitro susceptibility & microbial response. 3 pharmacodynamic parameter: the ratio of the area under the curved for the plasma concentration vs time curve to MIC (AUC/MIC), the ratio of the maximal serum concentration to the MIC (Cmax/MIC) & the time during a dosing interval that plasma concentration exceed the MIC (t>MIC) Concentration dependent (fluoroquinones, aminoglycoside) increase antibiotic concentration leads to a more rapid rate of bacterial death Time-dependent – (B-lactam) – reduction in bacterial density is proportional to the time of that concentration exceed the MIC.

C. Status of the Host • Patient’s age, sex, racial heritage, genetic background & excretory status – determine the incidence & type of side effect that can be expected with certain antibacterial agents. • Host’s antibacterial Immune function – relates to the opsonophaghocytic function, since the major host defense against acute, overwhelming bacterial infection

is the PMN leukocyte, patients with neutropenia & have deficient immunity must be treated aggressively & empirically with bactericidal (instead of bacteriostatic) drugs for suspected infection.

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Pregnancy – icreases the risk of toxicity of certain antibacterial drugs for the mother, affect drug desposition & because of the risk of fetal toxicity – severely limits the choice of agents for treating infections (Refer to Table 118-5, page 797 for antibiotics presenting toxicity during pregnancy) Patient with Concomitant Viral Infection – incidience of adverse reaction to antibacterial drugs may be unusually high.

D. Site of Infection

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Meningitis – should received drugs that can cross the blood-CSF barrier & the agent must be bactericidal due o the relative paucity of phagocytes & opsonins at the site of infection ex. Chloramphenicol Bacterial endocarditis vegetation – needs bactericidal, with the selected agent administered parentally over a long period and at a dose that produces serum levels at least 8x higher than the minimal bactericidal concentration (MBC) Osteomyolysis – site that is somewhat resistant to opsonophagocytic removal of infecting bacteria Chronic prostitis – difficut to cure because most antibiotics does not penetrate through the capillaries serving the prostrate. Intraocular Infection (sp. endopthalmitis) – difficult to treat because retinal capillaries lacking fenestration hinder drug penetration into the vitreous from blood. Abcess – poor penetration of antibiotics. Urinary Tract Infection (sp. in the bladder) – easy to cure because of higher concentration of antibiotics to urine than in blood. (Nitrofurantoin & methenamnie salt)

E. Combination Therapy Use of single agent therapy with a narrow spectrum of activity against the pathogen diminished the alteration of the normal flora thus limiting the overgrowth of resistant nosocomial organism, avoids potential toxicity of multiple-drug regimens & reduce the cost. Circumstances for the Use of Multiple–drug regimen 1. Prevention of Emergence of resistant mutants – a second antibacterial agent with a mechnismof action different from that of the first is added to prevent the emergence of resistant mutants. 2. Synergistic or Additive activity – involves the lowering of the MIC & MBC of each drugs tested in combination against a specific bacterium. (Synergy – each agentis more active when combined with a second drug than would be alone; Additive – combined activity of the drugs is equal to the sum of their individual activities). Ex. B-lactam/Aminoglycoside & Trimethoprim/Sulfamethoxazole. 3. Therapy directed against multiple potential pathogens (ex. Intraabdominal or brain abcesses) F. Empirical Theraphy Antibacterial therapy is begun before a specific bacterial pathogens has been identified. Situations in which empirical therapy is appropriate include the following: 1. Life threatening infection 2. Treatment of Community-acquired infections V. Choice of Antibacterial Therapy A. B-lactam – Penicillins (except for the semisynthetic & penicillinase-resistant antistaphylococcal agents) are ineffective against isolates procing B-lactamase enzymes.

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Penicillin G – spectrum including spirochete, streptococci, E. faecalis, most Neisseria sp., a few staphylococcus, many fastidious oral bacteria, clostridium sp., Pasteurella multocida, Erysipelothrix rhusiopathiae & Streptobacillus moniliformis. Ampicillin – extends the spectrum of penicillin G to some gram-negative rods active against some isolates of E. coli, Proteus mirabilis, Salmonella, Shigella & H. influenzae. Penicillinase-Resistant Penicillins (ex. Methicillin) – use solely for the treatment of Staphylococcal infection. Antipseudomonal Penicillin (ex. Piperacillin) – spectrum include bacteria covered by ampicillin as well as some nonpseudomonal enteric gram-negative bacilli First-Generation Cephalosporin – spectrum including penicillinase-producing, methicillin-susceptible staphylococci & streptococci but not a drug of choice of such infection. They have excellent activity against many isolates of E. coli, Klebsiella pneumoniae & P. mirabilis & are among the drug of choice in presumptive theraphy for community acquired pneumoniae. Parenteral Second-generation Cephalosporin (ex. Cefuroxime, Cefoxitin & cefotetan) – extends the gramnegative spectrum of first generation compound with good activity against B. fragilis. Oral second- & third-generation Cephalosporin – have fair activities against gram-positive cocci & H. influenzae & are widely used in patient with otitis media, sinusitis & lower respiratory tract infection. Third-generation parenteral cephalosporins (ex. Ceftaxidime & Cefepime) – all have broad spectrum of activity against enteric gram-negative rods & are useful for treatment of hospital-acquired infection caused by multiple resistant organism. Carbapenems (Imepenem, Meropenem, Ertapenem) – have excellent activity in vitro with virtually all bacterial pathogens except Stenotrophomonas, MR Staphylococci & E. faecium. They are usually in combination with renal dipeptidase inhibito cilastin to prevent renal inactivation. Monobactam (Aztreonam) – spectrum limited to gramnegative enteric bacilli.

B. Vancomycin – spectrum limited to gram-positive cocci, especially enterococci, streptococci & staphycocci which serve as a second-line therapy for most gram-positve bacterial infection; drug of choice for pseudomembranous colitis caused by C. deficille not responsive to metronidazole. C. Aminoglycosides (Gentamicin & Tobramycin)– rapidly bactericidal in vitro at low concentrations, with activity limited to gram-negative bacteria & staphylococci; drug of choice for any suspected gram-negative bacteremia infection & for severe infection of the upper urinary tract. Streptomycin is the drug of choice in initial therapy for tularemia, plague, glanders & brucellosis. D. Macrolides (Erythromycin) & Ketolides – has a broadspectrum activity against gram-positive bacteria with the additional activity against (drug of choice)Legionella, Mycoplasma, Camphylobacter, Bordetella pertusis and some Chlamydia isolates. Drug of choice to communit acquired pneumococcal pneumoniae & group A streptococcal pharyngitis to penicillin-allergic patient. Clarithroymycin, in combination of proton pump inhibitor has been the drug of choice for the treatment of gastric infection by H. pylori. E. Lincosamides (Clindamycin) – shares gram-positve coccal spectrum of erythromycin but is more active against susceptible staphylococci. Drug of choice for treatment of severe invasive group A streptococcal infection.

F. Chloramphenicol – broad spectrum of activity against gram-positive & gram-negative bacteria, although plasmid mediated resistance has diminished its effective spectrum. Remains the drug of choice for the treatment of typhoid fever & plague & still useful for the treatment of brucellosis & both pneumococcal & meningococcal meningitis in patient with severe penicillin allergy. G. Tetracycline (Doxycycline & Minocycline) – has broad spectrum of bacteriostatic activity against gram-positive & gram-negative bacteria & are widely used in a variety of community acquired infection. Drug of choice for acute bacterial exacerbations of chronic bronchitis, granuloma inguinale, brucellosis, tularemia, glanders, meliodosis, spirochetal infections caused by Borrelia, infectiondue to Vibrio vulnificus, some Aeromonas infections due to Stenotrophomonas, plague, ehrlichiosis & due to Mycobacterium marinum. H. Sulfonamides & Trimethoprim – has a broad spectrum of bacteriostatic activity individually & in combination against facultative gram-negative bacteria & Staphylococci. Drug of choice for the treatment of Nocardia Infections, Leprosy (dapsone) & toxoplasmosis (sulfadiazine), and uncomplicated urinary tract infection. I. Fluoroquinolones – excellent activity against most facultative gram-negative rods & variable activity against gram-positive cocci. Oral agents with greatest activity to p. aeruginosa (Ciprofloxacon). Drug of choice for urinary tract infection, bacterial gastroenteritis, community acquired pneumoniae & enteric fever & useful for serious hospitalacquired infections caused by gram negative organism. J. Rifampin – used for combination treatment of serious infection due to methicillin resistant staphylococci & for chemoprophylaxis in persons at risk of meningococcemia meningitis & for treatment of Legionella pneumonia. K. Metronidazole – spectrum limited to anaerobic bacteria, specially gram-negative species (ex. Bacteroides spp.). Drug of choice for the treatment of abscess in which the involvement of obligate anaerobes is suspected., treatment of bacteria vaginosis & antibiotic associated pseudomembranous colitis. L. Linezolid – bacteriosttic spectrum limited to gram-positive bacteria & is indicated for the treatment of infections caused by staphylococci, streptococci & enterococci. M. Polymixins – broad spectrum of activity that includes virtually all gram-negative bacteria used commonly as topical agent (ex. colistin). N. Streptogramins – combination of Streptogramins B (quinupristin) & streptogramin A (dalfopristin) has spectrum limited to gram-positive bacteria & is indicated for the treatment of staphylococci, streptococci & E. faecium. O. Urinary Tract Antiseptics (Nitrofurantoin & Methenamine salt) – are active only in the lower urinary tract & cannot be used as treatment for upper urinary tract or systemic infections, are most active against susceptible gram-negative bacteria. P. Topical Antibacterial Agents – mupuricin is available only as topical preparation for use against staphylococci & streptococci, which has major application for impetigo & eradication of staphylococcal carrier state. VI. Adverse Reaction – mechanism of either dose-related (“toxic”) effects of unpredictable reactions which is either idiosyncratic or allergic.

A. B-Lactam – generally concerned with all type allergic reaction Type 1 – immediate-hypersensitivity ex. Anaphylaxis Type 2 – cytotoxic reaction ex. Nephritis & coombs-positive hemolytic anemia Type 3 – immune-complex formation ex. Serum sickness Type 4 – cell-mediated effect ex. Contact dermatitis Type 5 – idiopathic reaction ex. Macvulopapular eruption Micellaneous reaction includes gastrointestinal side effect ranging from mild diarrhea to severe form of membranous colitis In high dose, penicillin can cause bleeding from impaired platelet aggregation B. Vancomycin – most common side effect is the red man syndrome, characterized by pruritus,flushing & erythema of the head & upper torso often mislabeled as allergy. • Can rarely cause nephrotoxicity, ototoxicity, leucopenia, skin rashes & true allergy C. Aminoglycoside – the two most common adverse reaction is nephrotoxicity (result from the accumulation of aminoglycoside in the peritubular space, with damage to the proximal tubule & a corresponding reduction in GFR) & Ototoxicity (auditory or vestibular damage since aminoglycoside can destroy hair cells in the inner ear)

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Neuromuscular depression from aminoglycosides is caused by reduced acetylcholine activity at postsynaptic membranes that can result in rare but severe respiratory depression.

D. Macrolides – Gastrointestinal effect such as burning, nausea & vomiting are the most common since macrolides bind to motilin receptor, increasing gastrointestinal motility. Less common side effect is hepatotoxicity & ototoxicity, and allergic cutaneous reaction. E. Lincosamides – most common adverse effect is gastrointestinal distress ranging from diarrhea to pseudomembranous colitis. Allergic reaction, hepatotoxicity & neutropenia are observed in only rarely. F. Chloramphenicol – causes two types of bone marrow suppression: a dose-related, reversible suppression of all elements which occur commonly during therapy at the maximal recommended dose, & an idiosyncratic, irreversible aplastic anemia.

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Both can also cause severe hematologic complications, including agranulocytosis, hemolytic & megaloblastic anemia & thrombocytopenia. Renal insufficiency, caused by crystals of the relatively insoluble acetyl metabolites, is observed primarily with the long-acting sulfonamides. It is recommended that sulfonamides not be administered in the newborns because of concerns that bilirubin may be displaced from protein-binding sites, with subsequent jaundice & kernicterus. Occasionaly could cause drug fever with serum sickness, hepatic toxicity & systemic lupus erythematosus.

I. Fluoroqunolones – are relatively safe but adverse reaction discontinuation of therapy which includes GI distress, central nervous system effect including insomnia & dizziness. Phototoxiciy is occasionally severe . Rarely hepatic & renal dysfunction & anaphylactoid & allergic reaction are observed. J. Rifampin – is generally well-tolerated but has several important side effect such as transient rise in hepatic aminotransferases although rifampin hepatitis is rare. Patient should also be warned that rifampin & its metabolites cause secretions such as urine, tears, sweat & saliva to turn orange & that contact lens may be stained. K. Metronidazole – GI side effect such as nausea are most frequent but rarely necessitate discontinuation of theraphy. A metallic taste is relatively common, & stomitis & glositis are occasionally reported

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Concerns about mutagenecity & carcinogenicity from metronidazole have led to recommendations that it not be used in pregnancy when alternative agents are available.

L. Linezolid – GI upset (nausea, vomiting & diarrhea) & headache. Of most concern is a reversible myelosuppresion that is directly related to the duration of theraphy. M. Quinupristin/Dalfopristin –venous irritation is frequent & potential adverse effect when the drug is given by peripheral intravenous infusion. In addition, arthralgia & myalgia are substantially more common among patient treated with quinupristin/dalfopristin. VII. Drug Interaction (Refer to Table 118-7, page 803)

In premature neonates & infants, it can cause doserelated “gray syndrome” characterized by cyanosis, hypotension & death that results from an inability of the newborn to metabolize the drug.

A. Macrolides & Ketolides – erythromycin, clarithromycin & telithromycin inhibit the p450 enzyme CYP3A4 & thus metabolism of other drugs, including cyclosporine, certain statins, theophylline, carbamazepine, warfarin, certain antineoplastic agents & ergot alkaloids.

G. Tetracyclines – GI effects (most common) which may be related to a direct irritant effect, since it could also cause esophageal ulcerations when they dissolve before reaching the stomach..

B. Quinupristin/Dalfopristin – also inhibitor of CYP3A4 similar to those of erythromycin

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Hepatotoxicity has been reported after administration of tetracycline intravenously at a lower doses during pregnancy, hence it is contraindicated in pregnant woman, Tetracyclines are contraindicated in children <8y/o because of mottling of the permanent teeth.

H. Sulfonamides & Trimethoprim – generally safe but may occasionally cause a number of allergic reactions, from relative minor skin rashes to severe life threatening reactions such as erythma multiforme, steven Johnson syndrome & toxic epidermal necrosis.

C. Linezolid – are monoamine oxidase inhibitor & its concomitant administration with sympathomimetics, with SSRI & with food with high concentration of tyramine should be avoided D. tetracycline – reduction in absorption when these drugs are coadministerd with divalent & trivalent cations such as antacids, iron compounds or dairy products. E. Sulfonamides – including sulfomethoxazole, increase the hypothrombinemic effect of warfarin by inhibition of its metabolism & possibly protein binding displacement. F. Fluoroquinolones – like tetracycline, are also chelated by divalent & trivalent cations. Certain fluroquinolones including

ciprofloxacin, inhibit hepatic enzymes that metabolized theophyllin, thus theophylline toxicity. G. Rifampin – an excellent inducer of many cytochrome P450 enzymes & increases the hepatic clearance of a number of drugs including oral contraceptive, warfarin, cyclosporine & prednisone, & verapamil & diltiazem. H. Metronidazole – can cause disulfaram-like syndrome when alcohol is ingested. VIII. Prophylaxis of Bacterial Infection (Refer to table 1188, page 804) Basic tenets of antimicrobial prophylaxis:

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Risk or potential severity of infection should be greater than the risk of side effectfrom the antibacterial agent The antibacterial agentshould be given for the shortest period necessary to prevent the target infections The antibacterial agent should be given before the expected period of risk (ex. Surgical prophylaxis) or as soon as possibleafter contact with the infected individual (ex. Prophylaxis for meningococcal meningitis)

IX. Duration of Theraphy & Treatment (Refer to table 1199, page 805) • The ultimate test of cure for a bacterialinfection is the absence of relapse (the occurrence of infection with the identical organism that cause the first infection. • In general, the duration of the therapy should be long enough to prevent relapse yet not excessive that could cause increase side effects of medication & encourage the selection of resistant microorganism X. Antibacterial Cost & Inappropriate Use Guidance through the antibiotic maze • Objective evidence regarding the merits of newer drugs is available through publication such as “The Medical Letter” & through online reference of John Hopkins Website. • Clinicians should became comfortable using a few drugs recommended dy independent experts and professional organizations and should resist the temptation to use a new drug unless the merit is clear. • Clinicians should be familiar with local bacterial susceptibility profile

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Appropriate empirical treatment with one or more broadspectrum agents may often be simplified, with the use of narrower spectrum agent or even an oral drug, once the results of cultures and susceptibility tests becomes available.

ZPDM 2005