OS 217: Systemic Diseases RATIONAL ANTIBIOTIC USE LECTURE 6

INFECTIOUS DISEASES MODULE 20 June 2012 NAFCILLIN/OXACILLIN SPECTRUM Dr. Cecilia Maramba-Lazarte

EXAM 1

PART 1: RATIONAL ANTIBIOTIC USE A. PENICILLIN (IN GENERAL) Mechanisms of resistance o Due to beta lactamase production o Altered penicillin binding proteins Renally excreted All not metabolized Generally well-tolerated GI side effects: common Hypersensitivity reactions: most feared PENICILLIN AND PNEUMOCOCCUS 0% resistance in the Philippines, 15-30% in other parts of the world Altered PBPs makes penicillin and sometimes cephalosporins ineffective Plasmid mediated, possibly transferred from other species Plasmid also carries resistance genes to other antibiotics: macrolides, tetracyclines, sulfa drugs #1 vaccine-preventable bacteria in the world PENICILLIN AND NEISSERIA Increasing resistance (91.2% in the Philippines) due to beta-lactamase production of N. gonorrhea Unless organism proven sensitive, do not use penicillin empirically for gonorrhea DOSING Mild infections cellulitis, pharyngitis, etc. Penicillin V 500mg PO QID Penicillin G 1-2 M units IV Q4 hours Serious infections meningitis, endocarditis Penicillin G 4M units IV Q4 hours The more serious, higher dose or shorter interval (Q6 to Q4) Syphilis Latent: 2.4M units benzathine penicillin IM Q week x 3 weeks Neurosyphillis: 4M units IV Q4 hours x 10 days Adjust dose for renal failure CLINICAL USES Syphilis S. pyrogenes pharyngitis Actinomyces infections Subacute acute bacterial endocarditis due to pen-sensitive Group A streptococci Penicillin-sensitive pneumococcal and meningococcal meningitis Pneumococcal pneumonia B. PENICILLIN TYPES AMPICILLIN SPECTRUM

Oxacillin-sensitive S. aureus Oxacillin-sensitive coagulase negative staph Okay against Lancfield group streptococci and viridans streptococci, but there are better drugs for these No gram negative or anaerobic coverage to speak of OXACILLIN PEARLS

Pretty narrow spectrum Most potent anti-staph drug made Excellent CNS penetration (staph meningitis) No dose adjustment for renal failure (predominantly hepatic excretion) Watch out for: Leukopenia, Thrombocytopenia, Interstitial nephritis CLINICAL USES

OXACILLIN

All MSSA infections Endocarditis Osteomyelitis PIPERACILLIN SPECTRUM

Meningitis Pneumonia

Abscesses cellulitis

Pseudomonas Enterobacteriacae group Beta-lactamase negative Moraxella, Neisseria, haemophillus Same gram positive spectrum as penicillin Same anaerobic (above the diaphragm) spectrum as penicillin DOSING

PIPERACILLIN

Mild to moderate gram negative (non-pseudomonal) or streptococcal infections 3 gm IV Q6 hours Moderate to severe pseudomonal infections 3 gm IV Q4 hours OR piperacillin/tazobactam 3.375 gm IV Q4 hours BETA-LACTAM, BETA-LACTAM INHIBITOR COMBINATIONS

BL Inhibitor binds to beta-lactamase so penicillin does not get inhibited Broadens the activity of the drug Ampicillin/sulbactam Ticarcillin/clavulanate Piperacillin/tazobactam AMPICILLIN-SULBACTAM SPECTRUM MSSA Enterococcus bacteriostatic Penicillin-sensitive pneumococcus

Streptococci All anaerobes Beta-lactamase-producing gramnegatives AMPICILLIN-SULBACTAM

DOSING

Same gram positives as penicillin Enteric gram negatives (if sensitive) o E. coli o Proteus o Salmonella (<5% resistance) o Shigella (70-90% resistance) Respiratory tract gram negatives o H. influenza: cause RTI, meningitis, and pneumonia o Moraxella morganii: 30-45% resistance in the US, but here still okay Pasteurella moltocida Listeria monocytogenes AMPICILLIN ENTEROCOCCUS

Mild infections: 1.5 gm IV Q6 hours Moderate infections: 3.0gm IV Q6 hours Adjust dose for renal failure AMPICILLIN-SULBACTAM CLINICAL USES

Head and neck infections Peritonsilar abscess Sinusitis Mastoiditis Mandibular osteomyelitis Actinomycocosis Infected bite wounds- human, dog, cat Diabetic foot infections (anaerobes cause the foul smell), inc osteomyelitis Culture negative endocarditis PIPERACILLIN-TAZOBACTAM SPECTRUM

Weak affinity for penicillin-binding proteins bacteriostatic Must add aminoglycoside (gentamicin) to create bactericidal regimen E. faecalis: usually sensitive E. faecium: usually resistant CLINICAL USES

Streptococci MSSA All anaerobes Enterococcus bacteriostatic Beta-lactamase-producing gram negatives PIPERACILLIN-TAZOBACTAM DOSING

AMPICILLIN

Amoxicillin for ampicillin-sensitive UTIs Pneumonia and meningitis due to pneumococcus and H. influenza In combo with gentamicin for enterococcal endocarditis Penicillin-sensitive alpha-streptococcal SBE DOSING

Usual dosing: 3.375 gm IV Q6 hours Fulminant sepsis: 4.5gm IV Q6 hours Pseudomonas sepsis: 3.375gm IV Q4 hours Adjust dose for renal failure CLINICAL USES

AMPICILLIN

Mild infections cystitis, pharyngitis Amoxicillin 500mg PO TID Moderate infections pyelonephritis, cellulitis, osteomyelitis Ampicillin 2gm IV Q4 hours Adjust dose for renal failure

PIPERACILLIN-TAZOBACTAM

Intra-abdominal infections Nosocomial aspiration pneumonia Diabetic foot infections when pseudomonas might be involved Pulmonary infections in patients with bronchiectasis or cystic fibrosis

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CEFAZOLIN (1ST GEN) Spectrum of Activity Gram (+) Gram (-) Others Streptococci Neisseria Treponema Pneumococci meningitides leptospira Corynebacterium H. influenza Listeria (high doses) Enterococcus Clostridium Oral Anaerobes Streptococci Staphylococci None None CLINICAL USES Any MSSA infection Cellulitis (2gm IV Q8 hours) Osteomyelitis Endocarditis Pneumonia NOT for meningitis (does not cross the BBB) Any Lancfield or viridans group streptococcal infections Endocarditis Cellulitis Table 3. 1st VS 2nd generation 1st generation H. influenza S. Aureus ++++ Streptococcus ++++ Moraxella Gram negatives + Anaerobes CEFUROXIME Neisseria meningitides H. influenza Salmonella E. Coli Enterobacter Proteus Neisseria meningitides H. influenza Salmonella E. Coli Proteus Enterobacter Pseudomonas piper and ticar only Acinetobacter CLINICAL USES

Table 1. Types of penicillin Penicillin Route Natural Penicillins Penicillin G, IV, IM K, or Na Benzathine IM Penicillin Penicillin VK PO poor gram (-) Anti-staphylococcus penicillins Oxacillin IM, IV Cloxacillin PO Aminopenicillin Ampicillin IV, IM Amoxicillin PO

Extended Spectrum Penicillins Carbenicillin Ticarcillin IV Piperacillin IV B-lactam-B-lactamase inhibitor combination AmoxillinPO clavulanic acid PiperacillinIV tazobactam TicarcillinIV clavulanic acid

Streptococci Pneumococci Corynebacterium Listeria Enterococcus Clostridium Oral Anaerobes Streptococci Pneumococci Corynebacterium Listeria Enterococcus Clostridium Oral Anaerobes Streptococci Pneumococci Corynebacterium Listeria Enterococcus Clostridium Oral Anaerobes Staphylococcus

Neisseria meningitides H. influenza Salmonella E. Coli

2nd generation H. infuenzae S. Aureus Streptococcus Moraxella Gram negatives Anaerobes (cefoxitin only)

++++ +++ ++++ ++++ ++ +++

Bacteroides including fragilis

Upper respiratory tract infections o Sinusitis o Peritonsilar abscess o Otitis media Lower respiratory tract infections o Pneumonia o Acute bacterial bronchitis UTI CEFOXITIN CLINICAL USES

Intra-abdominal infections Diverticulitis Intra-abdominal abscess Peritonitis Cholecystitis Etc. Osteomyelitis Diabetic foot infections CEFTRIAXONE CLINICAL USES

C. CEPHALOSPORINS Similar mechanism of action as penicillin 4-5 generations As increases in generations, increased activity to gram (-) Fourth generation: most broad spectrum Renally excreted

Meningitis (2gm Q4 hours or 2gm Q12 hours) Community-acquired pneumonia UTI URTI: (1) sinusitis, (2) peritonsillar abscess Intra-abdominal infections CLINICAL USES

Why prefer a cephalosporin over penicillin? During hypersensitivity reaction, if a rash or urticaria Penicillin and cephalosporins are both beta-lactam rings, so dont give during anaphylactic shock Table 2. Classification of Cephalosporins Gen. Prototype drugs 1st 2nd Cefazolin(IV) Cephalexin (PO) Cefuroxime (IV, PO) Cefaclor (PO) Cefoxitin (IV, IM) added activity against anaerobes Ceftriazone (IV, IM) Cefotaxime (IV) Cefixitime (PO) Ceftazidime (IV, IM) added activity against P. aeruginosa

CEFTAZIDIME

Useful spectrum Gram (+) Gram (-) Streptococci E.coli (high Staphylococci resistance) Klebsiella Streptococci E.coli Klebsiella H. influenza Enterobacter Streptococci Better activity than 2nd gen for: E.coli Klebsiella H. influenza Enterobacter New: Salmonella Proteus Acinetobacter Pseudomonas Streptococci Better activity than Staphylococci 3rd gen: E.coli, Klebsiella, H. influenza, Enterobacter, Salmonella, Proteus, Acinetobacter, Pseudomonas All of the above plus MRSA

Hospital-acquired Pneumonia (HAP) Hospital-acquired UTI Post-op meningitis Intra-abdominal infections Pulmonary infections in patients with cystic fibrosis or bronchiectasis CLINICAL USES

CEFEPIME

4th generation Hospital-acquired pneumonia Sepsis in prolonged hospitalization Intra-abdominal infections

3rd

Table 5. Cephalosporin spectrum activity. G(+) G(-) Anaer activity, activity, obes cocci rods 1st gen +++ + + 2nd gen ++ ++ +++ 3rd gen 4th gen 5th gen ++ +++ MRSA +++ ++++ + +

Comments

Do not cross BBB Cefoxitin with anaerobic activity Ceftazidime has Pseudomonas activity This gen should be reserv3d for the very resistant strains

4th

Cefepime (IV, IM)

Cefrobiprole (IV, IM) not FDA-approved NOTE: all cephalosporins have no activity against enterococci and listeria

5th

ADVERSE EFFECTS OF CEPHALOSPORINS 1. Hypersensitivity reactions less than penicillins, may cross-react with penicilins in 5-10% 2. Hematologic for cephs with methyltetrazole group (cefamamndole, cefoperazone)may cause hypoprothrombinemia and bleeding disorders 3. Diarrhea 2-5% 4. Abnormal Liver function test 5. Biliary sludging (esp. in Ceftriaxone hence not given to neonates with jaundice) 6.

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D. CARBAPENEMS Stenotrophomonas maltophila, M. catarrhalis, Listeria monocytogenes Pneumocystis carinii, atypical mycobacteria, Toxolasma gondii

ERTAPENEM, IMIPENEM, MEROPENEM Most active drug against a wide variety of bacteria including G(+), G(-), and anaerobic bacteria Reserved for serious infections with MDR bacteria or polymicrobial infections Renally excreted Table 6. Carbapenems spectrum of activity. Drug G(+) G(-) Meropenem, S. aureus (MSSA E.coli, Imipenem only), Strep H.influenzae, - same agalactiae, Strep Klebsiella, spectrum of pneumoniae M.catarrhalis, activity (including penicillinProteus resistant strains), mirabilis, P. Strep pyogenes aeruginosa including ESBL orgs Ertapenem S. aureus (MSSA E.coli, H. only), Strep influenzae (Bagalactiae, Strep lactamasepneumoniae neg only), (penicilln-susceptible K.pneumoniae isolates only), Strep M.catarrhalis, pyogenes Proteus mirabilis

Others

Anaerobes Bacteroides spp. Including fragilis, Clostridium clostridioforme, Peptostreptococc us spp, Porphyromonas asaccharolytica, Prevotella bivia Bacteroides spp. Including fragilis, Clostridium clostridioforme, Peptostreptococc us spp, Porphyromonas asaccharolytica, Prevotella bivia

COTRIMOXAZOLE INDICATIONS 1. Treatment and prophylaxis of Pneumocystis carinii pneumonia 2. First line drug for Typhoid Fever 3. Respiratory tract, and bone and joint infections due to susceptible H. influenzae or S. pneumoniae 4. Treatment of acute and chronic bacterial prostatitis 5. Treatment and prophylaxis of UTI due to susceptible E.coli. (approx 70% resistance in the Phils.) ADVERSE REACTIONS 75% adverse reactions involve skin urticarial rash as the most common while Steven-Johnsons Syndrome, exfoliative dermatitis, and toxic epidermal necrolysis are rare Allergic cholestatic hepatitis Reversible drop in creatinine clearance in patients with normal renal function Irreversible renal failure in patients with renal disease REVISIONS Between Vancomycin and Cotrimoxazole, which is more broad spectrum? Answer: Cotrimoxazole Why should Vancomycin be reserved for MRSA? Answer: to prevent resistance G. AMINOGLYCOSIDES SYNGERGISM The Beta-lactams inhibit cell wall synthesis and thereby increase the permeability of the aminoglycosides Different mechanisms of action Different binding sites Mechanisms of action which complement each other Absorption ORAL, poor bioavailability, given IV or IM Distribution Poor penetration into BBB Excretion 94-98% excreted unchanged in the urine Adverse Reaction ototoxicity, nephrotoxicity, neuromuscular blockade Table 8. Aminoglycoside spectrum of action. G(+) S. aureus, S. viridans G(-) E.coli, Klebsiella, Proteus, Pseudomonas, Enterobacter, Acinetobacter etc. Others Mycobacteria-streptomycin, amikacin Anaerobes No activity; O2 required for uptake of antibiotic Note: Aminoglycosides are not used as monotherapy, combined with betalactams except for UTI INDICATIONS UTI in hospitalized patients wherein G(-) bacilli is suspected Combnation therapy with a beta-lactam and/or anti-anaerobes in the following: Empiric therapy for serious infections, e.g. neonatal sepsis, febrile neutropenia, nosocomial infections Mixed infections (aerobic/anaerobic), e.g. peritonitis from ruptured viscus. Infective bacterial endocarditis Systemic Pseudomonas aeruginosa infections

ADVERSE EFFECTS 1. Immediate hypersensitivity 2. Rapid infusion can cause nausea and vomiting 3. Seizures in 0.4-1.5% of patients given Imipenem; Meropenem is less seizuregenic 4. Candidemia may occur REVISIONS How does canidemia occur when there is prolonged use of carbapenems? Can you use carbapenems for the treatment of MRSA? E. VANCOMYCIN Chemistry glycopeptide Mechanism of Action inhibits cellwall synthesis; inhibits transglycosylase preventing further elongation of peptidoglycan Very poor oral and erratic IM, usually given IV Table7. Vancomycin spectrum of activity G (+) S. pneumoniae, S. pyogenes, S.aureus including MRSA, S. viridans, S. epidermidis, Enterococcus G (-) none others none INDICATIONS IV serious MRSA infections patients allergic to penicillins and cephalosporins with G(+) infections Oral only for antibiotic associated diarrhea (Pseudomembranous colitis)poor oral bioavailability ADVERSE REACTIONS Phlebitis Chills and Fever Ootoxicity Nephrotoxicity Red man syndrome erythema multiforme-like reaction with intense pruritus, tachycardia, hypotension, rash, flushing associated with too rapid infusion Note: Vancomycin should not be skin tested because it naturally releases histamine hence always positive to Skin Test, just observe the adverse effects during the first infusion F. ANTI-FOLATE DRUGS: TRIMETHOPRIM-SULFAMETHOXAZOLE CHEMISTRY Sulfonamides structural similarity to PABA or para-aminobenzoic acid, inhibits pteridine synthetase Trimethoprim a diaminopyrimidine, inhibits dihydrofolate reductase, inhibits sequential steps in folic acid synthesis

H. TETRACYCLINES The tetracyclines reversibly bind to the 30S ribosome and inhibit binding of aminoacyl-t-RNA to the A-site on the 50S ribosome Not routinely recommended for children <8 years old Chelated by metals and calcium

Table 9. Classification of Tetracyclines Classification Drugs Short-acting Chlortetracycline Tetracycline Oxyttracycline Intermediate-acting Democlocycline Methacycline Long-acting Doxycycline Minocycline Tigecycline

T1/2 6-8 hrs

12 hrs 16-118 hrs 36 hrs

Table 8. Cotrimoxazole spectrum of activity. G(+) S. aureus, S. pyogenes, S. pneumoniae G(-) E.coli, Proteus mirabilis, H. influnzae, Shigella spp., Salmonella spp., Burkholderia cepacia, Malleomyces pseudomallei, Yersinia,

Table 10. Tetracycline spectrum of activity. G (+) Streptococcus, Staphylococcus, Actinomycetes, Bacills anthracis G(-) H. influenzae, E.coli, Vibrio cholerae, N. gonorrhea, Shigella, Yersinia, N. meningitides, Treponema pallidum, Leptospira, Spirillium

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Chlamydia, Mycoplasma, Legionella Bacteroides fragilis, Prevotella Plasmodium, Filaria Mode of Action bind to 50S ribosome and inhibits transpeptidation (peptide chain on tRNA in the P site is transferred to tRNA on the A site); inhibits peptidyl transferase Reserved for serious infections because of side effects Good CNS penetration, oral route has better bioavailability Table 12. Chloramphenicol spectrum of activity. G(+) S. pneumoniae, S. pyogenes, S. aureus, Enterococci, Bacillus anthracis G(-) H. influenzae, Shigella, Salmonella, E.coli, N.gonorrheae, N. meningitidis, B. pertussis, M. catarrhalis, Klebsiella, Vibrio, Yersinia, Pseudomonas (not aeruginosa) Anaerobes Bacteroides (including fragilis), Prevotella, Clostridium, Peptostreptococcus, Actinomycetes Others Rickettsia, Mycoplasma, Chlamydia

CLINICAL USES Drug of choice for: Chlamydia infections (urethritis, PID, lymphogranuloma venereum and psittacosis) Mycoplasma pneumoniae Cholera Leptospirosis Alternative drug actinomycosis, rat bite fever, syphillis, gonorrhea, tularemia, shigellosis and Yersinia enterocolitica enteritis Severe acne very broad spectrum ADVERSE EFFECTS 1. GIT nausea and vomiting, vaginal or oral candidiasis, enterocolitis 2. Teeth and Bones discoloration of teeth, hypoplasia of the enamel, binds to Ca an may cause deformity or growth inhibition of bone; contraindicated in pregnant women and children <8 y.o. 3. Liver toxicity especially in pregnancy 4. Kidney toxicity renal tubular acidosis 5. Photosensitization, SLE, allergic reactions 6. Vestibular reactions dizziness, vertigo I. MACROLIDES (ERYTHROMYCIN, AZITHROMYCIN, CLARITHROMYCIN) Usually bacteriostatic, but may be bactericidal in high concentrations Mode of Action inhibit translocation (tRNA translocation from A site to P site) hence protein synthesis is inhibited INDICATIONS Infections due to Chlamydia trachomatis, Mycoplasma pneumoniae, and Legionella pneumophillia; bordetella pertussis (whooping cough) therapy and prophylaxis Gastroenteritis due to Campylobacter jejuni Diphtheria infection or carrier state Alternative drug in patients with penicillin hypersensitivity in Streptococcal and Pneumococcal infections outside the CNS; Prevention of bacterial endocarditis after dental procedures; rheumatic fever prophylaxis; Syphillis ADVERSE EFFECTS GIT (more frequent for Erythromycin); abdominal pain, nausea, vomiting, cramping, diarrhea, stomatitis; HEPATIC cholestatic hepatitis, jaundice CVS ventricular arrhythmias, QT interval prolongation, bradycardia, hypotension with IV admin CNS fever, dizziness Others rash, eosinophilia, thrombophlebitis, ototoxicity, allergic reactions Table11. Macrolides spectrum of activity Gram Positive Gram Negative ERYTHROMYCIN S. pneumoniae N. gonorrhea S. pyogenes B. pertussis Clostridium S. aureus C. diphtheriae L. monocytogenes CLARITHROMYCIN S. pneumoniae N. gonorrhea S. pyogenes B. pertussis Clostridium H. influenzae S. aureus M. catarrhalis C. diphtheriae L. monocytogenes AZITHROMYCIN S. pneumoniae S. pyogenes Clostridium S. aureus C. diphtheriae L. monocytogenes DRUG INTERACTIONS Macrolides are CYP1A2 and CYP3A3/4 inhibitors, decreases hepatic metabolism of other drugs leading to increased effects and toxicities (e.g. Dicumarol, Carbamazepine,Digoxin, Theophylline, Ergot, Cyclosporin and Triazolam) Terfenadine and Astemizole (H-blockers with no sedating effect) given macrolides may cause life threatening cardiac arrhythmias. With Statins (except for azithromycin)can cause debilitating myopathy J. CHLORAMPHENICOL Chemistry palmitate for oral use; succinate for IV use INDICATIONS Life threatening H. influenzae infections (meningitis, acute epiglotittis, septic very severe pneumonia) Typhoid fever Bacterial meningitis due to susceptible organisms (meningococcus, H. influenzae, pneumococcus) Brain abscess Severe anaerobic infections ADVERSE EFFECTS Hematologic dose-dependent bone marrow aplasia at dosages >50mg/kg/day after 1-2 weeks idiosyncratic aplastic anemia (1 in 24,000-40,000), irreversible, unrelated to dose, any route, and may be fatal. Toxicity for newborn due to lack of conjugation mechanism GRAY BABY SYNDROME (abdominal distension, vomiting, flaccidity, cyanosis, circulatory collapse and death) Optic neuritis Hypersensitivity-rare K. CLINDAMYCIN Chemistry chlorine substituted derivative of Lincomycin, inhibits translocation; same binding sites as Macrolides and since they have the same mode of action, same binding sites, do not give together to avoid antagonism Hepatic metabolism Oral and IV preparations Table 13. Clindamycin spectrum of activity: narrow G(+) S. pneumoniae, S. pyogenes, S. aureus, S. viridans G(-) none Others Anaerobes, Toxoplasma gondii, Plasmodium, Pneumocystis carinii M. pneumoniae C. pneumoniae C. trachomatis INDICATIONS Anaerobic (including B.fragilis) infections outside the CNS Alternative for staphylococcal and streptococcal (except enterococcal) infections in patients allergic to beta-lactams, e.g. soft tissue and bone infections alternative treatment for Actinomycosis, Gardnerella vaginalis vaginosis, toxoplasmosis and P. carinii pneumonia ADVERSE EFFECTS Diarrhea frequency is 20% Pseudomembranous colitis frequecy is 0.01-10% Increased liver function tests (hepatotoxicity) and hematologic abnormalities rare L. QUINOLONES Mechanism of Action binds to DNa gyrase (topoisomerase II) and prevent supercoiling of DNA, thereby inhibiting DNa synthesis

IV VS ORAL Chloramphenicol is available as 250 mg capsules or as a liquid palmitate (125mg/5ml) Chloramphenicol palmitate ester is inactive, and is hydrolysed to active chloramphenicol in the small intestines. There is no difference in bioavailability between chloramphenicol and chloramphenicol palmitate. IV chloramphenicol is the succinate ester, because pure chloramphenicol does not dissolve in water. Succinate ester is inactive prodrug and must first be hydrolysed to chloramphenicol; the hydrolysis process is incomplete and 30% of the dose is lost unchanged in the urine, 70% bioavailability of IV route compared to oral. The oral route is preferred ot the IV route when possible

Others M. pneumoniae C. pneumoniae C. trachomatis

M. pneumoniae C. pneumoniae C. trachomatis

N. gonorrhea H. influenzae M. catarrhalis Salmonella

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AUC area under the curve; reflects total drug exposure; a common measure of the bioavailability of a drug Minimum Inhibitory Concentration (MIC) The primary measure of antibiotic activity The lowest concentration of an antibiotic that completely inhibits the growth of a microorganism in vitro

Inhibits topoisomerase IV and interferes with separation of replicated chromosomal DNA and respective daughter cells during cell division INDICATIONS

CIPROFLOXACIN

Urinary and GI infections including Campylobacter, Shigella and Salmonella Susceptible STD (including penicillin-resistant) and non-gonococcal (chlamydial) urethritis. Severe infections due to susceptible G(-) infections including Pseudomonas aeruginosa Treatment of multi-drug resistant typhoid fever Post-exposure prophylxis for meningococcal disease and anthrax in adults LEVOFLOXACIN INDICATIONS

C.

PK/PD INDEX

Severe infections due to susceptible G(-) infections (less active than Ciprofloxacin for P. aeruginosa) Treatment for MDR TB in combination with other drug. Post-exposure prophylxis for meningococcal disease and anthrax in adults Treatment of community acquired pneumonia including S. pneumoniae, H. influenzae, Mycoplasma, Legionella, Chlamydia. Table 14. Quinolones spectrum of activity. First Gen Second Gen Drugs Nalidixic acid Ciprofloxacin Ofloxacin G(+) none Staphylococcus

G(-)

E.coli, Proteus, Shigella

Others

E.coli, Klebsiella, H. influenzae, Enterobacter, Salmonella, Proteus, Acinetobacter, Pseudomonas Legionella Mycoplasma Chlamydia

Third Gen Levofloxacin Gatifloxacin Moxifloxcin Streptococci Pneumococci Staphylococci Same as 2nd generation, less activity for Pseudomonas and Acinetobacter Legionella Mycoplasma Chlamydia

1. Composite of a pharmacokinetic parameter (such as AUC, peak level) + 2. A microbiological parameter (such as MIC) = Cmax/MIC, T>MIC, AUC/MIC II. PATTERNS OF ACTIVITY

ADVERSE EFFECTS nausea, vomiting, diarrhea 3-17% frequency delirium, headache, hallucinations, seizures 0.9-11% frequency Allergic and Skin reactions 0.4-2.8% frequency Arthropathy in children (reversible) 0-14% frequency Prolonged QT interval - rare PART 2: UNDERSTANDING AND OPTIMIZING THE ATTRIBUTES OF YOUR ANTIBIOTIC I. INTRODUCTION OBJECTIVES 1) Understand PK-PD principles in antimicrobial therapy 2) Apply these principles with regards to appropriate dose and frequency of different classes of antibiotics

A.

ANTIBIOTIC FACTORS FOR EFFECTIVE PATHOGEN ERADICATION These PK/PD properties can be maximized to ensure successful outcome especially in critically ill patients. 1. THE ANTIBIOTIC MUST BIND TO ITS TARGET SITES IN THE BACTERIUM must penetrate the outer membrane of the organism (penetration resistance); avoid being pumped out of the membrane (efflux pump resistance); and remain intact as a molecule (e.g. avoid hydrolysis by Blactamases) On reaching its target, the antibiotic can still be frustrated if the binding site has changed its molecular configuration and now no longer allows the drug to attach. 2. ADEQUATE CONCENTRATION AT THE BINDING SITE The drug must not only attach to its binding target but also must occupy an adequate number of binding sites, which is related to its concentration within the microorganism. How much of the drug is given depends on the class of antibiotics 3. THE ANTIBIOTIC SHOULD REMAIN AT THE BINDING SITE FOR A SUFFICIENT PERIOD OF TIME FOR THE METABOLIC PROCESSES OF THE BACTERIUM TO BE SUFFICIENTLY INHIBITED. The amount of time needed depends on the class of drugs In the last 2 decades, major classes of antibiotics have been identified based on their distinct PK/PD properties.

A. CONCENTRATION-DEPENDENT KILLING AGENTS The higher the concentration, the more extensive and faster is the degree of killing The ideal dosing regimen would maximize concentration Cmax/MIC, AUC/MIC important PK/PD Parameters aminoglycosides, fluoroquinolones POST-ANTIBIOTIC EFFECT Persistent suppression of bacterial growth even if the concentration of the drug is below the MIC Bacterial species specific and drug specific Proposed mechanisms: prolonged recovery of microorganisms, persistence of drug at the binding site, need of the organism to synthesize new enzymes for growth AMINOGLYCOSIDES

B. PHARMACOKINETIC PARAMETERS Cmax maximum concentration of drug in serum at Tmax

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2. Increasing dosing frequency Penicillin G given every 4 hrs instead of every 8 hrs Entails more man hours, more materials, more costs 3. Continuous Infusion Ensures steady-state concentration using the same total daily dosage Minimizes serum concentration fluctuation Cost-effective as well Some Issues Stability of agent used in 24 hrs majority of B-lactams are stable for 4-8 hrs at room temperature frequent infusion bag changes or delivering drug through a system Necessity of a dedicated IV line

In the meta-analysis of single versus conventional three-times daily aminoglycosides regimen Once daily dosing (ODD) was 25% less nephrotoxic and just as effective

clinically as 2-3x/day dosing. Did not affect ototoxicity ODD was not significantly more effective in febrile neutropenia and in children. Benefit of ODD increased with increasing proportion of Pseudomonas isolates ODD more convenient, less costly to administer, and omission of measurements of peak antibiotic concentration ODD of aminoglycosides should be routine Another study showed Note from the figure above that continuous infusion was able to maintain antibiotic concentrations above MIC, while intermittent did not. 4. Extended Infusion Time Instead of infusing over 30 min, infuse for 3 hours More practical Less stability issues May infuse other drugs in between antibiotic infusions III. EXERCISES What would be the optimal dosing of Penicillin G at 100,000u/kg/ day for a 20 kg boy. Is Penicillin G a concentration dependent or time dependent antibiotic? Time-dependent Half-life? Short Answer 50,000 u/kg/dose q 6 hrs or 500,000 units q 6 hrs, or 350,000 q 4hrs Note that continuous infusion is theoretically better but penicillin G is unstable at room temperature (destroyed within 30mins 1hr What would be the optimal dosing of amikacin at 15 mg/kg/day for a 6 kg infant? Is amikacin a concentration dependent or time dependent antibiotic? concentration dependent Half-life Long Answer 15 mg/kg once a day or 90 mg IV once a day END OF TRANSCRIPTION

Cmax:MIC 10 translates into improvements in the rate and extent of clinical response ODD is advocated to maximize efficacy and minimize potential drug accumulation and toxicity the standard of care for adult patients However, aminoglycosides ODD is prohibited in the following: Ascites Burns>20% body surface area Pregnancy Dialysis Patients treated for suspected or documented endocarditis some evidence indicates that ODD is efficacious Patients treated for staphylococcal and enterococcal infections when aminoglycoside therapy is used for synergy PRACTICAL IMPLICATIONS Higher concentrations result in increased killing and faster killing of bacteria Post-antibiotic effect accounts for killing of bacteria when concentrations are low Appropriate dosing is a high dose, once or twice daily B. TIME-DEPENDENT KILLING AGENTS Kills bacteria only when the concentration at the site is higher than the MIC Maximal effect at 4x the MIC, at higher doses, additional killing is only modest Extent of killing is dependent on time of exposure (T>MIC) Penicillins, Cephalosporins, B-lactams, Erythromucin, Linezolid

T> MIC Refer to figure in PK/PD index The cumulative % of time over a 24 hr period that the drug concentration exceeds the MIC For example, if concentration of the drug is above the MIC for 12 hrs, (12/24)x100% = 50% T>MIC PRACTICAL WAYS TO MAXIMIZE T>MIC 1. Improved pharmacokinetic profile within class (Half-life) - Ceftriaxone 5.8-8.7 hrs - Ampicillin 1 hr VS - Ertapenem 4hrs - Ceftazidime 1.6 hr may be given q 24 hrs

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