Antibiotics Things to keep in your lab coat. ● The Sanford Guide to Antimicrobial Therapy ● Johns Hopkins Abx Guide (not free any more) ● Palm ○ iSilo program ○ Epocrates Tips for the boards ● Study hard and efficiently. Don’t waste time on a resource that isn’t making sense. ● Get the landscape first then the landmarks. ● Don’t be afraid to study outside of the review books. ● Think like a question writer. Anticipate questions for each topic. ● Forget about learning everything because the gaps in your knowledge will be random. Gram-positives Gram-negatives Imipenem Meropene m Amoxicillin Anti-staph PCN’s (nafcillin, methicillin, oxacillins) Ampicillin Anti-pseudomonal PCN’s (pipercillin, ticarcillin, carbenicillin) Macrolides Penicillin G/V Clindamycin Linezolid Fluoroquinolines Vancomyci n Rifampin Sulfonamides Aztreona m Aminoglycosides Tetracyclines 1st Generation Cephalosporin s 3rd Generation 2nd Generation How to approach the daunting task of learning antibiotics Create a general rule and know the exception to the rule. Rule: All cell-wall inhibitors are beta-lactams, except vancomycin. ● Beta-lactam ABX ○ Penicillins ○ Cephalosporins ○ Aztreonam ○ Carbapenems ● Exception ○ Vancomycin Beta-lactam structure Gram-positive vs. Gram-negative Mechanism of Action 1. All beta-lactams bind penicillin-binding proteins (PBP’s) 2. All beta-lactams block transpeptidase cross-linking of cell wall 3. Activate autolytic enzymes, causing osmotic damage (bactericidal) Beta-lactams: 1st mechanism of resistance Beta-lactamase production (i.e. S. aureus) We can get around this mode of resistance by making beta-lactamase resistant penicillins (i.e. nafcillin) Beta-lactams: 2nd mechanism of resistance Change the structure of PBP’s (i.e. Methicillin-Resistant S. Aureus) Once bugs have changed their PBP’s, we only have one drug that will work, vancomycin. Beta-lactams: 3rd mechanism of resistance Efflux pump or change in porin structure: Relevant for gram-negative bacteria Summary of resistances to betalactamases 1st beta-lactamase production (S. aureus) 2nd change in PBP (MRSA) 3rd efflux pump or change in porin structure (gram-negatives i.e. pseudomonas) 1st Generation ● Drugs ○ Penicillin G and V ● Clinical use ○ Narrow spectrum (mainly gram-positives) ● Sensitive to beta-lactamases ○ Means: on an exam, penicillin G or V is never the answer for treating Staph ● Exam questions: ○ DOC for syphillis (benzathine penicillin), ○ DOC in strep infections, especially to prevent rheumatic fever ○ DOC for susceptible pneumococci 2nd Generation ● Drugs ○ Nafcillin, Methicillin, Oxacillin, Cloxacillin, Diclaxicillin ● To overcome the beta-lactamase resistance, these drugs were developed but they became so narrow spectrum that they only clinically are used for Staph. ● These drugs created the superbug MRSA ○ Beta-lactamase ○ Altered PBP’s 3rd Generation ● Drugs ○ Aminopenicillins ■ Ampicillin ■ Amoxicillin ● Clinical use ○ Broad spectrum (gram positive and gram negatives, but NOT beta-lactamase resistant) ■ Famous for treating: ■ H. flu and Listeria (ampicillin) ■ Lyme Disease (amox) DOC in peds and pregnancy ■ Enterococci ○ Drug companies made body guards, clavulanic acid and sulbactam, to protect the aminopenicillins from beta-lactamases. 4th Generation ● Drugs ○ Anti-pseudomonal penicillins ■ Ticarcillin ■ Piperacillin ■ Carbenicillin ● Clinical use ■ Pseudomonas ■ Synergistic effect when combined with aminoglycosides. ■ Parenteral penicillins usually combined with beta-lactamase inhibitors Pharmacokinetics of Penicillins ● Rule: All penicillins are water soluble, except nafcillin. ● Water soluble substances: ○ Are excreted by the kidneys. ■ Means adjustments in renal failure and are potentially renal toxic ○ Do not cross the blood brain barrier ■ Means no good for meningitis ● Lipid soluble substances: ○ Are metabolized in the liver ■ Means many p450 interactions ○ Cross the blood brain barrier ■ Means could potentially be used for meningitis Toxicity ● Rule: Penicillins cause allergies ○ Come from fungal organisms ■ Means already immunogenic ○ Contain sulfur to enhance solubility ■ Means bad for allergies ○ Can cause ANY hypersensitivity reaction (Type I-IV) ■ Methicillin famous for interstitial nephritis (type III) ■ Hapten mediated hemolysis ■ About 5-10% cross-allergenicity with cephalosporins Toxicity ● Jarisch-Herxheimer reaction in Rx of syphilis ○ Fever, chills, headache, myalgias, and exacerbation of syphilitic cutaneous lesions ● Ampicillin causes a famous maculopapular rash when given to patients with infectious mono (EBV). Cephalosporins ● Mechanism of action and resistance: ○ same as penicillins 1st Generation Cephalosporins ● Drugs ○ Any drug with “ph” in name b/c from Europe ■ Cephalexin, cephradine ■ Except cefazolin (famous for surgical prophylaxis b/c of long half-life) ● Clinical use ○ Gram positives ■ And a few gram negatives PEcK (Proteus, E. coli, Klebsiella) ● Pharmacokinetics ○ Do not enter CNS 2nd Generation Cephalosporins ● Drugs ○ Cefoxitin, cefaclor, cefuroxime ● Clinical use ○ Gram negatives: HEN PEcKS (H. flu, Enterobacter, Neisseria, Proteus, E. coli, Klebsiella, Serratia) ● Pharmacokinetics ○ Do not enter CNS, except cefuroxime 3rd Generation Cephalosporins ● Drugs ○ Ceftriaxone, cefotaxime, ceftazidime ○ notice the “t’s” ● Clinical use ○ 1st generation + 2nd generation = 3rd generation (gram positive and negative) +anaerobes ● Pharmacokinetics ○ Ceftriaxone is lipid soluble ■ Means good entry into CNS ■ Means metabolized and excreted into bowel ■ Can cause sludge in gallbladder ● Boards: ○ Ceftazidime for pseudomonaz ○ Ceftriaxone for gonorrhea and meningitis 4th Generation Cephalosporins ● Drugs ○ Cefepime ○ Cefpirome ● Clinical use ○ 3rd Generation + more beta-lactamase resistance Toxicity ● Same as penicillins ● Disuliram-like reaction w/ ethanol ○ In cephalosporins with a methylthiotetrazole group, i.e. cefamandole, cefoperazone, cefotetan ■ “azole” portion gives us the disulfiram-like reaction ■ Metronidazole Aztreonam ● Mechanism: ○ Monobactam resistant to beta-lactamases ○ Inhibits cell wall synthesis (same as penicillins) ○ Synergistic with aminoglycosides ● Clinical use ○ Gram negative rods only (pseudomonas) ● Toxicity ○ No cross-allergenicity w/ penicillins Imipenem/cilastatin, Meropenem ● Mechanism ○ Carbapenems resistant to beta-lactamases ○ Inhibits cell wall synthesis (same as penicillins) ○ Cilastatin inhibits renal dihydropeptidase I which decreased inactivation of imipenem in kidney. ● Clinical use ○ “Decerebrate Antibiotics” ■ Don’t need to think about coverage, can work on almost anything ● Toxicity ○ Imipenem famous for CNS toxicity (seizures) ○ Meropenem has reduced risk of seizures Vancomycin ● Mechanism ○ Inhibits cell wall mucopeptide formation by binding ○ D-ala D-ala portion of cell wall precursors (USMLE TQ) ■ Resistance occurs when changed to D-ala D-lac ● Clinical use ○ Gram positive multidrug-resistant organisms ■ MRSA (IV) ■ C. difficile (PO) ● Toxicity ○ Nephro and ototoxic ○ “Red man syndrome” with rapid infusion ■ Can prevent w/ antihistamine pretreatment Gram-positives Anti-staph PCN’s (nafcillin, methicillin, oxacillins) Gram-negatives Imipenem Meropene m Amoxicillin Ampicillin Anti-pseudomonal PCN’s (pipercillin, ticarcillin, carbenicillin) Penicillin G/V 50s ribosome Vancomyci n Nucleus Aztreona m 30s ribosome 1st Generation Cephalosporin s 3rd Generation 2nd Generation Protein Synthesis Inhibitors Rule: All protein synthesis inhibitors are bacteriostatic, except for the aminoglycosides. Tetracyclines ● Drugs ○ Doxycycline ○ Minocycline ○ Demeclocycline ○ Tetracycline ● Mechanism ○ Reversibly bind to the 30S ribosome and inhibit binding of aminoacyl-t-RNA to the acceptor site. Tetracyclines ● Clinical use ○ Very broad spectrum ○ Important use for spirochetes and intracellular bugs ■ Rickettsial Infections ■ Chlamydia ● Toxicity ○ Chelators of divalent ions ■ Means they deposit in bones and teeth ■ Means contraindicated in pregnancy and in kids who are still growing ■ Means can’t take with antacids or iron. ○ GI distress ○ Fanconi’s syndrome ○ Photosensitivity ● Boards: ○ Doxycycline is lipid soluble; means good STD’s and prostatitis ○ Minocycline is very water soluble and enters all secretions, especially saliva; means useful for meningococcus prophylaxis ○ Demeclocycline inhibits the release of ADH; means can be used for SIADH Aminoglycosides ● Drugs ○ Gentamycin, neomycin, amikacin, tobramycin, streptomycin ● Mechanism ○ Taken up by an oxygen dependent pump and bind to the 30S ribosomal unit and Induce the binding of the “wrong” t-RNA-AA complex, resulting in the synthesis of false proteins. (Bactericidal) Aminoglycosides ● Clinical use ○ Gram negative aerobes only! (pseudomonas) ○ Synergistic w/ beta-lactams ○ Neomycin for bowel surgery ○ Tobramycin for Pseudomonas ● Toxicity ○ Amino (NH3) + glycoside (OH) makes extremely polar ■ Means membrane penetration in a bacteria is dependent on a special oxygen pump and only covers gram negative aerobes ■ Means renally excreted and renal toxic ■ Means can be trapped in inner ear and is ototoxic ○ Neuromuscular blockade Macrolides ● Drugs: ○ Erythromycin ○ Azithromycin ○ Clarithromycin ● Mechanism ○ Inhibit protein synthesis by blocking translocation, bind to 50S ribosomal subunit (resistance is through methylation at binding site) Macrolides ● Clinical use ○ Same broad coverage as tetracyclines ○ URI’s and atypical pneumonias (Mycoplasma, Legionella, Chlamydia) ○ Neisseria ○ Alternative for penicillin allergic patients ● Toxicities ○ Stimulate motilin receptor (erythromycin) causing GI upset ○ Lipid soluble, except azithromycin ■ Means P450 interactions (erythromycin is a famous inhibitor) and liver problems (acute cholestatic hepatitis) Clindamycin ● Mechanism ○ Blocks peptide bond formation at 50S ribosomal subunit (bacteriostatic) ● Clinical use ○ Gram-positives and anaerobes ■ Means can easily cause C. diff colitis ○ Good penetration into bones ■ Means can be used for S. aureus osteomyelitis Linezolid ● Mechanism ○ Linezolid binds on the 23S portion of the 50S subunit close to the peptidyl transferase and chloramphenicol binding sites. ● Clinical ○ Famous for treating gram-positive drug resistant bugs (MRSA, and multidrug resistant pneumococcus) ● Toxicity ○ Usually well tolerated ○ Thrombocytopenia ○ MAOI (avoid tyramine containing food) Quinupristin/Dalfopristin ● Mechanism ○ Protein synthesis inhibitors that bind the 50S ribosomal subunit ● Clinical use ○ VRE ● Toxicity ○ P-450 inhibitor Inhibitors of DNA synthesis Fluoroquinolones Rifampin Sulfonamides Fluoroquinolones ● Drugs ○ Ciprofloxacin ○ Gatifloxacin ○ Levofloxacin ○ Moxifloxacin ○ Ofloxacin ● Mechanism ○ Inhibits DNA gyrase (topoisomerase II) (Bactericidal) Fluoroquinolones ● Clinical use ○ Gram-negative rods of UTI and diarrhea ○ Were 1st oral treatment of gram-negative sepsis ■ Means were overused, leading to resistance ○ Distributes into all tissues and fluids (including bones) ■ Means can inhibit cartilage and tendon damage leading to tendonitis and tendon rupture in adults ■ Means can be used for Salmonella osteomyelitis ■ Means contraindicated in pregnancy and in children ○ Respiratory fluoroquinolones (levofloxacin) for drug resistant pneumococcus ○ Anthrax (ciprofloxacin) ● Toxicity ○ QT prolongation and arrhythmias ○ Hypo/hyperglycemia ○ Achilles tendon rupture or tendinitis has occurred rarely Rifampin ● Mechanism ○ Inhibits DNA-dependent RNA polymerase ● Clinical use ○ TB (in combo and in prophylaxis) ○ Famous for prophylaxis of meningococcus and H. flu ● Toxicity ○ Hepatotoxic ○ Revs up P-450 ○ R’s: ■ RNA polymerase inhibitor ■ Revs up P-450 ■ Red/orange body fluids Sulfonamides and Trimethoprim Sulfonamides ● Mechanism ○ Inhibits bacterial dihydropteroate synthase by competing for binding sites with paminobenzoic acid (PABA), a precursor required for bacterial synthesis of folic acid. ○ Trimethoprim binds tightly to bacterial dihydrofolate reductase. Synergistic with sulfonamides. Sulfonamides ● Clinical use ○ Resistance to sulfonamides is common ○ PCP prophylaxis (PO) and treatment (IV) ■ Trimethoprim–Sulfamethoxazole, (TMP-SMX) ■ If sulfa allergy use pentamidine (antiprotozoal agent) ○ Toxoplasmosis (Pyrimethamine + Sulfadiazine) ● Toxicity ○ Allergies (sulfa allergies, hemolytic anemia, SJS) ○ Carried by albumin ■ Means can cause kernicterus ○ Crystalluria ○ Folic acid can be given to avoid some toxicities Metronidazole ● Mechanism ○ Toxic metabolites ■ Means causes GI disturbance, glossitis (metallic taste in mouth), urethritis ● Clinical use ○ Anaerobes ○ “G.E.T. on the Metro” (Giardia, Entamoeba, Trichomonas) ○ C. diff colitis (PO) ● Toxicity ○ Metronidazole ■ Disulfiram-like reaction w/ ethanol Mechanisms of Resistance How to approach antibiotic coverage Rule: Every bacteria is gram negative, except for the gram-positives and oddballs. Exceptions to everything is gramnegative ● Gram-positives ○ Staph/Strep ○ Listeria ○ Bacillus ○ Clostridium ○ Corynebacterium ● Oddballs ○ Mycoplasma (no cell wall) ○ Ureaplasma (no cell wall) ○ Legionella (silver stain) ○ Chlamydia (obligate intracellular) ○ Rickettsia (obligate intracellular) ○ Mycobacterium (acid-fast) ○ Treponema (spirochete) ○ Borrelia (spirochete) Gram-positives Gram-negatives Cell Wall 50s ribosome Nucleus 30s ribosome Gram-positives Gram-negatives Cell Wall 50s ribosome Vancomyci n Nucleus 30s ribosome Aztreona m Gram-positives Anti-staph PCN’s (nafcillin, methicillin, oxacillins) Gram-negatives Cell Wall Anti-pseudomonal PCN’s (pipercillin, ticarcillin, carbenicillin) Penicillin G/V 50s ribosome Vancomyci n Nucleus 30s ribosome Aztreona m Gram-positives Anti-staph PCN’s (nafcillin, methicillin, oxacillins) Gram-negatives Cell Wall Anti-pseudomonal PCN’s (pipercillin, ticarcillin, carbenicillin) Penicillin G/V 50s ribosome Vancomyci n Nucleus Aztreona m 30s ribosome 1st Generation Cephalosporin s 3rd Generation 2nd Generation Gram-positives Anti-staph PCN’s (nafcillin, methicillin, oxacillins) Gram-negatives Amoxicillin Ampicillin Anti-pseudomonal PCN’s (pipercillin, ticarcillin, carbenicillin) Penicillin G/V 50s ribosome Vancomyci n Nucleus Aztreona m 30s ribosome 1st Generation Cephalosporin s 3rd Generation 2nd Generation Gram-positives Anti-staph PCN’s (nafcillin, methicillin, oxacillins) Gram-negatives Imipenem Meropene m Amoxicillin Ampicillin Anti-pseudomonal PCN’s (pipercillin, ticarcillin, carbenicillin) Penicillin G/V 50s ribosome Vancomyci n Nucleus Aztreona m 30s ribosome 1st Generation Cephalosporin s 3rd Generation 2nd Generation Gram-positives Gram-negatives Imipenem Meropene m Amoxicillin Anti-staph PCN’s (nafcillin, methicillin, oxacillins) Ampicillin Anti-pseudomonal PCN’s (pipercillin, ticarcillin, carbenicillin) Macrolides Penicillin G/V Clindamycin Linezolid Vancomyci n Nucleus Aztreona m Aminoglycosides Tetracyclines 1st Generation Cephalosporin s 3rd Generation 2nd Generation Gram-positives Gram-negatives Imipenem Meropene m Amoxicillin Anti-staph PCN’s (nafcillin, methicillin, oxacillins) Ampicillin Anti-pseudomonal PCN’s (pipercillin, ticarcillin, carbenicillin) Macrolides Penicillin G/V Clindamycin Linezolid Fluoroquinolines Vancomyci n Rifampin Sulfonamides Aztreona m Aminoglycosides Tetracyclines 1st Generation Cephalosporin s 3rd Generation 2nd Generation My rules for antibiotics questions. ● Is the bug gram-positive or gram-negative? ○ Use the chart we just made for what antibiotic to use ● Look for contraindications to using your antibiotic. Is the patient too young or too pregnant? ○ Don’t use tetracyclines, aminoglycosides, fluoroquinolones, sulfonamides. ● Is the bug intracellular ○ Use a tetracycline or macrolide Antibacterial Drugs in Pregnancy Antibacterial Drug Toxicity in Pregnancy Recommendation Aminoglycosides Possible 8th nerve toxicity Cautiona Chloramphenicol Gray syndrome in newborn Caution at term Fluoroquinolones Arthropathy in immature animals Caution Clarithromycin Teratogenicity in animals Contraindicated Ertapenem Decreased weight in animals Caution Erythromycin estolate Cholestatic hepatitis Contraindicated Imipenem/cilastatin Toxicity in some pregnant animals Caution Linezolid Embryonic and fetal toxicity in rats Caution Meropenem Unknown Caution Metronidazole None known, but carcinogenic in rats Caution Nitrofurantoin Hemolytic anemia in newborns Caution; contraindicated at term Quinupristin/dalfop ristin Unknown Caution Sulfonamides Hemolysis in newborn with G6PDb deficiency; kernicterus in newborn Caution; contraindicated at term Tetracyclines Tooth discoloration, inhibition of bone growth in fetus; hepatotoxicity Contraindicated Vancomycin Unknown Caution GBS, E. coli, H. flu, Listeria, Meningococcus, Pneumococcus Newbor n Adul t Practice Question A 16-year-old high school cheerleader presents with low grade fever, pleuritic pain and a nonproductive cough. A sample tube of her blood was placed in ice, and "grains of sand" appeared in the glass portion of the tube. Therapy should include which of the following? A. Ampicillin B. Erythromycin C. Oxygen and external cooling D. Penicillin G E. Ribavirin Practice Question A 58-year-old alcoholic man with multiple dental caries develops a pulmonary abscess and is treated with antibiotics. Several days later, he develops nausea, vomiting, abdominal pain, and voluminous green diarrhea. Which of the following antibiotics is most likely responsible for this patient's symptoms? A. Chloramphenicol B. Clindamycin C. Gentamicin D. Metronidazole E. Vancomycin Practice Question Which of the following organisms is most likely to be implicated as a cause of urethritis that persists after antibiotic therapy for gonorrhea? A. Actinomyces B. Chlamydia C. Mycobacteria D. Nocardia E. Rickettsia Practice Question A 33-year-old woman presents with fever, vomiting, severe irritative voiding symptoms, and pronounced costovertebral angle tenderness. Laboratory evaluation reveals leukocytosis with a left shift; blood cultures indicate bacteremia. Urinalysis shows pyuria, mild hematuria, and gram-negative bacteria. Which of the following drugs would best treat this patient's infection? A. Ampicillin and gentamicin B. Erythromycin C. Gentamicin and vancomycin D. Tetracycline Practice Question A 35-year-old male undergoes an appendectomy. Several days later, an abscess has formed at the surgical site. It does not improve with administration of a cephalosporin, but does respond to nafcillin. The infecting organism most likely produced an enzyme that would hydrolyze which bond in the above molecule? A. A B. B C. C D. D