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Antibiotics 101

Antibiotics 101. Steve Spencer, MD Pediatric Infectious Disease National Capital Consortium. Objectives. Uses of antibiotics Classes Specific antibiotics Coverage Toxicity Special Points Clinical Cases. Uses of antibiotics. Antibiotics . 3 uses Empiric therapy

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Antibiotics 101

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  1. Antibiotics 101 Steve Spencer, MD Pediatric Infectious Disease National Capital Consortium

  2. Objectives • Uses of antibiotics • Classes • Specific antibiotics • Coverage • Toxicity • Special Points • Clinical Cases

  3. Uses of antibiotics

  4. Antibiotics • 3 uses • Empiric therapy • Antibiotic choice based on clinical and laboratory data EXCEPT culture and sensitivity information • Specific therapy • Antibiotic choice based on specific culture/sensitivity information of organism causing infection • Prophylaxis • Antibiotic choice based on preventing anticipated infection

  5. Antibiotics- Empiric therapy • 3 Step process • Identify the clinical entity • Know which organisms can cause and typically cause the entity • Select an antibiotic that covers those organisms

  6. Empiric therapy- Example • Clinical entity: • UTI • Potential organisms: • E. coli, Klebsiella, Pseudomonas • Antibiotic choice: • Ampicillin, trimethoprim-sulfamethoxazide, Levofloxacin

  7. Clinical Question • A 4 mo female presents with 1-day history of fever to 103, irritability alternating with increased sleepiness and decreased PO intake. PE reveals a febrile, irritable infant with a full fontanelle, who stiffens and cries when attempts are made to move her head. Labs are significant for WBC of 26 with diff of 80%PMNs, 8%bands, 8% monos and 4% eos. CSF parameters are as follows: WBC-560 with 95% PMNs, glu-10, protein-120. In addition to vancomycin, which of the following antibiotics is most appropriate for the treatment of this infant?

  8. Clinical Question • A: Cefotaxime • B: Cefuroxime • C: Cephalexin • D: Clarithromycin • E: Clindamycin

  9. Antibiotics- Specific therapy • Antibiotics adjusted based on culture and sensitivity results • Usually available in 24-72 hours • Influencing factors: • Most effective • Least side effects • Narrow spectrum • Cost • Dosing schedule • Compliance issues

  10. Antibiotics- Prophylaxis • Reduce likelihood of acquiring disease in patients with increased risk • Examples: • Vesicoureteral reflux • Heart disease • Dog bite wounds

  11. Antibiotic classes

  12. Classes • Based on mechanism of action • Usually have similar properties within classes • Bacteriocidal vs Bacteriostatic • Bacteriocidal- • cause cell death • Bacteriostatic- • cause slowing of cell growth

  13. Cell wall Ribosome Metabolic pathways DNA topoisomerase Mechanism of action

  14. Beta-lactam antibiotics

  15. Beta-lactam antibiotics (Penicillin family antibiotics) • Basic structure • Additions/variations here contribute to different properties of individual antibiotics • Includes: • Penicillins • Monobactams • Cephalosporins • Carbapenems

  16. Beta-lactam antibiotics Cell wall Ribosome • Mechanism of action? • Cell wall inhibition • Competitively inhibits transpeptidase (PBP) • Enzyme that catalyzes cross-linkage of peptidoglycan • Static vs Cidal? • Bacteriocidal Metabolic pathways DNA topoisomerase

  17. Beta-lactam antibiotics • Resistance: • Alterations of porin • Gram-negative bacteria • Beta-lactamase production • Staph aureus, H. influenzae • Alteration of transpeptidase (PBP) structure • MRSA • Strep pneumo • Adverse effects: • Allergic reactions • Anaphylactic shock • Rash • GI symptoms- diarrhea

  18. Beta-lactam antibiotics • PENICILLINS • Monobactams • Cephalosporins • Carbapenems

  19. Beta-lactam antibiotics- Penicillins (PCN) • 3 Types of PCN • Penicillin G • Extended-spectrum PCNs • Aminopenicillins • Amoxicillin, Ampicillin • Carboxypenicillins • Ticarcillin • Ureidopenicillins • Piperacillin • Anti-Staphylococcus PCNs (Penicillinase-resistant PCN) • Target Staph aureus

  20. Penicillins-Penicillin G • PCN G • Original PCN • IM/IV • Usually given in crystalline form to increase half-life • Sensitive to B-lactamases • PCN VK • PO form • Acid stable

  21. Penicillins-Penicillin G • Spectrum • Group A Streptococcus • Group B Streptococcus • Streptococcus pneumoniae • Neisseria meningitidis • Pasturella multocida • Anaerobes • Except B. fragilis • Listeria

  22. Penicillins-Extended spectrum PCNs • Improved gram-negative coverage • Better penetration and binding to PBPs • Some get Pseudomonal coverage • Can be combined with beta-lactamase inhibitors • Sulbactam, tazobactam, clavulanate acid

  23. Penicillins-Extended spectrum PCNs • Aminopenicillins: • Amoxicillin/Ampicillin- PO/IV • Amoxicillin better absorbed- metabolized to Amp • Amoxicillin-clavulanate= Augmentin • Ampicillin-sulbactam= Unasyn • Spectrum: • PCN organisms • Enterococcus • E. coli • Proteus • Klebsiella • Salmonella, Shigella • H. influenza • Moraxella

  24. Penicillins-Extended spectrum PCNs • Carboxypenicillins • Ticarcillin • Ticarcillin+clavulanate= Timentin • Spectrum: • Previous + Enterobacter and Pseudomonas • Anaerobes- including B. fragilis • Ureidopenicillins • Piperacillin • Piperacillin+tazobactam= Zosyn • Similar to above

  25. Penicillins-Anti-staphylococcal PCNs • Anti-staph aka Penicillinase-resistant PCN • Not active against all penicillinase-producing organisms; poor GN activity • IV- Nafcillin, Oxacillin • Methicillin- no longer available in US due to interstitial nephritis; still used in nomenclature • PO- Cloxacillin, Dicloxacillin • Drug of choice for sensitive Staph aureus

  26. Beta-lactam antibiotics • Penicillins • MONOBACTAMS • Cephalosporins • Carbapenems

  27. Penicillins-Extended spectrum PCNs • Monobactams • Aztreonam • Single beta-lactam ring with side groups attached to the ring • Only binds transpeptidases/PBPs of gram-negative aerobes • Including Pseudomonas • Little cross-reactivity with other beta-lactams

  28. Beta-lactam antibiotics • Penicillins • Monobactams • CEPHALOSPORINS • Carbapenems

  29. Beta-lactam antibiotics-Cephalosporins (Ceph) • Similar to PCNs with some advantages • Additional bonds make the beta-lactam ring more stable • More resistant to beta-lactamases • Susceptibility to cephalosporinases • New side chain allows for more manipulations • New drugs, new spectrums of activity • Similar adverse events • Anaphylaxis • Rash • ~1-10% of patients with PCN allergies will have Ceph reactions

  30. Beta-lactam antibiotics-Cephalosporins (Ceph) • Generalizations: • Generations are somewhat helpful • Gain gram-negative and lose gram-positive with successive generations • 4th generation-Cefepime- is an exception • Cover all PCN sensitive organisms • Except PasturellaandListeria • None cover Enterococcus or MRSA • New generation of cephs coming that kill MRSA

  31. Beta-lactam antibiotics-Cephalosporins (Ceph) • First generation • IV- Cefazolin- Ancef • PO- Cephalexin- Keflex • All Cephalosporins with “ph” are first generation • Good gram positive coverage • Staph/Strep alternatives • Surgical prophylaxis • Gram negative coverage: • PEcK-Proteus, E. coli, Klebsiella

  32. Beta-lactam antibiotics-Cephalosporins (Ceph) • Second generation • IV- Cefuroxime • PO- Cefuroxime axetil- Ceftin • Extended gram-negative coverage • HEN PEcK- H. influenzae, Enterobacter, Neisseria, Proteus, E. coli, Klebsiella • Cephamycins included here: • Cefotetan and Cefoxitin • Anaerobic coverage

  33. Beta-lactam antibiotics-Cephalosporins (Ceph) • Third generation • IV-Ceftriaxone-Rocephin, Cefotaxime-Claforan, Ceftazidime- Fortaz • PO- Cefdinir- Omnicef; Cefpodoxime- Vantin • Improved gram negative coverage • Ceftazidime covers Psuedomonas • PseudoHEN PEcK • Improved CNS penetration • Ceftriaxone with long-half life • Fourth generation • Cefepime • extended gram negative including Pseudomonas • Gram positive coverage comparable with first/second generations • No anaerobic coverage

  34. Beta-lactam antibiotics • Penicillins • Monobactams • Cephalosporins • CARBAPENEMS

  35. Beta-lactam antibiotics-Carbapenems • Broad spectrum • Gram postives, gram negatives, anaerobes • DOES get some Pseudomonas, Enterococcus • DOESN’T get MRSA, some Pseudomonas, bacteria without cell wall (Mycoplasma) • Stable to beta-lactamases • Some organisms do produce carbapenamases (metalloproteases) • Imipenem-cilastin • Combined with cilastin to prevent renal breakdown • Lowers seizure threshold • Meropenem • Stable alone • Less potential for seizures • Ertapenem • Once a day • No Pseudomonas

  36. Clinical Question • A 3 yo boy who has myelomeningocele and a history of recurrent UTI presents with a 1-day history of temperature to 102 and cloudy urine. Laboratory test results include a peripheral WBC of 15 with 60% PMNs, 30% lymphs, and 10% monos. Urine obtained by catheterization is cloudy, with a strong odor, and is positive for nitrites, LE and blood. Microscopic analysis shows TNTC WBCs, and 50-100 RBCs with GNR seen on gram stain. One day later, the urine culture is positive for Pseudomonas aeruginosa. • Of the following, the most appropriate antibiotic for treatment of this patient is:

  37. Clinical Question • A: Ampicillin • B: Ceftazidime • C: Cefuroxime • D: Trimethoprim-sulfamethoxazole • E: Vancomycin

  38. Aminoglycosides

  39. Aminoglycosides Cell wall Ribosome Metabolic pathways • -Mechanism of action? • Inhibition of 30s ribosomal subunit • -Bacteriostatic vs Bacteriocidal? • -Bacteriocidal- has a second mechanism of action at the • cell wall. DNA topoisomerase

  40. Aminoglycosides • Spectrum • Gram-negative organisms • Pseudomonas • Many S. aureus, streptococci • Usually used in combination with cell-wall agents • endocarditis • Examples: • Gentamicin • Tobramycin • Amikacin-lowest incidence of resistance • alteration of drug structure to decrease modifying enzyme affinity • Dosing- In most instances, once daily dosing is superior • Exceptions- endocarditis, line infections

  41. Aminoglycosides • Resistance: • Production of aminoglycoside-modifying enzymes (aminoglycosidases) • Usually on transposons in plasmids with other antibiotic resistance determinants • Some Pseudomonalspp have decreased uptake • Adverse effects: • nephrotoxicity, ototoxicity, weak neuromuscular blockade. Toxicity associated with troughs • maintain within narrow therapeutic range • monitor troughs (and/or peak levels in certain instances)

  42. Macrolides

  43. Macrolides Cell wall Ribosome Metabolic pathways • Mechanism of Action? • Inhibit 50s ribosomal subunit • Bacteriostatic vs Bacteriocidal? • Bacteriostatic • Cidal to rickettsiae DNA topoisomerase

  44. Macrolides • Antibiotics made of lactone rings • Spectrum • Most streptococci- increasing resistance rates recently • Some staph aureus • M. cat, H. flu, some GC • Atypical organisms • Mycoplasma, Chlamydia, Legionella, Bordetella, Yersenia, Campylobacter, Tularemia • Examples: • Erythromycin • Clarithromycin • Azithromycin (an azolide, does not have same cytochrome P450 worries) • New related class- Ketolides • modifications of lactone rings • Telithromycin • Good activity against Macrolide-resistant organisms

  45. Macrolides • Resistance: • Two main types: • Methylation of the 50s ribosomal subunit (erm genes) • This type gives Clindamycin resistance also • Efflux pump (mef genes) • Antibiotics still effective if high enough levels • Preserve Clindamycin susceptibility • Adverse effects: • GI: diarrhea, emesis, abdominal pain • Pyloric stenosis in infants • Less common- rash, headahe, anaphylaxis, ototoxicity (reversible), hemolytic anemia

  46. Vancomycin

  47. Vancomycin Cell wall Ribosome Metabolic pathways • Mechanism of Action? • Inhibit cell wall formation • Secondary- inhibit ribosome • Bacteriostatic vs Bacteriocidal? • Bacteriocidal technically, but a slow killer DNA topoisomerase

  48. Vancomycin • Glycopeptide antibiotic • Spectrum: • Gram-positive organisms • Including : • MRSA • Beta-lactam resistant CoNS • Resistant S. pneumoniae • Drug of choice for PCN allergic pts with serious GP infection • Oral treatment used for C. dificile

  49. Vancomycin • Resistance: • Complicated; multiple gene interactions • Production of abnormal peptidoglycan precursors • reduced affinity for vancomycin • Other complicated mechanisms for VRE and S. aureusvancomycin-intermediate/-resistant isolates • Adverse effects: • Ototoxicity- rare • Nephrotoxicity- rare • “Red man syndrome” • Histamine reaction- NOT an allergy • Erythemamultiforme-like reaction • GI symptoms • Monitoring- WRAMC standard is a trough. • Peaks in selected patients

  50. Clinical Question • A 7 yo female presents to your clinic with a 2-3 day history of a nonproductive cough, malaise, and temperature to 101. On PE, you note that the girl does not appear ill and are surprised to hear widespread crackles in the lungs bilaterally. CXR demonstrates bilateral diffuse infiltrates. • Of the following, the most appropriate antimicrobial agent to treat this girl’s infection is:

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