1. Quinolones
    • Ciprofloxacin
    • Ofloxacin
    • Norfloxacin
    • Moxifloxacin
    • Levofloxacin: .
    • Gatifloxacin
    • Trovafloxacin
  2. Quinolones MoA, MoR,
    • Mechanism of Action: .
    • Inhibit DNA gyrase and topoisomerase IV
    • Are bactericidal
    • In general DNA gyrase is the primary target for quinolones with Gram negative activity, while Topoisomerase IV is the target for agents with better Gram positive activity
    • Mechanisms of Resistance:
    • Alteration in the binding to DNA gyrase and topoIV on a chromosomal basis
    • A 2-step mechanism of resistance for organisms like pneumococcus
    • First mutation sets the stage for selection of a second mutation in the same ORGANISM and increased bacterial resistance
    • (also altered membrane permeability)
  3. Quinolones: Antibacterial Activity
    • Most have excellent activity against basically all Gram negative aerobic bacteria including Pseudomonas
    • Original agents (first generation quinolones) are less active against Gram positive bacteria and anaerobic bacteria. Exception for anthrax.
    • Some of these agents have activity against intracellular organisms (Chlamycia and Legionella) in vitro. These agents also have some anti-mycobacterial activity(mycoplasma and pneumococcus, moraxella, etc. – 2nd generation)
  4. First Generation Quinolones
    • Ciprofloxacin: Highly active against Gram negatives, including Pseudomonas. Active against B. anthracis!
    • Excellent Legionella coverage, nosocomial Gram negative rods may have high rates of resistance
  5. Second Generation Quinolones
    • Also known as respiratory fluoroquinolones: .
    • Levofloxacin: better Gram positive, good Gram negative activity
    • Levotory form of ofloxacin.
    • Good activity against agents of atypical pneumonia such as Mycoplasma Chlamycia, and Legionella.
    • Most strain of penicillin-resistant pneumococcus. However, resistance is increasing.
    • Clearance is predominantly renal
    • Gatifloxacin: hypo and hyperglycemia are important. Recently given a contraindication in diabetics by FDA! No longer marketed in the US
    • Moxifloxacin: good Gram positive activity. Not as good for enteric Gram negatives; Hepatic Clearance
  6. Second Generation Quinolones – Toxicity
    • All agents share similar toxicity and a reported increased incident of prolonged QT interval: .
  7. Quinolones Adverse reactions
    • Cartilage damage seen in the initial toxicology studies in dogs
    • Tendonitis also reported: now a black box warning
    • Chelation of some quinolones with divalent cation will result in poor oral absorption of ciprofloxacin, less so for levofloxacin
    • May select for highly resistant strains of C. difficile
    • Increased serum concentration of theophylline!! are seen with use of some quinolones. Serum theophylline levels must be monitored closely during quinolone therapy
    • Other drug interactions ( expecially warfarin, cyclosporine, and drugs metabolized by cyc-P450
    • Nalidixic acid caused SEIZURE DISORDERS and caution advised in patients with history of seizures
  8. Clinical use of Quinolones
    • Community-Acquired Pneumonia – primary agents used
    • Second generation quinolones all have good pneumococcal and atypical coverage: remember Levofloxacin!
    • Resistance of second generation quinolones in Streptoccus Pneumoniae MAY be increasing
    • Indication for ciprofloxacin: for Bacillus anthracis
  9. Cephalosporins
    • Cefuroxime
    • Ceftriaxone
    • Ceftazidime
    • Cefepime
  10. Second generation cephalosporin drug with Haemophilus and Moraxella Activity
    • Cefuroxime
    • Used for: Haemophilus, Moraxella, and some more GNR
  11. Third Generation cephalosporin
    • Ceftriaxone
    • Used for: Gram negatives except pseudomonas
  12. Third generation cephalosporin with Pseudomonas activity
    • Ceftazidime:
    • Cefepime:
    • Gram negative plus Pseudomonas (ceftazidime does not have as good pneumococcal coverage)
  13. Second Generation Cephalosporin with increased Haemophilus and Moraxella activity
    • Cefuroxime: good oral absorption, Oral, IV, IM
    • Renal excretion
    • 1.8 hours
    • Excellent stability against Haemophilus influenzae beta-lactamase & Moraxella
  14. Third Generation cephalosporins
    • Ceftriaxone: .
    • Poor oral absorption
    • IV, IM administration
    • Renal, Hepatic excretion 8 hours half-life
    • Current treatment of choice for Neisseria gonorrhoeae: .
    • Very active against pneumococcus and gram negative rods, especially outside of the hospital, but not good against pseudomonas
    • Does NOT cover atypical agents: mycoplasma, clamydia, legionella
  15. Ceftriaxone
    Good Gram negative spectrum except for Pseudomonas
  16. Third Generation Cephalosporins with Pseudomonas Activity
    Ceftazidime and Cefepime
  17. Ceftazidime
    • Third Generation Cephalosporin with Pseudomonas Activity
    • Poor oral absorption
    • IV, IM administration
    • Renal excretion
    • 1.8 hours of half-life
    • Marked increase in Pseudomonas activity. Penetrates into CSF
  18. Cefemine
    • Poor oral absorption
    • IV, IM administration
    • Renal excretion
    • 2.1 hours half-life
    • Marked antipseudomonas activity. CNS penetration
  19. Ceftazidime and Cefepime
    • Both: have clinically useful Pseudomonas coverage
    • Increased likelihood of selecting for resistance if used as sole agent in treating Pseudomonas
    • Cefepime: Is useful for most Gram negative rods and Pseudomonas.
  20. Erythromycin: MoA, MoR
    • A Macrolide: Inhibits protein synthesis on the 50s ribosome, bacteriostatic
    • Mechanisms of Resistance: Efflux pump encoded by plasmids (macrolide-efflux – MEF)
    • Methylation of ribosome: (Erythromycin Ribosomal Methylase-ERM)
    • Alteration of 23s ribosomal subunit of 50s complex also codes for macrolide, lincomycins, streptogramins B; MLS-B
  21. Erythromycin Microbial Activity
    • Gram positives: Streptococcus, 40% of pen-intermediate pneumo are resistant and a >60% of penicillin resistant pnneumococci are resistant
    • Gram Negatives: Legionella, Bortedela – VERY active against Legionella
    • Chlamydia, mycoplasma pneumonia, bartonella activity as well: .
  22. Newer Macrolides
    • Clarithromycin: 2/day improved spectrum against Haemophilus and Moraxella
    • Azythromycin: 5-day treatment course, once daily therapy; improved spectrum against Haemophilus and Moraxella
    • Both: much better in terms of side-effects and longer half-life – better compliance
  23. Erythromycin Adverse Effects
    • GI
    • *** Possible prolongation of QT interval and Torsaides de Pointe: .
    • Interaction with cytochrome p450
    • Thrombophlebitis: so need to give via some type of central catheter
  24. Ketolides – Telithromycin
    • Keto linkage in erythromycin structure
    • Good activity, even against macrolide-resistant pneumococcus
    • Might have become a replacement for macrolides, BUT warning about HEPATOTOXICITY is likely: to doom the drug
    • Recent report of hepatic failure: .
    • Exacerbates Myesthenia Gravis too!
  25. Tetracyclines: MoA, MoR
    • Mechanism of Action: binds to the 30s ribosome and inhibit the addition of amino acids to the growing peptide chain; bacteriostatic
    • Mechanism of Resistance: Increased efflux through efflux pumps. These can be coded for on plasmids, transposons, or be on the chromosome
    • Decreased influx
    • Resistance to one is resistance to all
  26. Tetracyclines: Absorption, Distribution, Elimination
    • Absorption – good oral absorption
    • Distribution – wide
    • Elimination – all are eliminated by the kidney except for doxycycline
    • Tetracycline Interactions: not bactericidal – is not good agent where bactericidal activity is critical
  27. Tetracyclines: Adverse effects
    • Skin – photosensitivity
    • Bone, teeth – chelation effects – generall avoided in children
    • Contraindicated in Pregnant Women
    • Vertigo, especially with Minocycline – Rx for acne
  28. Glycylcycline - Tigecycline
    • Mechanism of Action: Bind to the 30s ribosomal subunit to prevent the amino-acyl tRNA
    • Mechanism of Resistance: Markedly decreased affinity of tigecycline for the plasmid encoded efflux pump than tetracyclines. Still susceptible to chromosomal efflux pumps found in Pseudomonas and Proteus
    • Pseudomonas and Proteus: are often resistant
  29. Tigecycline: Activity
    • Very broadly active against both Gram positive and Gram negative bacteria, both aerobic and anaerobic, with the NOTEABLE EXCEPTION of Pseudomonas and Proteus:
    • Active against MRSA, VRE, and anaerobes: .
    • Can be the only active agent against some ACINETOBACTER: .
    • Resistance in all Pseudomonas and Proteus: .
  30. Tigecycline: Adverse Effects
    • Nausea and vomiting: – major side effect – worse in younger pts.
    • Increased mortality in hospital acquired pneumonia, especially VAP: ventilator-associated pneumonia
    • ***Eosinophilic pneumonia as a complication – autoimmune
    • Others same as for tetracycline – teeth, bones, etc.
  31. Clindamycin: MoA, MoR
    • Mechanism of Action: binds to 50s ribosome; bacteriostatic
    • Mechanism of Resistance: Alteration of 50s ribosome site; MLSb resistance
  32. Clindamycin: Bacterial spectrum
    • Most aerobic Gram positive organisms including Staph and Strep
    • Most anaerobic Gram positive and Gram negative bacteria, although hospital specific resistance is well documented
  33. Clindamycin Adverse Effects
    • Diarrhea: Increased incidence pseudomembranous colitis with Clostridium difficile
    • Highest frequency of cases of C. difficile per dose, BUT NOT the leading associated cause of C. Difficile
    • Generally well-tolerated
  34. Clindamycin – Clinical use
    • Macrovolume aspiration pneumonia with lung abscess (see air-fluid level)
    • Anaerobic infections: .
    • Lung abscess and anaerobic infections above the diaphragm
    • Better Gram positive anaerobic activity (peptococcus and pepetostreptococcus and non-sporulation Gram positive bacilli) than metronidazole
    • Resistance with bowel anaerobes may approach 25% in some hospitals and careful consideration needs to be applied
    • Gram positive infections: .
    • Useful in penicillin allergic patients
    • Interesting data with Group A streptococcus and necrotizing fasciitis and toxic Strep syndrome
  35. Chloramphenicol MoA, MoR, Major Toxicities and Use
    • Binds to 50s ribosome: bacteriostatic
    • Excellent distribution, oral and IV
    • Major Toxicities!!: Aplastic anemia 1:40,000 FATAL – almost always
    • Use: Not the drug of choice in ANY infection – may be used in brain abscess, rickettsia, unusual infections – but seldom used in the U.S. because of the APLASTIC ANEMIA
  36. Penicillin Structure
    • Beta-lactam ring responsible for the activity
    • Piperacillin – know – extended spectrum
  37. Natural penicillins
    • Less commonly used as empiric therapy for S. pneumoniae
    • Use only if know the bacteria is sensitive
  38. Antistaphylococcal penicillins
    • Remember that staphylococcal pneumonia increases markedly following influenza outbreaks: associated with increased pediatric mortality from flu AND
    • Is a cause of nosocomial pneumonia. However, be aware of methcillin resistant Staph.!
  39. Bata-lactamase inhibitors – Tazobactam
    • Poor oral absorption
    • IV route of administration
    • Renal excretion
    • 1-1.5 hr half-life
  40. Cephalosporin Classification
    • First generation: little use in pulmonary infections (cefazolin)
    • Second generation: Increased Gram-Negative – cefuroxime
    • Good Haemophilus and Moraxella coverage
  41. Cephalosporins
    • Third Generation – ceftriaxone
    • Very useful for most Gram negative rods except Pseudomonas, pen-sensitive and pen-intermediate pneumococcus
  42. Third Generation cephalosporins with Pseudomonas activity
    • Ceftazidime: Gram negative rods including Pseudomonas
    • Cefepime: 4th generation – better pneumococcal coverage than ceftaz, may be active against ampC containing organisms (chromosomally-mediated inducible beta-lactamases)
    • Some recent questions about increased fatality with cefipime, may need new breakpoints.
  43. Other Cell Wall Active Agents
    • Monobactams – aztreonam: great for many gram negatives, but remember – NO GRAM POSITIVE (PNEUMOCOCCAL) OR ANAEROBIC ACTIVITY
    • Carbapenems – imipenem, meropenem, ertapenem: Useful for highly resistant Gram negatives and anaerobes.
    • Also has excellent Gram-positive activity.
    • Imipenem and meropenem active against Pseudomonas
    • Glycopeptides – Vancomycin: Useful for both high-level penicillin resistant pneumococcus and MRSA
  44. Quinopristin-dalfopristin
    • Vancomycin Substitute
    • Highly active against Staphylococcus, including MRSA but activity in pneumonia unknown also active against
    • S. Pneumoniae (including pen-resistant strains) and other streptococci: .
  45. Oxazolidinones – Linezolid
    • Vancomycin Substitute
    • Useful and available in ORAL FORM: gets the most “play”
    • May be more active but still unclear
  46. Daptomycin
    • Cell wall active agent
    • Not useful in lung infections
    • Binds to surfactant – so NOT VERY USEFUL in lung infections
    • Very active
    • Side effects include myositis
  47. Telavancin
    • Lipoglycopeptide
    • Vancomycin basic structure with lipid moiety
    • Use in pneumonia not yet documented
  48. Tigecycline
    • Active against most Gram positive bacteria
    • Also active against many gram negatives and anaerobes
    • No Pseudomonas or Poteus activity: .
    • Nausea and Vomiting common
    • May have higher mortality than other agents: .
  49. Aminoglycosides
    • MAJOR Nephrotoxicity: .
    • Streptomycin – IM
    • Gentamycin
    • Tobramycin
    • Netilmicin
    • Amikacin – most active: .!!
  50. Aminoglycosides
    • NEVER used as single drug in gram-nevative pneumonia, always in combination
    • Indications for Aminoglycosides
    • Treatment of Gram-negative rod infections
    • Not all clinical infections have optimal environment for aminoglycosides to work.
    • They don’t work well in acidic pH (purulent pulmonary secretions) or anaerobic environments (failure to transport drug across membrane)
    • Combination therapy for Pseudomonas: USE
  51. Sulfonamides and Trimethoprim
    • Pneumonias: Pneumocystis carinii ( now Pneumocystis jiroveci)
    • No longer a reliable choice for pneumococcus with up to 40% of penicillin resistant S. Pneumoniae resistant to TMP/SMX: .
    • Active against Haemophilus and Moraxella now
    • Active against some unusual nosocomial pathogens like Stenotrophomonal maltophila
    • Active against NOCARDIA!!: .
    • Otitis media – resistance a problem here too
    • UTIs
  53. Outpatient CAP Recommendations: previously healthy and no risk for drug-resistant S. pneumococcus (DRSP)
    • A macrolide (strong recommendation): arythromycin/clarythromycin used
    • Or doxycycline (weak recommendation):
    • Can use atypical mycoplasma, Clamydia interstitial pneumonia
  54. Outpatient CAP Recommendations: Comorbidities (COPD, diabetes, renal, CHF, or malignancy, asplenia, immunosuppression, or use of ATB in prior 3 months
    • 1) a respiratory fluoroquinolone (LEVOFLOXACIN, moxifloxacin, gemafloxacin): strong reccomendation
    • OR
    • 2) a beta-lactam plus a macrolide – strong recommendation for atypicals and Legionella
  55. Outpatient CAP Recommendations: Areas with high rates of DRSP even in healthy people
    A respiratory fluoroquinolone (Moderate recommendation)
  56. Inpatient Therapy for CAP
    • Medical Ward: .
    • A respiratory fluoroquinolone (levofloxacin)
    • OR
    • A beta-lactam plus a macrolide (strong recommendation, preferred Beta-lactam agents include cefotaxime, ceftriaxone, and ampicillin; ertapenem for selected
    • ***a respiratory fluoroquinolone should be used for penicillin-allergic patients***
  57. Inpatient: ICU - therapy for CAP when Pseudomonas infection is NOT an issue
    A beta-lactam (cefotaxime, ceftriaxone, or amicillin-sulbactam) PLUS either azythromycin or a fluoroquinolone
  58. ICU Inpatient: Pseudomonas infection is an issue
    • For Pseudomonas infection, use an antipneumococcal, antipseudomonal beta-lactam PLUS either ciprofloxacin or levofloxacin: b/c get Legionella coverage
    • OR
    • The above beta-lactam plus an aminoglycoside and azithromycin (also get Legionella coverage):
    • OR
    • The above beta-lactam plus an aminoglycoside and an antipneumococcal fluoroquinoloe
  59. ICU: CA-MRSA
    Add vancomycin or linezolid
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