-
Quinolones
- Ciprofloxacin
- Ofloxacin
- Norfloxacin
- Moxifloxacin
- Levofloxacin: .
- Gatifloxacin
- Trovafloxacin
-
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)
-
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)
-
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
-
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
-
Second Generation Quinolones – Toxicity
- All agents share similar toxicity and a reported increased incident of prolonged QT interval: .
- USE WITH CAUTION WITH AGENTS THAT PROLONG QT INTERVAL Torsaides!!:.
-
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
-
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
-
Cephalosporins
- Cefuroxime
- Ceftriaxone
- Ceftazidime
- Cefepime
-
Second generation cephalosporin drug with Haemophilus and Moraxella Activity
- Cefuroxime
- Used for: Haemophilus, Moraxella, and some more GNR
-
Third Generation cephalosporin
- Ceftriaxone
- Used for: Gram negatives except pseudomonas
-
Third generation cephalosporin with Pseudomonas activity
- Ceftazidime:
- Cefepime:
- Gram negative plus Pseudomonas (ceftazidime does not have as good pneumococcal coverage)
-
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
-
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
-
Ceftriaxone
Good Gram negative spectrum except for Pseudomonas
-
Third Generation Cephalosporins with Pseudomonas Activity
Ceftazidime and Cefepime
-
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
-
Cefemine
- Poor oral absorption
- IV, IM administration
- Renal excretion
- 2.1 hours half-life
- Marked antipseudomonas activity. CNS penetration
-
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.
-
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
-
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: .
-
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
-
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
-
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!
-
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
-
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
-
Tetracyclines: Adverse effects
- Skin – photosensitivity
- Bone, teeth – chelation effects – generall avoided in children
- Contraindicated in Pregnant Women
- Vertigo, especially with Minocycline – Rx for acne
-
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
-
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: .
-
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.
-
Clindamycin: MoA, MoR
- Mechanism of Action: binds to 50s ribosome; bacteriostatic
- Mechanism of Resistance: Alteration of 50s ribosome site; MLSb resistance
-
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
-
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
-
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
-
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
-
Penicillin Structure
- Beta-lactam ring responsible for the activity
- Piperacillin – know – extended spectrum
-
Natural penicillins
- Less commonly used as empiric therapy for S. pneumoniae
- Use only if know the bacteria is sensitive
-
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.!
-
Bata-lactamase inhibitors – Tazobactam
- Poor oral absorption
- IV route of administration
- Renal excretion
- 1-1.5 hr half-life
-
Cephalosporin Classification
- First generation: little use in pulmonary infections (cefazolin)
- Second generation: Increased Gram-Negative – cefuroxime
- Good Haemophilus and Moraxella coverage
-
Cephalosporins
- Third Generation – ceftriaxone
- Very useful for most Gram negative rods except Pseudomonas, pen-sensitive and pen-intermediate pneumococcus
-
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.
-
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
-
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: .
-
Oxazolidinones – Linezolid
- Vancomycin Substitute
- Useful and available in ORAL FORM: gets the most “play”
- May be more active but still unclear
-
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
-
Telavancin
- Lipoglycopeptide
- Vancomycin basic structure with lipid moiety
- Use in pneumonia not yet documented
-
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: .
-
Aminoglycosides
- MAJOR Nephrotoxicity: .
- OTOTOXICITY AND VESTIBULAR TOXICITY: .
- Streptomycin – IM
- Gentamycin
- Tobramycin
- Netilmicin
- Amikacin – most active: .!!
-
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
-
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!!: .
-
TRIMETHOPRIM/SULFONAMIDES clinical use
- Otitis media – resistance a problem here too
- UTIs
-
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
-
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
-
Outpatient CAP Recommendations: Areas with high rates of DRSP even in healthy people
A respiratory fluoroquinolone (Moderate recommendation)
-
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***
-
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
-
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
-
ICU: CA-MRSA
Add vancomycin or linezolid
|
|
