Antibiotics Review

ANTIBIOTICS REVIEW 

Source: Stanford Medicine: http://errolozdalga.com/medicine/pages/OtherPages/AntibioticReview.ChanuRhee.html

Antibiotic Dosing and Antibiogram for LPCH (2018), courtesy of Stanford/LPCH Antibiotic Stewardship Program

TABLE OF CONTENTS

ANTIBACTERIALS

I. BETA-LACTAMS

II. PROTEIN SYNTHESIS INHIBITORS

III. FLUOROQUINOLONES

IV. SULFONAMIDES = BACTRIM/SEPTRA (TMP/SMX)

V. "SUPER GRAM POSITIVE ANTIBIOTICS"

VI. "SUPER GRAM NEGATIVE ANTIBIOTICS" THAT COVER PSEUDOMONAS

VII. ANTIBIOTICS WITH ANAEROBE COVERAGE

VIII. Urinary Tract Infection-Specfic Antibiotics

IX. ANTI-C.DIFFICILE ANTIBIOTICS

X. RIFAMYCINS – include Rifampin, Rifaximin, Rifapentine, Rifabutin.

XI. Last Tidbit: Very common antibiotic regimen = VANCOMYCIN / ZOSYN

ANTIFUNGALS

I. AZOLES

II. ECHINOCANDINS

III. AMPHOTERECIN B

ANTIBACTERIALS

I.  BETA-LACTAMS = PCNs, Cephalosporins, Carbapenems, Monobactam(Aztreonam)

• Cell wall inhibitors: bind PBPs (Penicillin-binding proteins) in cell membrane and inhibit cell wall crosslinking  --> bactericidal.

• Main side effects: Hypersensitivity reactions including anaphylaxis, Rashes, Bone marrow suppression, Interstitial Nephritis,  GI (nausea, diarrhea, and C.diff) interstitial nephritis, GI (nausea, diarrhea, and C.diff), seizures (mainly with high doses in renal failure)

• As a general rule, if pathogen is susceptible and patient non-allergic, beta-lactams are the preferred drug for most situations due to high efficacy and cidal nature.

• Most oral beta-lactams have poor bioavailability and achieve low serum concentrations, making them poor choices for serious or deep seated infections (Amoxicillin has the best bioavailability).

• No beta-lactam has activity vs MRSA (except Ceftaroline), and none have activity vs atypical intracellular organisms (i.e. Legionella, Mycoplasma, Chlamydia).

• Beta-lactams exhibit time-dependent killing, meaning that efficacy depends on the amount of time the drug concentration is above the MIC.

• The SPICE-A organisms (Serratia, Pseudomonas/Providencia, Indole-positive Proteus, Citrobacter, Enterobacter, and Acinetobacter) have inducible, chromosomal beta-lactamases (AmpC) that may not be detected on initial susceptibility testing, but can lead to resistance while on therapy to all beta-lactams except carbapenems.  Cefepime and Piperacillin/Tazobactam can be used with caution as well.  

Overview of Beta-Lactam Allergies:

• Rash occurs in up to 5% of patients receiving PCN, but the overall rate of anaphylaxis to PCN is <1/10,000.

• Among all patients with reported PCN allergy, ~85-90% will tolerate PCN (either never truly allergic, or resolution of remote prior allergy). 

• Clinical cross-reactivity with cephalosporins and carbapenems is very low: of those with a positive PCN skin test, ~ 2% will have a cephalosporin reaction, and <1% will have a carbapenem reaction.

• There is no cross-reactivity between PCN and Aztreonam; however, cross-reactivity between Aztreonam and Ceftazidime has been reported (due to an identical side chain).

• Skin testing is useful to evaluate for potential Type I (IgE-mediated) allergic reaction (only 10-15% of those with reported allergy will have positive skin test).  Skin test has ~50% positive predictive value à give alternate drug, do graded challenge, or desensitize.   Skin test has very a high negative predictive value:  >98% will tolerate PCN, but not 100% à give 10% “test” dose and observe for 1 hour prior to full dose.

• If skin testing unavailable and beta-lactam is preferred, decision depends on prior type of reaction and how recently it occurred. If >10 years ago, and/or not characteristic of IgE, give cephalosporin or carbapenem (<1% of anaphylaxis).  If recent and/or features of IgE reaction, can give cephalosporin or carbapenem by graded challenge.  If probable history of anaphylaxis, desensitize. 

A. PENICILLINS

1. Penicillin G (IV) or V (PO)

Spectrum:  Many strains of Streptococci (Drug of choice for Group A Strep - universally PCN sensitive), minority of Staphylococci (most are resistant) and some Enterococcus, most oral anaerobes, Syphilis (universally PCN sensitive).

Used for: Strep throat and other infections due to Group A Strep, Syphilis (for neurosyphilis or pregnant women, must desensitize to PCN), bacteremia/endocarditis due to PCN sensitive Streptococcus, Enterococcus, or Staph aureus (<10% of S.aureus strains are PCN-sensitive), and more.  For most situations, generally start with broader antibiotics until pathogen and susceptibilities identified.

2. Aminopenicillins - Ampicillin (IV), Amoxicillin (PO) 

Spectrum: some Gram positives (Strep, Enterococcus, Listeria) but NOT MSSA, and limited Gram negative coverage.  Notable gram negative holes include Klebsiella, Moraxella, and SPICE A organisms.

Used for: Upper respiratory infections, sinusitis, otitis media, cellulitis, Listeria infections, UTI’s, early Lyme disease (alternative to Doxycycline), and more.

• Drug of choice for Enterococcal infections if susceptible (E.faecalis generally susceptible, E.faecium usually not).  Used with aminoglycosides for synergy for Enterococcal endocarditis.

• Amoxicillin is the best-absorbed beta lactam (75-90% bioavailability).  Little role for oral ampicillin due to inferior absorption vs Amoxicillin. 

3. Anti-Staphylococcal Penicillins - Methicillin / Nafcillin / Oxacillin (IV), Dicloxacillin (PO) 

Spectrum: MSSA, also with activity vs strep. 

Used for: Drug of choice for MSSA infections (unless PCN sensitive, which is rare).  Good choice for cellulitis, osteomyelitis, endocarditis, and bacteremia from MSSA. 

• No MRSA coverage and Coag negative Staph is usually resistant (>80%). 

• Dicloxacillin is a reasonable oral choice for non-severe cellulitis; otherwise, for all serious MSSA infections (e.g. bacteremia, osteomyelitis, endocarditis), in general the entire course of therapy must be given intravenously.

• Nafcillin tends to be better tolerated than Oxacillin (less hepatitis and rash)

4.  Anti-pseudomonal PCNs - Piperacillin, Ticarcillin

Usually combined with beta lactamase inhibitors (see below) which confers broader activity; however, beta-lactamase component does not add activity vs Pseudomonas (so if Pseudomonas is sensitive, could use Piperacillin alone).

B. COMBINED PENICILLIN/BETA-LACTAMASE INHIBITORS:addition of beta lactamase inhibitor confers broader spectrum against common beta-lactamase producing organisms (such as MSSA, some gram negatives including H.influenza, Moraxella, and virtually all anaerobes).

• Amoxicillin/Clavulanate (Augmentin) – PO

Spectrum: Relatively broad spectrum with some gram positive (MSSA, Strep), some gram negatives, and anaerobes.  Notable holes include NO Pseudomonal activity and other SPICE A organisms.

Used for:  Sinusitis, respiratory infections, otitis media, some skin/soft tissue infections (including bite wounds), and more. 

• Ampicillin/Sulbactam (Unasyn) – IV

Spectrum: Similar to Amoxicillin/Clavulanate, except has activity vs most Acinetobacter (sulbactam component has activity).  Still no activity against other SPICE organisms.

Used for: similar situations as for Amoxicillin/Clavulanate but where IV form is desirable; also, some intraabdominal and GYN infections, aspiration pneumonia and lung abscesses, and more. 

• Caution with Unasyn for polymicrobial intraabdominal infections due to high rate of resistance of E.coli (>50% at some institutions)

• Piperacillin/Tazobactam (Zosyn) – IV

Spectrum: similar to Unasyn in having gram positive, gram negative, anaerobic coverage, but better overall gram negative coverage, including Pseudomonas and most SPICE A organisms.

Used for: many purposes, including hospital-acquired/healthcare-associated PNA, severe skin/soft tissue infections including diabetic ulcers, intraabdominal infections.  

• Very broad antibiotics so easier to remember common bugs that it does NOT cover:  MRSA, most strains of VRE, many Coag negative staph strains, Atypicals (Chlamydia, Mycoplasma, Legionella), ESBLs.

• Note Zosyn’s higher dosing for PNA/Pseudomonas coverage: 4.5 g q6 hrs (vs. 3.375 g q6 for other indications)

• “Extended Infusion” strategy – 3.375 g over 4 hours, q8 hrs – some data suggesting better outcomes for treatment of Pseudomonas infections compared to standard dosing (goal to maximize time above MIC).

• Ticarcillin/Clavulanate (Timentin) – IV

• Similar to Zosyn, but Timentin has activity vs Stenotrophomonas, and is less effective vs Pseudomonas and Enterococci.

C. CEPHALOSPORINS - higher resistance to beta-lactamases à better anti-staph activity 

Spectrum (General Rules):

• • No cephalosporin covers Enterococcus (except Ceftaroline).

  • Only Ceftazidime and Cefepime cover Pseudomonas. 

  • Only Cefoxitin and Cefotetan have good anaerobic coverage.

1st Generation - Cefazolin (Ancef, Kefzol) - IV, Cephalexin (Keflex) - PO

Spectrum:  Excellent Gram positive (MSSA and strep), minor Gram negative = Proteus, E.coli, Klebsiella.

Used for: Mild-moderate nonpurulent cellulitis (if do not suspect MRSA).  Cefazolin ofted used for prophlaxis during surgery.  Sometimes used for UTIs as well (especially during pregnancy).

• In PCN-allergic patients, Cefazolin is drug of choice for severe MSSA infections(bacteremia, endocarditis, etc).  Some use it preferentially in prolonged treatment courses over Nafcillin/Oxacillin due to overall better tolerance (less rash, diarrhea, interstitial nephritis, hepatitis)

2nd Generation

• Cefuroxime (PO and IV)

Spectrum: Gram positive and more gram negative’s  than 1st generation - gains activity vs H.influenza, Enterobacter, Neisseria.  

Used for: respiratory infections (upper and lower tract), gonorrhea, UTIs, Lyme disease (alternative to Doxycycline), and more.

• ”Cephamycins” -  Cefoxitin, Cefotetan (IV)

  • Spectrum: get anaerobes and gram negatives, but no Pseudomonas and weak/unreliable  gram positive coverage.  

  • Used for: UTI’s, non-severe intraabdominal infections, pelvic/GYN infections.   

    • Bacteroides fragilis has high rates of resistance to Cefotetan (Cefoxitin is a bit better) – for serious intrabdominal infections, should use other agents.   

    • Cefotetan can cause elevated INR.

3rd Generation

a. Ceftriaxone (Rocephin) – IV, Cefotaxime - IV, Cefpodoxime - PO

Spectrum: Good gram positive (although possibly worse than 1st generation) and excellent gram negative coverage (E.coli, Proteus, Klebsiella, Neisseria, H.influenza, and most SPACE organisms, but not Pseudomonas), no anaerobes .  

Used for:  Ceftriaxone used in many situations including community acquired PNA (with Azithromycin), meningitis (CTX has excellent CSF penetration), spontaneous bacterial peritonitis, some skin/soft tissue infections, bacteremia/endocarditis from susceptible strep, urinary tract infections/pyelonephritis, bone and joint infections, late Lyme disease, gonorrhea, pelvic infections, and more. 

• Note small but important rate of resistance in Strep pneumo. 

• Ceftriaxone usually once daily dosing (1-2 g) except for meningitis (2 g IV q12 hours). Cefotaxime is more frequent dosing (often used preferentially for spontaneous bacterial peritonitis due to good track record and high levels achieved in ascitic fluid, but Ceftriaxone probably equivalent). 

• Cefpodoxime useful as a step-down to oral after IV Ceftriaxone, but like all beta lactams note poor serum bioavailability (so not suitable for bacteremia, deep-seated or serious infections). 

• Ceftriaxone can cause biliary sludging and cholecystitis. 

b. Ceftazidime (IV) (3rd/4th Generation Cephalosporin)

• Spectrum: only has Gram negative coverage (including Pseudomonas).  Virtually no Gram positive or anaerobic coverage.  

  • Used for: Pseudomonal infections, also can be used for neutropenic fever (but beware lack of staph/strep coverage, so Cefepime often preferred). 

• Most experts will avoid using Ceftriaxone or Ceftazidime (and any lower generation cephalosporin) for serious infections due to SPICE organisms, due to concern for inducible resistance from chromosomal beta-lactamase (AmpC ).  Preferable to useCefepime, Piperacillin/Tazobactam, or Carbapenem (best) in those situations as they are more stable, or non-beta lactams if susceptible.

4th Generation - Cefepime (IV) 

Spectrum: broad gram positive (MSSA, strep) and gram negative including Pseudomonas, but weak anaerobic coverage. 

Used for: empiric neutropenic fever (better than Ceftazidime due to strep coverage), hospital acquired PNA, meningitis if suspect gram negatives, complicated urinary tract infections, nosocomial meningitis, and more.

• For cefepime and ceftriaxone, beware CNS toxicity of encephalopathy, altered mental status, and seizures in the elderly and those with renal failure. 

• Ceftazidime and Cefepime sometimes have activity against certain ESBL producing organisms, but reports of failure in this setting so use with caution.

• Ceftazidime and Cefepime have <1% cross-reactivity for non-anaphylactic allergies/intolerance

5th Generation - Ceftaroline (IV)

Spectrum: Gram positive including MRSA, VISA, VRSA, Strep.   Similar gram negative coverage as Ceftriaxone – no Pseudomonas and other nonlactose fermenting GNRs, no ESBL. No entercoccus as monotherapy, though some evidence to support synergy with other drugs (e.g. dapto)

Used for: complicated SSTI and community-acquired PNA (FDA indications)

• Newest cephalosporin (FDA approved in 2010) and only one with activity vs MRSA.    

• Only 2 FDA approved indications, but being used more and more for off-label purposes (bone/joint infections, refractory MRSA/VISA bacteremia, etc.). 

D. CARBAPENEMS -  Imipenem/Cilastin, Meropenem, Ertapenem, Doripenem (all IV)

Spectrum: Broadest spectrum antibiotics, cover Gram positive, Gram negative including Pseudomonas (except Ertapenem) and ESBL (extended spectrum beta lactamase producers), also anaerobes.  

Used for: many serious infections due to resistant gram negatives, including hospital/health-care associated PNA, meningitis, intraabdominal infections, complicated skin and soft tissue infections

• The most reliable class of antibiotics against ESBL organisms and the SPICE-A organisms.

• Very broad – easier to remember common bugs that it doesn’t cover:  MRSA, most VRE, Atypicals, Stenotrophomonas (carbapenem use is a risk factor for Stenotrophomonas infection).

• Great penetration virtually everywhere, including CSF  .

• Ertapenem does NOT cover Pseudomonas, but does still cover ESBL (main advantage is convenient once/day dosing - great outpatient IV drug).  Other differences of Ertapenem (vs other carbapenems) is lack of activity vs Acinetobacter and Enterococci. 

• Doripenem – newest carbapenem, main theoretical advantage = increased in vitro potency against Pseudomonas, and lower likelihood of development of resistance in vitro (clinical benefit not yet demonstrated)

• Main additional side effect = Lower seizure threshold – greatest risk w/ Imipenem (esp with renal failure), less w/ Meropenem.

E. MONOBACTAM - Aztreonam

Spectrum: only has activity vs. aerobic gram negatives, no gram positive or anaerobes (similar activity as Ceftazidime).  

Used for: hospital acquired/healthcare associated PNA, UTIs, intraabdominal infections, sepsis, skin and soft tissue infections.  Generally used in combination with other antibiotics due to gram-negative limited spectrum. 

• Main advantages:1) No cross-reactivity with PCN allergy (except with Ceftazidime – cross-reactivity due to identical side chain) and 2) Does not cause renal failure (almost no significant toxicity)

• Beware significant rate of resistance of Pseudomonas in most institutions, so empiric double coverage often required.

Comparison of the 3 broadest spectrum beta-lactams: Cefepime, Zosyn, and Carbapenems (non-Ertapenem) have activity against both Gram positive (MSSA, Strep) and Gram negative including Pseudomonas.  They do NOT cover: MRSA, VRE, Atypicals, among others.

•  Cefepime – main weakness is weak anaerobe coverage and no Enterococcus

•  Zosyn (Piperacillin/Tazobactam) – broader due to excellent anaerobe coverage, activity vs Amp-susceptible Enterococcus.  No ESBL coverage.

• Carbapenems (except Ertapenem) – broadest yet due to anaerobic coverage, Amp-susceptible Enterococcus, and ESBL

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II. PROTEIN SYNTHESIS INHIBITORS

Mechanism: bind to either 30 S or 50 S ribosomal unit.  Most are bacteriostatic, except for Aminoglycosides (generally considered cidal due to irreversible binding and disruption of outer cell membrane)

1. Macrolides - Erythromycin, Clarithromycin, Azithromycin -50S Ribosomal Inhibitor (PO and IV)

Spectrum: Atypical organisms (Chlamydia, Mycoplasma, Legionella), also some activity vs. Gram positive cocci and some gram negatives.

Used for: Azithromycin - low-risk bronchitis, COPD exacerbations,  community-acquired pneumonia, sinusitis, Strep throat in PCN allergic patients, and more.  Used in conjunction with Ceftriaxone for CAP that requires hospitalization.  Used for MAC treatment (combination therapy) and for prophylaxis in HIV/AIDS patients with CD4 <50.   Also used for STD Chlamydia.   

• Azithromycin is the drug of choice for most atypical infections.

• Erythromycin now used mostly as GI motility agent – prior to endoscopy, or to advance feeding tubes.

• Clarithromycin also used for MAC treatment (in combination with other drugs).

• Azithromycin has better H.influenza activity than Clarithromycin/Erythromycin.

• ~25% of Strep pneumo is resistant to Azithromycin, so combine with Ceftriaxone for patients sick enough to hospitalize with community-acquired PNA (or recent abx use).

• Side effects: QT prolongation (recent NEJM article suggested slight  increased risk of cardiovascular death with Azithromycin), prominent GI side effects, rash.

2. Tetracyclines – Doxycycline, Tetracycline, Minocycline - 30S Inhibitors (PO and IV)

Spectrum: Fairly broad spectrum with some Staph and MRSA coverage, some gram negative coverage, and atypicals.   Has activity for unusual pathogens including: Rickettsia, Lyme disease, Tularemia, Vibrio, Brucella, Q fever, Anthrax

Used for: Doxycycline - Skin and soft tissue infections when suspect community-acquired MRSA, respiratory tract infections, and unusual infections as above.  Drug of choice for early Lyme disease, and for Lyme prophylaxis after tick bite.  Also used for malaria prophylaxis, acne and rosacea. 

• Side Effects: photosensitivity, GI discomfort, teeth discoloration, inhibits bone growth in children, teratogenic, steatosis and hepatotoxicity.

• Doxycycline is the preferred tetracycline in most cases due to convenient BID dosing, and lack of food-drug interactions.

• Often part of empiric therapy in toxic-appearing patients with fever and rash (mainly for Rocky Mountain Spotted Fever). 

• Good choice for mild-moderate skin/soft tissue infections due to community-acquired MRSA infection, but has poor strep coverage so often combined with beta lactam like Cephalexin.

• Doxycycline has excellent bioavailability .

3. Clindamycin -50 S inhibitor (PO and IV)

Spectrum: Excellent activity vs. Anaerobes and Gram positive cocci – Strep and Staph, including ~ 50% of community-acquired MRSA, but NOT Enterococci.   

Used for: skin/soft tissue infections, pelvic infections, lung abscess, sinusitis.  Also has activity vs PCP (combine with primaquine) and toxoplasmosis (combine with pyrimethamine)

• Beware increasing resistance among Bacteroides – not a good choice for severe intraabdominal infections.

• Reasonable empiric drug for cellulitis due to Strep/Staph coverage, but beware of resistant MRSA.   Also, ~10% of MSSA is resistant. 

• If MRSA (or MSSA) appears susceptible – always have lab check “D-test” à looks for inducible resistance to Clindamycin in strains that are resistant to Erythromycin.  If D-test positive, do not use Clindamycin.

• Also used often for its Antitoxin effect in Toxic Shock Syndrome or Necrotizing Fasciitisdue to Group A Strep (less evidence for MRSA).

• Does not penetrate CSF – cannot use for brain abscesses.

• Traditionally causes highest rate of C.diff among all Abxs (~10%). 

4. Aminoglycosides  - Gentamicin, Tobramycin, Amikacin, Streptomycin -30S inhibitor (all IV)

Spectrum: Extremely efficacious vs. aerobic Gram negatives including Pseudomonas.  NO activity vs. Gram positives (except when used for synergy) or anaerobes.   

Used for: serious gram negative infections especially when Pseudomonas is suspected (pneumonia, bacteremia, urinary tract infections). Used with beta-lactams against gram positive organisms for synergistic effect (mainly in endocarditis).

• For synergy, best evidence and utility for Enterococcal endocarditis (if susceptible).  Also strong recommendation for Strep enterocarditis (duration depends on Strep MIC).  Weakest evidence for Staph aureus native valve endocarditis – optional for max 3-5 days (decreases bacteremia by ~1 day, increases renal failure, and no effect on mortality) à most ID physicians now tend to avoid it for Staph infections.  For Staph prosthetic valve endocarditis, aminoglycoside recommended for 2 weeks with Rifampin. 

• Poor urine and CSF penetration.  Also less effective at low pH such as in lung/bronchial secretions – not great for PNA (avoid monotherapy).

• Ofted used as 2nd agent of “double coverage” when suspecting serious Pseudomonas infection (including for HAP/HCAP/VAP)

• Side effects = ATN/nephrotoxicity (manifests after 3-5 days, usually reversible) and oto/vestibular toxicity (irreversible, unlike Vancomycin).   If using long-term, check baseline audiology test and ~q2 weeks. 

• Aminoglycosides exhibit concentration-dependent killing – more effective with higher peak concentration relative to MIC (vs time-dependent killing of beta lactams – more important to maintain levels above MIC)

• Three ways to dose aminoglycosides (doses listed for Gentamicin). Check peak after 3rd dose, trough before 4th dose. 

• Traditional q8 dosing (~2 mg/kg q8 hrs) – goal peak >6-8 and trough <2

• Once-daily dosing (5-7 mg/kg) – generally do not measure troughs unless critically ill and high risk of toxicity (goal trough <1).  Avoid if unstable renal function/renal failure or increased volume of distribution.  Once daily dosing takes advantage of concentration-dependent killing and long “post-antibiotic effect” (killing/inhibition of bacteria even when abx is cleared) – other potential advantage is lower toxicity.

• Synergy dosing (~1 mg/kg q8-12 hrs) – goal peak 3-5, trough <1. 

5.  Chloramphenicol – 50S ribosomal inhibitor.   IV or PO (but PO form unavailable in U.S.)

Spectrum: Broad spectrum vs Gram positives (including MRSA, E.faecium/VRE); Gram negatives but NOT Pseudomonas; Anaerobes, and unusual pathogens including spirochetes, Rickettsia, Erhlichia, Coxiella, Typhoid/Paratyphoid Salmonella.

Used for: Limited use in the U.S. due to potential toxicity (see below) – mainly for bacterial meningitis in patients with severe beta-lactam allergy (has activity vs S.pneumo, N.meningitidis, and H.influenza).  Used more widely in developing countries where benefit often outweighs risk.

• A typical regimen in patients with bacterial meningitis and severe beta-lactam allergy would be Vancomycin + Chloramphenicol +/- Bactrim (for Listeria in the appropriate patients)

• Toxicity: 1. Bone marrow suppression – direct, dose-related effect that is reversible. 2. Aplastic anemia – rare, idiosyncratic reaction (occurs at rate of 1/40,000), but generally fatal event.  Usually occurs several weeks after drug is stopped.  3. Gray baby syndrome in infants – presents with hypotension, shock, and cyanosis.

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III. FLUOROQUINOLONES = DNA Gyrase  and Topoisomerase inhibitors àbactericidal

Mechanism: DNA Gyrase  and Topoisomerase inhibitors àbactericidal 

Side effects: QT prolongation (recent NEJM article suggested increased risk of cardiovascular death with Levofloxacin, but not Ciprofloxacin), tendon rupture (esp if on steroids), GI intolerance, cartilage damage, rare dysglycemias (Gatifloxacin removed from market for this reason), dizziness/HA’s, rashes, teratogenicity, transaminitis.   Fluoroquinolones also recently associated with increased risk of retinal detachment.  High rate of c.diff.

• Fluoroquinolones also have excellent TB coverage (Moxifloxacin > Levofloxacin > Ciprofloxacin). If patient has PNA, but suspect TB, do not use FQ’s!!(Do not want to use monotherapy against TB à will develop resistance)

• All fluoroquinolones have atypical coverage (but Cipro – relatively weaker against Chlamydia and Mycoplasma, but good vs Legionella).

• All fluoroquinolones have excellent bioavailability (except Norfloxacin), so use PO whenever possible.

1. Ciprofloxacin (PO and IV)

Spectrum: best gram negative coverage of FQs, but virtually no gram positive coverage.   Lacks good anaerobic coverage.

Used for: many purposes including UTIs, double coverage of Pseudomonas including for HAP/HCAP/VAP, bone and joint infections, prostatitis, GI/intraabdominal coverage - often with Flagyl, traveler’s diarrhea.  Also effective vs anthrax.

• Common myth is that it does not “penetrate” the lungs.  This is false – it is not used in community-acquired PNA due to lack of Strep pneumo coverage.  It is routinely used for HAP/HCAP/VAP as double-coverage for Pseudomonas (note more frequent dosing for PNA – 400 mg IV q8 hours)

2. Levofloxacin (Levaquin)(PO and IV)

Spectrum: “Respiratory Fluoroquinolone” -  excellent activity vs. Strep pneumo, slightly less reliable Pseudomonas coverage than Cipro.   Good for atypicals.  

Used for: Community Acquired PNA (can use as monotherapy), sinusitis/bronchitis, UTI’s, and double coverage of Pseudomonas including hospital acquired PNA.

3. Moxifloxacin (Avelox) (PO and IV)

• Also a Respiratory FQ, but main difference vs. Levofloxacin is virtually NO urine activity (can't use for UTIs) and NO Pseudomonas activity à no role in hospital/healthcare associated PNA.

• Best gram positive, atypical, and anaerobic coverage out of FQs à approved for complicated intraabdominal infections, although significant rate of resistance in Bacteroides (either avoid for serious intraabdominal infections, or combine with Metronidazole). 

• Both Moxifloxacin and Levofloxacin are not typically used for Staph aureus infections due to rapid emergence of resistance.

• Both Moxifloxacin and Levofloxacin have excellent Pneumococcal activity, but are 2nd-line at best for most other streptococcal infections (beta-lactams preferred).

• Norfloxacin (PO) – unlike the other Fluoroquinolones, poorly absorbed.  Main use is for spontaneous bacterial peritonitis (SBP) prophylaxis.

IV. SULFONAMIDES = BACTRIM/SEPTRA (TMP/SMX) - inhibit sequential steps in Folate synthesis --> bacteriostatic

Spectrum: Wide spectrum including typical bacterial pathogens – Gram positives (S.aureus including most CA-MRSA, some S.pneumo), and most Gram negatives but not Pseudomonas.  Notable highlights that set it apart from other agents are: activity vs Pneumocystis jiroveci, Nocardia, Toxoplasmosis, Listeria, Isospora, and Stenotrophomonas.

Used for: Many purposes including PCP PNA (drug of choice, both for treatment and prophylaxis), Community-acquired MRSA Skin infections, UTIs, Nocardiosis, Listeria infections in PCN-allergic patients, Salmonella infections, Traveler’s diarrhea, acute bronchitis, and otitis media.

• Good choice for skin/soft tissue infections due to MRSA coverage (best CA-MRSA coverage out of oral Abxs except for Linezolid), but weak strep coverage à consider adding Cephalexin for strep.

• ~100% PO bioavailability.  Shortage of IV formulation in the U.S. so use PO whenever possible.

• Dosing – SS = 400 mg (SMX) /80 mg (TMP), DS – 800/160 mg.  Dosing varies on indication.  Selected few: UTI – 1 DS tab po bid.  SSTI – 2 DS tab po bid.  PCP ppx – 1 DS tab po three times/week or qday, or 1 SS tab po qday.  PCP treatment – 5 mg/kg (TMP component) PO q8 hours x 21 days (usually 2 DS po q8 hours). 

• Many potential side effects:

• Common - Hypersensitivity (sulfas) and rashes, GI side effects, dose-dependent bone marrow suppression, increased creatinine (both from pseudo-Cr elevation due to blocked Cr secretion into tubules – average increase in Cr by ~20%, and true AKI from Interstitial Nephritis and ATN), hyperkalemia (esp high doses and with CKD)

• Uncommon - aseptic meningitis, methemoglobinemia and hemolysis in G6PD deficiency, transaminitis/cholestasis, pancreatitis, and more. 

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V. “SUPER GRAM POSITIVE ANTIBIOTICS”

Included are drugs with activity against MRSA, Coag-negative staph, Streptococci, Enterococcus including VRE (except Vancomycin)

1. Vancomycin (IV), dalbavancin (IV); (lipoglycopeptide antibiotics)

Mechanism: Glycopeptide -  inhibits cell wall synthesis in Gram positives (different protein than beta lactams – D-Ala-D-Ala).

Spectrum: gram positive agent with activity vs Staph (including MRSA), Strep, and nonVRE Enterococcus.  No gram negative coverage.   Considered the gold standard for MRSA infections. 

Used for:  all sorts of situations with suspected or proven gram positive infections from above organisms, including bacteremia, meningitis, PNA, skin/soft tissue, and more.  Drug of choice for gram positive infections in patients with severe beta-lactam allergy.

• Considered a slowly cidal drug (compared to beta-lactams), but static vs Enterococcus

• Not as effective as Nafcillin against MSSA, due to slowly cidal nature à increased treatment failure/relapse when used for MSSA bacteremia/endocarditis!

• VISA = MIC 4-8, VRSA = MIC ≥16.  Avoid for MRSA infections with MIC ≥2 à increased treatment failure

• PO form is not absorbed – used for severe C.diff infections (superior to Metronidazole)

• Side effects: Red man syndrome (due to histamine release àcan lessen by slowing the infusion rate and pretreatment with antihistamines), nephrotoxicity (ATN), and ototoxicity (reversible, as compared to aminoglycosides), bone marrow suppression (leukopenia > thrombocytopenia)

• Dosing – typical = 15 -20 mg/kg (actual body weight) q12 hrs, can load 25-30 mg/kg in critically ill patients.  The typical 1 g q12 dosing is inadequate for most patients.  For severe renal failure, can dose “by levels” – i.e. load 15 mg/kg, then check daily levels and redose when level <10-15.

• Check trough prior to 4th dose for severe infections or those with unstable renal function.  Goal trough 15-20 for severe/invasive MRSA infections (~20 for CNS infections), 10-15 for less severe infections (i.e. routine cellulitis, coag negative staph, etc.).   Some experts will not even check troughs in non-severe, non-MRSA infections in patients with stable renal function.

Dalbavancin (IV) - newer 2nd generation lipoglycopeptide antibiotic, with similar spectrum of vancomycin and indicated for skin and soft tissue infection. Main advantage is once a week dosing (injected at depot that slowly releases).

2. Linezolid (Zyvox) (PO and IV)

Mechanism: Oxazolidinone class –unique ribosomal inhibitor (acts on 50S subunit).  Bacteriostatic agent.

Spectrum: covers all Gram positives including strep, MRSA and VRE.  Also has good activity vs tuberculosis.  

Used for:  skin/soft titssue infections, HAP/HCAP/VAP with suspected MRSA, VRE infections

• Oral form has virtually 100% bioavailability

• Controversial: may be superior for MRSA pneumonia than Vancomycin à better lung penetration and antitoxin effect?   Also: may be superior vs Vancomycin for complicated skin/soft tissue infections due to MRSA – similar rationale (tissue penetration, antitoxin effect)

• Side effects: Expensive! Also: Bone marrow suppression especially thrombocytopenia(reports of reversal with pyroxidine) - ~5% rate after several weeks, increased risk with renal failure.   If using for >1 week, monitor CBC closely.  Also, Linezolid is a MAO inhibitor – risk of serotonin syndrome with SSRI’s, avoid co-administration.    Long term usage can lead to mitochondrial toxicity à lactic acidosis, peripheral neuropathy, optic neuritis and blindness.  In general, Linezolid is well tolerated for short-term, but not so much long-term.

• Since mechanism is static, in general prefer other agents for severe bacteremia, endocarditis. 

3. Daptomycin (IV)

Mechanism: Lipopeptide antibiotic – forms transmembrane channels and depolarizes cells.  Rapidly cidal drug.   

Spectrum: only covers Gram positives including MRSA, strep, and Enterococcus/VRE.  No gram negative activity.

Used for: complicated skin/soft tissue infections, also being used more for MRSA bacteremia/endocarditis (due to cidal nature)

• Cannot use for pneumonia (lacks activity in lung parenchyma due to inactivation by surfactant)

• Achieves high serum levels, but poor penetration into CNS, bone

• Main side effect = muscle toxicity (myalgias, rhabdomyolysis) àcheck baseline and weekly CK, and discontinue statins.  Also: peripheral neuropathy, GI side effects, pain at injection site

• Dosing depends on indication – 6 mg/kg (or higher - 8-10 mg/kg) qday for bacteremia/endocarditis, 4-6 mg/kg qday for skin/soft tissue infections.   

• Resistance commonly emerges when used long-term for MRSA and VRE infections.  Also, rise in Vancomycin MIC parallels emergence of Daptomycin resistance (if Vancomycin MIC ≥2, be sure to check for Daptomycin resistance).

4. Synercid (Quinupristin/Dalfopristin) (IV)

Mechanism: “Streptogramins”– inhibits sequential steps in ribosomal synthesis

Spectrum: covers MRSA and VRE due to E.faecium.  Does not cover E.faecalis (has natural efflux pump).

Used for:Not much, as it is very poorly tolerated due to thrombophlebitis at IV siteà generally need central line.  Also severe myalgis/arthralgias and lots of drug-drug interactions (CYP450 inhibitor).  Poor choice for bacteremia/endocarditis due to static nature.

5. Tigecycline(IV)

Mechanism: Glycylcycline class - structurally related to Tetracyclines (bacteriostatic).  Only IV.  

Spectrum: Broad coverage - Gram positive (including MRSA and VRE), Gram negatives, anaerobes, and atypicals.   Notable holes in coverage include Pseudomonas, Proteus, and Providencia. 

Used for: complicated intraabdominal infections, skin/soft tissue infections, and sometimes for pneumonia.

• Beware overall increased risk of death when used for severe infections (2010 metanalysis) – FDA black box warning!

• High rate of failure for HAP/VAP, use with caution

• Achieves low serum concentrations (distributes widely into tissues) – poor choice for bacteremia (also note its static mechanism)

• Sometimes effective against MDR gram negative pathogens including some ESBL and carbapenemase-producing strains – if dealing with such a bug, should ask micro to test susceptibility to tigecycline.

• Main side effects = GI (nausea/vomiting/diarrhea) and elevated LFTs

6. Ceftaroline (5th Gen Cephalosporin) – see Beta-lactam section above.  Covers MRSA, VISA, VRSA, Strep, Enterococcus faecalis/VRE (but not as good vs E.faecium).  Similar gram negative coverage as Ceftriaxone.

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VI. “SUPER GRAM NEGATIVE ANTIBIOTICS” THAT COVER PSEUDOMONAS

Pseudomonas aeruginosa is a non-fermenting Gram-negative bacillus that inhabits a variety of environments (soil, water) and causes nosocomial infections (HAP/VAP, catheter-related infections, UTIs, post-surgical) and commonly affects immunocompromised patients (common cause of neutropenic fever, ecthyma gangrenosum), cystic fibrosis, and burn patients.  It is feared due both for its inherent resistance to most antibiotics as well as its propensity to develop resistance.

• For serious infections due to suspected Pseudomonas, generally recommended to “empirically double cover” with two antibiotics from different classes until susceptibilities identified, then narrow appropriately to one drug.  However, the utility of “continued double-coverage” (after susceptibilities identified) is a long-standing point of controversy – some experts recommend this for serious infections including bacteremia in neutropenic patients, endocarditis, meningitis, and possibly pneumonia.

• Double coverage involves a beta-lactam plus either Fluoroquinolone or Aminoglycoside.  Use Aztreonam if PCN-allergic.  Avoid double beta-lactam therapy.

• Only Ciprofloxacin and Levofloxacin come in PO form, all other are IV only.

1. Zosyn(Piperacillin/Tazobactam)  and Timentin (Ticarcillin/Clavulanate) – note high rates of resistance to Ticarcillin.

2. Carbapenems – Meropenem, Imipenem , Doripenem.  Remember:  Ertapenem has no activity.

3. Ceftazidime, Cefepime (4th gen cephalosporin) 

4. Aztreonam – high rates of resistance at most institutions, so use only if PCN-allergic, and empirically double-cover.

5. Fluoroquinolones - Ciprofloxacin (~70% coverage) > Levofloxacin (~65%), NOT Moxifloxacin (0%)        - usually used as double coverage, not for monotherapy for empiric Pseudomonas treatment.

6. Aminoglycosides – On average, Amikacin >  Tobramycin  > Gentamicin - generally do not use as monotherapy for serious Pseudomonas infections except for UTIs (tend to have worse outcomes), only as 2nd agent added to primary beta lactam therapy.

7. Polymyxins - Colistin (Polymyxin E) and Polymyxin B(IV)

Mechanism: cationic detergent – binds to (and disrupts) lipids of bacterial cell membranes.  Cidal mechanism.

Spectrum: Active mainly against Gram negative organisms including Pseudomonas, Klebsiella, Enterobacter, Acinetobacter.  No activity vs Gram positives.  Limited activity vs anaerobes.  Proteus and Serratia are generally resistant.

Used for: generally reserved for multidrug-resistant gram negative infections from above organisms, including pneumonia, bacteremia, and others.

• Can be given in aerosolized form as well as IV (both forms used quite commonly in Cystic Fibrosis patients with resistant gram negative infections)

• Old drugs that had been long abandoned for routine use due to its toxicity à Nephrotoxicity (reversible, dose-dependent) and Neurotoxicity (dizziness, pareshtesias, vertigo, ataxia, etc), but recently experiencing a comeback due to rise in resistant gram negatives.  May be better tolerated than older literature suggests.

*Treatment of HCAP/HAP/VAP in patients with high risk of MDR organisms: Essential to empirically treat for MRSA, and Gram negatives including Pseudomonas *

• Empiric 2-3 Drug Regimen:

• Anti-MRSA Antibiotic: Vancomycin or Linezolid (Not Daptomycin)

• Anti-Pseudomonal Beta-lactam Antibiotic: Ceftaz/Cefepime, Piperacillin-Tazobactam, Carbapenem (not Ertapenem), or Aztreonam

• “Double Coverage” Agent for Pseudomonas (Optional – depending on severity of illness, local antibiotic susceptibility patterns, etc): Aminoglycoside, or Ciprofloxacin/Levofloxacin (Not Moxifloxacin).  FQ’s have additional advantage of atypical coverage in cases where this is a possibility. 

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VII. ANTIBIOTICS WITH ANAEROBE COVERAGE

Infections in which anaerobes are likely to play an important role include (from head to toe):

• CNS abscesses (Brain, epidural, subdural)

• Infections arising from the oral cavity (Dental abscesses, Peritonsillar abscess, Deep neck space infections) – major pathogens include Peptostreptococcus, microaerophilic streptococci, Fusobacterium, and others.

• Aspiration pneumonia/lung abscesses/empyema – same pathogens as oral infections

• Intraabdominal infections (e.g. perforation, peritonitis, intraabdominal abscesses) – major anaerobic pathogen is Bacteroides species

• Gynecological infections (endometritis, tuboovarian abscesses, pelvic inflammatory disease)– major pathogens include Prevotella species and others

• Certain skin and soft tissue infections (Fournier’s gangrene, diabetic foot ulcer, decubitus ulcers, bite wounds) – anaerobic pathogens depend on site. 

For intraabdominal infections, avoid Clindamycin, Moxifloxacin, and Cefotetan/Cefoxitin due to increasing resistance amongst Bacteroides.  Apart from these drugs, all antibiotics listed below have excellent Bacteroides coverage and as a general rule, do not need to “double cover” anaerobes.

1. Metronidazole (Flagyl)(PO and IV)

Mechanism: selectively taken up by anaerobic bacteria and reduced by proteins in the electron transport chain, leading to DNA disruption.

Spectrum: Anaerobes (including C.difficile), and Protozoans: Giardia, Trichomonas, Entameba histolytica, also Helicobacter pylori (part of triple therapy).   

Used for: Anaerobic infections usually in conjunction with other agents (since anaerobes usually part of a polymicrobial infection).  Also used for mild-moderate C.diff , and protozoal infections as above.

• Drug of choice for most anaerobes, but with notable lack of activity against Propionibacterium acnes, Actinomyces, and Lactobacillus.

• Classically best for infections “below the diaphragm” – mainly due to excellent activity vs Bacteroides, and less reliable activity vs Peptostreptococcus (gram positive oral anaerobe) and total lack of activity vs microaerophilic streptococci.  For this reason, should never use as monotherapy against above-the-diaphragm infections like lung abscesses, etc. (but fine to combine with beta-lactam, levofloxacin, etc).

• Excellent (virtually 100%) bioavailability

• Good CSF penetration (unlike Clindamycin).

• Side effects: nausea, diarrhea, metallic taste, dose-dependent and possibly cumulative peripheral neuropathy (avoid multiple courses for recurrent C.diff), also Disulfiram effect w/ EtOH.  Peripheral neuropathy is usually reversible.  Not well tolerated long-term.

2. Clindamycin – classically for infections above the diaphragm, as it also has activity vs microaerophilic streptococci; avoid in intraabdominal infections due high rates of resistance among Bacteroides species (up to 40% or more).

3. Combined PCN/Beta-Lactamase inhibitors: Augmentin, Unasyn, Zosyn, Timentin – all have excellent anaerobic activity, so no need to add Metronidazole (unless for C.diff).  Unasyn better for anaerobic infections above the waist, less so for intraabdominal infections (due to high rate of resistance in E.coli).

4. Carbapenems (Imipenem, Meropenem, Ertapenem, Doripenem) – all have excellent anaerobic activity.

5. 2nd Generation Cephalosporins (Cephamycins): Cefoxitin, Cefotetan – beware increasing resistance of Bacteroides (Cefoxitin is better than Cefotetan, but avoid both for serious intraabdominal infections)

6. Moxifloxacin – has data to support its use in intraabdominal infections, but beware increasing resistance among Bacteroides (up to 40%!)

7. Tigecycline – excellent anaerobic activity.

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VIII.  URINARY TRACT INFECTION-SPECIFIC ANTIBIOTICS

1. Nitrofurantoin (Macrobid) (PO)

Bactericidal agent that is excreted into urine, where its active metabolites attack multiple sites within bacteria. 

Spectrum:  Broad spectrum vs Gram positives including Staph, Strep, Enterococcus (including some VRE); most Gram negatives including some ESBL’s.  No activity vs Pseudomonas.

Used for: only for lower tract UTI’s (cystitis).  Generally given for 7 day course.  Cannot use for pyelonephritis (poor kidney tissue penetration).

• Avoid for long-term use due to potential pulmonary side effects: Hypersentivity Pneumonitis(occurs 7-10 days after therapy, usually resolves)  and Chronic Pulmonary Fibrosis (develops after several months of therapy, some recovery but often persistent fibrosis)  

• Contraindicated in renal failure with CrCl < 60 (poor excretion into urine)

2. Fosfomycin (PO)

Bactericidal agent that is excreted into the urine and inhibits cell wall synthesis by interfering with peptidoglycan synthesis.

Spectrum: Broad spectrum vs Gram positive including MRSA, VRE; Gram negative including Pseudomonas and some ESBL’s.  

Used for: Uncomplicated urinary tract infections in women, especially in those with history of resistant bugs.  Given as a one-time mega-dose of 3 g (excreted into urine and achieves high levels there for several days.   Sometimes used for complicated UTI’s in males with resistant pathogens (3 g PO q3 days x several doses), although this is an off-label use.

• Like nitrofurantoin, cannot use for pyelonephritis due to poor kidney tissue penetration.

• Resistance develops rapidly – not suitable for sustained therapy for severe infections.

• Minimal side effects and very well tolerated.

3. Methenamine (PO)

Antimicrobial agent that is converted to formaldehyde in the bladder, leading to bacteriostatic effect.  Requires acidic environment to work (pH < 5.5) so ineffective vs Proteus.

Used for: prevention of recurrent UTI’s (as opposed to treatment of active infection).

• Actual efficacy is controversial but some evidence to support use for short-term prophylaxis. Long-term efficacy is unclear.

• Contraindicated in renal failure – decreased excretion into urine leads to systemic accumulation and toxicity.

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IX. ANTI-C.DIFFICILE ANTIBIOTICS

1. Metronidazole – (see anti-anaerobe section above for more details).  First-line therapy for first or second episode of mild-moderate C.difficile infection (defined as WBC <15 k, no acute renal failure).  PO preferred if able, but IV is also effective.  IV form used for severe, complicated cases (e.g. ileus or toxic megacolon) where absorption of PO vancomycin may be unreliable.  Not recommended after 1st relapse due to cumulative neurotoxic effect.

2. Oral Vancomycin – first-line therapy for severe C.diff infection (WBC >15k, or acute renal failure).  Shown to be superior in severe cases of C.diff vs Metronidazole (CID 2007).  

• Dose = 125 mg po q6 hours, or 250-500 mg po q6 hours for severe complicated disease (ileus, hypotension, toxic megacolon), although no supporting evidence for this higher dose.  Also consider vancomycin enemas (and surgical consult) in those situations.   

• No systemic absorption, and thus no side effects (main side effect = cost!)

• It is a myth that PO vancomycin increases risk of VRE compared to Metronidazole (both increase the risk of VRE – Metronidazole disrupts anaerobic flora of the gut, promoting overgrowth of VRE).

3. Fidaxomicin (PO)

Mechanism: new macrocyclic antibiotic with narrow spectrum of activity against only C.diff (inhibits C.difficile RNA polymerases). 

• Minimal absorption and thus minimal side effects.  Dose = 200 mg bid.

• Noninferior (and likely superior) to oral vancomycin for initial treatment of C.difficile.  Main advantage is reduced rates of relapse, but this benefit not seen so far for NAP-1 strain.  Also has higher cure rate when used in patients with C.diff who require continued systemic antibiotic therapy for other reasons.

4. Other options - Rifaximin (sometimes used at the end of a prolonged course to prevent relapse in high-risk patients), Nitazoxanide, Tigecycline (case reports of success).   Non-antibiotic options include IVIG, Monoclonal Antibody vs C.diff, stool transplant, and surgery.

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X. RIFAMYCINS – include Rifampin, Rifaximin, Rifapentine, Rifabutin.

Mechanism: Inhibits bacterial DNA-dependent RNA polymerase (unique mechanism).

1. Rifampin (PO and IV)

Spectrum: Broad spectrum including Mycobacteria and other intracellular pathogens, Gram positive (Staph, Strep, Listeria), Gram negatives. Despite broad spectrum, only used for select indications.

Used for: Active TB (in combination with other drugs), Latent TB (2nd-line), N.meningitidis contact prophylaxis, Staphylococcal prosthetic infections

• Aside from its role in mycobacterial infections, Rifampin’s other main use is its adjunctive role in treating Staphylococcal (both S.aureus and Coag-negative Staph) infections involving prosthetic material (due to its unique ability to penetrate biofilms) -  prosthetic valve endocarditis, prosthetic joint infections, etc. 

• Resistance develops rapidly, so two important caveats: 1. Never use as monotherapy.  2. Do not use for Staphylococcal infections until low burden of disease (i.e. after initial induction period with IV therapy, debridement, etc). 

• Side effects: Orange discoloration of body fluids (urine, tears, sweat), hepatotoxicity, rare bone marrow toxicity, rash.  Multiple drug interactions (potent CYP inducer).

2. Rifaximin (PO)

Nonabsorbable analog of rifampin, used for treatment of traveler’s diarrhea, hepatic encephalopathy(both in the acute phase and for long-term prophylaxis), and C.difficile infection (usually as a tail to a prolonged taper).

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XI. IMPORTANT HOLES IN COVERAGE WITH VANCOMYCIN / ZOSYN

Vanc/Zosyn is not elegant, but will cover most infections:  Gram positives including MRSA, Gram negatives including most Pseudomonas, and anaerobes.  Excellent range of site penetration including lungs, abdomen, urine, and skin/soft tissues.  Not a bad choice if patient is very ill and unclear source of infection.

But what does it not cover?  I.e., what to worry about if pt spiking through Vanc/Zosyn – a selected list:

 1) Atypical infections – Legionella, Chlamydia, Mycoplasma.  Vanc/Zosyn is not adequate for Community-Acquired Pneumonia.

2) VRE – suspect especially if patient previously on vancomycin 

3) ESBL – think of this if patient has been hospitalized recently and received broad spectrum Abxs

4) Fungal infections – be on the lookout for this, esp if spiking through broad spectrum abxs, and

other risk factors (TPN, Central lines, Bowel surgery, Immunosuppressed/Neutropenic)

5) Clostridium difficile 

6) Stenotrophomonas maltophilia – nonlactose fermenting gram negative rod that causes infections, usually in ICU patients (esp with prior Carbapenem use) or immunocompromised.

7) Mycobacterial infections – especially consider in patients with “pneumonia” and high risk for TB

8) Viral Infections – Influenza, HSV/VZV/CMV etc. (esp in immunocompromised pts)

 9) Parasites – consider your patient’s demographics

10) Any gram negative can develop resistance, and so can Staph – VISA, VRSA (very rare)

11) Source control – Abxs will not cure infection if source not controlled – undrained abscess,              infected line, empyema, etc.

12) Non-infectious causes of fever – DVT’s, hematoma, drug fever, malignancy,  transfusion reactions, pancreatitis, and more

Note:  Typical “Step up” from Vanc/Zosyn à Linezolid/Meropenem – gains VRE and ESBL coverage, also possibly better MRSA PNA coverage.

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ANTIFUNGALS

I. AZOLES 

Mechanism:  inhibit ergosterol synthesis (important component of fungal cell membranes)

• Main metabolism is hepatic, main toxicity is elevated LFTs.

• Only Fluconazole has adequate urinary penetration.  Itraconazole has poor CNS penetration compared to the others. 

1. Fluconazole(PO or IV)

Drug of choice for non-severe Candida infections, including C.albicans, EXCEPT C.glabrata (can potentially overcome with higher doses – check susceptibilities) and C.krusei (Kompletely resistant). 

Also used for Cryptococcus infections (maintenance phase for cryptococcal meningitis after induction with Ampho B), Coccidioidomycosis, Histoplasmosis (but inferior to Itraconazole), and others.

• Toxicity: elevated LFTs, GI side effects

• Good urine penetration – used for symptomatic candidal cystitis. 

• Best bioavailability of the azoles – if GI system intact, perfectly acceptable to treat even invasive candidiasis with oral Fluconazole. 

• Selected dosing: Candidemia - 800 mg load then 400 mg qday.  Thrush – 100 mg qday x 7 days. Esophageal candidiasis - 200 mg qday or higher x 14-21 days.  Dose reduce in renal failure.

2. Itraconazole(PO or IV)

Best activity among azoles vs Histoplasmosis – used for non-severe cases, and can also follow induction phase with Ambisome for severe disease.  Also used for Blastomycosis, sometimes Cocci and Paracocci infections, and onychomycosis. Commonly used for prophylaxis in transplant patients

• Toxicity: elevated LFTs and also negative inotrope – can worsen or cause CHF in predisposed pts (black box warning)!

• Many drug-drug interactions

• Capsule form has poor bioavailability and absorption depends on acidic environment (avoid PPI/H2 blockers).  Liquid form is superior (must take with empty stomach)

• Poor CNS penetration

3. Voriconazole(PO or IV)

Cidal for many molds à drug of choice for Invasive Aspergillosis! (appears to be superior to Ampho B and better tolerated -  NEJM 2002 ).  Active vs Fusarium and Scedosporium.  Also effective against most Candida, but little reason to use over Fluconazole, and ~50% cross-resistance. 

• One important hole in coverage is no Zygomycetes (Mucormycosis)

• Liver toxicity, also Visual toxicity – transient visual changes (common) and visual hallucinations (~4%, also reversible).  Encephalopathy with supratherapeutic levels.

• Usually loaded intravenously, then can transition to oral form.  If given long-term, need to check troughs to ensure adequate dosing (goal trough 1-5).

• Problem with IV form is that it is solubilized in cyclodextrin, which accumulates in renal failure (potentially nephrotoxic).

4. Posaconazole(PO only)

Broad spectrum of activity: yeast (including many Fluconazole-resistant Candida), molds, endemic fungi, zygomycetes (only azole other than Isavuconazole with activity).  Fusarium is resistant in vitro.

Used as 2nd-line / salvage therapy for many severe fungal infections, and for fungal prophylaxis in high-risk patients (e.g bone marrow recipients).

• Main problem is that it is only available PO, and must be given with fatty foods for maximal absorption .  Takes ~1 week to reach steady-state levels, and hence unsuitable for acute treatment of severe fungal infections.

• Similar toxicity profile as Fluconazole

5. Isavuconazole(PO or IV)

Newest triazole currently undergoing Phase III trials.  Broad activity vs virtually all fungi (like Posaconazole) including Candida, Aspergillus, Mucormycosis, Fusarium, Scedosporium, Cryptococcus.

• Advantage over Posaconazole is that it has IV formulation as well as PO, so more suitable for initial therapy of acute infection.

• Advantage over Voriconazole is that the IV formulation does not require cyclodextrin, and thus safe to use in renal failure.

• Still undergoes CYP metabolism so problem with drug interactions.  Similar toxicity as Fluconazole (well tolerated) .

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II. ECHINOCANDINS 

Mechanism: Inhibit glucan synthesis in fungal cell wall by blocking beta 1,3 D-glucan synthase à fungicidal agent.  All are IV only.

Cidal vs Candida -> Drug of choice for severe Candida infections – covers virtually all species including Fluconazole-resistant C.krusei and C.glabrata.  But higher MICs in vitro for C.parapsilosis (commonly associated with TPN) – unclear significance as it still usually works clinically.  Also, rare reports of resistance in C.lusitaniae, C.guilliermondii.

Static vs Aspergillus -> 2nd-line for Aspergillus infections (often as combination therapy or as salvage therapy, never as initial monotherapy)

All Echinocandins lack activity vs Cryptococcus, Zygomycetes, and Fusarium.

• Remarkably non-toxic, but can rarely cause elevated LFTs, also GI upset (n/v)

• Poor penetration into urine – not used for UTIs.  Also, not much data on CSF penetration – not recommended for fungal meningitis. 

• Not well studied for Candida endocarditis (prefer Amphoterecin)

• All 3 agents are essentially interchangeable in terms of spectrum of activity

1. Caspofungin

First approved echinocandin. Load 70 mg IV qday, then 50 mg qday.  Hepatically cleared.

2. Micafungin

Similar to Caspofungin. 100 mg daily, no loading dose.  Hepatically cleared.  

3. Anidulafungin          

Newest echinocandin.  Unique metabolism: chemically degraded in the blood, no hepatic or renal clearance àsafer in liver/renal failure.  Also no significant drug-drug interactions. 

Load 200 mg IV once, then 100 mg IV qday

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III. POLYENES – Amphoterecin B, Abelcet, Ambisome

Mechanism: binds ergosterol in membrane and forms membrane pores à fungicidal.

Drug of choice for many severe fungal infections: Zygomycetes, Cryptococcal Meningitis (induction phase with flucytosine), Severe Histoplasmosis/Blastomycosis/Coccidioidomycosis

2nd-line for invasive aspergillosis (voriconazole is drug of choice).  2nd-line for candida infections – because echinocandins are at least as effective, and less toxic.

• Note that some candida are resistant, often C.lusitaniae and C.guilliermondi

• Significant toxicity: Nephrotoxic (including Mg and K wasting), Hypotension, Bradycardia, Fevers/chills during infusion (“shake and bake”), Seizures

• Lipid preparations (Ambisome, Abelcet) are designed to reduce binding to mammalian cell membranes.  They are as effective as conventional Amphoterecin and less toxic (especially with renal toxicity), although more expensive.  Ambisome is less toxic than Abelcet.  Nowadays, rarely use non-liposomal amphoterecin B. 

IV. Flutycosine

Mechanism: 5-FC interferes with DNA and protein synthesis.  Only available PO in the US

Used in combination with Amphoterecin B for initial management of several severe fungal infections: Severe cryptococcal pneumonia and meningitis, severe candidal infections (endocarditis, meningitis)

• Virtually never used as monotherapy due to high incidence of primary and acquired resistance (monotherapy reserved for non-severe candida urinary tract infections)

• Main adverse effects = Hematologic (Leukopenia and Thrombocytopenia) and Hepatic toxicity.  Drug levels should be monitored to reduce toxicity.

In Summary:

1. Mild-Moderate Candidemia -> Fluconazole

2. Severe Candidemia -> Echinocandin (> Amphoterecin)

** Other principles of management of Candidemia – remove central lines and foreign bodies, check ophtho exam to evaluate for endophthalmitis, treat for minimum 14 days from clearance of blood cultures**

3. Invasive Aspergillosis -> Voriconazole (> Amphoterecin, Echinocandin as 2nd-line)

4. Mucormycosis à Amphoterecin B

EMPIRIC ANTIBIOTIC CHOICES FOR COMMON INFECTIONS