Med I: Principles of Antimicrobial Therapy

Empiric versus definitive coverage

Empiric: best guess based on body part or type of infection

Definitive: based on culture and sensitivity results

• Problem: C and S take about 2-3 days for final results

Site of infection

Penetration: harder in bone and lung

Minimum inhibitory concentration (MIC)

• The lowest concentration of an antimicrobial that will inhibit the visible growth of an organism

Post-antibiotic effect

• Period of time after complete removal of an antibiotic during which there is no growth of the target organism

Drug-specific factors

IV versus PO

Bacteriostatic versus bacteriocidal

Cost per day

• i.e., UTI: range from $4/day to $76/day to treat same bug

Bacterial Resistance Mechanisms

Inactivation by various beta-lactamases

• “Traditional” beta lactamases

• Now seeing carbapenemases as well

Development of new binding proteins that have decreased affinity for the antibiotics

Decreased permeability of cell wall

Modification of cell membrane constituents in certain orgs >>> prevent penetration

Drug broad classes

Cell Wall Active, Beta Lactams

– Penicillins, Cephalosporins, Thienamycins (“Penems”), Monobactams

Protein-Synthesis Active

– Aminoglycosides, Tetracyclines, Macrolides, Lincosamides

Cell Wall Active, Non-Beta Lactam

– Vancomycin

Other mechanisms

Fluoroquinolones

• DNA gyrase

TMP-sulfa

• Purine synthesis inhibition

Static versus Cidal

Bacteriostatic

• We're ECSTaTiC about bacteriostatic

– Erythromycin (macrolides)

– Clindamycin

– Sulfonamides (Bactrim®)

– Tetracyclines

– Trimethoprim (Bactrim®)

– Chloramphenicol

Bacteriocidal

• Very Finely Proficient At Cell Murder

– Vancomycin

– Fluoroquinolones

– Penicillins

– Aminoglycosides

– Cephalosporins

– Metronidazole

Penicillins

Cell wall active drugs

• Disrupt bacterial cell wall formation by inhibiting certain enzymes that create cross-linking

  • Activation of the endogenous autolytic systems of these bacteria causes cell lysis and death

• Divided into several subclasses

• Most need to be dose adjusted for CrCl < 50 ml/min

  • Some need hepatic adjustment instead

• Spectrum of activity

  • Mostly Gram positive, some Gram negative

Classes

• Four subclasses:

  • Natural penicillins

  • Aminopenicillins

  • Penicillinase-resistant

    • a/k/a anti-staph penicillins

  • Beta-lactamase inhibitor combinations

    • Includes antipseudomonal PCNs

Adverse Events

• Hypersensitivity reactions

• Neutropenia

• Interstitial nephritis

• Central nervous system toxicity (seizures)

Pharmacokinetics

• Absorption

  • Most are destroyed by gastric acid; others absorbed in duodenum; reach peak concentrations in 1-2 hours

• Widely distributed to many tissues and fluids

• Minimal or no metabolism by the liver

• Elimination

  • Half-life is generally short

  • Excreted primarily by the kidneys (some biliary)

Considerations

• Pregnancy/Lactation

  • Generally compatible; crosses placenta; excreted in milk

• Geriatrics

  • More susceptible to side effects; monitor renal and liver function

• Renal Impairment

  • Dose adjust when CrCl < 50–60 (as previously stated)

Natural Penicillins

• Active against Streptococcal spp. (including Enterococcus spp.), T. pallidum, and some anaerobic cocci (Peptococcus and Peptostreptococcus)

• Products: penicillin G, penicillin V, procaine penicillin, benzathine penicillin

• Distribution: lung, ascites, synovium, pericardium, ascitic fluid, soft tissues

• Dose adjustment is necessary for decreased renal function (CrCl < 50 ml/min)

• Drug of choice

  – Syphilis, Strep infections

Aminopenicillins

• Retain the activity of naturals, but have extended Gram negative spectrum (H.

  influenzae, E. coli, K. pneumoniae)

• More active against Enterococcus than other penicillins

• Not very β-lactamase stable

• Drugs: ampicillin, amoxicillin

  – Amoxicillin more completely absorbed

• Distribution: renal tissue, septic joints, ascitic fluid, CSF (inflamed meninges)

• Drug of choice for sensitive Enterococcal infections

• Dose adjust for CrCl ≤ 50

Penicillinase-Resistant PCNs

• Drugs: oxacillin, nafcillin, dicloxacillin

• Activity:

  – Streptococcal spp.

  – Staphylococcus aureus

  – Peptostreptococcus

• Key points:

  – No gram negative activity

  – Good Strep activity, excellent Staph activity

• Distribution: bone, septic joint effusions, cardiac tissue

• Drug of choice for methicillin sensitive S. aureus infections (MSSA)

  – Structure hinders β-lactamase made by S. aureus from attacking the β-lactam nucleus

• Big sodium load with nafcillin (is IV)

• Dosage adjustment needed for severe

  hepatic impairment

Ureidopenicillins (Anti-Pseudomonal Penicillins)

• Product: piperacillin (always given with a BLI)

– Significantly improved activity against Gram negatives (pseudomonas, Bacteroides)

– Some Enterococcal activity

– Good activity against anaerobes (piperacillin)

– NO activity against Staphylococcus

– Not very beta-lactamase stable

• Distribution:

  – Pleural fluid, ascitic fluid, wound fluids

• Dose adjustment

  – Necessary for CrCL < 50 ml/min

Beta-Lactam/Beta-Lactamase Inhibitors

• Activity: adds H. influenzae, M. catarrhalis, N. gonorrhoeae, and B. fragilis

• Key points:

  – Extends Gram negative and Gram positive activity

  • Also extends the activity of Gram negative anaerobes

  – Very useful in “mixed” infections or for broad empiric coverage as a single agent

• β-lactamase inhibitor (BLI) blocks attack of β-lactam nucleus, thus allowing binding to transpeptidase enzymes and disruption of cell wall formation; BLIs HAVE NO ANTIMICROBIAL ACTIVITY

• Products:

  – Ampicillin/sulbactam (Unasyn®)

  – Amoxicillin/clavulanic acid (Augmentin®)

  – Piperacillin/tazobactam (Zosyn®)

• Newer BLI combinations

  – Adds a BLI to a cephalosporin or a penem (coming

  up)

• Distribution: good throughout all tissues

Cephalosporins

• Mechanism of action

  – Same as the penicillins

• General activity

  – Varies, but no ceph covers Enterococcus

• Some have a methyltetrazolethiol (MTT) side

  chain

  – Prolongation of prothrombin time/INR

  – Disulfiram reaction with alcohol

  • Cefotetan

• Absorption:

  – Rapidly and thoroughly absorbed

• Distribution:

  – Penetrate well into most tissues and fluids

• Metabolism:

  – Ceftriaxone is ~ 40% metabolized by the liver

• Elimination:

  – Half-life mostly short (except ceftriaxone)

  – Most are excreted unchanged in the urine

  • Some undergo biliary excretion

• Considerations

  • Pregnancy/Lactation: Generally compatible

    • cross placenta; may see increased Vd and increased clearance; most cross breast milk in small amounts

  • Geriatrics

    • Dose adjust based on renal insufficiency as previously mentioned

  • Renal Impairment

    • Most dose adjust at Crcl < 50

First Generation Cephs

• Cefazolin (IV); cephalexin, cefadroxil (PO)

• Activity:

  – Very active against Streptococcal spp. and MSSA

  – Limited activity against Gram negative organisms

  – NO anaerobic coverage

  – Poor CSF penetration

• Distribution: (cefazolin)

  bone tissue synovial fluid

  pleural fluid wound fluids

  ascitic fluid inflammatory exudate

• Dose adjustment necessary for CrCl < 50

  ml/min

Second Generation Cephs

• Divided into two groups:

  • Group 1 (Cefuroxime, cefaclor)

    • Very active against Strep spp. and MSSA

    • Significantly improved activity against Gram negative organisms

    • No activity against Gram negative anaerobes (B.fragilis)

    • Variable CSF levels

  • Group 2 (aka cephamycins); (Cefoxitin, cefotetan)

    • Inferior activity against Strep spp. and MSSA

    • Enhanced activity against Gram negatives compared to the 1st and 2nd generation true cephalosporins

    • Good activity against Bacteroides spp. (B. fragilis)

• Distribution

  – General: penetrates into various tissues/fluids

  • Lung, female genital tract, kidney, synovial fluid, pericardial/peritoneal fluid, pleural fluid

  • Cephamycins: best for “dirty” surgery

  • Cefuroxime: penetrates well into the CSF

• Dose adjustment necessary for decreased renal function

Third Generation Cephs

• Anti-pseudomonal

  – Ceftazidime

• Others

  – Cefotaxime, ceftriaxone, cefixime, cefpodoxime proxetil

• Distribution:

  – Extensive for all

• Dose adjustment necessary for decreased renal function and/or hepatic function

• Ceftazidime only: has excellent activity against P. aeruginosa

  – Ceftazidime against Streptococcal spp. is adequate but significantly less than that of other cephalosporins

  – Poor activity against gram negative anaerobes (most cover < 50% of B. fragilis)

• All 3rds: Activity against MSSA is weak

• Ceftriaxone: excellent CSF levels

Fourth Generation Cephs

• Activity:

  – Basically same as third generation cephalosporins

  • Only one: cefepime

• Key points:

  – Staph and Strep coverage comparable to the earlier generation cephalosporins

  – Superior gram negative activity, with good activity against P. aeruginosa

  – NO MRSA coverage

• Distribution: same as 3rd generation cephs

• Dose adjust for decreased renal function

Fifth Generation Cephalosporins

• Ceftaroline

  – Very broad spectrum

  • GN, GP, aerobic coverage; limited anaerobic activity

  • Effective versus respiratory infections

  • Also effective versus MRSA, S. pneumo, but does NOT cover Pseudomonas

• Ceftobiprole (FDA approved 2024)

  – Does have Pseudomonas coverage

Thienamycins (“Penems”)

• Drugs

  – Imipenem/cilastatin, ertapenem, meropenem, doripenem

  Newer combos: imipenem/cilastatin/relebactam (Recarbrio), meropenem/vaborbactam (Vabomere)

  – True “gorillacillins”; broad coverages

  – Cell wall active; MOA similar to PCNs/cephs

  – 5-10% cross allergy with penicillins

  – Common side effect: nausea/vomiting with IV infusion

  – Good thing: see post antibiotic effect (PAE)

• Active against most GP/GN aerobes

  – Except MRSA and E. faecium

• Active against virtually 100% of Gram negative anaerobes including B. fragilis

• Mero: best activity against P. aeruginosa

• Erta: no P. aeruginosa cvg but great vs ESBLs

• Imipenem/Cilastatin- lowers seizure threshold

  – Especially in CNS pathology or decreased renal fxn

• Widely distributed into most body compartments/fluids and into inflamed meninges

  – Also penetrates bile, bone, synovial fluid, and most tissues

• Dose reduction in renal insufficiency

  – Imipenem metabolized to nephrotoxic product; cilastatin blocks this reaction

  • That’s why they are always together

Monobactams

• Drug: aztreonam

• No activity against Gram positive species

• Moderate to excellent activity against Gram negative aerobic pathogens

  – Including P. aeruginosa

  – No activity against Gram negative anaerobes

• Good substitute for the aminoglycosides in patients at risk for toxicity

• Cross allergy with PCNs/cephs unlikely

  – Except ceftazidime

• Widely distributed

• Used a lot in combination to get greater coverage

  – Used with clindamycin, macrolides

• Dose reduce in renal problems

Non-Beta Lactam, Cell Wall Active: Glycopeptides

• Drug: vancomycin

• Mechanism of action:

  – Binds to the D-alanyl-D-alanine terminal residue in the growing peptidoglycan chain, inhibiting cell wall synthesis

• Key points:

  – Bacteriocidal

  – Oral vanco, used to treat C. difficile, not systemically absorbed

  • IV vancomycin is not used to treat C. difficile

  – AUC/MIC-guided dosing recommended (target 400-600 mg*h/L per 2020 consensus guidelines; trough-only monitoring no longer recommended)

• Adverse event profile:

  – Red Man’s Syndrome (infusion time-related)

  – Neutropenia

  – Ototoxicity

  – Nephrotoxicity (with other nephrotoxic drugs)

• Activity:

  – Streptococcal spp., Staphylococcal spp. (MSSA and MRSA, MSSE and MRSE), Enterococcal spp.

  – No activity against Gram negatives

  – No activity against any anaerobes except C. difficile

• Distribution:

  – Adequate concentrations found in pleural, pericardial, synovial and ascitic fluids

  – Bacteriocidal concentrations in CSF with inflamed meninges

• Doses:

  – Vancomycin IV 15-20 mg/kg/dose

  AUC/MIC 400-600 target

  – Vancomycin PO 125 mg PO q6h

• Elimination:

  – Half-life for vancomycin = 5 hrs to many days

  – Dose adjustment for renal impairment/ failure

• 
  

Considerations for Penems, Monos, Glycos

• Pregnancy/Lactation

  • Generally compatible except imipenem (limited data)

• Geriatrics

  • decrease doses, usually based on GFR

• Renal impairment

  • watch for accumulation with vanco; dose adjust all others as listed

Aminoglycosides

• Drugs:

  – Gentamicin, tobramycin, amikacin, streptomycin

  • Poorly absorbed orally; need intravenous for systemic infections

• Mechanism of action:

  – Binds to 30S ribosomal subunits which decreases protein synthesis

  • Also increases misreading of messenger RNA leading to bactericidal activity

• Key points:

  – BBW: Nephro/ototoxic, need to get drug levels

• Activity:

  – Aerobic Gram negative bacilli including Pseudomonas

  – NO anaerobic or Gram positive activity

  – Very active against Gram negative aerobic organisms

  – Synergistic with cell wall active β-lactams (pen, amp, vanco) and vancomycin for MSSA, MRSA, Enterococcus, and Pseudomonas

• Distribution:

  – Vascular and interstitial spaces of most tissues

  – Good penetration in the urine

  – Poor penetration into lungs, CSF fluid, biliary tract

• Adverse event profile:

  – Nephrotoxicity

  • Injury or death of the proximal renal tubule cells decreasing the glomerular filtration rate

  • Reversible because tubule cells can regenerate

  – Ototoxicity

  • Binds to inner and outer hair cells of the cochlea

  • May be unilateral or bilateral

  • Patients complain of tinnitis or fullness in their ears

  • High frequency hearing loss is commonly asymptomatic

  • Can cause conversational hearing loss

  • Can also see irreversible vestibular ototoxicity

• Elimination:

  – Half-life = 1-72 hours or more

  – 100% excreted by the kidneys

• Dose adjustment needed for decrease renal function

  – Pharmacokinetics sometimes necessary

• Considerations

  • Pregnancy/Lactation

    • Avid in pregnancy (ototoxicity risk); small amount excreted in milk

  • Geriatrics

    • Dose adjust carefully

  • Renal Impairment

    • Dose adjust carefully; dose by levels if indicatied

Tetracyclines

• Drugs: tetracycline, minocycline, doxycycline

• Mechanism of action:

  – Reversibly binds to 30S subunit on the ribosome, preventing protein synthesis

• Key points:

  – Bacteriostatic at therapeutic concentrations

  – Tetracycline and minocycline: avoid in patients with renal and hepatic impairment

  • Dose adjustment necessary

• Activity:

  – Good activity against Gram positive AND Gram negative aerobes (except Pseudomonas)

  – No activity against Gram negative anaerobes

  – Doxycycline: good for MRSA in cellulitis

  – Very good activity against atypical pathogens of pneumonia

• Distribution:

  – Penetration in synovial fluid

  – Maxillary sinus mucosa

  – Bile

  – Small amounts in lung, liver, kidney, brain, sputum, CSF, and mucosal fluid

• Elimination:

  – Half-life = 8-16 hours

• Adverse event profile:

  – Hypersensitivity/photosensitivity reactions

  – Depression of skeletal growth in children

  – Gastrointestinal symptoms

  – Hepatotoxicity

  – CNS symptoms

  • Dizziness, vertigo, loss of balance

  – Aggravation of pre-existing renal failure

• Oral absorption decreased by administration with di- and trivalent cations (milk, antacids, sucralfate, didanosine); 2-4 hour window

  – Tetra >>> Doxy

• Major toxicities

  – GI intolerance, phototoxicity, and Fanconi Syndrome

  – Esophageal irritant; lots of water, no laying down

• Dose adjustment necessary for tetracycline and minocycline with decreased renal/hepatic fxn

• Considerations:

  • Pregnancy/lactation

    • avoid in pregnancy (tooth/bone effects); into breast milk in varying concentrations

  • Geriatrics

    • No issue

  • Renal Impairment

    • adjsut TCN only; doxy OK

Macrolides

• Drugs

  – Erythromycin, clarithromycin, azithromycin

  – Good activity against Gram positive aerobes (erythromycin > clari > azithro)

  – Good activity against Gram negative aerobes (azithro > clari > erythromycin

  – No activity against Gram negative anaerobes

  – Very good activity against atypical pathogens of pneumonia

  • Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae

• Activity:

  – Streptococcus pneumoniae and other Strep spp.

  – H. influenzae, M. catarrhalis, Legionella pneumoniae, Mycoplasma pneumoniae,

  Chlamydophila pneumoniae, Chlamydia trachomatis, Ureaplasma urealyticum, Borrelia burgdorferi

  – H. pylori (clarithromycin, azithromycin)

• Key points:

  – Erythromycin has many drug interactions due to metabolism through the CYP450 enzyme system

  – Clarithromycin and azithromycin active against MAC

  • Mycobacterium avium complex

  – Azithromycin:

  • Tissue half-life is 5 days (lends itself to short course of therapy)

  • Activity against atypical organisms may be superior to fluoroquinolones

  • QTc prolongation issues (less than the others)

• Adverse event profile:

  – Erythromycin

  • Dose-related: abdominal cramps, nausea, vomiting, diarrhea

  – GI seen even with IV form

  • Thrombophlebitis with IV infusion

  • Cholestatic hepatitis (rare)

  – Clarithromycin/azithromycin

  • Nausea, diarrhea, abdominal pain (less than erythromycin)

  • Tinnitis and dizziness with high doses

• Distribution:

  – Erythromycin

  • Poor penetration into many body tissues and fluids

  – Clarithromycin/azithromycin

  • Penetrate well into tissues

  • Particularly good penetration into sputum and lungs

  • Achieves high concentration in alveolar macrophages

• Elimination:

  – Erythromycin and clarithromycin have shorter half-lives

  – Azithromycin half-life = 68 hours

  – Most are excreted in the bile w/ small amounts found in the urine

• Dose adjustment in hepatic/renal impairment

• Considerations

  • Preg/Lact

    • Generally compatible; into breast milk at low concs

  • geriatrics

    • watch for renal insufficiency

  • renal impairments

    • consider dose adjust with GFR<30

Lincosamides

• Drug: clindamycin

• Mechanism of action:

  – Binds to 50S ribosomal subunit, ↓ protein synthesis

• Distribution:

  – Concentrates in bone, bile, most other tissues

  – Does not penetrate well into the CSF

• Key points:

  – Very active against MSSA, MRSA and Streptococcus (better than the macrolides)

  – Very active against Gram negative anaerobes including B. fragilis group

  – NO activity against Gram negative aerobes

  – Good activity against Gram positive anaerobes (Peptococcus, Peptostreptococcus)

  – Good activity against toxoplasmosis

  – Excellent bone penetration

• Elimination:

  – Half-life = 2.4 hours

  – Excreted by various routes (amounts unknown); multiple metabolites with varying antibacterial activity

• Adverse event profile:

  – GI intolerance/diarrhea/pseudomembranous colitis

  – Elevated LFTs and hepatotoxicity (rare)

  – Reversible neutropenia and thrombocytopenia (isolated cases)

  – Esophageal irritation; lots of water, no laying down

• Dose adjustment for renal failure not required

• Considerations

  • preg/lact

    • limited data, excreted into breast milk in varying concentrations

  • geriatrics

    • watch for diarrhea, esp in this pop

  • renal impairment

    • non necessary

Fluoroquinolones

• Drugs: ciprofloxacin, levofloxacin, moxifloxacin

• Mechanism of action:

  – Inhibits DNA gyrase

  • This inhibits bacterial DNA synthesis and results in breakage of bacterial DNA

• Very active against Gram negative aerobe including P. aeruginosa

  – Ciprofloxacin > Levofloxacin

  – Moxifloxacin: no appreciable Pseudomonas coverage

• Variable activity against Gram positive aerobes

  – MSSA: good activity; MRSA: poor activity

  – Streptococcal spp.: Moxi/Levo > Cipro

• No activity against Gram negative anaerobes

  – Exception: some with moxifloxacin

• Key pts:

  • Excellent bone penetration (cipro/levo)

    Good activity against atypical pathogens of pneumonia (moxi, levo)

    Activity against S. aureus and Strep in vitro may not correlate with clinical response

    Oral absorption of levofloxacin almost 100%

    Only oral agents available to treat Pseudomonas

    Resistance now occurring to S. pneumoniae

    Exhibit concentration dependent killing

• Adverse event profile:

  – Mild GI, mild headache and dizziness, insomnia

  – Phototoxicity

  – BBW: Disabling/potentially permanent effects on tendons, muscles, joints, nerves, CNS (2016)

  – Aortic aneurysm/dissection risk (2018 FDA warning) Peripheral neuropathy (may be irreversible) Transient increases in LFTs, hepatotoxicity Hypoglycemia/dysglycemia

  – QTc prolongation (Torsades de pointes)

• Distribution:

  – Concentrations in urine, kidney, prostate, stool, bile, and lung exceed serum concentrations

  – Concentrations in saliva, prostatic fluid, bone and CSF are less than serum concentrations

• Elimination:

  – Half-life = 3-20 hours; urinary excretion

• Dose adjust with renal impairment for most quinolones

• Avoid with milk, dairy, antacids (2-4 hour window)

• Considerations

  • preg/lact

    • avoid in pregnancy (cartilage/tendon risk)

  • geriatrics

    • watch for tendon rupture, DIs with antacids

  • renal impariment

    • dose adjustment needed based on indication with cipro; not needed with moxi

Sulfas: TMP-Sulfa

• Drug: trimethoprim/sulfamethoxazole

• Mechanism of action

  – Inhibition of bacterial folic acid synthesis results in inhibition of bacterial cell growth

  • Inhibits sequential steps in the formation of tetrahydrofolate in bacteria, which inhibits purine synthesis

• Distribution:

  – Penetrates well into many tissues and fluids

  • Concentrations exceed serum in kidney, lung, sputum, bile, and saliva

  – CSF levels are 40% of serum levels

• Key points:

  – One of only a few oral drugs for MRSA cellulitis

  – Must hydrate as crystalluria can form

  – Increases anticoagulation of warfarin - displaces from binding sites – see INR ↑

  • Can also markedly increase phenytoin levels

  – Can cause hyperkalemia

  – Should be avoided in hemodialysis patients

• Good activity against Gram negative and positive aerobes (including moderate activity versus MRSA)

  – Noted exceptions: P. aeruginosa, Group A Streptococcus, and Enterococcus spp.

• No activity against Gram negative

• Very active against P. carinii (P. jiroveci)anaerobes

• Adverse event profile:

  – Gastrointestinal intolerance

  – Hypersensitivity

  • Can see Stevens-Johnson syndrome

  – Anemia, neutropenia, hyperkalemia

  – Elevated serum creatinine so hydrate well

• Elimination:

  – Half-life: 9-11 hours based on component

• Dose adjustment necessary for renal impairment

  – Should not use when CrCl < 15 ml/min

• DI with warfarin – increases INR

• 
  

Nitroimidazoles: Metronidazole

• Mechanism of action:

  – Enters into the cell, then is reduced to free radicals which damage bacterial DNA

  – Is bacteriocidal

• Key points

  – No renal dose adjustment needed; reduce dose 50% in severe hepatic impairment (Child-Pugh C)

  – Big DI with warfarin (INRs increase)

  – Disulfiram reaction with ANY form of alcohol

• Activity:

  – Not active against most Gram positive organisms or Gram negative organisms (no aerobic coverage)

  – Covers all anaerobes including C. difficile

  – Active against H. pylori

• Adverse event profile:

  – Metallic taste

  – Gastrointestinal disturbances

  – Reversible neutropenia

  – Dark urine

  – Rash

Oxazolidinones

• Drug: linezolid

• Mechanism of action:

  – Binds to the 50S ribosomal subunit; inhibits the early phase of protein synthesis

  – No cross-resistance with other marketed compounds

  – Bacteriostatic

• Excellent activity against many organisms

  – Gram positive pathogens including Enterococci (faecium and faecalis; vancomycin sensitive and resistant),

  – Staphylococci (methicillin sensitive and resistant)

  – Streptococci (including penicillin resistant strains)

• In vitro activity has been demonstrated against many other organisms

  – Chlamydia pneumoniae, anaerobic Streptococci, and Mycobacteria (including M. tuberculosis)

• Common toxicities

  – Diarrhea, nausea, taste perversion

  – Labs: mild increases in LFTs, decrease platelets

  – BBW: Serotonin syndrome risk (linezolid is a reversible, nonselective MAO inhibitor; avoid with SSRIs, SNRIs, MAOIs)

• No dose adjusting for renal/hepatic insufficiency

Lipopeptides

• Drug: daptomycin

• Mechanism of Action

  – Binds to bacterial cell membranes, causing rapid depolarization of membrane potential

  • Leads to inhibition of protein, DNA and RNA synthesis

  • Result is bacterial cell death

• Gram positive activity:

  – Streptococci, S. epidermidis, Enterococci (VRE), S. aureus (MSSA, MRSA, Glycopeptide ISA/RSA)

• Key points

  – First drug bacteriocidal against resistant Gram-positive organisms

  – Widely distributed into tissues EXCEPT lungs

  – Dosing: per FDA label, dose by ACTUAL BW; some institutions use ADJ BW in obesity (evidence evolving)

• Adverse Events

  – Transient increases in CK elevations; measure often

  – Dose reduce in renal insufficiency

Considerations for Sulfas, Nitros, Oxals, Lipos

Preg/lactation

• bactrim: avoid near term

• Linezolid: limited data

• Metro, dapto: generally compatible; dapto def excreted in milk

geriatrics

• watch dapto with MAOId; monitor for myopathy

Renal Impairment

• dose adjustment needed for Bactrim, metro, dapto

• give bactrim with significant hydration