Antibiotic choices

Antibiotic Choices

Outline

General Considerations:Host FactorsGeographic ConsiderationsMicrobial FactorsAntimicrobial FactorsAdjunctive ApproachesPharmacoeconomics

Outline

Review of antibiotic classes:Beta-lactamsMacrolidesFluoroquinolonesAminoglycosidesLincosamidesTetracyclinesOthers: vancomycin, metronidazole,

chloramphenicol, linezolid

Empiric Therapy

Often microbiologic diagnosis is not knownDecision regarding optimal empiric treatment based on: host factorsmicrobial factorsgeographic factorsantimicrobial factors

Empiric Therapy

17 yr old previously healthy man with 2 day hx of fever, sore throat, cough.

Diagnostic possibilities? Can he wait or should be be treated? What would you treat him with?

17 yr old with HIV and 2 day hx of fever, sore throat, cough.

Diagnostic possibilities? Can he wait or should he be treated? What should he be treated with?

Host Factors

Age

Immune adequacy

Underlying diseases

Renal/hepatic impairment

Presence of prosthetic materials

Ethnicity

Pregnancy

Age

Can help to narrow the diagnosis with certain infections:Ex: Meningitis:

What bugs would you consider in neonate? In adult?

Ex: EBV infection In what age group would you consider this

diagnosis?

Ex: UTI: How does age affect your interpretation of laboratory

results?

Immune Adequacy

Immune status important clue: Ex: Asplenic patients: at risk for encapsulated bacterial

infections Ex: HIV/AIDS patients: at risk for variety of opportunistic

infections Ex: Transplant patients: at risk for a variety of infections

depending on timeline etc.

Previous use of antibiotics: Prolonged broad spectrum Diarrhea

Underlying Disease

Diabetes

Transplant

HIV

Cancer

Renal impairment

Autoimmune diseases

Renal/Hepatic Impairment

Implications for treatment:Dose adjusting for renal impairmentAvoiding nephrotoxic drugsAvoiding hepatotoxic drugs

Implications for monitoring: If unavoidable

ensure good hyrdrationMonitor renal and liver function

Presence of Prostheses

Implications for diagnosis:What bug is more pathogenic with artificial

joints/valves?

Implications for Treatment: Infected hardware needs to be removedAddition of rifampin in certain situations

(effective in treatment of prosthetic infections)

Ethnicity

Consider diseases endemic in country of origin:Ex: TB in patients from TB endemic areas

as well as aboriginal patientsEx: Stronglyoides in patients from tropical

countries

Geographic Factors

Need to know common microbial causes of infection in your area:

Ex: MRSA: 40% of S. aureus isolates in US but only 3% of isolates in Canada

Consider patient ethnicity

Travel history is important:Ex: fever in traveller returning from Sudan vs

fever in person who has never left Edmonton

Pregnancy

Issues of antibiotic use in pregnancy have to be considered

Risks of transmission to baby:HIVGBSHSVSyphilis

Microbial Factors

Probable organisms

Probable susceptibility patterns

Natural history of infections

Likelihood of obtaining good microbiologic data

Site of Infection

Probable Organisms

Have to know most likely organisms for various common infections:CAPCellulitis Intra-abdominal infectionsEndocarditis

Microbial Susceptibilities

Know general microbial susceptibilities as well as those which are geographicaly specific: S pneumoniae: 15% resistant to erythromycin, 3%

to penicillin P. aeruginosa: 30-40% resistant to ciprofloxacin,

20-25% to ceftazidime MRSA: account for 3-4% of S aureus isolates

*For Capital Health Region for 2004

Natural History

Rapidly fatal vs slow growing:Ex: Meningococcemia – can be rapidly

fatal Ex: TB meningitis often more indolent

course

HIV

Hep C

Likelihood of Obtaining Microbiologic Data

May be difficult to get specimen: Ex: brain abscess

If patient has been on antibiotics, it will affect culture results

Antimicrobial Factors

Site of infection

Route of Administration

Bactericidal vs Bacteristatic

Combination vs single therapy

Site of Infection

Susceptibility testing is geared to attainable serum levelsDoes not account for host factors or conditions that alter antimicrobial accessEx: diffusion into CSF is limited in many drugs Ex: abscesses:

Difficult to penetrate abscess wall High bacterial burden Low pH and low oxygen tension can affect antibiotic

activity

Route of Administration

Many options exist:EnteralParenteralSmall particle aerosol IntrathecalTopical

Enteral Administration

Must know oral bioavailability

Must be resistant to breakdown by gastric juicesSome drugs must be given with bufferSome require acidity for absorption

Other drugs cannot be given in high enough doses orally

Bactericidal vs Bacteristatic

Cidal: B-lactams, aminoglycosides, quinolones

Static: tetracyclines. Macrolides, lincosamides

But there are exceptions:Chloramphenicol thought to be bacteriostatic is

cidal in H influenza, S pneumonia, N. menigitidis

Combination Therapy

Three main reasons: Broader coverage: may be necessary for empiric

treatment of certain infections. Ex. Intra-abdominal sepsis

Synergistic activity: eg amp + gent for serious enterococcal infections

Prevent resistance: eg TB

Disadvantages: antagonism – theoretically should avoid combining

bacteriostatic and bactericidal agents Potential for increased toxicity

Adjunctive Approaches

Shock and Sepsis: supportive care with fluids, possibly steroidsBacterial meningitis: steroidsDrainage and Debridement of abscessesRemoval of prosthetic materialsCorrection of trace nutrient deficienciesCorrection of protein calorie malnutritionAssisted organ function with ventilator, dialysis, vasopressors/ionotropes

Monitoring Response to Therapy

Certain amount of gestaltMonitor infectious parameters: fever, WBC, ESR etc.Knowledge of natural historyImagingRepeat cultures useful in endocarditis, complicated UTI (ie normally sterile areas)

Duration of Therapy

Very few studies to establish minimum durations of therapyEx. Viridans strep endocarditis:

5 days therapy: 80% failure 10 days: 50% 20 days: 2%

Duration usually based on anecdoteMost uncomplicated bacterial infections can be treated for –14 days4-6 weeks for endocarditis, osteo, 6-12 months: Mycobacterial diseases, endemic mycoses

Pharmacoeconomics

Cost of illness includes:MedicationsProvider visitsAdministration of medicationsLoss of productivity

Cost is a tertiary consideration after effectiveness and safety

Antibiotics: drugs for bugs

Beta Lactams

Includes: Penicillins, cephalosporins, carbapenems, monobactams

Mechanism of Action: Inhibits cell wall synthesis by binding to PBP and

preventing formation of peptidoglycan cross linkage

Toxicity: Hypersensitivity reaction 10-20% X-reactivity with carbapenems 10% x-reactivity with 1st generation cephalosporins 1% x-reactivity with 3rd generation cephalosporins

Beta-Lactams

Natural Penicillins: Pen G, Pen V, benzathine penicillin

Spectrum of activity: Viridans group strep, B-hemolytic strep, many Strep

pneumoniae Most N. menigiditis Staph spp Oral anaerobes L monocytogenes, Pasteurella multocida, Treponema

pallidum, Actinmyces israelii enterococcus (1/3) pen sensitive

Aminopenicillins

Prototypes: Ampicillin, Amoxicillin

Covers:Strep sppDoes not cover enterococcus

Spectrum extended to include some GNB:

E. coli, Proteus mirabilis, Salmonella spp, Shigella, Moraxella, Hemophilus spp

Penicillinase Resistant Penicillins

Protoype: Cloxacillin

Covers:Staph spp including MSSA, 2/3 of Staph epiStrep spp

No coverage for enterococcus

No coverage for gram negative organisms or anaerobes

Carboxypenicillins

Prototype: Ticarcillin

Covers:Covers Stenotrophomonas, Pseudomonas

Problems with hypernatremia, hypokalemia, platelet dysfunction

Ureidopenicillins

Prototype: PiperacillinCovers

Strep spp (less than earlier generations)EnterococcusAnaerobic organismsPseudomonasBroad Gram negative coverage

If tazobactam added – increases Staph coverage and anaerobic coverage

Cephalosporins

Divided into 4 generations

Increasing gram negative coverage with less gram positive coverage with increasing generations

Enterococci are not covered by any of generations

1st Generation

Prototype: Cefazolin

Covers:Staph spp (MSSA)Strep sppE. coli, Klebsiella, Proteus mirabilis

No anaerobic activity

2nd Generation

Prototype: CefuoximeCovers:

Gram positives (Staph, Strep)H influenzaM catarrhalis

Cefoxitin:Some serratia coverageAnaerobic activityUsed for intra-abdominal infection and PID

3rd Generation

Divided into two main groups: Ceftazidime:

Pseudomonas Good gram negative coverage Lose gram positive coverage (poor against Strep)

Ceftriaxone/cefotaxime: Reasonable Strep coverage, poor Staph coverage Good gram negative coverage Little anti-pseudomonal activity Little anaerobic activity Good CSF penetration Toxicity includes biliary sludge

4th Generation

Prototype: Cefepime

Coverage:Maintains gram positive activity (Strep)PsuedomonasLower potential for resistance

Cefixime – oral version Good against gram negatives and StrepNo pseudomonal activity

Carbapenems

Imipenem, Meropenem, ErtapenemImipenem/Meropenem:

Staph (MSSA), Strep Anaerobic activity Gram negatives (Legionella, Chlamydia, Mycoplasma, B

cepacia, Stenotrophomonas) Pseudomonas Enterococcus faecalis but not faecium

Ertapenem Allows once a day dosing Does not cover pseudomonas

Monobactam

Prototype: AztreonamAerobic GNBPseudomonasNo gram positive or anaerobic coverage

Similar spectrum to aminoglycosides without renal toxicityCross reactivity to penicillin is rare but increases with ceftazidime

Aminoglycosides

Includes: Gentamycin Tobramycin Amikacin Streptomycin

MOA: binds to 30S/50S ribosomal subunit inhibit protein synthesis

Toxicity: CN VIII - irreversible Renal toxicity – reversible Rarely hypersensitivity reactions

Aminoglycosides

Covers:Aerobic GNB including pseudomonasMycobacteria Brucella, FranscicellaNocardiaSynergy with B-lactams (Enterococci,

Staphylococci)

Fluoroquinolones

Includes: Ciprofloxacin Ofloxacin Levofloxacin Gatifloxicin Moxifloxacin

Mechanism of Action: DNA gyrase inhibitors

Toxicity: GI symptoms

Fluoroquinolones

All cover: Mycoplasma, Legionella, Chlamydia Francisella, Rickettsia, Bartonella Atypical mycobacteria

Cipro: Good gram negative coverage Poor gram positive coverage N gonorrhea, H influenza Good for UTI, infectious diarrhea In combination for pseudomonas

Fluoroquinolones

Ofloxacin: Better gram positive coverage (Strep but min staph

coverage) No pseudomonas activity

Levofloxacin: L-entomer of ofloxacin so identical coverage Used for LRTI

Gatifloxacin: Increased activity against strep No pseudomonas activity

Fluoroquinolones

Moxifloxacin:Activity against Strep and StaphAnaerobic coverageNo pseudomonas activity

Macrolides

Includes:ErythromycinClarithromycinAzithromycin

Mechanism of Action: Binds to ribosomal subunit Blocks protein synthesis

Toxicity: GI upset (especially with erythromycin)

Erthromycin

Active against Strep spp

Also effective against: Legionella Mycoplasma Campylobacter Chlamydia N gonohhrea

Poor for H influenza

Used infrequently due to GI upset

Clarithromycin

Active against:Strep including pneumoniaeMoraxella, Legionella, ChlamydiaAtypical mycobacteriaMore active against H influenza

Used in combination against H pylori

Less GI side effects

Azithromycin

Active against:Mycoplasma, Legionella, ChlamydiaH influenzaStrep spp

Long half life

5 day course is adequate

Less GI side effects

Clindamycin

Mechanism of Action: Blocks protein synthesis by binding to ribosomal subunits

Toxicity: Rash GI symptoms C diff colitis seen in 1-10%

No gram negative or enterococcus coverage

Covers Staph spp (MSSA), Strep spp and anaerobes

Metronidazole

Mechanism not well understood

Covers: Most anaerobes except Peptostreptococci,

Actinmycetes, Proprionobacterium acnes Parasitic protozoa: Giardia lamblia, E. histolytica

Toxicity: Neutropenia Disulfuram reaction Potentiation of warfarin

Tetracyclines

Includes: Tetracycline Doxycycline Minocycline

Mechanism of Action: Binds to 30S ribosomal subunit Blocks protein synthesis

Toxicity: Rash, Photosensitivity, impairs bone growth and stains

teeth of children, increased uremia

Tetracyclines

Spectrum includes unusual organisms Rickettsia Chlamydia Mycoplasma Vibrio cholera Brucella Borreila burgdorferii

Minocycline: Active against stenotrophomonas and P acnes May be active against MRSA

Doxycycline: Used for prophylaxis against Plasmodium spp

Glycopeptides

Prototype: Vancomycin

Mechanism of Action: Inhibits cell wall synthesis

Toxicity:Ototoxicity – rareCan induce histamine release – red man

syndrome

Glycopeptides

Coverage:Gram positives: Staph (incl. MRSA), strep,

enterococcusGram positive anaerobesExceptions: VRE, Leuconostoc, Lactobacillis

Inferior to beta-lactams in terms of cure rates for beta-lactam sensitive organisms

Sulfa drugs

Includes: TMP/SMX

Mechanism of Action:Folate reductase inhibitor

Toxicity:Hypersensitivity reactionsThrombocytopenia rash

Sulfa

Coverage: Strep, Staph H influenza L monocytogenes Many GNG (E coli, Klebsiella) PCP Nocardia Isospora belli

Because of frequent allergic rxns, only used in special circumstances (eg PCP pneumonia)

Chloramphenicol

Broad spectrum activity: GPC, GNB Menigitis organisms Rickettsia spp No activity against Klesiella, Eterobacter, Serratia,

Proteus, Pseudomonas

Toxicity: Dose related marrow toxicity Idiosyncratic aplastic anemia Gray syndrome – abdominal distention, cyanosis,

vasomotor collapse (seen in liver failure pts)

Linezolid

Mechanism of Action: Binds to ribosomal subunit inhibiting protein synthesis

Oral drug

Active against: VRE, MRSA Enterococcus

No activity against gram negatives

Very expensive ($140/day) and currently not covered

Questions