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OVERVIEW OF ANTIMICROBIAL THERAPY

By

AWADH ALANAZI, MD

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Infectious Diseases (ID) Leading Cause of• Morbidity & Mortality Worldwide• Ability of bacteria, mycobacteria, viruses,

fungi, protozoa, chlamydiae, richettsia, mycoplasmas, spirochetes & helminths to cause infection is balance between:

a. Inoculume size, virulence andb. Adequacy of host defenses.

• Despite of ability Antimicrobials to Augment normal host defenses and prevent/control infection, prescribing errors are common, including:

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1. Treating Colonisation

2. Suboptimal empiric theraphy

3. Inappropriate combination theraphy

4. Dosing and duration errors

5. Mismanagement of apparent ABX failure

6. Inadequate Consideration of ABX Resist Potential

7. Tissue penetration

8. Drug interaction, S.E., Cost

• These Limit Antimicrobial Effectiveness

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I. Factors in Antibiotic Selection

A. Spectrum

• ABX with “Concentration Dependent” Kinetics (e.g. Quinolones and Aminoglycosides) display increasing killing with increasing concentration above organism MIC. But

• ABX with “time-dependent” Kinetics (e.g. beta-Lactams and vancomycin) DONOT.

B. Tissue penetration

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C. ABX Resistance

• Bacterial Resist: Natural/Acq.

Relative/Absolute

• Natural/Intrinsic R: pattogens not covered by usual ABX spectrum e.g. 25% of S. pneumoniae naturally resist to Macrolides

• Acquired Resist: amp. H. inflenzae

• Organism with intermediate/relative res. Show increases in MIC, but remain subsceptible to ABX at achievable serum/tissue conc. (e.g. pen. R.S. pneum.)

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• Organisms with high/absolute resist. Show no increase in MIC, thus cannot be overcome with higher ABX doses (e.g. genta. Resist. P. aerogenosa)

• Resist. Not related to volume or use duration• Successful ABX Resist. Control strategies:

a. Eliminating ABX from animal feedsb. Early detection of resistance by screeningc. Infection control precautiond. Restricted ABX formulary = i.e. Controlled use of ABX with high resist potentialsc. Preferential use of ABX with low resist potentials by clinicians

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• Unsuccessful Strategies:

a. Rotating formularies

b. Restricted use of certain ABX classes e.g. Quinolones, third generation cephalosporius

e. Use of combination therapy

• In choosing between similar ABX select with low Resist. Potential: a. ceftaz. Assoc. with MRSA prevalence, b. vanco. Assoc. with URE prevalence

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D. Safety Profile

• Cost: single most important cost saving early shift from I.V. to po. bec. cost of adm. I.V. alone $10/dose. (i.e. may exceed ABX cost itself)

• Monotheraphy vs. combination

• ABX SE, outbreaks of Resist. Organism

• Prolonged Hospitalization

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II. Factors in Antibiotic Dosing

A. Renal Insufficiency and Dosing Adjustment• ABX with wide “Toxic-To-Therapeutic” Ratio

and Creati Clearance.• ABX with narrow toxic-with-therapeutic ratio• Patients with pre existing renal disease or

receiving other nephrotoxics.

a. Loading and maintenance dosing in renal insuff.

Initial/Loading unchanged, but maint. dose modified

Moderate R.I. (Crcl 50-80 ml/min): M.D. halved but dosing interval unchanged

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Severe R.I. (Crcl 10-50 ml/min): M.D. halved and dosing interval doubled

Selected ABX with similar spectrum, but eliminated by hepatic route.

b. AMG Dosing SDS. Not in Enterococcal IE. AMG induced Tubular Dysfunction:

Best assessed by Serum creatinine Renal tubular cast counts in urine

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B. Hepatic insufficiency• More problematic than R.I…………?• Dosing Adj usu. Not required for Mild or

Moderate H.I.• Severe H.I. Adjust ABX with hepatoxic

potentials• Select ABX with Renal route of elimination

C. Combined Renal and Hepatic Insuff:• No dosing Adj. Guidelines

Q: Which is mere accurately reflects AMG nephrotoxicity

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• If R.I. worse than HI: ABX eliminated by liver given at half total daily dose.

• If HI worse than RI: Renally eliminated ABX Admn. according to Renal function

D. Mode of ABX and Excretion/Excretory organ toxicity.

• Mode of elimination/Excretion does not, per se, predispose to excretory organ toxicity e.g. Nafcillin, though eliminated by Liver, but not hepatotoxic.

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Table 1. Major Route of Elimination

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ChloramphinicolNafcillinMost B-LactamsGemifloxacin

CefoperazoneLinezolidAMGVancomycin

DoxycyclineINH/RIF/EMBMonobactamsNitrofurantoin

MinocyclinePZACarbapenemsFluconazole

MoxifloxacinItraconazolePolymycin BAcyclovir

MacrolidesCaspofunginColistinValacyclovir

TelithromycinMicafunginCiprofloxacinFamciclovir

ClindamycinAnidulafunginOfloxacinValgaciclovir

MetronidazoleKetoconazoleLevofloxacinTetracycline

TigecyclineVoriconazoleGatifloxacinFlucytosine

Quinupristin/

dalfopristinPosaconazoleAmantadine

Daptomycin

Rimantadine

HEPATABILITYRENAL

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• Hepatic insuffDecrease dose of ABX by 50% in clinical

severe liver dis.Alternative: Use ABX of renal elimination

• Renal InsuffCrcl 40-60 ml/min: decrease dose by 50%,

maintain dosing intervalCrcl 10-40 ml/min: decrease dose by 50%

and double dosing intervalAlternatively use Hepatilly eliminated route

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III. Microbiology and Susceptibility Testing

A. Overview• Testing informative about microbial sens. of

pathogen to various ABX thus guiding theraphy.

• Assess in-vitro results consistency with clinical situation

B. Limitation of Microbiol Suscept. Testing• In-vitro data donot diff. coloniser and

pathogens• Treat patient not Lab. Results• Differentiate between pathogen and coloniser

S

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• In-vitro results Donot necessarily mean in-vivo efficacy

• In-vitro testing depends on microbe, methodology and ABX concentration

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Table 2: ABX organisms combination in which in-vitro suscept. unreliable

ABX“Sensitive” Organism

penicillinH. Influenzae, yersinia pestis

TMP-SMXKlebsiella, Enterocci, Bartonella

Polymyxin BProteus, salmonella

imepenemStenotrophomonas maltophilia (f.pseudo)

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gentamicinMTB

vancomycinErysipelothrix rhusiopathiae

AMGStreptococci, salmonella, shigella

clindamycinFusobacteria, clostridia, enterococci and listeria

macrolidesp. multocida

1st, 2nd gen. cephalosSalmonella, shigella, bartonella

3rd, 4th gen. CephalosEnterococci, listeria, bartonella

All ABX except vauco, linezolid, tigecycline, minocycline quinupristin/dalfopristin

MRSA

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• Unusual susceptibility patternsOrganisms have predictable patternsIn case of unusual pattern of an isolate,

further testing should be performed by micro. Lab. and expanded suscept. testing needed.

S

S

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Table 3: Unusual S. patterns requiring further testing

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organismUnusual S. patternUnusual S. pattern

N. MeningitidisPenicill. R.Penicill. S.

staphylococciVanco/clinda. R, but erylhro S.Vanco. S.

Viridans strep.

S. Pneumoniac

Beta-hem. Strep

Enterobacteriacae

and klebsiella

Vanco. I/R

Vanco I/R

Pens I/R

Imipenem R

Vanco S.

Vanco S.

Penc. S.

Imipenem S.

Enterobater and serratia

Amp/Cefazolin S.Amp/cefazolin R.

Morganella and providencia

Amp/Cefazolin S.Amp/cefazolin R.

klebsiellaCefotetan , ceftazCefotetan , ceftaz

p. aeroginosaAmk , genta/tobraAmk ,genta/tobra

Stenotrophomonas

maltophilia

TMP/SMX

Imipenem

TMP/SMX S. RS

S RR S

RS

SR

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Table 4: Screening for extended-spectrum Beta-Lactamase (ESBL)Activity

PalhogenPositive Screening Result (MIC)

k. Pneumoniae

k. Oxytoca, E. coli

Cefpodoxime 4mcg/ml

Ceftaz 1mcg/ml, aztreonam 1mg/ml

Cefotaxime 1mcg/ml, cefriaxone 1mcg/ml

p. mirablis

Cefpodoxine 4mcg/ml, ceftaz mcg/ml

Cefotaxime 1mcg/ml

NB positive test for ESBL imp therapeutic implicaton

NB confirm ESBL requires 2 fold or more decrease in MIC for either:- ceftaz + clavulanic acid or cefotaxime + clav. acid

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2

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Summary

• In-vitro suscept. Testing useful but should not be followed blindly

• Suscept. is conc. dependent thus

• IV-to-po switching using ABX of same class, best made using po. ABX that can achieve similar blood/tissue levels as I.V. ABX.

* e.g. cefazolin lg 200 mcg/ml to cephalexin 500 mg 16 mcg/ml

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IV. Other Consideration in Antimicrobial Therapy

A. Bactricidal vs. Bacteriostatic Therapy

• For most infections Bacteriotastic and Bactericidal ABX inhibit/kill organisms at same rate, thus should not be factor in ABX selection

• Bactricidal ABX have advantage in certain infections: IE, meningitis, febrile neutropenia

B. Monotheraphy vs. Combination Theraphy

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Table 5. Combinations Theraphy and ABX Resistance

* Examples of ABX combination preventing resistance

• Anti-psedomenal penicillin [carben, cillin] + AMG [genta, tobra, AMTC]

• Rif + INH, EMB, PZA

• 5-flucytosine + Ampho B

* Examples of ABX combinations not preventing resist

TMP-SMX AMG+imipenem

aztreonam+ceftaz. most other ABX Cefepime+Cipro combinations

NB: These combinations often prescribed to prevent resist., when, infact they DONOT.

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C. I.V. vs. PO. switch therapy• Patients adm.to hospital usu. Started on

IV. ABX then switched to equivalent PO. after clinical improvement (usu 72 hr).

• Advantages of early IV-to-PO include:- Reduced Cost- Shorter hospital stay- Less need for home I.V.- Elimination of I.V. line infections- Drugs suitable for IV-to-PO switch or entirely by PO adm. include:

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Doxycycline, minocycline Clindamycin, metronidazole Amoxicillin, chloramphinicol TMP/SMX, Quinolones Linezolid Some penicillins and cephalosporins unusefule for

IV-to-PO switch bec. limited bioavailability

• Most infectious diseases should be treated orally unless:

Patient critically ill Cannot take PO

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No equivalent oral ABX If patient can take PO, there is no difference in

clinical outcome using IV or PO, thus: -

• Think in terms of: ABX spectrum Rather than: Route of admn. Bioavailability Tissue penetration Nearly all non-critically ill patients should be

treated in part or entirely with PO ABX When switching from IV to PO, oral ABX should

achieve same blood tissue levels as the equivalent I.V.

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Table 6. Biovailability of Oral Antimicrobials BioavailabilityAntimicrobials

Excellent > 90% ie PO gives equiv. Blood/tissue levels as same IV dose

(PO = IV)

Amox, TMP, linezolid, cephalexin, TMP-SMX, fluconazole, cefadroxil, minocycline, rifamp. Clindamycin, chloramphinicol, INH Quinolones, metronidazole, PZA EMB, cycloserine

Good: PO < IVMostbeta-lactams, cefuroxime, EMB, 5 FCU cefixime, valacyclovir, famciclovir, cefactor, cefpodoxime, valgonaclovir, telithromycin, ceftibuten, posaconazole, itraconazole, macrolide

Poor: PO results in adequate blood/tissue levels

Vancomycin, cefdinir, cefditoren

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D. Duration of Therapy• Most bacterial infections in normal host

treated with ABX for 1-2 wks.• ABX therapy may be extended in patient

with: Impaired immunity: DM, SLE,

neutropenia, diminished splenic function Ch. bacterial infections: IE, osteomyelitis Ch. viral and fungal inf. Certain intracellular pathogens Infections as HIV, CMV in compromised

host require life long suppressive theraphy

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ABX should ordinary not be more than 2 wk even if low grade fevers persist

Prolonged theraphy offers no benefit rather increases risk of SE, drug interactions and superinfections.

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Table 7. I.D. Requiring Prolonged Antimicrobial Therapy

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THERAPY DURATIONINFECTIOUS DISEASES

3 wksLymphogranuloma venereum (LGU) syphilis (late latent)

4 wksCh. O.m, ch. Sinusitis, ac. Osteomyelitis, ch. Pyelonephritis, brain abscess, SBE (vividans strept) legionella

6 wksAc. bact. endoc. (S. aureus, Enterococcus), H. pylori.

3 monthsLung Abscess, ch. prostatitis

6 monthsPTB, EPTB (usu > 6M), actinomycosis, nocardia, ch. osteomyelitis

12 monthsWhipple’s deisease

More than 12 monthsLepromatous leprosy, bartonella, CMV, HIV (lifelong), prosthetic-related, ch. Suppressive therapy for PCP

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NB

• Lung Abscess: treat until resolved or CXR remained unchanged

• Actino: treat till resolved

• Nocardia may need prolonged treat. in compromised hust

• Osteomyelitis: require adequate surgical debridement for cure

• Prosthetic-related infections: may need removal, if not need prolonged suppressive theraphy, but clinical failure is the rule.

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V. Imperic ABX Therapy• Susceptibility results usu. Not available

prior to treatment• Direct imperic ABX against most likely

pathogens• Mildly ill patients, inpatient, or

ambulatory: may be treated with oral ABX with high bioavailability

• Moderely or severely ill pateint usu treatment with I.V.

• Obtain spp. For micro diagnism (stains, cultures) prior to starting ABX

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VI. Antibiotic Failure

• Many causes for apparent AB failure: ABX unresponsive infections Febrile non-infectious disease Drug fever Most common ERROR in managing

apparent ABX failure is changing/adding additional ABX rather than attempts to determine the cause.

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Causes of Apparent /Actual ABX Failure1. In-vitro suscept. but inactive in-vivo.2. ABX tolerance with GPC3. Inadequate coverage/spectrum4. Inadequate blood levels5. Inadequate tissue levels:-• Undrained abcess• Foreign body related infection• Protected focus (eg. CSF)• Organ hypoperfusion: reduced blood

supply, eg. ch. osteo. in DM.

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6. Drugs induced interactions• ABX inactivation• ABX antagonism

7. Decreased ABX activity in tissue

8. Fungal super infection

9. Treating colonisation not infection

10. Non-infectious Diseases• Midical disorder mimiking infection (eg. SLE)• Drug fever

11. Antibiotic unresponsive infectious disease• Most viral infections

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VII. Drug FeverClinical Features of Drug FeverHistory: - Many but not all patients atopic

- Patients on sensitising medications for days or years “without problem”

Physical Exam• Fever low or high-grade, but usually between 38.9

– 40.7 ºC (102º - 140ºF) may exceed 41.1ºC (106ºF)

• Patient appears “inappropriately well” for degree of fever.

• Relative brody cardiaNB: second, CHB, pacemaker-induced rhythm beta

blocker, diltiazem, verapamel treatment

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• Appropriate Temp.-pulse RatePulse (beat/min) Temp

150 41.1ºC (100ºF)140 40.6ºC (105ºF)130 40.1ºC (104ºF)120 39.4ºC (103ºF)110 38.9ºC (102ºF)

Lab Tests• High WBC (usu. with left shift)• Eosinophils present, but eosinophilia

uncommon

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• High ESR in majority of cases

• Early, transient, mild elevation of transaminases

• Negative blood cultures

VIII. Pitfalls in ABX prescribing

1. Use of ABX to treat non-infectious diseases (e.g. viral infections) or colonisation

2. Overuse of combination therapy

3. Use of ABX for persistent fevers:

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• Reassess your patient, if faced with apparent ABX failure (ie persistent fever despite being on ABX regimen)

• Causes of prolonged fevers:

- undrained septic foci

- non-infectious medical disorder

- drug fever

- undiagnosed causes of leukocytosis/low-grade fevers shouldnot be treated with prolonged ABX courses

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4. Inadequate surgical therapy- infected prosthetic materials or fluid collections (eg Abscesses) often require surgical therapy for cure.- for infections like ch. osteomyetitis surgery is only way (if feasible) to cure infection, while ABX useful only to suppress or to prevent local infection complications

5. Home I.V. therapy: Less needed in view of available excellent oral ABX, [eg Quinolones and Linezolid].