Treating Infectious Illness in the ICU

Resident ICU Course 1

Slide Sub-Title

Principles of Treating Infectious Illnesses in Principles of Treating Infectious Illnesses in Critical Care: Focus on Antibiotic Resistance Critical Care: Focus on Antibiotic Resistance and Choiceand Choice

Robert Owens, PharmDGil Fraser, PharmD, FCCMUniversity of Vermont College of Medicine and Maine Medical Center, Portland

““We shall now discuss in a little We shall now discuss in a little more detail the struggle for more detail the struggle for existence.” C Darwin 1859existence.” C Darwin 1859


Discussion TopicsDiscussion Topics

• Using antibiotics wisely– Impact on microbial resistance– Impact on patient outcomes

• Choosing initial antibiotics and tailoring when data become available

• Using pharmacology and pharmacodynamics to optimize bacterial killing

• Applying clinically relevant specific antibiotic information


Post-Antibiotic Era Mortality: What the Post-Antibiotic Era Mortality: What the Future Holds?Future Holds?


Clinical Relevance of ResistanceClinical Relevance of Resistance Ann Intern Med 2001; 134:298Ann Intern Med 2001; 134:298

• Increased morbidity/mortality 60-80,000 deaths

• Increased hospitalization• Transmission to others• Influences antibiotic choices• Direct/indirect costs

2 million pts suffer nosocomial infections/yr; 50-60% involve resistant pathogens

• Cost = <$30 billion/yr at $24K per case


Mechanisms of Bacterial Resistance to Mechanisms of Bacterial Resistance to AntibioticsAntibiotics


The Pharmacology of Infectious Diseases The Pharmacology of Infectious Diseases Involves Many FactorsInvolves Many Factors

HOST

BUG

DRUG

Nicolau DP Am J Man Care 1998:4(10 Suppl) S525-30


Selection of Antimicrobial Therapy:Selection of Antimicrobial Therapy:Host FactorsHost Factors

• Allergies, age, pregnancy, hepatic and renal function, concomitant drug therapy, immunocompentence, and co-morbidities

• Site of infection– Must cover common pathogens for specific infectious diagnosis until

culture results return• Must consider temporal relationships

– Organisms differ with early vs late onset hospital-acquired pneumonia

– Organisms may reflect selective pressure if antibiotics previously administered (Antimicrobial history taking is extremely important!)


Selection of Antimicrobial Therapy: Selection of Antimicrobial Therapy: Drug Drug FactorsFactors

• Variable antibiotic tissue penetration• Protected sites: pulmonary secretions, the central nervous system, eye, prostate,

abscess, bone• Drug clearance: many are renally cleared

• Exceptions: the macrolides, amphotericin, caspofungin, voriconazole, clindamycin, tetracyclines, moxifloxacin, linezolid, ceftriaxone, and the antistaphylococcal penicillins

• Bioavailability • Good absorption for most quinolones, linezolid, cotrimoxazole, metronidazole,

fluconazole, voriconazole, clindamycin, cephalexin, doxycycline, minocycline• Toxicity profile• Cost truths: generic cheaper than brand name and oral/enteral cheaper than

parenteral, BUT: antimicrobial costs represent a small fraction of infection treatment


Selection of Antimicrobial Therapy:Selection of Antimicrobial Therapy:Pathogen FactorsPathogen Factors

• Susceptibility patterns– Vary from institution to institution and even among nursing units– Change quickly if resistant clone becomes established and spreads– Antibiograms are available from the laboratory at most hospitals and

updated regularly, and are essential to choose appropriate empirical therapy

• Using MIC (minimum inhibitory concentration) data– Requires knowledge of achievable drug concentrations at the site of

infection– Comparisons within a class of antibiotics can be helpful; example =

Tobramycin with an MIC of <1mcg/ml for P aeruginosa is preferred over gentamicin with MIC of 4 for that organism

Kollef MH, et al. Chest. 1998;113:412-420; Ibrahim EH, et al. Chest. 2000;118:146-155

Mortality (%)

Initial Appropriate Therapy

Luna et alCrude Mortality

0 20 40 60 80 100

Ibrahim et alInfection-Related Mortality

Kollef et alCrude Mortality

Rello et alInfection-Related Mortality

Initial Inappropriate Therapy

Correct Initial Choice of Abx Offers Survival Benefit

Luna CM, et al. Chest. 1997;111:676-685; Rello J, et al. Am J Respir Crit Care Med. 1997;156:196-200.


Targeted Approach to Antimicrobial TreatmentTargeted Approach to Antimicrobial Treatment

When microbiologic data are known, narrow antibiotic coverage

Kollef M. Why appropriate antimicrobial selection is important: Focus on outcomes. In: Owens RC Jr, Ambrose PG, Nightingale CH., eds. Antimicrobial Optimization: Concepts and Strategies in Clinical Practice. New York:Marcel Dekker Publishers, 2005:41-64.


Treatment Duration?Treatment Duration?Refer to Guidelines Cited on Slide 23 for More Complete Information

• Uncomplicated UTIs – Depends on antibiotic (Single dose: gatifloxacin; 3 days:

ciprofloxacin, TMP/SMX; 7 days: nitrofurantoin, oral cephalosporins)

• Endocarditis (4- 6 weeks) • Osteomyelitis (4-6 weeks)• Catheter-related infections? Depends on organism

– S. epidermidis and line removed: 5-7 days, line not removed, 10-14 days

– S. aureus: 14 days +/- TEE



• Pneumonia– Hospital/healthcare-associated with good clinical

response: 8 days (unless etiologic pathogen is P. aeruginosa, ~10-14 days)

– Assumes active therapy administered initially

No. at risk197 187 172 158 151 148

147204 194 179 167 157 151

147

8 vs 15 Day Treatment of VAPNo difference in outcome except if P. aeruginosa involved

0.0

0.2

0.4

0.6

0.8

1.0

0 10 20 30 40 50 60

Pro

bab

ility

of

su

rviv

al

Days after Bronchoscopy

P=0.65

Antibiotic regimen8 days15 days

JAMA 2003 290:2588


Treatment Duration of Community-Associated Treatment Duration of Community-Associated Pneumonia : No ConsensusPneumonia : No Consensus

• Guidelines– IDSA (2000)—treat Streptococcus pneumoniae until

afebrile 72 hours; gram negative bacteria, Staphylococcus aureus, “atypicals” = 2 weeks

– Canadian IDS/TS (2000) = 1–2 weeks– ATS (2001)—standard is 7–14 days, but with new agents, may

shorten duration (ie, 5–7 days for outpatients)– BTS (2001)—subject to clinical judgment (7–21 days)

• Evidence– “The precise duration of treatment … is not supported

by robust evidence”–BTS– “Not aware of controlled trials”–IDSA

Bartlett JG, et al. Clin Infect Dis. 2000;31:347-382.Mandell LA, et al. Clin Infect Dis. 2000;31:383-421.British Thoracic Society. Thorax. 2001;56 (Suppl 4): iv1-iv64.American Thoracic Society. Am J Respir Crit Care Med. 2001;163:1730-1754.



• Meningitis (Tunkel et al. Clin Infect Dis 2004;39:1267-84)– Neisseria meningitidis (7days)– Haemophilus influenzae (7 days)– Streptococcus pneumoniae (10-14 days)– Streptococcus agalactiae (14-21 days)– Aerobic gram negative bacilli (21 days)– Listeria monocytogenes (21 days)


When is Combination Therapy Considered When is Combination Therapy Considered Appropriate?Appropriate?

• Initial empirical “coverage” of multi-drug resistant pathogens until culture results are available (increases chances of initial active therapy)

• Enterococcus (endocarditis, meningitis?)• P. aeruginosa (non-urinary tract = controversial; limit

aminoglycoside component of combination after 5-7 days in responding patients)

• S. aureus, S. epidermidis (Prosthetic device infections, endocarditis)-Rifampin/gentamicin+ vancomycin (if MRSA or MRSE) or antistaphylococcal penicillin

• Mycobacterial infections• HIV


Recently Published Guidelines:Recently Published Guidelines:

– Hospital/healthcare/ventilator pneumonia Am J Respir CCM 2005; 171:388

– Bacterial Meningitis IDSA: Tunkel, CID, 2004;39:1267-84.

– Complicated intra-abdominal infections IDSA: Solomkin, CID, 2003;37;997-1005.

– Guidelines for treatment of Candidiasis IDSA: Pappas, CID, 2004;38:16-89.

– Prevention of IV catheter infections IDSA: O’Grady, CID, 2002, 35:1281-307.

– Management of IV Catheter Related Infections IDSA: Mermel, CID 2001;32:1249-72.

– Updated community acquired pneumonia IDSA: Mandell, CID, 2003, 37:1405-33.

– Treatment of tuberculosis ATS et al.: 2003, AJRCC

– Empiric therapy of suspected Gm+ in Surgery Solomkin, 2004, AJS; 187:134-45.

– Use of Antimicrobials in Neutropenic Patients IDSA: Hughes, CID, 2002;34:730-51.

– Guide to Development of Practice Guidelines IDSA: CID, 2001;32:851-54.


Antibiotic Pharmacology and the Antibiotic Pharmacology and the Pharmacodynamics of Bacterial KillingPharmacodynamics of Bacterial Killing


Bacterial Targets for AntibioticsBacterial Targets for Antibiotics


Pharmacodynamics of BacterialPharmacodynamics of Bacterial Killing Killing Concentration-dependent (greater bacterial kill at higher Concentration-dependent (greater bacterial kill at higher

concentrations) vs. Concentration-independentconcentrations) vs. Concentration-independent


The Pharmacodynamics of Bacterial KillingThe Pharmacodynamics of Bacterial KillingConcentration-Independent: Optimal kill defined by time

over the minimum inhibitory concentration (T>MIC)

T>MIC

Concentration

Time (hours)

MIC

Beta-lactamsVancomycinClindamycinMacrolides

Dandekar PK et al. Pharmacotherapy. 2003;23:988-991.

Meropenem 500 mg Administered as a 3 h Infusion Extends the Time Over

the MIC vs a 0.5 h infusion

MIC

0 2 4 6 80.1

1.0

10.0

100.0

ConcentrationConcentration(mcg/mL)(mcg/mL)

Time (h)Time (h)

Rapid Infusion (30 min)

Extended Infusion (3 h)

Additional T>MIC gained


Dosing Adjustments in Renal Disease?Dosing Adjustments in Renal Disease?• Yes

– Almost all cephalosporins and most other beta-lactams (penicillins, aztreonam, carbapenems)– Most quinolones– Vancomycin– Cotrimethoxazole– Daptomycin– Fluconazole

• No– Doxycycline– Erythromycin, azithromycin– Linezolid– Clindamycin– Metronidazole– Oxacillin, nafcillin, dicloxacillin– Ceftriaxone– Caspofungin– Voriconazole PO– Amphotericin b

• Avoid use altogether– Tetracycline– Nitrofurantoin (CrCl <40)– Voriconazole IV (CrCl<50)– Aminoglycosides (if possible)


Selected Review of Specific AgentsSelected Review of Specific Agents


PenicillinPenicillin

• Mechanism of activity– Interferes with cell wall synthesis

• Adverse reactions– CNS toxicity—encephalopathy and seizures with high doses and

renal dysfunction– Allergic reactions

• Treatment of choice for susceptible enterococcal and streptococcal pathogens as well as Treponema pallidum (syphilis)

Penicillin Resistance with Streptococcus pneumoniae in the United States

0

5

10

15

20

25

30

35

40

1979-87 1988-89 1990-91 1992-93 1994-95 1997-98 1999-00

Per

cent

Resistant (MICs >2)

Intermediate (MICs 0.12-1)

5589 487 524 799 1527 1601 1531 1940 1828 35 15 17 19 30 34 33 45 44

2001-02

1980’s 1990’s

2002-03

2000’s


Antistaphylococcal PenicillinsAntistaphylococcal Penicillins

• Agents– Nafcillin, oxacillin

• Mechanism of action– Interferes with cell wall synthesis

• Active against penicillinase producing, methicillin susceptible S. aureus (MSSA)– preferred over vancomycin (faster killing, better

outcomes, see following slide)• Side effect profile as per the penicillins• Role in therapy: directed therapy against MSSA

– Current rate of MRSA = 40-50%


Oxacillin Oxacillin Bactericidal ActivityBactericidal Activity


Broad-Spectrum PenicillinsBroad-Spectrum Penicillins

• Ampicillin, piperacillin, with and without beta-lactamase inhibitors

• Interferes with cell wall synthesis

• Adds additional gram negative activity and with beta-lactamase inhibitor adds anaerobic and antistaphylococcal activity

• Adjust dosing for renal dysfunction


Are there any beta-lactams that can be used in a Are there any beta-lactams that can be used in a true beta-lactam allergic patient?true beta-lactam allergic patient?

• Aztreonam

active against gram negative enterics, but remember, NO activity against gram positive nor anaerobic organisms

What is the rate of cross-reactivity in What is the rate of cross-reactivity in patients with history of anaphylaxis to patients with history of anaphylaxis to penicillin?penicillin?

• Cephalosporins (2-18%)Opportunity for x-reaction decreases as generations

increase• Carbapenems (50%)

Imipenem, meropenem, ertapenem


CephalosporinsCephalosporins

• Prototypical agents– First generation: cefazolin– Second generation: limited utility– Third generation: ceftazidime, ceftriaxone– Fourth generation: cefepime

• Mech of action: interferes with cell wall synthesis• Microbiologic activity dependent on generation and specific

agent (see next slides)– None are effective against enterococci nor listeria

monocytogenes• Toxicity

– Seizures, bone marrow depression


Cephalosporin SpecificsCephalosporin Specifics

• First gen: cefazolin– Good activity against gram positive organisms, and commonly

effective against E. coli, P. mirabilis, K. pneumoniae—NO CNS PENETRATION

• Second gen: cefuroxime and cefoxitin– Limited utility: cefoxitin for GI surgery prophylaxis

• Third gen: ceftriaxone– Good activity against gram positives and gram negative

enterics, not for P. aeruginosa– Adequate CNS concentrations achieved

• Third gen: ceftazidime– Little activity against gram positive organisms, good activity

against enterics and P. aeruginosa


Cephalosporin SpecificsCephalosporin Specifics

• Fourth gen: cefepime– Good activity against gram positive and gram negative

organisms including P. aeruginosa– Does not induce beta-lactamase production– Good CNS penetration


CarbapenemsCarbapenems

• Prototypical agents: imipenem/cilastatin, meropenem, ertapenem• Mech action

– Interferes with cell wall synthesis• Spectrum of activity

– Gram positive, gram negative, and anaerobic organisms– Not active against methicillin resistant S. aureus and epidermidis, S.

maltophilia – Commonly results in candida overgrowth

• Side effect profile– Nausea and vomiting with rapid administration– Seizures (imipenem > meropenem = ertapenem)

• Risk factors: underlying CNS pathology and decreased renal function


QuinolonesQuinolones

• Prototypical agents (available both IV and PO)– Ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin

• Mech of action: interferes with bacterial DNA replication• Spectrum of activity

– Pneumococcus: moxi = gati > levo– Gram negative enterics: all– P. aeruginosa: cipro = levo 750mg > moxi, gati

• Resistance in P. aeruginosa to all quinolones sharply increasing!• Adverse events

– Mania, tremor, seizures, QTc prolongation (gati, moxi, levo), hypo- hyperglycemia (gati > levo, moxi, cipro)

• Drug interactions– Oral formulations with concurrent GI ingestion of bi and trivalent cations– Enzyme inhibition by ciprofloxacin with warfarin and theophylline– Concurrent use of agents with prolong QTc with moxifloxacin, gati, levo– Avoid gatifloxacin in diabetics, particularly if on type II sulfonylureas

0

5

10

15

20

25

30P

erc

en

t R

esis

tan

ce

Alarming Increase in Rate of Quinolone Resistance in P. aerugniosa

Fluoroquinolone-resistant Pseudomonas aeruginosa

Non-Intensive Care Unit Patients

Intensive Care Unit PatientsSource: National Nosocomial Infections Surveillance (NNIS) System


Important Reduction in GI Tract Quinolone Absorption Important Reduction in GI Tract Quinolone Absorption with Bi and Tri-Valent Cationswith Bi and Tri-Valent Cations


Vancomycin (also formerly known as Mississippi Mud)Vancomycin (also formerly known as Mississippi Mud)Name derived from the word “Vanquish”Name derived from the word “Vanquish”


VancomycinVancomycin

• Mech of action– Interferes with cell wall synthesis

• Spectrum of activity– All common gram positive pathogens except

• Enterococcus faecium (VRE)– Enteral formulation effective against Clostridium difficile

(after failing metronidazole)– Not active against gram negative organisms


VancomycinVancomycin

• Toxicity– Ototoxicity? Rare, if at all– Nephrotoxicity? Only when combined with

aminoglycosides– Red man syndrome: local histamine release

• Slow infusion, pretreat with antihistamines– Bone marrow depression after long-term use

• Dosing: 10-20mg/kg at an interval determined by CrCl initially and subsequently by trough determinations – Target trough serum levels = 5-15 mg/dL for line

infections and 15-20 mg/dL for pulmonary, CNS or deep seated infections (ie endocarditis, osteomyelitis)


Linezolid (Zyvox)Linezolid (Zyvox)

• Novel class; oxazolidinone– Inhibits protein synthesis

• Activity: virtually all gram positive organisms• Resistance already seen (during long term use and in

patients with indwelling prosthetic devices)• Favorable pharmacokinetics; IV = po (600mg every 12

hours)• Bone marrow depression (usually >2wks tx), GI


LinezolidLinezolid

• Potential roles in therapy– Infections caused by vancomycin-resistant enterococci– Infections caused by staphylococci in patients who

cannot tolerate beta-lactam agents or vancomycin– Use in patients who have failed initial treatment for

staphylococci infections?– As a vancomycin alternative in patients receiving

concurrent aminoglycosides – As an enteral dosing formulation alternative for

parenteral vancomycin treatment for MRSA infections

Lipopeptides

Pharmacology:

Dosing Form: IV only

Regimens: 4 mg/kg q24h (FDA approved for MRSA, MSSA skin soft tissue infections)

& 6 mg/kg q24h (under investigation for Enterococci, endocarditis)

Highly protein bound

Concentration-dependent killing

Side Effects: myopathy, check CKs

Microbiology:

Activity against VRE, MRSA, VISA, PRSPBaltz RH. Biotechnology of Antibiotics. 1997.

Tally FP, DeBruin M. J Antimicrob Chemother 2000;46:523-26.

MOA: disruption of plasma membrane function

Daptomycin (Cubicin)

Rifampin

50 5030 30

Ribosomes

DFHA

THFA

DNA

mRNA

mRNA

New Protein

Benefits: Most potent anti-

staphylococcal agent (only used adjunctively)

IV & PO QD dosing Inexpensive PO (IV $$$$

$$)Disadvantages: RESISTANCE Develops

rapidly, CANNOT be used as a single agent

Drug Interactions: MANY!!Substrate of: CYP2A6, 2C9, 3A4INDUCES: CYP1A2, 2A6, 2C9, 2C19, 3A4Owens RC Jr. Treatment guidelines for MRSA in the

elderly. Omnicare Formulary Guide. 2004.

Interstitial nephritis

Rifampin

Monitor: CBCChemistry

(Scr, BUN)LFTs

Monitor: CBCChemistry

(Scr, BUN)LFTs

hepatitis

Rash, Stevens Johnson Syndrome, Toxic Epidermal

Necrolysis

Thrombocytopenia


AminoglycosidesAminoglycosides

• Prototypical agents– Gentamicin, tobramycin, amikacin

• Mech of action– Inhibition of protein synthesis, concentration dependent activity on bacterial kill

• Spectrum of activity– Enterobacteriaceae, P. aeruginosa, Acinetobacter spp, enterococci (synergy only)– Adjunctive agents, not optimal as single agents except for UTIs

• Toxicity– Ototoxicity, nephrotoxicity– Risk factors: pre-existing renal dysfunction, duration of therapy >5 days, age, use of

other nephrotoxins• Dosing

– Conventional: gentamicin/tobramycin (1-2mg/kg), amikacin (7.5mg/kg) at an interval determined by CrCl

– Extended interval: gentamicin/tobramycin (5-7mg/kg), amikacin (15-20mg/kg) every 24 hours or longer depending on CrCl

• Not for pregnant patients, those on renal replacement therapy or end stage renal disease, cystic fibrosis, or burns >20% body surface

Conventional (three-times daily regimen)

Nicolau et al. Antimicrob Agents Chemother 1995;39:650–655

Concentration (mg/L)

00

88

1414

44

66

1010

1212

Time (hours)00 1212 2424202044 88 1616

Once-daily regimenOnce-daily regimen

22

Once-daily vs. Conventional Three-times Daily Aminoglycoside Regimens Once-daily vs. Conventional Three-times Daily Aminoglycoside Regimens Optimizes Concentration-dependant Effect on Bacterial KillOptimizes Concentration-dependant Effect on Bacterial Kill


MetronidazoleMetronidazole

• Mech of action: complex---toxic to bacterial DNAMech of action: complex---toxic to bacterial DNA• Microbial activityMicrobial activity

– AnaerobesAnaerobes– Initial treatment of choice for C. difficileInitial treatment of choice for C. difficile

• 100% bioavailable: IV = oral dose100% bioavailable: IV = oral dose• Toxicity minimalToxicity minimal

– Neurotoxic at high dosesNeurotoxic at high doses

• No dose adjustments in renal diseaseNo dose adjustments in renal disease


TetracyclinesTetracyclines

• Inhibit protein synthesis• Microbial activity

– minocycline = MRSA, MRSE, Acinetobacter– doxycycline = CAP (pneumococcus and atypicals),

enteroccocci• Well absorbed, hepatobiliary clearance• Toxicity = discoloration of teeth, photosensitivity,

esophageal ulceration (doxy), ataxia (minocycline)• Interactions: bi and trivalent cations, oral contraceptives


MacrolidesMacrolidesErythromycin (IV,PO) Clarithromycin (PO), Azithromycin (IV,PO)Erythromycin (IV,PO) Clarithromycin (PO), Azithromycin (IV,PO)

• Interfere with protein synthesis• Microbial activity = atypicals, pneumococcus?• Kinetics: relatively poor bioavailability, hepatic clearance• Toxicity: hearing loss (IV erythromycin) and QTc

prolongation (erythromycin, clarithromycin), GI• Interactions: CYP3A4 inhibition • Prokinetic effects (GI tract)

Macrolide Resistance with Streptococcus pneumoniae in the United States

0

5

10

15

20

25

30

1979-87 1988-89 1990-91 1994-95 1997-98 1999-00 2001-02

Per

cent

2002-03


Cotrimoxazole (TMP-SMX)Cotrimoxazole (TMP-SMX)

• Interferes with folic acid synthesis• Microbial spectrum similar to ceftriaxone except for poor

pneumococcal activity• Treatment of choice for S. maltophilia, B. cepacia• IV formulation requires significant fluid, 100% bioavailable,

renal excretion• Toxicity

– Hypersensitivity; rash; Stevens Johnson Syndrome– Hyperkalemia

• Interactions: warfarin!

Antifungal TreatmentCandida as a Pathogen in Nosocomial Bloodstream

Infections in 49 US Hospitals

* Surveillance and Control of Pathogens of Epidemiologic Importance.* Surveillance and Control of Pathogens of Epidemiologic Importance.

Adapted with permission from Edmond et al. Adapted with permission from Edmond et al. Clin Infect DisClin Infect Dis. 1999;29:239-244.. 1999;29:239-244.

The SCOPE* Program (1995-1998)The SCOPE* Program (1995-1998)

1 Coagulase-negative staphylococci 3908 31.9 21

2 Staphylococcus aureus 1928 15.7 25

3 Enterococci 1354 11.1 32

4 Candida species 934 7.6 40

No. of CrudeNo. of CrudeRank Pathogen Rank Pathogen Isolates % Isolates % Mortality(%)Mortality(%)


FluconazoleFluconazole• Inhibits fungal ergosterol synthesis

• Spectrum: C. albicans, less active against krusei, glabrata, not for aspergillus

• Kinetics: good absorption, renal clearance

• Toxicity: liver, QTc prolongation

• Interactions: CYP 3A4 inhibition, WARFARIN!


AmphotericinAmphotericin

• Binds to ergosterol• Active against most fungi• Kinetics: not orally absorbed, not renally cleared• Toxicity: infusion related (fever, chills, nausea), renal and

electrolytes (hypokalemia and hypomagnesemia)• Hydration and sodium repletion prior to amphotericin B

administration may reduce risk of developing nephrotoxicity

Efficacy: Fluconazole vs Conventional Amphotericin B in Nonneutropenic Patients With Candidemia

BUN = blood urea nitrogen.

Rex et al. N Engl J Med. 1994;331:1325-1330.

0 10 20 30 40 50 60 70 80 90

Fluconazole(400 mg/d)

ConventionalAmphotericin B(0.5-0.6 mg/kg/d)

Patients (%)

Successful Outcome

Elevation of BUN/ Serum Creatinine

Hypokalemia

Elevation of Liver Enzymes

(P=NS)

(P<.001)

(P=.006)

(P=.43)

7079

372

102

10

14

Comparative Microbiologic Activity

Candida albicans

C. g

labr

ata

Fluconazole

Res

ista

nt

C. a

lbic

ans

Cry

ptoc

occi

Asp

ergi

llus

spp.

Fusa

rium

spp

.Zy

gom

ycet

es

Susceptible, dose-dependent

Caspofungin

Voriconazole

Some cross-resistance

No activity indicated in black

C. k

ruse

i


Clinical Scenario #1Clinical Scenario #1

• 61 year old patient with respiratory failure has been mechanically ventilated for 5 days and develops a fever associated with purulent secretions and radiologic findings consistent with a pneumonia.

• How important is it to correctly select an antibiotic regimen?• What factors must be considered in developing an antibiotic

regimen?


Clinical Scenario #1--answersClinical Scenario #1--answers

• Initiating the “right” initial antibiotic regimen (one that effectively kills all isolated pathogens) is associated with a 50% mortality reduction vs when the wrong initial antibiotics are chosen

• Empiric antibiotic choice is driven by factors such as the probable organisms at the site of the infection, institution specific (and nursing unit specific) antimicrobial susceptibility data, recent history of antibiotic use, gram stain results (if available) and patient immuocompetency

• Antibiotic specific factors such as penetrance into the site of the infection, pharmacokinetics, costs, and toxicity profiles also help to guide treatment choice.



• Klebsiella pneumoniae was isolated from the sputum of patient #1 and the antibiotic regimen was changed from cefepime and vancomycin to cefazolin (after susceptibility reports indicated an MIC of 2 mcg/ml).

• Is this an appropriate choice?• How long do we treat this patient?



• If the isolated organism is thought to represent the likely pathogen and if MIC/susceptibility data support it’s use, the most appropriate antibiotic choice is one that has a narrow but effective spectrum of activity, is safe, inexpensive, preserves normal bacterial flora, and does not promote microbial resistance. Cefazolin satisfies these criteria.

• Recent data suggest that outcomes are similar if antibiotic duration for VAP is 8 vs 15 days (except if P aeruginosa is involved) in patients who have responded to therapy



• A 41 year old 100kg male develops sepsis requiring vasoactive support 7 days after being admitted to the ICU. The source of the infection is unclear but possibilities include the lungs or intravenous catheters. Gram stain of the blood shows gram positive cocci in clusters. His creatinine has risen from 0.8 to 1.6 mg/dl in two days and his urine output is now <800ml/24 hours. Vancomycin is begun (along with cefepime).

• What is an appropriate initial vancomycin dose?• How would you decide on subsequent doses?• What serum vancomycin levels are considered optimal for

this patient?• Are there toxicities that you should consider?



• Appropriate vancomycin doses are determined using body weight (15mg/kg), not a generic 1000mg dose. For this patient, the initial dose would be 1500mg

• Since vancomycin is cleared by the kidneys and these organs are not functioning well in this patient, it may be appropriate to allow serum vancomycin levels to guide subsequent dosing. Levels between 15 and 20 mcg/ml are indicators of the need for more vancomycin.

• Vancomycin is not thought to be a nephrotoxin (except when used in combination with aminoglycosides). Red man syndrome (local histamine release in the upper trunk) is a possibility which can be remedied by slowing the infusion rate and pretreating with antihistamines. With long-term use, vancomycin can cause bone marrow toxicity

Treating Infectious Illness in the ICU

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