Principles of Treating Infectious Illnesses in

Critical Care: Focus on Antibiotic Resistance

and Choice

We shall now discuss in a little

more detail the struggle for
existence. C Darwin 1859

Robert Owens, PharmD

Gil Fraser, PharmD, FCCM
University of Vermont College of Medicine and
Maine Medical Center, Portland
Slide Sub-Title

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 Discussion 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

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Post-Antibiotic Era Mortality: What the
Future Holds?

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 Clinical Relevance of Resistance
Ann 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

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Mechanisms of Bacterial Resistance to
Antibiotics

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Resident ICU Course 6
The Pharmacology of Infectious Diseases
Involves Many Factors

HOST

BUG

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

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 Selection of Antimicrobial Therapy:
Host 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!)

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 Selection of Antimicrobial Therapy: Drug
Factors

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

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 Selection of Antimicrobial Therapy:
Pathogen 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

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 Correct Initial Choice of Abx
Offers Survival Benefit
Rello et al
Infection-Related Mortality
Initial Appropriate Therapy
Ibrahim et al
Infection-Related Mortality Initial Inappropriate Therapy
Kollef et al
Crude Mortality
Luna et al
Crude Mortality

0 20 40 60 80 100
Mortality (%)

Kollef MH, et al. Chest. 1998;113:412-420; Luna CM, et al. Chest. 1997;111:676-685;
Ibrahim EH, et al. Chest. 2000;118:146-155 Rello J, et al. Am J Respir Crit Care Med. 1997;156:196-200.
Targeted 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.

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 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

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

Pneumonia
Hospital/healthcare-associated with good clinical
response: 8 days (unless etiologic pathogen is P.
aeruginosa, ~10-14 days)
Assumes active therapy administered initially

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 8 vs 15 Day Treatment of VAP
No difference in outcome except if P. aeruginosa involved
1.0
Probability of survival

0.8
Antibiotic regimen
0.6 8 days
15 days P=0.65

0.4
No. at risk
0.2 197 187 172 158 151 148 147

204 194 179 167 157 151 147

0.0
0 10 20 30 40 50 60
Days after Bronchoscopy JAMA 2003 290:2588
 Treatment Duration of Community-Associated
Pneumonia : No Consensus
Guidelines
IDSA (2000)treat Streptococcus pneumoniae until
afebrile 72 hours; gram negative bacteria, Staphylococcus aureus,
atypicals = 2 weeks
Canadian IDS/TS (2000) = 12 weeks
ATS (2001)standard is 714 days, but with new agents, may
shorten duration (ie, 57 days for outpatients)
BTS (2001)subject to clinical judgment (721 days)
Evidence
The precise duration of treatment is not supported
by robust evidenceBTS
Not aware of controlled trialsIDSA
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.

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

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)

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 When is Combination Therapy Considered
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

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 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: OGrady, 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.

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 Antibiotic Pharmacology and the
Pharmacodynamics of Bacterial Killing

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Bacterial Targets for Antibiotics

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Pharmacodynamics of Bacterial Killing
Concentration-dependent (greater bacterial kill at higher
concentrations) vs. Concentration-independent

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 The Pharmacodynamics of Bacterial Killing
Concentration-Independent: Optimal kill defined by time
over the minimum inhibitory concentration (T>MIC)

Concentration Beta-lactams
Vancomycin
Clindamycin
Macrolides

MIC
T>MIC

Time (hours)

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 Meropenem 500 mg Administered
as a 3 h Infusion Extends the Time Over
the MIC vs a 0.5 h infusion
100.0
Rapid Infusion (30 min)

10.0 Extended Infusion (3 h)

Concentration
(mcg/mL)

1.0
MIC
Additional T>MIC gained

0.1
0 2 4 6 8
Time (h)

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

 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)

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Selected Review of Specific Agents

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 Penicillin

Mechanism of activity
Interferes with cell wall synthesis
Adverse reactions
CNS toxicityencephalopathy 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)

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 Penicillin Resistance with
Streptococcus pneumoniae in the United States
40
Resistant (MICs >2)
35
Intermediate (MICs 0.12-1)
30
25
20
Percent

15
10
5
0
1979-87 1988-89 1990-91 1992-93 1994-95 1997-98 1999-00 2001-02 2002-03
5589 487 524 799 1527 1601 1531 1940 1828
35 15 17 19 30 34 33 45 44
1980s 1990s 2000s
 Antistaphylococcal 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%

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 Oxacillin
Bactericidal Activity

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 Broad-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

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 Are there any beta-lactams that can be used in a
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

patients with history of anaphylaxis to
penicillin?

Cephalosporins (2-18%)
Opportunity for x-reaction decreases as generations
increase
Carbapenems (50%)
Imipenem, meropenem, ertapenem

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 Cephalosporins
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

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 Cephalosporin Specifics
First gen: cefazolin
Good activity against gram positive organisms, and commonly
effective against E. coli, P. mirabilis, K. pneumoniaeNO
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

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 Cephalosporin 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

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 Carbapenems
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

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 Quinolones
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

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 Alarming Increase in Rate of Quinolone
30 Resistance in P. aerugniosa
Percent Resistance
25
Fluoroquinolone-resistant
20 Pseudomonas aeruginosa
15

10

0
8 9 90 91 92 93 94 95 96 97 98 99 00
19 19 19 19 19 19 19 19 19 19 19 20

Non-Intensive Care Unit Patients

Intensive Care Unit Patients
Source: National Nosocomial Infections Surveillance (NNIS) System
Important Reduction in GI Tract Quinolone Absorption
with Bi and Tri-Valent Cations

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

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 Vancomycin

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

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 Vancomycin
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)

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 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

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 Linezolid
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

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 Lipopeptides
Daptomycin (Cubicin)
MOA: disruption of plasma
membrane function
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:
Baltz RH. Biotechnology of Antibiotics. 1997. Activity against VRE, MRSA, VISA, PRSP
Tally FP, DeBruin M. J Antimicrob Chemother 2000;46:523-26.
 Rifampin
Benefits:
Most potent anti-
staphylococcal agent
(only used adjunctively)
DNA
mRNA IV & PO
THFA
QD dosing
Ribosomes Inexpensive PO (IV
$$$$$$)
DFHA New
50 50
30 Protein Disadvantages:
mRNA
30
RESISTANCE Develops
rapidly, CANNOT be
used as a single agent
Drug Interactions: MANY!!
Substrate of: CYP2A6,
2C9, 3A4
Owens RC Jr. Treatment guidelines for MRSA in the INDUCES: CYP1A2, 2A6,
elderly. Omnicare Formulary Guide. 2004. 2C9, 2C19, 3A4
Rifampin

Rash, Stevens Johnson

Syndrome, Toxic Epidermal
Necrolysis
Monitor:
CBC
Chemistry
hepatitis (Scr, BUN)
LFTs

Interstitial nephritis

Thrombocytopenia
 Aminoglycosides
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

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

14
12 Once-daily regimen

10 Conventional (three-times daily regimen)

Concentration
(mg/L) 8

6
4
2

0
0 4 8 12 16 20 24
Time (hours)
Nicolau et al. Antimicrob Agents Chemother 1995;39:650655
 Metronidazole

Mech of action: complex---toxic to bacterial DNA

Microbial activity
Anaerobes
Initial treatment of choice for C. difficile
100% bioavailable: IV = oral dose
Toxicity minimal
Neurotoxic at high doses
No dose adjustments in renal disease

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 Tetracyclines

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

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 Macrolides
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)

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 Macrolide Resistance with Streptococcus
pneumoniae in the United States
30
25
20

15

10

5
0
1979-87 1988-89 1990-91 1994-95 1997-98 1999-00 2001-02 2002-03
 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!

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 Antifungal Treatment
Candida as a Pathogen in Nosocomial Bloodstream
Infections in 49 US Hospitals
The SCOPE* Program (1995-1998)
No. of Crude
Rank Pathogen Isolates % Mortality(%)

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

* Surveillance and Control of Pathogens of Epidemiologic Importance.

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

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 Amphotericin

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

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

Successful Outcome 70 (P=NS)

79

Elevation of BUN/ 2
(P<.001) Fluconazole
Serum Creatinine 37
(400 mg/d)
2 Conventional
Hypokalemia 10 (P=.006) Amphotericin B
(0.5-0.6 mg/kg/d)
Elevation of 14
(P=.43)
Liver Enzymes 10

0 10 20 30 40 50 60 70 80 90
BUN = blood urea nitrogen. Patients (%)
Rex et al. N Engl J Med. 1994;331:1325-1330.
 Susceptible,
Comparative Microbiologic Activity dose-dependent

Fluconazole

Voriconazole

Some
Caspofungin cross-resistance

Candida
albicans

No activity
indicated
in black
 Clinical 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?

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 Clinical 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.

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 Clinical Scenario #2

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?

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 Clinical Scenario #2--answers

If the isolated organism is thought to represent the likely

pathogen and if MIC/susceptibility data support its 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

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 Clinical Scenario #3
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?

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 Clinical Scenario #3--answers

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

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