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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
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
• Cost = <$30 billion/yr at $24K per case
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pathogens
4
Mechanisms of Bacterial Resistance to
Antibiotics
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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 comorbidities
• 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
Initial Inappropriate Therapy
Infection-Related Mortality
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;
Ibrahim EH, et al. Chest. 2000;118:146-155
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 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
Probability of survival
1.0
0.8
Antibiotic regimen
8 days
15 days
0.6
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
Days after Bronchoscopy
40
50
60
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) = 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.
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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: 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.
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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)
Beta-lactams
Vancomycin
Clindamycin
Macrolides
Concentration
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)
Extended Infusion (3 h)
10.0
Concentration
(mcg/mL)
1.0
MIC
Additional T>MIC gained
0.1
0
2
4
Time (h)
Dandekar PK et al. Pharmacotherapy. 2003;23:988-991.
6
8
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 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)
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Penicillin Resistance with
Streptococcus pneumoniae in the United States
40
35
Resistant (MICs >2)
Intermediate (MICs 0.12-1)
30
Percent
25
20
15
10
5
0
1979-87 1988-89 1990-91 1992-93 1994-95 1997-98 1999-00 2001-02 2002-03
5589
35
1980’s
487
15
524
17
799
19
1527
30
1990’s
1601
34
1531
33
1940
45
2000’s
1828
44
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 betalactamase 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. 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
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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), hypohyperglycemia (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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Percent Resistance
Alarming Increase in Rate of Quinolone
Resistance in P. aerugniosa
30
25
20
Fluoroquinolone-resistant
Pseudomonas aeruginosa
15
10
5
19
89
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
0
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.

Tally FP, DeBruin M. J Antimicrob Chemother 2000;46:523-26.
Activity against VRE, MRSA, VISA, PRSP
Rifampin
Benefits:

DNA

mRNA

THFA

Ribosomes
DFHA
50
30
mRNA
50
30
New
Protein
Most potent antistaphylococcal agent
(only used adjunctively)
IV & PO
QD dosing
Inexpensive PO (IV
$$$$$$)
Disadvantages:
 RESISTANCE Develops
rapidly, CANNOT be
used as a single agent
 Drug
Owens RC Jr. Treatment guidelines for MRSA in the
elderly. Omnicare Formulary Guide. 2004.
Interactions: MANY!!
Substrate of: CYP2A6,
2C9, 3A4
INDUCES: CYP1A2, 2A6,
2C9, 2C19, 3A4
Rifampin
Rash, Stevens Johnson
Syndrome, Toxic Epidermal
Necrolysis
Monitor:
 CBC
 Chemistry
hepatitis
Interstitial nephritis
Thrombocytopenia
(Scr, BUN)
 LFTs
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
8
(mg/L)
6
4
2
0
0
4
8
12
Time (hours)
16
20
Nicolau et al. Antimicrob Agents Chemother 1995;39:650–655
24
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)
Rank
Pathogen
No. of
Isolates
Crude
%
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
70
Successful Outcome
(P=NS)
79
2
Elevation of BUN/
Serum Creatinine
37
(P<.001)
2
Hypokalemia
10
Elevation of
Liver Enzymes
(P=.006)
14
Fluconazole
(400 mg/d)
Conventional
Amphotericin B
(0.5-0.6 mg/kg/d)
(P=.43)
10
0
10
20
30
BUN = blood urea nitrogen.
Rex et al. N Engl J Med. 1994;331:1325-1330.
40
50
60
Patients (%)
70
80
90
Comparative Microbiologic Activity
Fluconazole
Voriconazole
Caspofungin
Some
cross-resistance
Candida
albicans
No activity
indicated
in black
Susceptible,
dose-dependent
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 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
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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?
Resident ICU Course
64
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
Resident ICU Course
65