Resident ICU Course 1 Slide Sub-Title Principles of Treating Infectious Principles of Treating Infectious Illnesses in Critical Care: Focus on Illnesses in Critical Care: Focus on Antibiotic Resistance and Choice Antibiotic Resistance and Choice “ We shall now discuss in We shall now discuss in a little more detail the a little more detail the struggle for existence.” struggle for existence.” C Darwin 1859 C Darwin 1859
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Resident ICU Course1 Slide Sub-Title Principles of Treating Infectious Illnesses in Critical Care: Focus on Antibiotic Resistance and Choice “We shall.
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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
““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
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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
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Post-Antibiotic Era Mortality: What the Post-Antibiotic Era Mortality: What the Future Holds?Future Holds?
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Clinical Relevance of ResistanceClinical Relevance of Resistance Ann Intern Med 2001; 134:298Ann Intern Med 2001; 134:298
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 Mechanisms of Bacterial Resistance to AntibioticsAntibiotics
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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
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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!)
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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
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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.
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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.
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Treatment Duration?Treatment Duration?Refer to Guidelines Cited on Slide 23 for More Complete Information
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:Recently Published Guidelines:
– Hospital/healthcare/ventilator pneumonia Am J Respir CCM 2005; 171:388
– 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 Antibiotic Pharmacology and the Pharmacodynamics of Bacterial KillingPharmacodynamics of Bacterial Killing
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Bacterial Targets for AntibioticsBacterial Targets for Antibiotics
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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
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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
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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
• 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 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
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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
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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
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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
• 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
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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
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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”
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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
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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)
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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
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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
• 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
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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
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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
• 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(%)
• 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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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
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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
• 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 #2Clinical 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?
• 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 #3Clinical 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?
• 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