Infectious Disease in the Critically Ill - St. Barnabas Hospital

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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

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

                               Resident ICU Course                            1
                   Discussion Topics

• Using antibiotics wisely
   – Impact on microbial resistance
   – Impact on patient outcomes
• Choosing initial antibiotics and tailoring when data become
• 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?

               Resident ICU Course    3
         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

             Resident ICU Course        5
Resident ICU Course   6
The Pharmacology of Infectious Diseases
        Involves Many Factors



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

               Resident ICU Course                                  7
        Selection of Antimicrobial Therapy:
                   Host Factors

• Allergies, age, pregnancy, hepatic and renal function,
  concomitant drug therapy, immunocompentence, and co-
• 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
         – Organisms may reflect selective pressure if antibiotics previously
           administered (Antimicrobial history taking is extremely important!)

                              Resident ICU Course                            8
      Selection of Antimicrobial Therapy: Drug

•   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

                                      Resident ICU Course                                   9
        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
• Using MIC (minimum inhibitory concentration) data
   – Requires knowledge of achievable drug concentrations at the site of
   – 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

                             Resident ICU Course                      10
           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,

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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
• 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

                              Resident ICU Course                          13
                    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

                              Resident ICU Course                          14
                                8 vs 15 Day Treatment of VAP
                                    No difference in outcome except if P. aeruginosa involved
Probability of survival

                                      Antibiotic regimen
                          0.6                8 days
                                             15 days                                   P=0.65

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

                                               204         194        179        167        157        151   147
                                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) = 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.

                                                       Resident ICU Course   16
                     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)

                              Resident ICU Course                          17
  When is Combination Therapy Considered
• 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

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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)

   Concentration                             Beta-lactams


                             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
                                    Rapid Infusion (30 min)

                10.0                                          Extended Infusion (3 h)

                            Additional T>MIC gained

                       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

            Resident ICU Course      26

• 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
                 Resistant (MICs >2)
                 Intermediate (MICs 0.12-1)

               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
                 1980’s                   1990’s                       2000’s
           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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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

                    Resident ICU Course         31
 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

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

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• 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
• 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
• 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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• 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.
   – 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

                              Resident ICU Course                       36
•   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

                                   Resident ICU Course                              37
                      Alarming Increase in Rate of Quinolone
                      30   Resistance in P. aerugniosa
 Percent Resistance
                      20      Pseudomonas aeruginosa

























                              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”

                  Resident ICU Course                 40

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

                        Resident ICU Course              42
                  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
• Bone marrow depression (usually >2wks tx), GI

                        Resident ICU Course              43
• 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

                        Resident ICU Course              44
                                                                      Daptomycin (Cubicin)
                                                                  MOA: disruption of plasma
                                                                  membrane function
                                                                 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
Baltz RH. Biotechnology of Antibiotics. 1997.                 Activity against VRE, MRSA, VISA, PRSP
Tally FP, DeBruin M. J Antimicrob Chemother 2000;46:523-26.
                                                                     Most potent anti-
                                                                      staphylococcal agent
                                                                      (only used adjunctively)
                                           mRNA                      IV & PO
                                                                     QD dosing
                               Ribosomes                             Inexpensive PO (IV
               DFHA                                  New
                            50      50
                                     30             Protein   Disadvantages:
                                                               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

     Rash, Stevens Johnson
    Syndrome, Toxic Epidermal
                                    CBC
                                    Chemistry
       hepatitis                     (Scr, BUN)
                                    LFTs

Interstitial nephritis

•   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

                                     Resident ICU Course                                 48
   Once-daily vs. Conventional Three-times Daily Aminoglycoside Regimens
         Optimizes Concentration-dependant Effect on Bacterial Kill

           12                                Once-daily regimen

           10                                Conventional (three-times daily regimen)
(mg/L)       8


                 0   4           8         12            16         20            24
                                     Time (hours)
                     Nicolau et al. Antimicrob Agents Chemother 1995;39:650–655

• 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

                             Resident ICU Course     50

• Inhibit protein synthesis
• Microbial activity
   – minocycline = MRSA, MRSE, Acinetobacter
   – doxycycline = CAP (pneumococcus and atypicals),
• 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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     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



     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!

                          Resident ICU Course                54
                   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.
• 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!

                         Resident ICU Course                56

• 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

                         Resident ICU Course                 57
Efficacy: Fluconazole vs Conventional Amphotericin
  B in Nonneutropenic Patients With Candidemia

Successful Outcome                                                     70         (P=NS)

  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
    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.
 Comparative Microbiologic Activity           dose-dependent



Caspofungin                cross-resistance


                      No activity
                      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

                          Resident ICU Course                60
            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.

                          Resident ICU Course                 61
                  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?

                         Resident ICU Course               62
           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

                         Resident ICU Course                 63
                 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

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