Docstoc

Infectious Disease in the Critically Ill - St. Barnabas Hospital

Document Sample
Infectious Disease in the Critically Ill - St. Barnabas Hospital Powered By Docstoc
					    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
  available
• Using pharmacology and pharmacodynamics to optimize
  bacterial killing
• Applying clinically relevant specific antibiotic information




                         Resident ICU Course                 2
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



                          Resident ICU Course                  4
Mechanisms of Bacterial Resistance to
            Antibiotics




             Resident ICU Course        5
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




               Resident ICU Course                                  7
        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!)




                              Resident ICU Course                            8
      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




                                      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
     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



                             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,
                           2005:41-64.




                Resident ICU Course                                            12
                    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


                              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
                          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) = 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
              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


                        Resident ICU Course             18
            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.




                                      Resident ICU Course                                    19
  Antibiotic Pharmacology and the
Pharmacodynamics of Bacterial Killing




              Resident ICU Course       20
Bacterial Targets for Antibiotics




           Resident ICU Course      21
Pharmacodynamics of Bacterial Killing
Concentration-dependent (greater bacterial kill at higher
   concentrations) vs. Concentration-independent




                     Resident ICU Course                    22
     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)




                       Resident ICU Course                   23
             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)




                                                Resident ICU Course                                     25
Selected Review of Specific Agents




            Resident ICU Course      26
                             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)




                             Resident ICU Course                       27
             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
                 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%


                         Resident ICU Course             29
     Oxacillin
Bactericidal Activity




     Resident ICU Course   30
          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
     penicillin?

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

                          Resident ICU Course                 32
                    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

                         Resident ICU Course               33
                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


                           Resident ICU Course                  34
              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




                        Resident ICU Course              35
                          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




                              Resident ICU Course                       36
                                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



                                   Resident ICU Course                              37
                      Alarming Increase in Rate of Quinolone
                      30   Resistance in P. aerugniosa
 Percent Resistance
                      25
                              Fluoroquinolone-resistant
                      20      Pseudomonas aeruginosa
                      15

                      10

                       5

                       0
                         89

                         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




                   Resident ICU Course                 39
Vancomycin (also formerly known as Mississippi Mud)
     Name derived from the word “Vanquish”




                  Resident ICU Course                 40
                       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




                          Resident ICU Course                 41
                      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)



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




                        Resident ICU Course              43
                        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



                        Resident ICU Course              44
                                                     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




                                     Resident ICU Course                                 48
   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;39:650–655
                         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




                             Resident ICU Course     50
                       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




                          Resident ICU Course                   51
                           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)




                            Resident ICU Course                       52
     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!


                          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.
                       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!



                         Resident ICU Course                56
                      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




                         Resident ICU Course                 57
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?




                          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

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:2
posted:3/13/2012
language:
pages:65