ICU Case Presentation: Double antimicrobial coverage for gram negative infections. Christine Rizkalla, RPh, BScPhm Pharmacy Resident May 16, 2007

Transcription

1 ICU Case Presentation: Double antimicrobial coverage for gram negative infections Christine Rizkalla, RPh, BScPhm Pharmacy Resident May 16, 2007

2 Objectives Understand the theoretical advantages and disadvantages of using double antimicrobial coverage for gram negative infections. Know the available data comparing single vs. combination antimicrobial therapy for gram negative infections and understand the limitations of the literature. Review case hepatic cirrhosis + sepsis

3 49 y.o. female RFA: septic shock Case: Mrs. JD DOA: May 3 (from community hospital Apr 22) PMH: Hep C (1970) Portal hypertension, ascites, thrombocytopenia, lowgrade esophageal varices, mild encephalopathy For LDLT Hysterectomy, leg pain

4 HPI Acute decompensation Admitted to community hospital Deteriorated postparacentesis: LOC, WBC s, sats, bp, GIB Apr 29 Ascitic fluid C&S: Pseudomonas aeruginosa Sensitive to ceftazidime, ciprofloxacin, gentamicin, imipenem, piperacillin

5 Medications on Transfer Pantoprazole 40mg iv od Lactulose enema qid Kayexalate 15g od Insulin ss Dopamine 5-15mcg/kg/min Ceftriaxone 1g iv q24h

6 Medications on Transfer Pantoprazole 40mg iv od Lactulose enema qid Kayexalate 15g od Insulin ss Heparin 5000U sc bid Dopamine 5-15mcg/kg/min Ceftriaxone 1g iv q24h

7 Presentation CNS GCS=3, SAS=1 unresponsive Resp PC = 16 O%=70%, Peep 20 ARDS CVS HR=65 BP=110/50 MAP=60 CVP=9 GI GU ID No BM s with lactulose Massive ascites ARF: anuric CRRT SLED Afebrile Peritoneal fluid: pseudomonas

8 Labs Glucose: 5.6 mmol/l Na: 126 mmol/l K: 4.2 mmol/l Cr: 344 umol/l Ca: 1.80 mmol/l PO4: 2.56 mmol/l Alb: 33 g/l AST: 69 U/L ALT: 35 U/L ALP: 57 U/L Bili: 216umol/L Hb: 75 g/l WBC: 27.5 bil/l Plt: 46 bil/l Lactate: 9.4mmol/L

9 Medications Medications in hospital: Lactulose 30ml ng q6h Ciprofloxacin 400mg iv bid Piperacillin/tazobactam 3.375g iv q8h Hydrocortisone 100mg iv tid Vitamin K 10mg sc oto Famotidine 20mg iv bid Heparin 5000U sc bid Fentanyl 100mcg/hr Propofol Norepinephrine 3mcg/hr

10 Medications Medications in hospital: Lactulose 30ml ng q6h Ciprofloxacin 400mg iv bid Piperacillin/tazobactam 3.375g iv q8h Hydrocortisone 100mg iv tid Vitamin K 10mg sc oto Famotidine 20mg od Heparin 5000U sc bid Fentanyl 100mcg/hr Propofol Levophed 3mcg/hr

11 Issues Septic shock Fluid resuscitation Pressors Insulin Steroids Activated protein C Antibiotics Hepatic Failure INR: bleed risk Encephalopathy Portal hypertension Hepatorenal syndrome Esophageal varices Hypoalbuminemia Anemia Thrombocytopenia Ascites peritonitis GIB DVT px Ulcer px

12 Drug Related Problems Mrs. JP is experiencing signs and symptoms of septic shock and requires appropriate antimicrobial therapy?corticosteroid Pressor support

13 Double Antimicrobial Coverage in Gram Negative Infections Why use double coverage? What (if any) impact is there on mortality and/or treatment success? What do the experts say?

14 WHY: Theoretical Advantages Enhanced bactericidal killing through synergism Prevent emergence of resistant bacteria

15 In Vitro Data Evidence for synergy against P.aeruginosa with AMG + BL combinations Variably present Strain dependent Varies with different AMG and BL concentrations Less evidence for BL + FQ, but has been shown Antagonism is possible (i.e. at [] s < MIC) Lancet Inf Dis 2004;4:

16 Limitations of In Vitro Data Host Drug Disease Host

17 Clinical Trials

18 Prospective Randomized Comparison of Imipenem Monotherapy with Imipenem plus Netilmicin for Treatment of Severe Infections in Nonneutropenic Patients Cometta et al. Antimicrob Agents Chemother 1994;38(6):

19 Study Design Prospective RCT, Jan , multicentre No ITT analysis Population: Surgical ICU and surgery pts nosocomial pneumonia, nosocomial sepsis, and severe diffuse peritonitis N= Comparison: imipenem vs. imipenem + netilmicin as empiric tmt Endpoint: Primary: treatment success, tolerance Secondary: emergence of resistance + incidence of superinfection

20 Methods Inclusion 16y.o. Nosocomial pneumonia, nosocomial sepsis, severe diffuse peritonitis

21 Exclusion Peritonitis secondary to perforated UGIT or acute appendicitis Hypersensitivity to carbapenem or AMG ANC<1 Likelihood of death in 48h Presence of an organism intrinsically resistant to imipenem, ie. Burkholderia cepacia or maltophilia (stenotrophomonas)

22 Primary diagnosis of fungal, viral, or mycobacterial infection, previously enrolled in trial Previous treatment with netilmicin or another AMG within 4 weeks of randomization Pregnancy and lactation

23 Definitions Nosocomial Pneumonia New or progressive infiltrate seen on chest X ray 48h post admission in the presence of 2 symptoms ie. Temp 38 C, cough, sputum, WBC 10, hypoxemia (PaO 2 <70 on RA or 25% from original value) Sputum or tracheal aspirate containing predominant isolate, 25 PMN s and <10 epithelial cells

24 Nosocomial sepsis 48hrs post admission Sudden clinical deterioration + evidence of infection + temp 39 C or 35 C + at least 1 of: LOC, hypoxemia (PaO 2 <75 on RA) Oliguria (<30mL/hr) Lactate >2 Microbiologically documented if: + cultures or primary focus responsible for sepsis was microbiologically documented

25 Severe Diffuse Peritonitis Clinical evidence of peritoneal infection post-surgery associated with lesion in large bowel (i.e. perforation, abscess, fistula) Must be microbiologically documented

26 Randomization Randomly assigned to 1 of 2 regimens by sealed numbered envelopes Stratified according to type of infection

27 Treatment Regimen and Regimen Monitoring Imipenem 500mg qid vs. Imipenem 500mg qid + netilmicin 150mg bid (Doses adjusted for renal function) Monitoring Q other day by unblinded investigator

28 Results

29 313admitted 30 excluded 3stopped d/t toxicity (cutaneousrash thrombocytopenia, diarrhea) 280 evaluatedfor efficacy 7 ineligible 12 early death 11 protocol violation

30 Patient Characteristics Younger pts Males> females Pneumonia

31 Type of Infection Mostly GNB and other Variety of bugs Variety of bugs Fewer bacteremias

32 Efficacy OVERALL: No statistically significant difference in number of success or failures, no difference in # of deaths, no difference in length of treatment PERITONITIS: Fewer number of failures (p=0.09)

33 Adverse Events

34 Superinfection and colonization No significant difference in superinfections in the 2 groups Combo therapy did not prevent emergence of resistant P. aeruginosa

35 Discussion Authors conclusion Success rate not improved by combination therapy Combination therapy did not reduce emergence of resistant bacteria Monotherapy with imipenem a valid option for treatment of severe infections in non-neutropenics Study limitations Unblinded Choice of antibiotics Sample size ITT? Heterogenous group of bacteria

36 Prospective Observational Study of Klebsiella Bacteremia in 230 Patients: Outcome for Antibiotic Combinations versus Monotherapy Korvick et al. Antimicr Agents Chemother 1992; 36(12):

37 Design Prospective, observational, multicentre Population N=230 With K.pneumonia, K.oxytoca, K. ozaenae bacteremia Intervention BL + AMG vs. monotherapy

38 Methods Definitions Onset of bacteremia: date of first + blood culture Monotherapy: single antibiotic active in vitro against Klebsiella strain isolated for 2 days within first 3 days since +ve culture Combination: treatment with 2 antibiotics active in vitro against the organism for 2 days within first 4 days from date of +ve culture

39 Immunosuppression: 1 of: LKC < 2.7 ANC <1 Hematologic malignancy Corticosteroid therapy Cancer chemotherapy Severity of Illness (Ill = score of 4+) SBP <90 within 3 days prior to or on day of +ve culture Temp > 38 C (1pt) or >39 C (2 pts) Mental status: alert coma (0 4 pts) Mechanical resp support (2 pts) Cardiac arrest (4 pts)

40 Endpoint: survival or death at 14 days from date of positive culture Data Analysis: Categorical data analyzed by chi-square test or Fisher exact test Continuous variables compared using t test or Mann-Whitney test Survival analysis using Gehan-Breslow test to compare diff s between 2 Kaplan-Meier curves Stepwise regression model to examine effects of multiple risk factors on mortality. Factors use included those found to be significant by univariate analysis and for monotherapy vs. combo

41 Results

42 Patient Characteristics # pts with immunosuppression, malignancy No statistically sig. differences

43 Lower severity of illness, not septic

44 Antibiotics Used for Monotherapy

45 Combination Therapy

46 Mortality OVERALL: No difference in mortality HYPOTENSION: lower mortality rate obtained with combination therapy (statistically significant)

47 Discussion Authors conclusion: monotherapy with an antibiotic that is active against Klebsiella spp. In vitro is sufficient therapy for less severely ill patients Combination antibiotic therapy is preferred for severely ill patients, especially if hypotension has occurred Limitations Observational (bias introduced) Heterogeneity of patients (age 1 day to 95 years) Patients less sick Focus on Klebsiella (less virulent than ie. Psuedomonas) Choice of antibiotics No ITT

48 Effectiveness of Combination Antimicrobial Therapy for Pseudomonas aeruginosa Bacteremia Chamot E et al. Antimicrob Agents Chemother 2003; 47(9):

49 Design Retrospective cohort ( ) Unicentre (Switzerland) ITT Population 115 P.aeruginosa infection episodes Intervention Combination vs. monotherapy for empiric treatment of Pseudomonas aeruginosa bacteremia Endpoint Survival rate

50 Methods Identified all pts with +ve P. aeruginosa blood cultures Chart review for SIRS symptoms at time of bacteremia and received antibiotic treatment that included at least one antipseudomonal agent Allowed multiple pseudomonal episodes in one pt

51 Definitions Pseudomonal bacteremia Documented +ve culture No antecedent of inadequately treated P.aeruginosa bacteria No +ve blood culture for 30 days post completion of adequate antimicrobial therapy for a previous episode

52 Monotherapy Piperacillin ceftazidime Imipenem Cefepime Ciprofloxacin piperacillin/tazobactam was used infequently and was grouped with piperacillin Combination therapy 1. piperacillin, ceftazidime, imipenem, or cefepime PLUS an an AMG (gentamicin or amikacin) OR ciprofloxacin 2. AMG + ciprofloxacin

53 Adequate [empiric/definitive mono/combo] therapy: Pseudomonas susceptible to Rx d antibiotic(s) and dose was appropriate Inadequate [empiric/definitive mono/combo] therapy: resistant to drug(s), gentamicin 5.1mg/kg monotherapy

54 Categories of Treatment Empirical antipseudomonal therapy Treatment including at least 1 antipseudomonal started 24hrs after the +ve blood culture drawn Definitive antipseudomonal therapy Tmt included 1 antipseudomonal continued or commenced on the day that the antibiogram results were reported to the clinician

55 Statistical Analysis Assessed other prognostic factors (age, gender, year of infection), presentation, mono- vs. polymicrobial infection, underlying medical condition, neutropenia Fisher s to compare categorical variables Kaplan-Meier univariate analysis to estimate risk of death by empirical treatment categories

56 Primary Endpoint Time to death from all causes

57 Results

58 Patient Characteristics: Empiric

59 Antibiotics Used Drug Imipenem Piperacillin Ceftazidime Cefepime Gentamicin Amikacin Ciprofloxacin % of Patients 28.7% 19.1% 19.1% 10.4% 48.7% 13.9% 23.5%

60 Early Follow-Up Time from bacteremia receipt of antibiogram Median = 5 days Mean (p=ns): IET group: 5.5 days AEMT: 5.2 days AECT: 5.1 days Risk of death: no relation between empirical therapies and risk of death before the receipt of the antibiogram

61 Summary of Univariate HR s until receipt of biogram in empiric therapy No difference between combo and monotherapy

62

63 Risk of Death in AECT vs AEMT vs. IET Difference in risk of death not statistically significant

64 Entire Follow-Up Achieved for 99% of participants 37.4%% AECT 47.8% AEMT 14.8% IET Unadjusted probability of survival until day 30, p=0.01: Empiric combination: 72.1% (95% CI = ) Empiric monotherapy: 61.2% (95% CI = ) Inadequate therapy: 29.4% (95% CI =10.7 to 51.2%)

65 For entire follow-up, empiric combo therapy until receipt of biogram was associated with improved survival, but definitive combo or monotherapy did not make a difference.

66 Discussion Author s conclusions Adequate empirical combination therapy independently associated with better survival at 1 month compared with adequate empirical monotherapy Limitations Retrospective Unblinded Choice of antibiotics

67 Does combination antimicrobial therapy reduce mortality in Gram- negative bactaeremia? A meta-analysis analysis Safdar N, Handelsman J and Maki DG Lancet Inf Dis 2004;4:

68 In Brief Design Meta-analysis of 17 studies Purpose: determine whether combo of 2+ antimicrobials reduces mortality in pts with gram negative bacteremias

69 Results No mortality benefit with combination Even when adjusted for year of publication, study design, severity of illness Significant mortality benefit in Pseudomonas aeruginosa (OR 0.50, 95% CI )

70 Studies Analyzed Included 17 studies 5 prospective cohort 2 prospective randomised 10 retrospective cohort Most studies used BL s or AMG s alone or in combination Time 1974, 1980, 1984, 1985, 1987, 1989, 1990, 1991, 1996, 1998, 1999, 2000, 2002

71 ATS HAP/VAP/HCAP Guidelines The commonly cited reason to use combination therapy is to achieve synergy in the therapy of P. aeruginosa. However, synergy has been clearly documented to be valuable only in vitro The in vitro finding of synergy has been inconsistently demonstrated, and has been difficult to show as being clinically relevant (258, 259). Am J Respir Crit Care Med 2005;171:

72 IDSA/ATS Guidelines for CAP (Inpatient, ICU treatment) For Pseudomonas infection, use an antipneumococcal, antipseudomonal b-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) plus either ciprofloxacin or levofloxacin (750-mg dose) or the above b-lactam plus an aminoglycoside and azithromycin CID 2007;44:S27-72

73 or the above b-lactam plus an aminoglycoside and an antipneumococcal fluoroquinolone (for penicillin-allergic patients, substitute aztreonam for the above b-lactam). (Moderate recommendation; level III evidence.) CID 2007;44:S27-72

74 Summary Evidence is poor Design (lack of RCT s) Choice of antibiotics Evidence available does not show clear mortality benefit in gram negative infections Controversial!

75 Course in Hospital Responded to ACTH stimulation test d/c HC Persistent LOC (despite d/c propofol and fentanyl sedation) Initially, no BM s in response to lactulose ng + enema qid Persistent thrombocytopenia (liver disease?) Ascitic fluid + blood cultures since TGH admission all negative Cipro + pip/tazo combination continued

76 Spiked fevers over weekend: Changed pip/tazo meropenem Add fluconazole 400mg iv od Changed lines + vancomycin 1g iv x1 dose Keep cipro

77 Questions?