Mono- versus Bitherapy for Management of HAP/VAP in the ICU

Mono- versus Bitherapy for Management of HAP/VAP in the ICU Jean Chastre, www.reamedpitie.com Conflicts of interest: Consulting or Lecture fees: Nektar-Bayer, Pfizer, Brahms, Sanofi- Aventis, Janssen-Cilag, Astellas

Why Combining Two Antibiotics When Treating HAP/VAP? High prevalence of polymicrobial infections and/or infections caused by multidrug-resistant strains Need to start antimicrobial therapy before culture results and to be appropriate ASAP Need to maximize bacterial killing as much as possible High risk of selecting resistant mutants during treatment

Monotherapy vs. Bitherapy Since infection is likely to result from highly resistant organisms or to be polymicrobial, combining two antibiotics initially is mandatory in nearly all cases in order to avoid inappropriate treatment.

Empiric Antibiotics for HAP - 2005 ATS-IDSA Joined Guidelines HAP, HCAP or VAP Suspected (All Disease Severity) Late Onset or Risk Factors for Antibiotic - resistant (MDR) Bacteria No Yes Limited Spectrum Antibiotic Therapy Broad Spectrum Antibiotic Therapy For MDR Pathogens

Potentially resistant microorganisms in intubated patients with HAP/VAP Martin-Loeches I, et al. Intensive Care Med 2013;39:672-81

Why Combining Two Antibiotics When Treating VAP? High prevalence of polymicrobial infections and/or infections caused by multidrug-resistant strains Need to start antimicrobial therapy before culture results and to be appropriate ASAP Need to maximize bacterial killing as much as possible High risk of selecting resistant mutants during treatment

Appropriateness of antimicrobial therapy and survival in 5715 patients with septic shock Kumar et al. Chest 2009;136:1237-48

Selection of initial antimicrobial therapy is difficult Appropriateness of antimicrobial therapy and survival in 5715 patients with septic shock Kumar et al. Chest 2009;136:1237-48 80% 76%

Pathogens Associated with Inappropriate Initial Therapy in Patients with VAP 100% 80% 60% 40% 20% 0% Alvarez-Lerma Kollef Luna Rello Pseudomonas Acinetobacter MR S. aureus BLSE-producing Enterobacteriaceae Others

Klebsiella pneumoniae: proportion of invasive isolates with combined resistance to 3 rd gen. cephalosporins, FQ and AG in 2011 European Antimicrobial Resistance Surveillance Network (EARS-Net)

P. aeruginosa: proportion of invasive isolates with combined resistance to 3 or more antibiotic classes in 2011 European Antimicrobial Resistance Surveillance Network (EARS-Net)

Emerging KPC and VIM carbapenemases in Klebsiella Greece Clone with KPC replacing epidemic of bla VIM plasmids VIM KPC Widespread >1 outbreak 1 outbreak Sporadic http://www.ecdc.europa.eu; Grundmann et al. Euro Surveill 2010;15:19711; ARMRL, data on file; http://www.hpa.org.uk/web/hpawebfile/hpaweb_c/1294740725984

P. aeruginosa VAP: Importance of Initial Treatment Combining Two Effective Antibiotics in 183 Episodes Appropriate initial treatment, % Mortality, % Garnacho-Montero et al.ccm 2007 100 80 60 40 20 90 100 P <0.0001 P =0.09 80 57 60 51 40 20 37 0 Monotherapy (38/67) Combination (105/116) 0 Monotherapy (34/67) Combination (43/116)

Appropriateness of Antibiotic Therapy in Patients Receiving or not an AG as Empirical Therapy Martinez JA, et al. AAC 2010;54:3590-6 Microorganism Combination Beta-lactam OR (95% CI) P No./total no. (%) No./total no. (%) Non-ESBL E. coli 242/248 (98) 2,454/2,489 (99) 0.6 (0.2-1.7) 0.3 ESBL E. coli 21/28 (75) 62/122 (51) 2.9 (1.1-8.2) 0.02 Non-ESBL Klebsiella 62/63 (98) 393/420 (94) 4 (0.7-177) 0.2 ESBL K. pn. 18/20 (90) 38/63 (60) 2 (1.2-4.2) 0.01 P. mirabilis 10/10 (100) 116/118 (98) 1 Salmonella spp. 15/15 (100) 108/109 (99) 1 AmpC organisms 78/82 (95) 258/326 (79) 5.1 (1.8-20) 0.001 P. aeruginosa 133/143 (93) 201/319 (63) 7.8 (3.8-16) <.0001 Other NF-GNB 24/51 (47) 53/105 (51) 0.9 (0.4-1.8) 0.7 Miscellaneous 18/18 (100) 105/114 (92) 0.4

Antimicrobial Treatment of Hospital-acquired Pneumonia o In patients with HAP/VAP and risk factors for MDR should an aminoglycoside or a fluoroquinolone be selected when a regimen combining two antibiotics is used to improve initial therapy efficacy?

Escherichia coli: percentage of invasive isolates with resistance to aminoglycosides or quinolones, 2011 European Antimicrobial Resistance Surveillance Network (EARS-Net)

Klebsiella pneumoniae: proportion of invasive isolates resistant to AG or fluoroquinolones in 2011 European Antimicrobial Resistance Surveillance Network (EARS-Net) European Centre for Disease Prevention and Control. Antimicrobial resistance surveillance in Europe 2009. Annual Report of the European Antimicrobial Resistance Surveillance Network (EARS-Net). Stockholm: ECDC; 2011.

P. aeruginosa: proportion of invasive isolates with resistance to AG or FQ in 2011 European Antimicrobial Resistance Surveillance Network (EARS-Net) European Centre for Disease Prevention and Control. Antimicrobial resistance surveillance in Europe 2009. Annual Report of the European Antimicrobial Resistance Surveillance Network (EARS-Net). Stockholm: ECDC; 2011.

Mono- vs. Bi-therapy for Treating HAP/VAP There is no clinical benefit associated with a regimen combining two antibiotics when the infection is mild or moderate, and/or caused by a microorganism easily targeted by a very effective antimicrobial agent penetrating well into the lung.

A survival benefit of combination antibiotic therapy for sepsis and septic shock is contingent only on the risk of death: A metaanalytic/meta-regression study Kumar A, et al. Crit Care med 2010;38:1651-64 Non-RCT, n=44) RCT, n=12) >25% >25%

Randomized trial of combination versus monotherapy for the empiric treatment of suspected VAP Heyland DK, et al. Crit Care Med 2008;36:737 44 o 740 patients who developed VAP. Patients known to be colonized or infected with Pseudomonas or MRSA or who were immunocompromised were excluded. o Patients were allocated to receive meropenem (1 g q8 h) and ciprofloxacin (400 mg q12 h) or meropenem alone. o There was no difference in 28-day mortality between the two groups (RR 1.05, 95% Cl 0.78 1.42, p 0.74).

Empirical Treatment With Moxifloxacin and Meropenem vs Meropenem in Patients With Severe Sepsis: A Randomized Trial Brunkhorst FM, et al. JAMA. 2012;307:2390-9

Clinical implications of betalactam AG synergism: systematic review of randomised trials Marcus R, et al. Intern J Antimicrob Agents 2011;37:491 503 All-cause mortality was similar with monotherapy versus combination therapy [risk ratio = 0.96, 95% CI 0.78 1.18, 28 trials, 3756 episodes] Clinical failure was not significantly different (RR = 0.88, 95% CI 0.74 1.05, 27 trials, 2500 episodes) Combination therapy resulted in a significantly higher incidence of adverse events, mainly nephrotoxicity Overall, no clinical benefit was found for the use of a betalactam with an AG compared with a betalactam alone

Mono- vs. Bi-therapy for Treating HAP/VAP In contrast, when the infection is severe, associated with severe sepsis or septic shock, and/or caused by a difficult-to-treat microorganism, such as P. aeruginosa or NF-GNB, combining two effective antimicrobial agents is a superior option, at least initially.

Effect of Antimicrobial Therapy on Survival of Neutropenic Rats Challenged Intraperitoneally with 1.7x10 8 cfu of P. aeruginosa Johnson and Thompson, Am J Med 1986

o o o Randomized trial of combination versus monotherapy for the empiric treatment of suspected VAP Heyland DK, et al. Crit Care Med 2008;36:737 44 There was no difference in 28-day mortality between the two groups (RR 1.05, 95% Cl: 0.78 1.42). Duration of ICU and hospital stay, clinical and microbiological treatment response, emergence of antibiotic-resistant bacteria, and isolation of C. difficile were also similar in the two groups. In patients with MDR GNB infection (n=56), the adequacy of initial antibiotics (84% vs. 19%, p <.001) and microbiological eradication of infecting organisms (64% vs. 29%, p<0.05) were higher in the combination group.

Subgroup analysis of patients with difficult-to-treat GNB Heyland DK, et al. Crit Care Med 2008;36:737 44

Adjusted Cox proportional hazards of mortality associated with combination antibiotic therapy of septic shock Kumar A, et al. Crit Care Med 2010; 38:1773 85

Relations between Both Empirical and Definitive Antimicrobial Therapy and Mortality in 98 P.aeruginosa Bacteremia Chamot et al. Antimicrob Agents Chemother. 2003;47:2756-64. CHARACTERISTIC Empirical antimicrobial Rx. Adequate combination Adequate monotherapy Inadequate therapy Definitive antimicrobial Rx. Adequate combination Adequate monotherapy Inadequate therapy HAZARD RATIO 1.0 3.7 5.0 1.0 0.7 2.6 95% CI P VALUE 1.0-14.1 1.2-20.4 0.3-1.7 1.1-6.7 0.05 0.02 0.42 0.04

Impact of Definitive Therapy with Beta-Lactam Monotherapy or Combination with an AG or a FQ for P. aeruginosa Bacteremia Bliziotis IA, et al. PLoS One. 2011;6(10):e26470 o Retrospective cohort study of 54 episodes of Pa BSI from 3 tertiary hospitals (2 in Greece and 1 in Italy). o Treatment success was higher with combination therapy (85%) compared to beta-lactam monotherapy (65%), however not statistically significantly [OR 3.1; 95% CI 0.69-14.7, p = 0.1]. o All-cause mortality did not differ significantly between combination therapy [19%] and monotherapy [42%], p = 0.11. o Only Charlson comorbidity index was associated with excess mortality (p = 0.03).

The growing challenge of multidrug resistant GNB Carbapenem-resistant Klesiella pneumoniae (VIM+, KPC+, NDM-1+) Pseudomonas aeruginosa (Stably derepressed chromosomal AmpC enzyme, OprD downregulated, VIM+) Acinetobacter baumannii (VIM+, OXA+, Efflux pumps+, NDM-1+)

Doripenem combined with colistin is bactericidal and synergistic against colistin-r, carbapenemase-producing K. pneumoniae Jernigan MG, et al. AAC, Published Ahead of Print 19 March 2012. Colistin Colistin + doripenem

Impact of Different Antimicrobial Regimens on Resistance Emergence in an in-vitro Model of P. aeruginosa Infection Louie A, et al. Antimicrob Agents Chemother 2010;54(6):2638-2645 Total population Wild-type PAO1 strain Imipenem 1g q8h, Doripenem 1h infusion 1g q8h, 4h infusion Total population Resistant population Resistant population

Relationship Between Development of Resistance and Antimicrobial PK/PD in Patients with LRT Infection Thomas JK, et al. Antimicrob Agents Chemother. 1998;42:521-7. AUC 0-24 /MIC ratio > 100 AUC 0-24 /MIC ratio < 100 Type 1 beta-lact. organisms betalactam monotherapy

Limited Value of Combination Therapy in Patients with Severe Infection Paul et al. BMJ 2004; 328: 668 Meta-analysis of beta-lactam monotherapy vs. beta-lactam/aminoglycoside combination for severe infection 64 randomized trials, non-neutropenic,7586 patients No difference in mortality (RR for monorx. 0.90) No differences in clinical and bacteriologic failures (RR=0.87 and 0.86) No advantage for P. aeruginosa infection (426 pts) No difference in emergence of resistance Significantly less nephrotoxicity (RR =0.36)

Campaign to Prevent Antimicrobial Resistance in Healthcare Settings Selection for antimicrobial-resistant Strains Resistant Strains Rare Antimicrobial Exposure Resistant Strains Dominant

Mono- vs. combination therapy for treating HAP/VAP Combining a broad-spectrum betalactam and an aminoglycoside for the first 2-3 days of therapy improve appropriateness and efficacy of initial therapy in patients with risk factors for MDR. Such a strategy should be coupled with a strong commitment to de-escalate once culture results are available, i.e., stopping AG and restricting broad-spectrum betalactams to infection caused by pathogens only susceptible to these agents. Whether or not using a combination therapy after days 2-3 in patients infected with NF-GNB pathogens remains to be elucidated.