Treatment Strategies for Infections due to MDR-GNR Michael Satlin, MD Instructor in Medicine Division of Infectious Diseases Weill Cornell Medical College, New York, NY October 16, 2012 1
2 Faculty Disclosure The Association of Public Health Laboratories adheres to established standards regarding industry support of continuing education for healthcare professionals. The following disclosures of personal financial relationships with commercial interests within the last 12 months as relative to this presentation have been made by the speaker(s): Michael Satlin Nothing to disclose. 2
3 Objectives Outline the limited antimicrobial armamentarium available to combat infections caused by MDR-GNR Demonstrate the relationship between timely active antibacterial therapy and survival in patients with severe sepsis Review treatment strategies for the Big 3 Pseudomonas aeruginosa Acinetobacter baumannii Enterobacteriaceae Special considerations: pneumonia, UTIs 3
4
New antibacterial agents approved in the US from 1983-2007 Incidence and diversity of MDR GNR pathogens 5 Boucher HW, et al. Clin Infect Dis 2009.
Clinical case of a patient with a MDR GNR infection 60 year-old man with cholangiocarcinoma who presents with fever and hypotension. Blood cultures grow Klebsiella pneumoniae Antibacterial MIC (μg/ml) Susceptibility Amikacin >=64 R Aztreonam >=64 R Cefepime 32 R Ceftazidime >=64 R Ceftriaxone >=64 R Levofloxacin >=8 R Meropenem >=16 R Tobramycin >=16 R Trimethoprim/Sulfa >=320 R 6
What s left? What approved antimicrobials are active against gram-negatives that are resistant to all beta-lactams? Polymyxins Tigecycline Aminoglycosides, sometimes SUBOPTIMAL 7
Problems with Polymyxins 2 types: Colistin (polymyxin E) and Polymyxin B 1) Toxicities Nephrotoxicity: 40-60% with either colistin 1 or polymyxin B 2 Neurotoxicity 3 : paresthesias, visual alterations, ataxia, neuromuscular blockade; less common 2) Poor PK/PD data Example: we don t know how to dose in renal failure 4 3) Questionable efficacy data Independently associated with mortality compared to betalactams 5 4) Unreliable susceptibility testing by Etest 6 8 1 Pogue JM, et al. Clin Infect Dis. 2 Kubin CJ, et al. J Infect 2012. 3 Lim LM, et al. Pharmacotherapy 2010. 4 Zavascki AP, et al. Clin Infect Dis 2008. 5 Paul M, et al. J Antimicrob Chemother 2010. 6 Tan TY, et al. Clin Microbiol Infect. 2007.
Troubles with Tigecycline 1) Not active against Pseudomonas aeruginosa 1 2) Bacteriostatic, not bactericidal 1 3) Low bloodstream and urine levels 1 Limits their use in bacteremias and UTIs Only approved for complicated skin-soft tissue infections, complicated intraabdominal infection, and community-acquired pneumonia 4) Increased mortality in RCTs? 2 9 1 MacGowan AP. J Antimicrob Chemother 2008. 2 Prasad P, et al. Clin Infect Dis 2012.
RCTs comparing tigecycline to comparator agents since obtained FDA approval in 2005 10 Prasad P, et al. Clin Infect Dis 2012.
What about aminoglycosides? 1) Not reliably active vs. carbapenem-resistant gram-negatives Particularly for carbapenem-resistant enterics 1 2) Toxicities Nephrotoxicity: 10-20% of patients have their kidney function reduced by at least 50% 2 Otovestibular toxicity: Less common but can be permanent 3 3) Poor penetration into lungs 4, abscesses 5 4) Poor efficacy as monotherapy 11 1 Patel G, et al. Infect Control Hosp Epidemiol 2008. 2 Moore RD, et al. Ann Intern Med 1984. 3 Guthrie OW. Toxicology 2008. 4 Brun-Buisson C, et al. Am J Respir Crit Care Med 2001. 5 Ristuccia AM, et al. Med Clin North Am 1982.
Comparison of beta-lactams to gentamicin and polymyxin for Pseudomonas aeruginosa bacteremia 12 Bodey GP, et al. Eur J Cancer 1973.
Comparison of beta-lactams to aminoglycosides for Pseudomonas aeruginosa bacteremia β-lactam monotherapy (n=90): 70% overall cure β-lactam-ag combination therapy (n=156): 72% overall cure Aminoglycoside monotherapy (n=128): 29% overall cure 13 Bodey GP, et al. Arch Int Med 1985.
Managing patients with Gram-negative sepsis: The importance of timely, appropriate therapy MDR GNR infections are associated with increased mortality, even after adjusting for other factors 1-3 One major factor for increased mortality is delay until receipt of active antibacterial therapy 14 1 Patel G, et al. Infect Control Hosp Epidemiol 2008. 2 Esterly JS, et al. Antimicrob Agents Chemother 2012. 3 Pena C, et al. Antimicrob Agents Chemother 2012.
Patients with septic shock: The importance of timely, appropriate therapy 15 Deresinski S. Clin Infect Dis 2007.
Pseudomonas aeruginosa bacteremia 16 Lodise TP, et al. Antimicrob Agents Chemother 2007.
Pseudomonas aeruginosa bacteremia 17 Bodey GP, et al. Arch Intern Med 1985.
Treatment of MDR GNR Infections The faster the susceptibility data is available, the faster appropriate therapy can be administered We don t mean to be a nag, I promise! It s not just drug vs. bug Source control: associated with survival for infections caused by carbapenem-resistant enterics 1 Drainage of abscesses Removal of infected central venous catheters Augmenting host immunity: Decreasing immunosuppression Granulocyte-stimulating factors in neutropenic patients 18 1 Patel G, et al. Infect Control Hosp Epidemiol 2008.
The first of the Big 3 MDR GNRs Pseudomonas aeruginosa 19
Pseudomonas aeruginosa: Combination Therapy vs. Monotherapy Empirical therapy: antibacterials given prior to susceptibility data available Definitive therapy: antibacterials given after susceptibility data available Given high rates of antimicrobial resistance, use of 2 anti-pseudomonal agents generally recommended for empirical therapy 20
Pseudomonas aeruginosa: Rationale for combination definitive therapy Synergy Prevention of the emergence of resistance Increased adverse effects Cost 21
Comparison of clinical outcomes with combination vs. monotherapy for P.a. Improves Outcomes 22 No quality randomized controlled trials Doesn t improve outcomes Hilf M, et al. Am J Med 1989. Safdar N, et al. Lancet Infect Dis 2004. Chamot E, et al. Antimicrob Agents Chemother 2003. Chatzinikolaou I, et al. Arch Int Med 2000.
Use of combination therapy to prevent the emergence of resistance in P.a. A major problem Resistance emerges on therapy in at least 10% of cases (highest with carbapenems) 1 Is this prevented by combination therapy? In vitro models: Combinations that have prevented the emergence of resistance to the β-lactam Adding tobramycin to cefepime 2 Adding levofloxacin to meropenem or imipenem 3-4 Animal models of Pseudomonas aeruginosa peritonitis: Adding an anti-pseudomonal β-lactam to a fluoroquinolone (FQ) prevented the emergence of FQ resistance 5 Not yet shown in human studies (underpowered?) 23 1 Carmeli Y, et al. Antimicrob Agents Chemother 1999. 2 Drusano GL, et al. Antimicrob Agents Chemother 2012. 3 Louie A, et al. Antimicrob Agents Chemother 2010. 4 Lister PD, et al. J Antimicrob Chemother 2006. 5 Michea-Hamzehpour M, et al. Antimicrob Agents Chemother 1987.
Prolonged Infusions of β-lactams Rationale β-lactams: best predictor of bacterial kill is related to the time that the concentration of the free drug (not bound by protein) exceeds the MIC (ft>mic) For penicillins, ft>mic > 50% achieves near maximal killing of bacteria Monte Carlo simulations show with a given dosing schedule what the probability of obtaining ft>mic > 50% for each MIC This is why accurate MICs matter! (and just susceptible vs. resistant is not enough) 24
Probability of getting free piperacillin levels > MIC for 50% of the dosing interval 25 Lodise TP, et al. CID 2007.
Clinical Data to Support Prolonged Infusions Single-center study of pip-tazo for P.a. infections 2000-2002: used intermittent infusion: 3.375 g over 30 mins every 4-6 hrs (102 infections) 2002-2004: used extended infusion: 3.375 g over 4 hrs every 8h (92 infections) 26 Lodise TP, et al. CID 2007.
Similar principles apply to other β-lactams Meropenem 27 Jaruratanasirikul S, et al. Antimicrob Agents Chemother 2005.
What about β-lactam-resistant Pseudomonas aeruginosa? This leaves just aminoglycosides and polymyxins as active drugs Remember A compelling argument for combination therapy 28
What are rational combinations against MDR (β-lactam-resistant) P.aeruginosa? What about aminoglycoside-polymyxin? Concern: cumulative nephrotoxicity Little in vitro data to support synergy Combinations that have shown in vitro synergy Colistin-rifampin 1, colistin-carbapenem 2, colistinceftazidime 3 Animal data Improved mortality with colistin-rifampin 4 and colistincarbapenem combinations 5 than with colistin alone 29 1 Giamarellos-Bourboulis EJ, et al. J Chemother 2003. 2,5 Cirioni O, et al. Antimicrob Agents Chemother 2007. 3 Hill D, et al. J Clin Microb 2005. 4 Cirioni O, et al. Crit Care Med 2007.
Colistin monotherapy vs. colistin-based combination therapy against MDR P.a. Retrospective study of colistin use for 136 GNR infections susceptible only to polymyxins -~60% Acinetobacter baumannii (A.b.), ~30% P.a. Antimicrobial(s) COL only COL + Meropenem COL + Other(s) Cure rate 18/20 (90%) 70/84 (83%) 17/31 (55%) -Independent predictors of cure: -higher colistin dose, use of COL only or COL-Mero 30 Falagas ME, et al. Int J Antimicrob Agents 2010.
The second of the Big 3 MDR GNRs Acinetobacter baumannii 31
Considerations in treating MDR Acinetobacter baumannii infections High rates of resistance to β-lactams and other commonly used antibacterials 55,000 U.S. A.b. hospital isolates (2002-08): 32 Mera RM, et al. Microb Drug Resist 2010.
A. baumannii: On the other hand Compared to P.aeruginosa, 2 additional antibiotics are available in the armamentarium Sulbactam Available as ampicillin-sulbactam in the US High doses often used: 3 g every 4-6 hours 1 retrospective study of 48 patients with A.b. bacteremia showed similar outcomes with imipenem vs. amp-sulbactam 1 Tigecycline Remember its limitations vs. bacteremia/uti 70% clinical success in 73 patients w/ VAP from MDR A.b. 2 33 1 Jellision TK, et al. Pharmacotherapy 2001. 2 Curcio D, et al. J Chemother 2009.
Combination Therapy for MDR A.b. Rationale similar to that of MDR P.a. Reports of resistance developing on monotherapy with sulbactam 1 and tigecycline 2 Heteroresistance to colistin common 3 Combinations that have shown in vitro synergy Colistin-rifampin 4-5 Animal models Imipenem-amikacin: no benefit in pneumonia model 6 Colistin-rifampin: 2 studies, conflicting 7-8 Clinical data very limited 34 1 Tatman-Otkun M, et al. New Microbiol 2004. 2 Peleg AY, et al. J Antimicrob Chemother 2007. 3 Cai Y, et al. J Antimicrob Chemother 2012. 4 Giamarellos-Bourboulis EJ, et al. Diagn Microbiol Infect Dis 2002. 5 Song JY, et al. J Antimicrob Chemother 2007. 6 Bernabeu-Wittel M, et al. Clin Microbiol Infect 2005. 7 Montero A, et al. J Antimicrob Chemother 2004. 8 Pantopoulou A, et al. Int J Antimicrob Agents 2007.
The third of the Big 3 MDR GNRs Enterobacteriaceae 35
ESBLs: They are not all the same! TEM, SHV, CTX-M, OXA, etc. Susceptible to carbapenems and cephamycins (e.g., cefoxitin) Although can have other resistant mechanisms (e.g., porin mutation) that confer carbapenem resistance Variable susceptibility to β-lactam/β-lactamase inhibitors, cefepime Can they be used when active? Inoculum effect : higher MICs noted with higher inoculum (not seen w/ carbapenems) 1-2 Often carry other plasmid-mediated genes that confer fluoroquinolone and aminoglycoside resistance 3 36 1 Thomson KS, et al. Antimicrob Agents Chemother 2001. 2 Jacoby G, et al. Antimicrob Agents Chemother 1997. 3 Paterson DL, et al. Clin Infect Dis 2004.
Treatment of ESBL Infections No large, randomized controlled trials Observational data supports the use of carbapenems Retrospective cohort study of 85 episodes of bacteremia caused by ESBL-Klebsiella pneumoniae Antibiotic that was used as monotherapy 14-day mortality Carbapenem 1/27 (4%) Cefepime or pip-tazo 4/9 (44%) 37 Paterson DL, et al. Clin Infect Dis 2004.
What about Ertapenem? Advantage: once-daily dosing Observational data support its use if susceptible 1 Resistance emerging with lower breakpoints 2 ESBL type N of isolates % with MIC > 0.25 % with MIC > 0.5 E. coli 111 16% 8% K.pneumoniae 140 24% 10% 38 1 Collins VL, et al. Antimicrob Agents Chemother 2012. 2 Lee NY, et al. Antimicrob Agents Chemother 2012.
Emerging data for β-lactam/β-lactamase inhibitors Post hoc analysis of patients with ESBL-E.coli bacteremia in 6 prospective cohorts Compared use of carbapenem or BL/BLI as monotherapy either empirically or as definitive therapy 39 Rodriguez-Bano J, et al. Clin Infect Dis 2012.
BLBLI vs. ESBL E.coli continued Patients who received carbapenems were sicker BLBLI use either empirically or as definitive therapy not associated w/ increased mortality even after for adjusting for other co-variates 30-day mortality based on MIC in patients who received empirical BLBLI Notably: all E.coli, mostly CTX-M, mostly bacteremias from urinary or biliary source, for pip-tazo the highest dose used (4.5 g every 6 h), dose not apply to ampicillin-sulbactam 40 Rodriguez-Bano J, et al. Clin Infect Dis 2012.
Carbapenem-resistant Enterobacteriaceae 41 CMAJ 2010.
Klebsiella pneumoniae carbapenemase (KPC) KPC is the most common mechanism of carbapenem resistance among enterics in the US 42 Nordmann P, et al. Lancet Infect Dis 2009.
Treatment of KPC-E Infections Which antibacterials are active in vitro? 1 Polymyxins Tigecycline Gentamicin or amikacin (~50%). Tobramycin inactive Fosfomycin 2 Invasive KPC-E infections have very high mortality rates Bacteremia: mortality rates 47-58% 3-4 KPC-Klebsiella pneumoniae most common, but other KPC-producing enterics emerging 43 1 Bratu S, et al. J Antimicrob Chemother 2005. 2 Endimiani A, et al. Antimicrob Agents Chemother 2010. 3 Bratu S, et al. Arch Intern Med 2005. 4 Neuner EA, et al. Diagn Microbiol Infect Dis 2011.
Evidence for combination therapy Given limitations of tigecycline, polymyxin-based therapy most often used for invasive KPC-E infections Combinations that show in vitro synergy Polymyxin-rifampin 1-3 Polymyxin-carbapenem 3-4 Emergence of polymyxin resistance while on therapy 5-6 Only 1 of 7 patients treated with polymyxin monotherapy had clinical success 7 44 1 Bratu S, et al. J Antimicrob Chemother 2005. 2 Elemem A, et al. J Clin Microbiol 2010. 3 Pankey GA, et al. Diagn Microbiol Infect Dis 2011. 4 Jernigan MG, et al. Antimicrob Agents Chemother 2012. 5 Marchaim D, et al. Antimicrob Agents Chemother 2011. 6 Lee J, et al. J Clin Microbiol 2009. 7 Hirsch EB, et al. J Antimicrob Chemother 2010.
Clinical data supporting combination therapy Largest observational study of KPC-Kp bacteremia (n=125). From Italy. P=0.002 A combination that was particularly successful was colistin, meropenem + tigecycline: 14/16 patients survived and this regimen was independently associated with survival 45 Tumbarello M, et al. Clin Infect Dis 2012.
Considerations in Treating MDR GNR Pneumonia Most cases of MDR GNR pneumonia are ventilator-associated pneumonias (VAP) Many antibiotics, including aminoglycosides, achieve concentrations in the lung epithelium of < 50% of serum concentrations 1 An option is to administer aerosolized antibacterials (usually aminoglycoside or colistin) 46 1 Kiem S, et al. Antimicrob Agents Chemother 2008.
Aerosolized Colistin for VAP 100 patients with GNR VAP (½ MDR) Randomized to inhaled colistin vs. saline All received IV antibiotics, left up to clinician Bronchospasm more common with inhaled colistin than inhaled aminoglycosides 47 Rattanaumpawan P, et al. J Antimicrob Chemother 2010.
Aerosolized Colistin for VAP Cont d 43 patients with MDR GNR VAP who received IV colistin + aerosolized colistin Matched by APACHE score to 43 controls who received IV colistin alone 48 Kofteridis DP, et al. Clin Infect Dis 2010.
Aerosolized Aminoglycosides for VAP Only significant RCT from 1979! 1 Used antibiotics that are not used anymore (carbenicillin, sisomicin) Showed benefit to adding endotracheal sisomicin What about using aerosolized antibacterials without IV antibacterials? Goal: avoid systemic toxicities of IV therapy A phase 2 RCT using ceftazidime/amikacin showed equivalent outcomes (n=40) 2 Many cases series showing success with aerosolized antibiotics alone 49 1 Klastersky J, et al. Chest 1979. 2 Lu Q, et al. Am J Respir Crit Care Med 2011.
Considerations in Treating MDR GNR Urinary Tract Infections Drug elimination pathways must be considered Certain agents achieve levels in the urinary tract that are much higher than serum levels (e.g., β-lactams) Perhaps can overcome resistance Certain agents achieve very low levels in the urinary tract (e.g., tigecycline) Perhaps can fail despite being active in vitro 50
Comparison of treatments for Carbapenemresistant K.pneumoniae UTIs Microbiologic Clearance Rates by Cohort (%) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 88% P = 0.02 64% Minimal renal clearance P < 0.001 43% P < 0.001 36% AG PB TG UN Aminoglycoside Polymyxin B Tigecycline Untreated 51 Satlin MJ, et al. Antimicrob Agents Chemother 2011.
Summary: Take-home points Our armamentarium to treat infections due to MDR GNR is very limited New drugs are needed! (Avibactam?) Rapid diagnostics are needed to decrease time to identification of MDR GNR infections Accurate MIC data are essential to guide therapy (S/R not enough) Multicenter, randomized studies are needed to help us use what we have Combination vs. monotherapy Extended infusion strategies Use of localized therapy (e.g., aerosolized) 52
53 THANK YOU!