Antibacterial Antibiotic Resistancein 2016 What Should an Internist Know? Michael Satlin, MD, MS Assistant Professor of Medicine Division of Infectious Diseases Weill Cornell Medicine March 4, 2016 1 Disclosures Achaogen: Local PI on clinical trial of an investigational agent for CRE Allergan: Research grants CLSI: Member of the Subcommittee for Antimicrobial Susceptibility Testing 2 Objectives Overview of the problem Specific problematic pathogens 1) Drug resistant Neisseria gonorrhoeae 2) MRSA 3) MDR Enterobacteriaceae ESBLs CREs 4) Pseudomonas aeruginosa Rapid diagnostics Take home points 3 1
New antibacterial agents approved in the US from 1983 2012 Incidence and diversity of MDR bacteria 2013-2016 Boucher HW, et al. Clin Infect Dis 2013. 4 CDC 2013. 5 CDC 2013. 6 2
Drug resistant Gonorrhea 820,000 new cases each year in the USA The Gonococcal Isolate Surveillance Project (GISP). CDC 2013. 7 7% treatment failure rate with cefixime If elevated cefixime MIC -> 25% treatment failure rate (vs. 1.9%) Allen VG, et al. JAMA 2013. The Gonococcal Isolate Surveillance Project (GISP). CDC 2013. 8 Current CDC Treatment Recommendations Ceftriaxone 250 mg IV x 1 + Azithromycin 1 gm po x 1 Cefixime 400 mg x 1 can be used with azithromycin only if ceftriaxone is not available 1) Penicillin allergy: If no anaphylaxis/sjs/ten -> give above If anaphylaxis, etc.: Gemifloxacin 320 mg po OR gentamicin 240 mg IM x 1) + azithromycin 2 gm po x 1 Azithro 2 gm alone not recommended 2) Pharyngeal infection: Cefixime not appropriate: <90% cure rates 3) Who to send routine test-of-cure on? Pharyngeal infection treated with an alternative regimen CDC 2015. 9 3
MRSA: Methicillin resistant Staph aureus CDC 2015. 10 MRSA: Skin soft tissue infections MRSA resistant to all β-lactams except ceftaroline 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% %Susceptible: 2007 skin S. aureus from outpatients in USA 100% 99% 99% 65% 64% 85% 34% 44% Tillotson GS, et al. J Antimicrob Chemother 2008. McDougal LK, et al. Antmicrob Agents Chemother 2010. 11 MRSA Skin soft tissue infections Paradigm shift with long acting agents with MRSA activity? Oritavancin 1 Dalbavancin 3 12 1200 mg over 3 hours x 1 Half-life: 10 days! ALT increases: 2-3% Cost: $2900 2 Single-dose non-inferior to 2 doses 4 1500 mg over 30 mins x 1 Half-life: 14 days! No increased AEs Cost:? for 1 time-dose of 1500 mg ($3000-4500?) 1 Corey GR, et al. N Eng J Med 2014. 2 Jensen IS, et al. Clin Drug Investig 2016. 3 Boucher HW, et al. N Eng J Med 2014. 4 Dunne MW, et al. Clin Infect Dis 2016. 4
MRSA: Invasive disease Vancomycin MIC creep 1 Rising MICs, but still in susceptible range ( 2 μg/ml) Vancomycin MICs of >1 μg/ml independently associated with treatment failure in MRSA bacteremia 2 Should other agents be used in MRSA bacteremia when vancomycin MIC >1 μg/ml? No randomized trials 2 cohort studies: Clinical failure and mortality less when switched to daptomycin than if stayed on vancomycin 3 4 Definitively should target vancomycin troughs of 15 20 despite increased risk of nephrotoxicity 2,4 1 Moise PA, et al. Lancet Infect Dis 2009. 4 Murray KP, et al. Clin Infect Dis 2013. 2 Kullar R, et al. Clin Infect Dis 2011. 5 van Hal SJ, et al. Antimicrob Agents Chemother 2014. 3 Moore CL, et al. Clin Infect Dis 2012. 13 Invasive MRSA Infections Alternative agents to vancomycin High dose TMP SMX (Bactrim)? Increased treatment failure compared to vanco 1 2 Daptomycin? 3 2 cohort studies: high rates of success for L sided MRSA endocarditis 4 5 Don t use for MRSA pneumonia: inactivated by surfactant Ceftaroline? Success rates: Pneumonia 86% (n=92); Bacteremia: 79% (n=141) 6 Linezolid? PROBABLY DEPENDS Pneumonia: RCT: increased clinical success with linezolid vs. vanco 7 Problem with bacteremia: toxicities if >2 weeks of therapy 1 Paul M, et al. BMJ 2015. 2 Markowitz N, et al. Ann Intern Med 1992. 3 Fowler VG Jr, et al. N Engl J Med 2006. 4 Kullar R, et al. J Antimicrob Chemother 2013. 5 Dohmen PM, et al. J Antimicrob Chemother 2013. 6 Casapao AM, et al. Antimicrob Agents Chemother 2014. 7 14 Wunderink RG, et al. Clin Infect Dis 2012. Staph aureus bacteremia: Role of an ID Consult Lahey T, et al. Medicine 2009. Dartmouth (n=240) Honda H, et al. Am J Med 2010. St. Louis (n=341) Rieg S, et al. J Infect 2009. Germany (n=521) Forsblom E, et al. Clin Infect Dis 2013. Finland (n=342) Tissot F, et al. J Infect 2014. Finland (n=156) Bai AD, et al. Clin Infect Dis 2015. Canada (n=847) 15 5
MDR Enterobacteriaceae 16 Why focus on MDR Enterobacteriaceae? Data from a CDC HAI surveillance network in 2009 2010 Extended spectrum cephalosporin resistance (%) Bacteremia 19% 2% 29% 13% Carbapenem resistance (%) Bacteremia All Klebsiella pneumoniae Sievert DM, et al. Infect Control Hosp Epidemiol 2013. Braykov NP, et al. Infect Control Hosp Epidemiol 2013. ESBL producing Enterobacteriaceae Extended Spectrum Beta Lactamases 1 Many 100s of different types: not all the same Many highly mobile and on plasmids Enzymes that hydrolyze and inactivate penicillins and most cephalosporins Don t hydrolyze cefoxitin/cefotetan and carbapenems Plasmids often have genes that also confer fluoroquinolone, aminoglycoside, and sulfonamide resistance ESBL carriage rates increasing in the community 2 National surveillance of patients admitted with UTI complicated by bacteremia: 3 E. coli: 8% ESBL K. pneumoniae: 12% ESBL 1 Paterson DL, et al. Clin Microbiol Rev 2005. 2 Woerther PL, et al. Clin Microbiol Rev 2013. 3 Sader HS, et al. J Chemother 2014. 18 6
ESBL rates: Isolates from hospitalized patients in USA in 2012 Castanheira M, et al. Antimicrob Agents Chemother 2014 19 How do I know I have an ESBL? Antibiotic MIC (μg/ml) Interp. Ampicillin >16 R Ampicillin/sulbactam >16 R Aztreonam >16 R Cefepime 8 S DD Cefoxitin 8 S Ceftazidime >16 R Antibiotic MIC (μg/ml) Interp. Ceftriaxone >32 R Gentamicin 2 S Levofloxacin >4 R Meropenem <=1 S Piperacillin/tazobactam <=8 S TMP/SMX >2/38 R Escherichia coli or Klebsiella that is ceftriaxone resistant, meropenem susceptible Some labs will do a phenotypic test to confirm this Susceptibility rates of ESBL E Ceftazidime: 20 60% OR Cefepime: 60 75% (many have elevated MICs: S DD) Piperacillin tazobactam (Zosyn): 70 100% 1 Park SH, et al. Antimicrob Agents Chemother 2012. 2 Castanheira M et al. Antimicrob Agents Chemother 2014. 3 Doi Y, et al. Clin Infect Dis 2013. Should we always treat with carbapenems? Can we use cefepime and pip-tazo when ESBLs are susceptible? 20 ESBLs: Inoculum effect 10 5 CFU/mL is the standard inoculum for susceptibility testing and getting an MIC What if you use 10 7 CFU/mL? (e.g., pneumonia)? Meropenem Cefepime Pip tazo 1 Similar findings have been shown for CTX-M ESBLs (E. coli and K.pneumoniae) 2 1 Thomson KS, et al. Antimicrob Agents Chemother 2001. 2 Harada Y, et al. Clin Microbiol Infect 2014. 7
Clinical observational studies also show poor outcomes with cefepime, even when susceptible 178 patients with ESBL producing bacteremia Beware of cefepime for serious ceftriaxone-resistant E.coli or Klebsiella infections! Lee NY, et al. Clin Infect Dis 2013. Cefepime S-DD; MIC 4-8 μg/ml 22 Cefepime Susceptible: Dose dependent? Based on 1 g q12h dosing Use 2 g q8h dosing 23 What about β lactam β lactamase inhibitors (like piperacillin tazobactam)? 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 No difference in mortality in multivariate analysis Notably: all E.coli, mostly CTX-M, mostly bacteremias from urinary or biliary source, the highest dose of pip-tazo was used (4.5 g q 6h), does not apply to ampicillin-sulbactam Rodriguez-Bano J, et al. Clin Infect Dis 2012. 24 8
ESBLs: Clinical Data: Pip tazo vs. Carbapenem 213 patients with ESBL bacteremia (Ec, Kp, Proteus mirabilis) All received definitive treatment with a carbapenem All isolates susceptible to pip tazo and a carbapenem Pip tazo (n=103) Empirical therapy 1 st 3 days Carbapenem (n=110) 14-day mortality 17% P=0.05 8% Multivariate model Adjusted HR of death 1.9 (1.1-3.5) if received pip-tazo empirically Only 40% received 4.5 g IV q6h Urine and biliary sources: only 25% Included Klebsiella pneumoniae Tamma PD, et al. Clin Infect Dis 2015. 25 Carbapenem resistant Enterobacteriaceae (CRE) Enzymes that hydrolyze not only penicillin and cephalosporins, but also carbapenems Klebsiella pneumoniae carbapenemase (KPC) is by far the most common mechanism for carbapenem resistance for the Enterobacteriaceae in the NE USA (but CRE KPC) Most common with Klebsiella pneumoniae KPC is encoded on a plasmid Usually test susceptible to polymyxin B/colistin, tigecycline sometimes susceptible to gentamicin, amikacin, doxycycline, and fosfomycin CRE bacteremia: 40 50% mortality rate Munoz-Price LS, et al. Lancet Infect Dis 2013. Satlin MJ, et al. Clin Infect Dis 2014. Where is KPC? Nordmann P, et al. Emerg Infect Dis 2011. 27 9
The CRE armamentarium: Early 2015 What agents are left that are active vs. CRE? Colistin Polymyxins Polymyxin B Tigecycline All have major limitations Aminoglycosides Sometimes ~50% susceptible to gent Tobra almost never active Fosfomycin 28 Problems with Polymyxins 1) Toxicities Nephrotoxicity: 40 60% with either colistin 1 or poly B 2 Neurotoxicity 3 : paresthesias, NM blockade; less common 2) PK/PD data only now becoming available For Poly B: we recently learned that we should not adjust for renal failure 4 Can t easily check levels 3) Unreliable susceptibility testing 5 No CLSI breakpoints for the Enterobacteriaceae 1 Rocco M, et al. Crit Care 2013. 2 Rigatto MH, et al. J Antimicrob Chemother 2015. 3 Landman D, et al. Clin Microbiol Rev 2008. 4 Nation RL, et al. Clin Infect Dis 2014. 5 Hindler JA, et al. J Clin Microbiol 2013. 29 Troubles with Tigecycline 1) Bacteriostatic, not bactericidal 2) Low bloodstream and urine levels 1 Limits their use in bacteremias and UTIs Only approved for skin soft tissue and intraabominal infections and community acquired pneumonia Microbiologic clearance rates for CRKP UTI 2 Mortality in RCTs of FDA-approved indications 3 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 88% P = 0.02 64% P < 0.001 43% P < 0.001 36% AG PB TG UN 1 MacGowan AP, et al. J Antimicrob Chemother 2008. 2 Satlin MJ, et al. Antimicrob Agents Chemother 2011. 3 Prasad P, et al. Clin Infect Dis 2012. 30 10
Fosfomycin Seldom used agent that is FDA approved for UTIs Available as an IV formulation in Europe, only as a sachet in the USA Susceptibility rates of CRE: 45 93% 1 2 Resistance may develop rapidly on therapy 3 Study of 13 patients with CRKP UTI who received 3 doses 4 : Only 6/13 had microbiologic cure 1 Endimiani A, et al. Antimicrob Agents Chemother 2010. 2 Chen S, et al. Antimicrob Agents Chemother 2011. 3 Karageorgopoulos DE, et al. J Antimicrob Chemother 2012. 4 Neuner EA, et al. Antimicrob Agents Chemother 2012. 31 Combination therapy for CRE? Tumbarello et al: 125 patients with KPC Kp bacteremia 2 active drugs Daikos et al: 175 patients with carbapenemaseproducing Kp bacteremia (not all CRKP, not all KPC) Tumbarello M, et al. Clin Infect Dis 2012. Daikos GL, et al. Antimicrob Agents Chemother 2014. Ceftazidime/avibactam (Avycaz ) The first approved β lactam/β lactamase inhibitor with excellent in vitro activity vs. ESBL, AmpC, and KPCproducing Enterobacteriaceae 1 Not reliably active vs. metallo β lactamases (e.g. NDM) or an improvement vs. Acinetobacter Active vs. ~80% of ceftazidime resistant Pseudomonas 2 Bacteroides coverage limited 3 FDA approved in Feb 2015 for complicated intraabdominal and urinary tract infections No clinical data for use for KPC Kp or bacteremia Animal data also limited Dose: 2.5 g IV q8h (2 g ceftaz, 0.5 gm avibactam) Expensive! ($800 900/day) 1 Castanheira M, et al. Antimicrob Agents Chemother 2015. 2 Sader HS, et al. Antimicrob Agents Chemother 2015. 3 Citron DM, et al. Antimicrob Agents Chemother 2011. 11
Pseudomonas aeruginosa 34 Pseudomonas aeruginosa Susceptibility rates: 5328 USA isolates 100% 80% 84% 85% 80% 83% 75% 89% 97% 92% 60% 40% 20% 0% Ceftazidime Cefepime Pip tazo MeropenemLevofloxacin Gentamicin Amikacin Tobramycin Empirical therapy in a sick patient (while awaiting susceptibility results) Reasonable to give β-lactam + aminoglycoside OR fluoroquinolone Sader HS, et al. Diagn Microbiol Infect Dis 2015. 35 Pseudomonas aeruginosa: Rationale for combination definitive therapy No quality randomized controlled trials But, most studies do not find a benefit Synergy Prevention of the emergence of resistance Increased adverse effects Cost Paul M, et al. Clin Infect Dis 2013. 36 12
Pseudomonas aeruginosa Emergence of resistance while on therapy Resistance emerges on therapy in at least 10% of cases 1 Highest with carbapenems and pneumonia 1 Solutions? 1) Use higher doses: pip tazo (4.5q6h) or cefepime (2q8h) 2) Add an aminoglycoside or a FQ to the β lactam (some supportive in vitro and animal models) 2 4 3) Prolonged infusion of β lactam (eg: over 3 4 h vs. 30 min) More likely to achieve PK target of keeping the concentration of β lactam > MIC for at least 50% of dosing interval 4 2 observational studies of prolonged infusion pip tazo and cefepime showed decreased mortality for serious Pa infections 5 6 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 Michea-Hamzehpour M, et al. Antimicrob Agents Chemother 1987. 5 Lodise TP, et al. Clin Infect Dis 2007. 6 Bauer KA, et al. Antimicrob Agents Chemother 2013. 37 Treatment options for MDR Pa resistant to all β lactams Polymyxins and aminoglycosides Not effective as monotherapy for Pa bacteremia in neutropenic patients Bodey GP, et al. Eur J Cancer 1973. Ceftolozane/tazobactam (Zerbaxa ) Ceftolozane is a new cephalosporin that is similar to ceftazidime, but less susceptible to AmpC hydrolysis Active against 70% of Pa isolates that are non susceptible to ceftazidime, pip tazo, and meropenem 1 Tazobactam gives it activity against most ESBLs 1 Gram positive coverage similar to ceftazidime and Bacteroides coverage not reliable 2 FDA approved in Dec 2014 for complicated intra abdominal (with metronidazole) and urinary tract infections No clinical data for use for MDR Pa OR bacteremia/pneumonia OR neutropenic patients Phase 3 clinical trial for pneumonia ongoing: using dose of 3 gm IV q8h (FDA approved dose 1.5 gm IV q8h) I recommend this dose for MDR Pa bacteremia or pneumonia Not as expensive as ceftazidime/avibactam (~$250 per day) 1 Farrell DJ, et al. Antimicrob Agents Chemother 2013. 2 Snydman DR, et al. Antimicrob Agents Chemother 2014. 13
Patients with severe sepsis: The importance of rapid diagnostics and timely, appropriate therapy Kumar A, et al. Crit Care Med 2006. 40 Rapid PCR systems from blood cultures 1) BioFire FilmArray Blood Culture ID Panel 2) Nanosphere Verigene Blood Culture Panels Organism ID (80-85%) of organisms 1 Resistance genes: MecA -> MRSA ID VanA and VanB -> VRE KPC (and other carbapenemases) -> 2 hrs CRE PCR CTX-M -> ESBL Final Hours 0 18 24 48 72 Banerjee R, et al. Clin Infect Dis 2015. 41 Antibacterial Resistance 2016 Take home messages 1) Slowing of antibiotic development has exacerbated the problem of resistance 2) Combination therapy recommended for gonorrhea 3) 1 dose treatments for skin/soft tissue infections (oritavancin, dalbavancin) 4) Call an ID Consult for Staph aureus bacteremia 5) Carbapenems are preferred treatments for invasive ESBL infections (pip tazo an alternative for less severe infections): 6) New treatment options available for CRE (ceftazidime avibactam) and β lactam resistant Pseudomonas (ceftolozane tazobactam) 7) Prolonged infusion β lactams should be considered for Pseudomonas 8) Rapid diagnostics are critical: Blood culture PCR systems a major potential advance 42 14
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