Antibacterial Antibiotic Resistancein 2016 What Should an Internist Know? Disclosures. Objectives 3/6/2016. Achaogen: Allergan:

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1 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, 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

2 New antibacterial agents approved in the US from Incidence and diversity of MDR bacteria Boucher HW, et al. Clin Infect Dis CDC CDC

3 Drug resistant Gonorrhea 820,000 new cases each year in the USA The Gonococcal Isolate Surveillance Project (GISP). CDC % treatment failure rate with cefixime If elevated cefixime MIC -> 25% treatment failure rate (vs. 1.9%) Allen VG, et al. JAMA The Gonococcal Isolate Surveillance Project (GISP). CDC 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

4 MRSA: Methicillin resistant Staph aureus CDC 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 McDougal LK, et al. Antmicrob Agents Chemother MRSA Skin soft tissue infections Paradigm shift with long acting agents with MRSA activity? Oritavancin 1 Dalbavancin mg over 3 hours x 1 Half-life: 10 days! ALT increases: 2-3% Cost: $ Single-dose non-inferior to 2 doses mg over 30 mins x 1 Half-life: 14 days! No increased AEs Cost:? for 1 time-dose of 1500 mg ($ ?) 1 Corey GR, et al. N Eng J Med Jensen IS, et al. Clin Drug Investig Boucher HW, et al. N Eng J Med Dunne MW, et al. Clin Infect Dis

5 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 despite increased risk of nephrotoxicity 2,4 1 Moise PA, et al. Lancet Infect Dis Murray KP, et al. Clin Infect Dis Kullar R, et al. Clin Infect Dis van Hal SJ, et al. Antimicrob Agents Chemother Moore CL, et al. Clin Infect Dis 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 Markowitz N, et al. Ann Intern Med Fowler VG Jr, et al. N Engl J Med Kullar R, et al. J Antimicrob Chemother Dohmen PM, et al. J Antimicrob Chemother Casapao AM, et al. Antimicrob Agents Chemother Wunderink RG, et al. Clin Infect Dis Staph aureus bacteremia: Role of an ID Consult Lahey T, et al. Medicine Dartmouth (n=240) Honda H, et al. Am J Med St. Louis (n=341) Rieg S, et al. J Infect Germany (n=521) Forsblom E, et al. Clin Infect Dis Finland (n=342) Tissot F, et al. J Infect Finland (n=156) Bai AD, et al. Clin Infect Dis Canada (n=847) 15 5

6 MDR Enterobacteriaceae 16 Why focus on MDR Enterobacteriaceae? Data from a CDC HAI surveillance network in Extended spectrum cephalosporin resistance (%) Bacteremia 19% 2% 29% 13% Carbapenem resistance (%) Bacteremia All Klebsiella pneumoniae Sievert DM, et al. Infect Control Hosp Epidemiol Braykov NP, et al. Infect Control Hosp Epidemiol 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 Woerther PL, et al. Clin Microbiol Rev Sader HS, et al. J Chemother

7 ESBL rates: Isolates from hospitalized patients in USA in 2012 Castanheira M, et al. Antimicrob Agents Chemother 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): % 1 Park SH, et al. Antimicrob Agents Chemother Castanheira M et al. Antimicrob Agents Chemother Doi Y, et al. Clin Infect Dis 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 Harada Y, et al. Clin Microbiol Infect

8 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 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

9 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 ( ) 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 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 Satlin MJ, et al. Clin Infect Dis Where is KPC? Nordmann P, et al. Emerg Infect Dis

10 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 Rigatto MH, et al. J Antimicrob Chemother Landman D, et al. Clin Microbiol Rev Nation RL, et al. Clin Infect Dis Hindler JA, et al. J Clin Microbiol 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 = % P < % P < % AG PB TG UN 1 MacGowan AP, et al. J Antimicrob Chemother Satlin MJ, et al. Antimicrob Agents Chemother Prasad P, et al. Clin Infect Dis

11 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 Chen S, et al. Antimicrob Agents Chemother Karageorgopoulos DE, et al. J Antimicrob Chemother Neuner EA, et al. Antimicrob Agents Chemother 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 Daikos GL, et al. Antimicrob Agents Chemother 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! ($ /day) 1 Castanheira M, et al. Antimicrob Agents Chemother Sader HS, et al. Antimicrob Agents Chemother Citron DM, et al. Antimicrob Agents Chemother

12 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 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

13 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 Carmeli Y, et al. Antimicrob Agents Chemother Drusano GL, et al. Antimicrob Agents Chemother Louie A, et al. Antimicrob Agents Chemother Michea-Hamzehpour M, et al. Antimicrob Agents Chemother Lodise TP, et al. Clin Infect Dis Bauer KA, et al. Antimicrob Agents Chemother 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 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 Snydman DR, et al. Antimicrob Agents Chemother

14 Patients with severe sepsis: The importance of rapid diagnostics and timely, appropriate therapy Kumar A, et al. Crit Care Med 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 Banerjee R, et al. Clin Infect Dis 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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