TABLE 1

Mortality of infections caused by carbapenemase-producing Enterobacteriaceae or CRE among different antibiotic treatment regimens

OrganismsFirst author, yr of study (reference)Study design; period, countryPopulation characteristics; most common underlying diseasesSite of infection (% of total population)No. of infected patients who received definitive antibiotic treatmentCausative pathogen(s)Susceptibility breakpoints used (agent), yrjMortality assessedAntibiotic treatment administered, no. of patients (% mortality)
Combination therapyMonotherapy
KPC-producing Klebsiella spp.Capone, 2013 (11)MC prospective cohort; 2010–2011, ItalyInpatients (48.4% were ICU patients); DM, COPD, chronic kidney or liver disease, malignancyBSI (37.4), UTI (31.9), septic shock (16.5), LRTI (15.4), SSTI (12.1)b67 (appropriate antibiotic treatment was known for 58)KPC-producing Klebsiella pneumoniaeEUCAST, NRIn hospitalColi-Tige, 16 (25)Gen, 16 (6.3)
Tige-Fos, 6 (33)Coli, 10 (40)
Coli-Fos, 5 (0)
Coli-Gen, 5 (40)
Alexander, 2012 (9)SC retrospective cohort; 2006–2008, USAInpatientsUTI, 2 patients developed bacteremia14KPC-producing K. pneumoniae and Citrobacter freundiiCLSI, 2006In hospitalNRdGen, 5 (40)
FDA (Tige)cCipro, 4 (0)
Dox, 1 (0)
Ntf, 1 (0)
Bergamasco, 2012 (10)SC retrospective cohort; 2009–2010, BrazilSolid-organ transplant recipients; DM, cardiovascular disease, liver disease, renal diseaseBSI (33.3), UTI (33.3), SSI (16.7), pneumonia (16.7)12KPC-producing K. pneumoniaeCLSI, 2009At 30 daysCarba-PoB, 3 (67)Carba, 2 (100)
FDA (Tige)cTige-PoB, 3 (0)PoB, 3 (33)
Carba-Tige, 1 (0)
Qureshi, 2012 (19)SC retrospective cohort; 2005–2009, USAInpatients (53.7% were ICU patients at enrollment); DM, cardiovascular disease, CRF, renal dialysis, COPD, malignancy (51.2% had an Apache II score of ≥20)Bacteremia, the sources for which were pneumonia (24.4), line related (31.7), UTI (17.1), primary (14.6)34KPC-producing K. pneumoniaeCLSI, 2011At 28 daysColi-Carba, 5 (20)Coli, 7 (57)
Coli-Tige, 1 (0)Tige, 5 (80)
Coli-FQ, 1 (0)Carba, 4 (50)
Tige-Carba, 3 (0)Gen, 1 (0)
Tige-AG, 2 (0)A-S, 1 (0)
Carba-FQ, 1 (100)Tzp, 1 (100)
Azt-FQ, 1 (0)
Cfpm-Gen, 1 (0)
Tumbarello, 2012 (25)MC retrospective cohort; 2010–2011, ItalyInpatients (13.6% were in shock); DM, heart failure, CRF, malignancyBSI, the sources for which were LRTI, CVC, UTI, other, and unknown125KPC-producing K. pneumoniaeCLSI, 2011At 30 daysTige-Coli, 23 (30)Tige, 19 (53)
FDA (Tige)cTige-Gen, 12 (50)Coli, 22 (50)
Coli-Gen, 7 (57)Gen, 5 (80)
Other 2-drug combinations, 14 (43)
Tige-Coli-Carba, 16 (13)
Tige-Gen-Carba, 6 (17)
Coli-Gen-Carba, 1 (100)
Zarkotou, 2011 (28)SC prospective cohort; 2008–2010, GreeceInpatients (71.7% were in the ICU at admission)BSI, the sources for which were primary (43.4) and catheter related (22.6)35KPC-producing K. pneumoniaeCLSI, 2010Infection relatedTige-Coli, 9 (0)Coli, 7 (57)
EUCAST, 2010 (Coli)Tige-Gen, 3 (0)Tige, 5 (40)
Tige-Coli-Carba, 2 (0)Gen, 2 (0)
Tige-Coli-Gen, 1 (0)Carba, 1 (100)
Tige-Carba, 1 (0)
Tige-Amk, 1 (0)
Coli-Gen, 2 (0)
Carba-Gen, 1 (0)
Souli, 2010 (22)SC retrospective cohort; 2007–2008, GreeceInpatients (61% were ICU patients); DM, cardiovascular disease, COPD, renal failure, malignancyBSI (77.8), SSI (11), UTI (5.6), HAP (5.6)17KPC-producing K. pneumoniaeCLSI, 2009
EUCAST, 2009 (Fos, Coli)
FDA (Tige)c
OverallCarba-Coli, 6 (67)
Coli-Tige, 2 (0)
Carba-Coli-Gen, 1 (100)
Carba-Coli-Cipro, 1 (0)
Carba-Coli-Tige, 1 (100)
Carba-Coli-Tige-Amk, 1 (100)
Coli-Tige-Amk-Tzp, 1 (100)
Tzp-Cipro-Coli-Gen and then Tige-Amk, 1 (100)
Tzp-Amk and then Tige, 1 (100)
Carba, 1 (0)
Tzp and then Tige, 1 (0)
Weisenberg, 2009 (26)SC retrospective cohort; 2006, USAInpatientsBacteremia (19), pneumonia (23.8), UTI (9.5), urosepsis (15.3), other RTIs (19), CSF infection (4.8), wound infection (4.8), line-related infection (4.8)21KPC-producing K. pneumoniaeNRUndeterminedTige-Gen, 1 (0)
Tige-Carba, 1 (100)
Carba, 11 (9)
Tige, 5 (0)
Gen, 2 (0)
Amk, 1 (0)
MBL- or OXA-producing Klebsiella spp.Navarro-San Francisco, 2013 (17)SC prospective cohort; 2010–2012, SpainElderly patients; septic shock or severe sepsis (60%), malignancy (57.5%)BSI, the sources for which were UTI (30), deep IAI/SSI (25), primary (17.5), catheter related (10), other (17.5)34OXA-48-producing Enterobacteriaceae (K. pneumoniae, Escherichia coli)CLSI, 2012
FDA (Tige)c
At 30 days≥2 active drugs (Carba not included), 21 (52.4)
≥2 active drugs (Carba included), 6 (33)
Amk, 3 (33)
Tige, 2 (0)
Coli, 1 (0)
Carba, 1 (100)
Sanchez-Romero, 2012 (21)SC retrospective cohort; 2009, SpainICU patientsPneumonia (29.2),e other LRTI (20.8), UTI (12.5), meningitis (8.3), CAB (25),e IAI (8.3), soft tissue (4.2)24VIM-1-producing K. pneumoniaeCLSI, 2011
EUCAST, 2011 (Tige)
UndeterminedTige-Coli, 11 (64)
Amk-Tige-Coli, 1 (0)
Tige, 9 (44)
Amk, 1 (0)
Mero, 1 (0)
Erta, 1 (0)
Mouloudi, 2010 (16)SC retrospective case-control study; 2007–2008, GreeceICU patients; DM, cardiovascular, disease, respiratory disease, liver disease, trauma, transplant recipientBSI59KPC- or MBL-producing K. pneumoniaeCLSI, 2007In hospitalColi-Gen, 18 (61)fColi, 35 (51)f
EUCAST, 2010 (Coli)
FDA (Tige)c
Daikos, 2009 (12)MC prospective cohort; 2004–2006, GreeceInpatientsBSI67VIM-1-producing K. pneumoniaeCLSI, 2004At 14 daysCarba-Coli, 8 (0)Carba, 14 (21)
Carba-AG, 4 (25)Coli, 15 (27)
AG, 8 (38)
No active drug, 18 (28)i
Souli 2008 (23)SC retrospective cohort; 2003–2006, GreeceInpatients (58.8% were ICU patients); congestive heart failure, renal failure, malignancy, DMBSI (88.2), VAP (11.8)17VIM-1 MBL-producing Enterobacteriaceae (Klebsiella spp., Enterobacter spp.)CLSI, 2006OverallCarba-Coli, 6 (50)Coli, 3 (33)
BSAC (Coli)gColi-Tzp-Gen, 1 (100)Tige, 1 (100)
FDA (Tige)cCarba-Coli-Lzd, 1 (0)
Coli-Tzp-Lzd, 1 (100)
Carba-Coli-Amx-Gen-Van, 1 (100)
Carba-Coli-Tzp-Gen-Dox, 1 (100)
Coli-Cipro-Van-Dox, 1 (100)
Coli-Amk-Van-Caz, 1 (100)
Carbapenem-resistant Klebsiella spp.Capone, 2013 (11)MC prospective cohort; 2010–2011, ItalyInpatients (48.4% were ICU patients); DM, COPD, chronic kidney or liver disease, malignancyBSI (37.4), UTI (31.9), septic shock (16.5), LRTI (15.4), SSTI (12.1), IAI (3.3)b67 (appropriate antibiotic treatment was known for 58)Carbapenem-resistant K. pneumoniaeEUCAST, NRIn hospitalColi-Tige, 16 (25)Gen, 16 (6.3)
Tige-Fos, 6 (33)Coli, 10 (40)
Coli-Fos, 5 (0)
Coli-Gen, 5 (40)
Huang 2012 (13)SC prospective cohort; 2010–2011, TaiwanNRUndetermined33Carbapenem-resistant K. pneumoniae and E. coliCLSI, 2009At 30 daysNRTige, 15 (73)
Carba, 14 (50)
Coli, 4 (50)
Trevino, 2011 (24)SC prospective cohort; 2009–2010, SpainPatients submitted to surgery and/or who presented with severe underlying disease; cancer, transplant, cardiovascular disease, otherMiscellaneous infections10Carbapenem-resistant Klebsiella spp.CLSI, 2010UndeterminedAmk-Carba, 4 (50)Cipro, 1 (0)
Tige-Amk, 2hAmk, 1 (0)
Fos-Amk, 1hTige, 1 (100)
Amk-Carba-Lvf, 1 (0)
Michalopoulos, 2010 (15)SC prospective cohort; 2008, GreeceICU patients; DM, COPDHospital-acquired infections11Carbapenem-resistant K. pneumoniaeNR (Fos [the organism was susceptible when the zone of inhibition was ≥16 mm])In hospitalFos-Coli, 6 (33)Fos, 1 (0)
Fos-Gen, 3 (0)
Fos-Tzp, 1 (0)
Nguyen, 2010 (18)SC retrospective cohort; 2004–2008, USAInpatients (52.1% were ICU patients, 42% were solid organ transplant recipients, and 42% were in septic shock); DM, cardiovascular disease, malignancy, liver diseaseBacteremia48Carbapenem-resistant K. pneumoniaeCLSI, NRAt 30 daysPoB-Tige, 13 (31)PoB, 9 (44)
Tige, 10 (70)
Other, 9 (22)i
No potentially active treatment, 7 (43)i
Other carbapenemase-producing EnterobacteriaceaeYan, 2013 (27)SC retrospective cohort; NR, TaiwanInpatients (37.8% had a stay in the ICU); malignancy, DM, chronic renal diseaseBSI, the sources for which were pneumonia (29.7), wound infection (21.6), peritonitis (16.2), UTI (13.5), unknown (13.5), catheter related (2.7), liver or biliary tract infection (2.7)32IMP-8-producing Enterobacteriaceae (Enterobacter cloacae, K. pneumoniae, E. coli, C. freundii)CLSI, 2010At 28 daysNRCarba, 20 (10)
Non-Carba (extended-spectrum cephalosporins, 6; FQ, 5; Azt, 1), 12 (16.7)
  • a CRE, carbapenem-resistant Enterobacteriaceae; KPC, Klebsiella pneumoniae carbapenemase; SC, single center; MC, multicenter; NR, not reported; CLSI, Clinical and Laboratory Standards Institute; EUCAST, European Committee on Antimicrobial Susceptibility Testing; FDA, Food and Drug Administration; BSAC, British Society for Antimicrobial Chemotherapy; DM, diabetes mellitus; COPD, chronic obstructive pulmonary disease; BSI, bloodstream infection; UTI, urinary tract infection; RTI, respiratory tract infection; LRTI, lower RTI; SSTI, skin and soft tissue infection; IAI, intra-abdominal infection; CVC, central venous catheter; ICU, intensive care unit; HAP, hospital-acquired pneumonia; SSI, surgical-site infection; CRF, chronic renal failure; CSF, cerebrospinal fluid; CAB, catheter-associated bacteremia; VAP, ventilator-associated pneumonia; Carba, carbapenem; Coli, colistin; PoB, polymyxin B; Tige, tigecycline; Ntf, nitrocefin; Mero, meropenem; Erta, ertapenem; Fos, fosfomycin; Gen, gentamicin; Amk, amikacin; A-S, ampicillin-sulbactam; AG, aminoglycoside; Azt, aztreonam; FQ, fluoroquinolone; Cipro, ciprofloxacin; Caz, ceftazidime; Lvf, levofloxacin; Cfpm, cefepime; Tzp, piperacillin-tazobactam; Van, vancomycin; Lzd, linezolid; Dox, doxycycline; Amx, amoxicillin; Tob, tobramycin.

  • b In this study, certain patients had more than one site of infection.

  • c The susceptibility breakpoint for tigecycline according to the FDA was ≤2 μg/ml.

  • d In this study, 3 patients were excluded because it was unclear whether the antibiotic treatment was combination or monotherapy.

  • e Two patients had both pneumonia and catheter-associated bacteremia.

  • f The antibiotic treatment was unclear for six patients in this study; however, they did not receive either colistin in combination with gentamicin or colistin monotherapy.

  • g The susceptibility breakpoint for colistin according to the BSAC was ≤ 4 μg/ml.

  • h Two patients received the combination tigecycline-amikacin; one was cured, but the final outcome of the other was unknown at the time of the follow-up. One patient received the combination fosfomycin-amikacin, but the final outcome was also unknown at the time of the follow-up.

  • i In these studies, it was unclear whether the treatment regimens were combination therapy or monotherapy.

  • j The CLSI and EUCAST susceptibility breakpoints used in the included studies were the following: for CLSI, 2004, Carba ≤ 4; CLSI, 2006, Gen ≤ 4, Cipro ≤ 1, Dox ≤ 4, Ntf ≤ 32, Amx ≤ 8, and Tzp ≤ 16 and ≤ 4; CLSI, 2007, Gen ≤ 4; CLSI, 2009, Carba ≤ 4, Gen ≤ 4, Cipro ≤ 1, Amk ≤ 16, and Tzp ≤ 16 and ≤ 4; CLSI, 2010, Carba ≤ 4, Gen ≤ 4, Amk ≤ 16, Cipro ≤ 1, Lvf ≤ 2, Azt ≤ 4, Cfpm ≤ 8, and Tob ≤ 4; CLSI, 2011, Carba ≤ 1, Erta ≤ 0.25, Gen ≤ 4, Amk ≤ 16, A-S ≤ 8 and ≤ 4, Azt ≤ 4, and Tzp ≤ 16 and ≤ 4; CLSI, 2012, Carba ≤ 1 and Amk ≤ 16; EUCAST, 2009, Coli ≤ 2 and Fos ≤ 32; EUCAST, 2010, Coli ≤ 2; and EUCAST, 2011, Tige ≤ 1.