Double carbapenem as a rescue strategy for the treatment of severe carbapenemase-producing Klebsiella pneumoniae infections: a two-center, matched case-control study

Gennaro De Pascale, Gennaro Martucci, Luca Montini, Giovanna Panarello, Salvatore Lucio Cutuli, Daniele Di Carlo, Valentina Di Gravio, Roberta Di Stefano, Guido Capitanio, Maria Sole Vallecoccia, Piera Polidori, Teresa Spanu, Antonio Arcadipane, Massimo Antonelli, Gennaro De Pascale, Gennaro Martucci, Luca Montini, Giovanna Panarello, Salvatore Lucio Cutuli, Daniele Di Carlo, Valentina Di Gravio, Roberta Di Stefano, Guido Capitanio, Maria Sole Vallecoccia, Piera Polidori, Teresa Spanu, Antonio Arcadipane, Massimo Antonelli

Abstract

Background: Recent reports have suggested the efficacy of a double carbapenem (DC) combination, including ertapenem, for the treatment of carbapenem-resistant Klebsiella pneumoniae (CR-Kp) infections. We aimed to evaluate the clinical impact of such a regimen in critically ill patients.

Methods: This case-control (1:2), observational, two-center study involved critically ill adults with a microbiologically documented CR-Kp invasive infection treated with the DC regimen matched with those receiving a standard treatment (ST) (i.e., colistin, tigecycline, or gentamicin).

Results: The primary end point was 28-day mortality. Secondary outcomes were clinical cure, microbiological eradication, duration of mechanical ventilation and of vasopressors, and 90-day mortality. Forty-eight patients treated with DC were matched with 96 controls. Occurrence of septic shock at infection and high procalcitonin levels were significantly more frequent in patients receiving DC treatment (p < 0.01). The 28-day mortality was significantly higher in patients receiving ST compared with the DC group (47.9% vs 29.2%, p = 0.04). Similarly, clinical cure and microbiological eradication were significantly higher when DC was used in patients infected with CR-Kp strains resistant to colistin (13/20 (65%) vs 10/32 (31.3%), p = 0.03 and 11/19 (57.9%) vs 7/27 (25.9%), p = 0.04, respectively). In the logistic regression and multivariate Cox-regression models, the DC regimen was associated with a reduction in 28-day mortality (OR 0.33, 95% CI 0.13-0.87 and OR 0.43, 95% CI 0.23-0.79, respectively).

Conclusions: Improved 28-day mortality was associated with the DC regimen compared with ST for severe CR-Kp infections. A randomized trial is needed to confirm these observational results.

Trial registration: ClinicalTrials.gov NCT03094494 . Registered 28 March 2017.

Keywords: Critically ill patients; Double carbapenem; Ertapenem; Infections; Klebsiella pneumoniae; Meropenem; Multidrug-resistant bacteria.

Conflict of interest statement

Ethics approval and consent to participate

The study was approved by the local ethics committees (approval numbers: Comitato Etico UCSC 14669/15; Comitato Etico Palermo 2 n° 359/2015). Because of its observational, noninterventional design, informed consent was waived.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
a Clinical cure rate according to antibiotic resistance. *p = 0.03, **p = 0.05. b Microbiological eradication rate according to antibiotic resistance. *p = 0.04. R resistance, DC double carbapenem, ST standard treatment, Coli colistin, Genta gentamicin, Tige tigecycline
Fig. 2
Fig. 2
Kaplan–Meier curves showing the impact of DC therapy (black line) versus ST (gray line) on a 28-day mortality and b 90-day mortality. DC double carbapenem, ST standard treatment

References

    1. Tumbarello M, Trecarichi EM, Tumietto F, Del Bono V, De Rosa FG, Bassetti M, Losito AR, Tedeschi S, Saffioti C, Corcione S, et al. Predictive models for identification of hospitalized patients harboring KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2014;58(6):3514–20. doi: 10.1128/AAC.02373-13.
    1. Baraniak A, Izdebski R, Fiett J, Herda M, Derde LP, Bonten MJ, Adler A, Carmeli Y, Goossens H, Hryniewicz W, et al. KPC-Like Carbapenemase-producing enterobacteriaceae colonizing patients in Europe and Israel. Antimicrob Agents Chemother. 2015;60(3):1912–7. doi: 10.1128/AAC.02756-15.
    1. Albiger B, Glasner C, Struelens MJ, Grundmann H, Monnet DL. Carbapenemase-producing Enterobacteriaceae in Europe: assessment by national experts from 38 countries, May 2015. Euro Surveill. 2015;20(45):1-18. doi:10.2807/1560-7917.ES.2015.20.45.30062
    1. Dautzenberg MJ, Wekesa AN, Gniadkowski M, Antoniadou A, Giamarellou H, Petrikkos GL, Skiada A, Brun-Buisson C, Bonten MJ, Derde LP. The association between colonization with carbapenemase-producing enterobacteriaceae and overall ICU mortality: an observational cohort study. Crit Care Med. 2015;43(6):1170–7. doi: 10.1097/CCM.0000000000001028.
    1. Gutierrez-Gutierrez B, Salamanca E, de Cueto M, Hsueh PR, Viale P, Pano-Pardo JR, Venditti M, Tumbarello M, Daikos G, Pintado V, et al. A predictive model of mortality in patients with bloodstream infections due to carbapenemase-producing enterobacteriaceae. Mayo Clin Proc. 2016;91(10):1362–71. doi: 10.1016/j.mayocp.2016.06.024.
    1. Karaiskos I, Giamarellou H. Multidrug-resistant and extensively drug-resistant Gram-negative pathogens: current and emerging therapeutic approaches. Expert Opin Pharmacother. 2014;15(10):1351–70. doi: 10.1517/14656566.2014.914172.
    1. Poulakou G, Matthaiou DK, Bassetti M, Erdem H, Dimopoulos G, Curcio DJ, Carlet J, Lipman J, Timsit JF, Giamarellou H et al. “Salvage treatment” for infections by extensively- and pan-drug-resistant pathogens is common and often sub-optimal. Intensive Care Med. 2017. doi:10.1007/s00134-017-4796-y. [Epub ahead of print]
    1. Decker B, Masur H. Bad bugs, no drugs: are we part of the problem, or leaders in developing solutions? Crit Care Med. 2015;43(6):1153–5. doi: 10.1097/CCM.0000000000001039.
    1. Bassetti M, De Waele JJ, Eggimann P, Garnacho-Montero J, Kahlmeter G, Menichetti F, Nicolau DP, Paiva JA, Tumbarello M, Welte T, et al. Preventive and therapeutic strategies in critically ill patients with highly resistant bacteria. Intensive Care Med. 2015;41(5):776–95. doi: 10.1007/s00134-015-3719-z.
    1. Munoz-Price LS, Rosa R, Castro JG, Laowansiri P, Latibeaudiere R, Namias N, Tarima S. Evaluating the impact of antibiotic exposures as time-dependent variables on the acquisition of carbapenem-resistant Acinetobacter baumannii. Crit Care Med. 2016;44(10):e949–56. doi: 10.1097/CCM.0000000000001848.
    1. Tumbarello M, Trecarichi EM, De Rosa FG, Giannella M, Giacobbe DR, Bassetti M, Losito AR, Bartoletti M, Del Bono V, Corcione S, et al. Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study. J Antimicrob Chemother. 2015;70(7):2133–43. doi: 10.1093/jac/dkv086.
    1. Tumbarello M, Viale P, Bassetti M, De Rosa FG, Spanu T, Viscoli C. Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study—authors’ response. J Antimicrob Chemother. 2015;70(10):2922. doi: 10.1093/jac/dkv200.
    1. Gutierrez-Gutierrez B, Salamanca E, de Cueto M, Hsueh PR, Viale P, Pano-Pardo JR, Venditti M, Tumbarello M, Daikos G, Canton R et al. Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT): a retrospective cohort study. Lancet Infect Dis. 2017;17:726-34. doi:10.1016/S1473-3099(17)30228-1.
    1. Tzouvelekis LS, Markogiannakis A, Piperaki E, Souli M, Daikos GL. Treating infections caused by carbapenemase-producing Enterobacteriaceae. Clin Microbiol Infect. 2014;20(9):862–72. doi: 10.1111/1469-0691.12697.
    1. Zusman O, Altunin S, Koppel F, Dishon Benattar Y, Gedik H, Paul M. Polymyxin monotherapy or in combination against carbapenem-resistant bacteria: systematic review and meta-analysis. J Antimicrob Chemother. 2017;72(1):29–39. doi: 10.1093/jac/dkw377.
    1. Shields RK, Potoski BA, Haidar G, Hao B, Doi Y, Chen L, Press EG, Kreiswirth BN, Clancy CJ, Nguyen MH. Clinical outcomes, drug toxicity, and emergence of ceftazidime-avibactam resistance among patients treated for carbapenem-resistant enterobacteriaceae infections. Clin Infect Dis. 2016;63(12):1615–8. doi: 10.1093/cid/ciw636.
    1. Oliva A, Gizzi F, Mascellino MT, Cipolla A, D’Abramo A, D’Agostino C, Trinchieri V, Russo G, Tierno F, Iannetta M, et al. Bactericidal and synergistic activity of double-carbapenem regimen for infections caused by carbapenemase-producing Klebsiella pneumoniae. Clin Microbiol Infect. 2016;22(2):147–53. doi: 10.1016/j.cmi.2015.09.014.
    1. Bulik CC, Nicolau DP. Double-carbapenem therapy for carbapenemase-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2011;55(6):3002–4. doi: 10.1128/AAC.01420-10.
    1. Souli M, Karaiskos I, Masgala A, Galani L, Barmpouti E, Giamarellou H. Double-carbapenem combination as salvage therapy for untreatable infections by KPC-2-producing Klebsiella pneumoniae. Eur J Clin Microbiol Infect Dis. 2017. doi:10.1007/s10096-017-2936-5. [Epub ahead of print]
    1. Giamarellou H, Galani L, Baziaka F, Karaiskos I. Effectiveness of a double-carbapenem regimen for infections in humans due to carbapenemase-producing pandrug-resistant Klebsiella pneumoniae. Antimicrob Agents Chemother. 2013;57(5):2388–90. doi: 10.1128/AAC.02399-12.
    1. Cprek JB, Gallagher JC. Ertapenem-containing double-carbapenem therapy for treatment of infections caused by carbapenem-resistant Klebsiella pneumoniae. Antimicrob Agents Chemother. 2015;60(1):669–73. doi: 10.1128/AAC.01569-15.
    1. Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA. 1993;270(24):2957–63. doi: 10.1001/jama.1993.03510240069035.
    1. Ferreira FL, Bota DP, Bross A, Melot C, Vincent JL. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA. 2001;286(14):1754–8. doi: 10.1001/jama.286.14.1754.
    1. van Zanten AR, van der Meer YG. Prolonged infusion of carbapenems in critically ill patients: time to extend our practice. Crit Care Med. 2013;41(2):676–7. doi: 10.1097/CCM.0b013e3182741e68.
    1. File TM., Jr Recommendations for treatment of hospital-acquired and ventilator-associated pneumonia: review of recent international guidelines. Clin Infect Dis. 2010;51(Suppl 1):S42–7. doi: 10.1086/653048.
    1. Mermel LA, Allon M, Bouza E, Craven DE, Flynn P, O’Grady NP, Raad II, Rijnders BJ, Sherertz RJ, Warren DK. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;49(1):1–45. doi: 10.1086/599376.
    1. Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ, O’Neill PJ, Chow AW, Dellinger EP, Eachempati SR, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(2):133–64. doi: 10.1086/649554.
    1. Stevens DL, Bisno AL, Chambers HF, Dellinger EP, Goldstein EJ, Gorbach SL, Hirschmann JV, Kaplan SL, Montoya JG, Wade JC. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014;59(2):e10–52. doi: 10.1093/cid/ciu296.
    1. Hooton TM, Bradley SF, Cardenas DD, Colgan R, Geerlings SE, Rice JC, Saint S, Schaeffer AJ, Tambayh PA, Tenke P, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(5):625–63. doi: 10.1086/650482.
    1. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165–228. doi: 10.1007/s00134-012-2769-8.
    1. Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307(23):2526–33.
    1. Rasheed J. Detction and characterization of antimicrobial resistance genes in pathogenic bacteria. In: Murray PRBE, Jorgensen JH, Landry ML, Pfaller MA, editors. Manual of clinical micribiology, vol. 1. 9. Washington, DC: American Society of Microbiology; 2007. pp. 1248–67.
    1. Oliva A, D’Abramo A, D’Agostino C, Iannetta M, Mascellino MT, Gallinelli C, Mastroianni CM, Vullo V. Synergistic activity and effectiveness of a double-carbapenem regimen in pandrug-resistant Klebsiella pneumoniae bloodstream infections. J Antimicrob Chemother. 2014;69(6):1718–20. doi: 10.1093/jac/dku027.
    1. Perez F, El Chakhtoura NG, Papp-Wallace KM, Wilson BM, Bonomo RA. Treatment options for infections caused by carbapenem-resistant Enterobacteriaceae: can we apply “precision medicine” to antimicrobial chemotherapy? Expert Opin Pharmacother. 2016;17(6):761–81. doi: 10.1517/14656566.2016.1145658.
    1. Poirel L, Kieffer N, Nordmann P. In vitro evaluation of dual carbapenem combinations against carbapenemase-producing Enterobacteriaceae. J Antimicrob Chemother. 2016;71(1):156–61. doi: 10.1093/jac/dkv294.
    1. Ceccarelli G, Falcone M, Giordano A, Mezzatesta ML, Caio C, Stefani S, Venditti M. Successful ertapenem-doripenem combination treatment of bacteremic ventilator-associated pneumonia due to colistin-resistant KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2013;57(6):2900–1. doi: 10.1128/AAC.00188-13.
    1. Daikos GL, Tsaousi S, Tzouvelekis LS, Anyfantis I, Psichogiou M, Argyropoulou A, Stefanou I, Sypsa V, Miriagou V, Nepka M, et al. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother. 2014;58(4):2322–8. doi: 10.1128/AAC.02166-13.
    1. Oliva A, Scorzolini L, Castaldi D, Gizzi F, De Angelis M, Storto M, D’Abramo A, Aloj F, Mascellino MT, Mastroianni CM, et al. Double-carbapenem regimen, alone or in combination with colistin, in the treatment of infections caused by carbapenem-resistant Klebsiella pneumoniae (CR-Kp) J Infect. 2017;74(1):103–6. doi: 10.1016/j.jinf.2016.10.002.
    1. Sbrana F, Malacarne P, Viaggi B, Costanzo S, Leonetti P, Leonildi A, Casini B, Tascini C, Menichetti F. Carbapenem-sparing antibiotic regimens for infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae in intensive care unit. Clin Infect Dis. 2013;56(5):697–700. doi: 10.1093/cid/cis969.
    1. Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, Spanu T, Ambretti S, Ginocchio F, Cristini F, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis. 2012;55(7):943–50. doi: 10.1093/cid/cis588.
    1. Cheng A, Chuang YC, Sun HY, Sheng WH, Yang CJ, Liao CH, Hsueh PR, Yang JL, Shen NJ, Wang JT, et al. Excess mortality associated with colistin-tigecycline compared with colistin-carbapenem combination therapy for extensively drug-resistant Acinetobacter baumannii bacteremia: a multicenter prospective observational study. Crit Care Med. 2015;43(6):1194–204. doi: 10.1097/CCM.0000000000000933.
    1. De Pascale G, Montini L, Pennisi M, Bernini V, Maviglia R, Bello G, Spanu T, Tumbarello M, Antonelli M. High dose tigecycline in critically ill patients with severe infections due to multidrug-resistant bacteria. Crit Care. 2014;18(3):R90. doi: 10.1186/cc13858.
    1. Tumbarello M, De Pascale G, Trecarichi EM, De Martino S, Bello G, Maviglia R, Spanu T, Antonelli M. Effect of aerosolized colistin as adjunctive treatment on the outcomes of microbiologically documented ventilator-associated pneumonia caused by colistin-only susceptible gram-negative bacteria. Chest. 2013;144(6):1768–75. doi: 10.1378/chest.13-1018.
    1. Rocco M, Montini L, De Pascale G, Antonelli M. Dose of colistin: a work in progress? Crit Care. 2015;19:65. doi: 10.1186/s13054-015-0743-x.
    1. Buehrle DJ, Shields RK, Chen L, Hao B, Press EG, Alkrouk A, Potoski BA, Kreiswirth BN, Clancy CJ, Nguyen MH. Evaluation of the in vitro activity of ceftazidime-avibactam and ceftolozane-tazobactam against meropenem-resistant Pseudomonas aeruginosa isolates. Antimicrob Agents Chemother. 2016;60(5):3227–31. doi: 10.1128/AAC.02969-15.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel