Aloj, F.

Castaldi, D.

D'Abramo, A.

De Angelis, M.

Gizzi, F.

Mascellino, M. T.

Mastroianni, C. M.

Oliva, Alessandra

Scorzolini, L.

Storto, M.

Vullo, V.

English

Archivio della ricerca- Università di Roma La Sapienza

Letters to the Editor 103Double-carbapenem regimen, alone or incombination with colistin, in the treatmentof infections caused by carbapenem-resistant Klebsiella pneumoniae (CR-Kp)Dear Editor,We read with interest the article published by Zhanget al., concerning the emergence of infection caused by ahypervirulent (hv) carbapenem-resistant Klebsiella pneu-moniae (CR-Kp) strain.1Infections caused by CR-Kp represent an emerging threatworldwide due to high mortality rate and limited thera-peutic options.2 Although considered as part of antimicro-bial combinations against CR-Kp, colistin use might belimited by its potential nephrotoxicity and resistance;thus, colistin-free unconventional approaches such as thedouble-carbapenem (DC) regimen have recently beenproposed.3e6In the present study, we evaluated the clinical effec-tiveness and the in-vitro activity of the DC regimen [ertape-nem (ERT) plus high dose of meropenem (MEM)], alone or incombination with colistin (COL), in the treatment of infec-tions caused by CR-Kp.Over a 3-years period (2012e2015), we enrolled allconsecutive patients with CR-Kp infection treated withthe DC regimen, with or without colistin, at the Departmentof Public Health and Infectious Diseases of “Sapienza”University (Rome) and at the Mediterranean NeurologicalInstitute “Neuromed” (Pozzilli).The use of these combinations was decided by theattending Infectious Diseases Specialist according to pa-tients’ clinical condition, renal function and strains sus-ceptibility pattern. Early response was defined asresolution of signs and symptoms of infection at 5th dayof antimicrobial treatment whereas the overall follow-upwas set up at 60-days. Patients gave informed writtenconsent.Clinical samples underwent microbiological proceduresas for daily practice. Additional in-vitro studies includedphenotypic determination of carbapenemases7 and evalua-tion of MEM þ ERT and COL þ MEM þ ERT synergismthroughout killing studies. In the triple combination,we decided to lower MEM rather than COL or ERT concen-trations because in the presence of high MEM MICs, whichwere far above the achievable concentration of the drug,there was a higher probability of reaching serum MEM con-centration with 0.5 MIC and 0.25 MIC concentrationsthan with 1 MIC. The area under the curve (AUC)of each combination, expressed as mean  SD, wascalculated. The number of CFU/mL was expressed asmean  standard error of the mean (SEM). For statisticalanalyses we used GraphPad Prism version 5 (Graphpad Soft-ware MacKiev).A total of 32 patients with CR-Kp infection were enrolledin the study: subjects receiving ERT þ MEM (Group A;nZ 18) and subjects receiving COL þ MEM þ ERT (Group B;n Z 14). Clinical characteristics of study population areshown in Table 1.Overall, clinical success was achieved in 75% of subjects.The triple combination therapy was used more frequentlyin patients with a more severe condition at the time ofinfection (i.e. septic shock). Although patients in Group Btended to have an earlier clinical response than those inGroup A, no statistical difference was found between the 2groups regarding early response to therapy and mortality at60-days.Killing studies were performed on 28 CR-Kp strains (16from Group A, 12 from Group B) whereas the remaining 4strains were not available. MICs50/90 of both MEM and ERTwere 128 and 256 mg/mL by macrobroth dilution. All thestrains were KPC producers. Results of killing studies areshown in Fig. 1.In the DC group (n Z 16 strains, Fig. 1a), bactericidalactivity of ERT þ MEM was observed in 12/16 (75%) at 8 hand raised to 14/16 (87.5%) at 24 h whereas in theCOL þ DC group (n Z 12 strains, Fig. 1b), the triple com-bination (COL1 MIC þ MEM1 MIC þ ERT1 MIC) showed amore rapid bactericidal activity than the double-carbapenem regimen at MEM1 MIC þ ERT1 MIC (8/12versus 6/12 at 8 h) and this effect was confirmedeven when sub-inhibitory concentrations of drugs weretested. Furthermore, the triple combination at all thetested concentrations was bactericidal at 24 h. Interest-ingly, the bactericidal effect of the combinationCOL þ MEM þ ERT was confirmed even in the presence ofCOL MIC 2 mg/mL.In the present study, we enrolled patients treated withtwo types of unconventional regimens (MEM þ ERT in 18patients and COL þ MEM þ ERT in 14 subjects).In the in-vitro analyses, we showed that the addition ofCOL to the DC regimen obtained a rapid bactericidal activ-ity, which was maintained up to 24 h. Of note, the activityof this combination was observed even at sub-inhibitoryconcentrations of the drugs, with no statistically significantdifferences in the AUCs of the tested concentrations.Based on our results, the addition of colistin toMEM þ ERT might be useful by inducing an earlierantibacterial activity than that obtained with thedouble-carbapenem regimen alone. This effect might becrucial in the setting of more severe infections, where arapid antibacterial effect of an antimicrobial regimen isauspicable in order to improve the clinical outcome of thepatients, even when the presence of colistin resistancemight discourage its use. Our results could lead to thehypothesis that starting with an aggressive treatment ofcolistin þ ertapenem þ meropenem followed by atherapeutic switch to a less toxic regimen (i.e. thedouble-carbapenem regimen) might be a reasonabletherapeutic options against systemic infections causedby CR-Kp.8Furthermore, our experiments showed that even in thepresence of higher COL MICs (2 mg/mL) the combination ofCOL þ MEM þ ERTwas highly effective. In particular, all thepatients with COL resistance (n Z 3) had clinical improve-ment at 60-days of follow-up. In these cases, thedetergent-like property of colistin might have a crucialrole in facilitating the penetration of the other drugs intothe bacteria.9One of the major features of the present study is thepresence of both clinical and in-vitro results. In an era inTable 1 General characteristics of study population.Study population(n Z 32)DC groupa(n Z 18, Group A)COLb þ DC group(n Z 14, Group B)p-valueDemographic characteristics Age (years), M  SD 55.1  15.2 55.6  13.6 54.4  17.5 0.74 Sex (M:F) 23:9 14:4 9:5 0.45 APACHE III score, M  SD 64.9  29.6 50.7  28.1 83.2  20.3 0.001 2 Comorbidities 14 (43.7) 5 (27.7) 9 (64.2) 0.07Classification of infection, n (%) CA:HCA:HA 0:6:26 0:6:12 0:0:14 0.0001 Length of hospitalization before infection, daysc 17.5 (2e437) 14 (2e65) 23 (5e437) 0.005Risk factors for infection (previous 12 months), n (%) Previous hospitalization 22 (68.7) 15 (83.3) 7 (50) 0.02 Intensive care unit 22 (68.7) 10 (55.5) 12 (85.7) 0.06 Vescical catheter 18 (56.2) 12 (66.6) 6 (42.8) 0.12 Central venous catheter (CVC) 11 (34.3) 9 (50) 2 (14.2) 0.28Risk factors for infection (previous 72 h), n (%) Naso-gastric tube 18 (56.2) 6 (33.3) 12 (85.7) 0.004 Fibrobroncoscopy 14 (43.7) 4 (22.2) 10 (71.4) 0.01 Parenteral total nutrition 14 (43.7) 4 (22.2) 10 (71.4) 0.01 CVC 20 (62.5) 7 (38.8) 13 (92.8) 0.002Previous antibiotic therapy (90 days), n (%) 29 (90.6) 15 (83.3) 14 (100) 0.23 Cephalosporin 10 (31.2) 3 (16.6) 7 (50) 0.06 Penicillins 18 (56.2) 7 (38.8) 11 (78.5) 0.03 Carbapenems 15 (46.8) 6 (33.3) 9 (64.2) 0.45 Beta-lactams (overall) 27 (84.3) 13 (72.2) 14 (100) 0.05 Fluoroquinolones 10 (31.2) 5 (27.7) 5 (35.7) 0.71 Colistin 9 (28.1) 4 (22.2) 5 (35.7) 0.45CR-Kp rectal colonization, n (%) 27 (96.4) 13/14 (92)e 14/14 (100) 0.37Colistin-resistance, n (%) 11 (34.3) 8 (44.4) 3 (21.4) 0.26Clinical presentationd, n (%) Sepsis 5 (15.6) 3 (16.6) 2 (14.2) 0.99 Severe sepsis 13 (40.6) 7 (38.8) 6 (42.8) 0.99 Septic shock 8 (25) 2 (11.1) 6 (42.8) 0.09 Type of infectionPneumonia 9 (28.1) 4 (22.2) 5 (35.7) 0.99EV infection 3 (9.3) 2 (11.1) 1 (7.1) 0.87UT infection 9 (28.1) 8 (44.4) 1 (7.1) 0.04CVC infection 6 (18.7) 0 (0) 6 (42.8) 0.003Primary bacteremia 6 (18.7) 4 (22.2) 2 (14.2) 0.67 Presence of bacteremic infection 18 (56.2) 8 (44.4) 10 (71.4) 0.16Definitive therapy, n (%) Early responsee 23 (71.8) 11 (61.1) 12 (85.7) 0.23 Length of definitive therapy, daysc 21 (7e150) 18.5 (7e150) 25 (7e34) 0.04 Clinical response (days)c 4 (2e15) 4 (2e15) 4 (3e12) 0.68 Microbiological response (days)f c 4 (2e17) 3 (2e17) 5 (3e10) 0.43 Adverse events, n (%)g 6 (18.7) 3 (16.6) 3 (21.4) 1.00Outcome at 60 days, n (%) Exitus 6 (18.7) 3 (16.6) 3 (21.4) 0.99 Relapseh 2 (6.2) 2 (11.1) 0 (0) 0.49 Improvement 24 (75) 13 (72.2) 11 (78.5) 0.89DC: double-carbapenem; COL: colistin; CR-Kp: carbapenem-resistant Klebsiella pneumoniae; CA: community-acquired; HCA: health-care associated; HA: hospital-acquired; EV: endo vascular; UT: urinary tract; CVC: central venous catheter.a The DC regimen consisted of ERT 1 g (1-h infusion) followed by high dose of MEM (2 g every 8 h, 3-h infusion).b COL administration was 9,000,000 UI as a loading dose followed (after 12 h) by 4,500,000 UI every 12 h.c Data are expressed as median (range).d Clinical presentation (sepsis, severe sepsis and septic shock) was determined according to period guidelines.10.e Early clinical response was defined as resolution of signs and symptoms of infections (i.e. defervescence, improvement of clinicalconditions, reduction of white blood cells, C-reactive protein) achieved at 5th day of antimicrobial treatment.f Microbiological response was defined as negativity of cultures performed after 5 days of antimicrobial treatment.g Type of adverse events included: mild sodium-disorder (n Z 1, Group A), vomiting (n Z 1, Group A), seizures (n Z 2, 1 Group A, 1Group B), leukopenia (n Z 2, Group B).104 Letters to the Editorh Infection relapse was defined as recrudescence of CR-Kp infection within the 60-day of follow up after an initial response.Figure 1 Bactericidal activity and killing studies of double-carbapenem regimen (a) and colistin (COL) plus double-carbapenemregimen (b). DC: double-carbapenem; MEM: meropenem; ERT: ertapenem; GC: growth control; AUC: area under the curve; SD:standard deviation. Dashed line represents bactericidal activity. a: bactericidal activity was defined as 3-log10 CFU/ml reductionof the initial bacterial count at each time point; b: synergistic activity was defined as a 100-fold decrease in CFU/mL between thecombination and its most active constituent at the same concentration after 24 h.Letters to the Editor 105which traditional antimicrobial susceptibility reportsseem to be no longer informative, we believe that per-forming in-vitro synergy studies could represent an addi-tional tool in order to guide treatment decisions andpredict the potential clinical efficacy of the chosencombination.In conclusion, we were able to demonstrate that boththe double-carbapenem alone and the double-carbapenem106 Letters to the Editorregimen plus colistin were clinically and microbiologicallyeffective in the treatment of infections caused by CR-Kp,the latter even at sub-inhibitory concentrations.MEM þ ERT might be a valid therapeutic option when COLuse is discouraged whereas COL þ MEM þ ERT might beconsidered in subjects presenting with more severe condi-tions (i.e. septic shock), where an early clinical response isauspicable.FundingThis work was supported by a grant of Sapienza Universityof Rome, 2014 (Number: C26N14S7RB).Conflict of interestNone declared.AcknowledgementsThe authors thank the nurses and the technician staff fortheir contribution in laboratory sample collection andprocessing.References1. Zhangg Yawei, Zengg Ji, Liu Wenen, Zhao Feng,Hu Zhidong, Zhao Chunjiang, et al. Emergence of ahypervirulent carbapenem-resistant Klebsiella pneumoniaeisolate from clinical infections in China. J Infect 2015;71(5):553e60.2. Kontopidou F, Giamarellou H, Katerelos P, Maragos A,Kioumis I, Trikka-Graphakos E, et al. Infections caused bycarbapenem-resistant Klebsiella pneumoniae among patientsin intensive care units in Greece: a multi-centre study on clin-ical outcome and therapeutic options. Clin Microbiol Infect2014;20:O117e23.3. Oliva A, Gizzi F, Mascellino MT, Cipolla A, D’Abramo A,D’Agostino C, et al. Bactericidal and synergistic activity ofdouble-carbapenem regimen for infections caused bycarbapenemase-producing Klebsiella pneumoniae. Clin Micro-biol Infect 2015. http://dx.doi.org/10.1016/j.cmi.2015.09.014.Sep 25. pii: S1198-743X(15)00869-1.4. Bulik CC, Nicolau DP. Double-carbapenem therapy forcarbapenemase-producing Klebsiella pneumoniae. AntimicrobAgents Chemother 2011 Jun;55(6):3002e4.5. Oliva A, D’Abramo A, D’Agostino C, Iannetta M, Mascellino MT,Gallinelli C, et al. Synergistic activity and effectiveness of adouble-carbapenem regimen in pandrug-resistant Klebsiellapneumoniae bloodstream infections. J Antimicrob Chemother2014;69:1718e20.6. Chua NG, Zhou YP, Tan TT, Lingegowda PB, Lee W, Lim TP,et al. Polymyxin B with dual carbapenem combination therapyagainst carbapenemase-producing Klebsiella pneumoniae. JInfect 2015;70:309e11.7. Giske CG, Gezelius L, Samuelsen Ø, Warner M, Sundsfjord A,Woodford N. A sensitive and specific phenotypic assay fordetection of metallo-beta-lactamases and KPC in K. pneumo-niae with the use of meropenem disks supplemented with ami-nophenylboronic acid, dipicolinic acid and cloxacillin. ClinMicrobiol Infect 2011;17:552e6.8. Oliva A, Mascellino MT, Cipolla A, D’Abramo A, De Rosa A,Savinelli S, et al. Therapeutic strategy for pandrug-resistantKlebsiella pneumonia severe infections: short-course treat-ment with colistin increases the in vivo and in vitro activityof double carbapenem regimen. Int J Infect Dis 2015 Apr;33:132e4.9. Gaibani P, Lombardo D, Lewis RE, Mercuri M, Bonora S,Landini MP, et al. In-vitro activity and post-antibiotic effectsof colistin in combination with other antimicrobials againstcolistin-resistant KPC-producing Klebsiella pneumoniae blood-stream isolates. J Antimicrob Chemother 2014;69:1856e65.10. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H,Opal SM, et al. Surviving sepsis campaign: international guide-lines for management of severe sepsis and septic shock: 2012.Crit Care Med 2013;41(2):580e637.Alessandra Oliva*L. ScorzoliniD. CastaldiF. GizziM. De AngelisDepartment of Public Health and Infectious Diseases,“Sapienza” University of Rome, ItalyM. StortoMediterranean Neurological Institute “Neuromed”,Pozzilli, ItalyA. D’AbramoDepartment of Public Health and Infectious Diseases,“Sapienza” University of Rome, ItalyF. AlojMediterranean Neurological Institute “Neuromed”,Pozzilli, ItalyM.T. MascellinoC.M. MastroianniV. VulloDepartment of Public Health and Infectious Diseases,“Sapienza” University of Rome, Italy*Corresponding author.E-mail address: alessandra.oliva@uniroma1.it (A. Oliva)Accepted 9 October 2016http://dx.doi.org/10.1016/j.jinf.2016.10.002ª 2016 The British Infection Association. Published by Elsevier Ltd.All rights reserved.

Double-carbapenem regimen, alone or in combination with colistin, in the treatment of infections caused by carbapenem-resistant Klebsiella pneumoniae (CR-Kp)

Alessandra Oliva

L. Scorzolini

D. Castaldi

F. Gizzi

M. De Angelis

M. Storto

A. D'Abramo

F. Aloj

M.T. Mascellino

C.M. Mastroianni

V. Vullo

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Journal of Infection

https://iris.uniroma1.it/bitstream/11573/927801/1/Oliva_Double-carbapenem_2017.pdf

Double-carbapenem regimen, alone or in combination with colistin, in the treatment of infections caused by carbapenem-resistant Klebsiella pneumoniae (CR-Kp)

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