We present the case of a patient with ventilator-associated pneumonia (VAP) caused by a pan-resistant Acinetobacter baumannii successfully treated with the combination colistin plus vancomycin plus rifampin, whose in vitro activity was investigated by checkerboard method and killing testing. Furthermore, the serum bactericidal activity (SBA) was assessed. Our case shows that an innovative regimen consisting of colistin plus antimicrobials active only against Gram-positive microorganisms might represent a valid therapeutic option for severe infections caused by colistin-resistant A. baumannii

Cipolla, Alessia

Falcone, Marco

Mastroianni, Claudio Maria

Oliva, Alessandra

Venditti, Mario

Vullo, Vincenzo

English

Archivio della Ricerca - Università di Pisa

SHORT COMMUNICATIONNEW MICROBIOLOGICA, 40, 3, 205-207, 2017, ISN 1121-7138Clinical and in vitro efficacy of colistin plus vancomycin and rifampin against colistin-resistant Acinetobacter baumannii causing ventilator-associated pneumoniaAlessandra Oliva, Alessia Cipolla, Vincenzo Vullo, Mario Venditti,  Claudio Maria Mastroianni, Marco FalconeDepartment of Public Health and Infectious Diseases, “Sapienza” University of Rome, ItalyA 77-year-old man was admitted to the Intensive Care Unit (ICU) for an acute subarachnoid hemorrhage. His recent medical history included a diagnosis of culture negative brain abscess treated with a combination ther-apy of linezolid and meropenem six weeks prior to ICU admission. The patient underwent neurosurgery and mechanical ventilation was started. During the early post-operative period the patient had an acute worsen-ing of respiratory gas exchanges, associated with leu-kocytosis. Chest radiography showed left pneumonia and tracheal aspirate was positive for Extended Spec-trum Beta Lactamases (ESBL)-producing E. coli. Thus, therapy with meropenem 1 g every 8 hours was started, with improvement of clinical conditions. However, af-ter 12 days after intubation the patient developed fever and hypotension with sudden worsening of respiratory gases and metabolic acidosis. A CT scan of the chest revealed bilateral multiple areas of consolidation of the lungs. Bronchoalveolar lavage culture was positive for colistin- (COL) and carbapenem-resistant Acinetobacter baumannii and methicillin-resistant S. aureus (MRSA). Meropenem was discontinuated and therapy with i.v. colistin 9.000.000 UI loading dose followed by 4.500.000 UI every 12 hours plus rifampin (RIF) 600 mg/day plus vancomycin (VAN) 1g loading dose followed by 2 g/day was initiated. Aerosolized COL (1.000.000 UI every 8 hours) was also administered. The clinical conditions of the patient improved. However, a significant increase Corresponding author:Alessandra OlivaE-mail: alessandra.oliva@uniroma1.it©2017 by EDIMES - Edizioni Internazionali Srl. All rights reservedin creatinine level was observed (up to 3 mg/dL), lead-ing to the reduction of COL dosages to 2.500.000 ev-ery 12 hours and discontinuation of VAN after 6 days of therapy. Serum bactericidal activity (SBA) performed at day 3 of therapy was 1:16 (pre-dose) and 1:64 (after dose). COL and RIF were stopped after 2 weeks of ther-apy, with resolution of the infection and progressive im-provement of renal function after 4 weeks. The patient was then transferred to a rehabilitation center 7 weeks after ICU admission. Considering its challenging antimicrobial susceptibility pattern, the clinical isolate was immediately submitted to additional in vitro analyses including synergy testing by both checkerboard method and killing tests.Minimal inhibitory concentrations (MICs) of COL, VAN and RIF were determined by broth macrodilution method (BMD) in cation-adjusted Mueller Hinton broth (CAM-HB) (CLSI, 2012). Furthermore, for COL MIC determina-tion a gradient strip test (E-test) was used. Synergy tests were performed throughout the checkerboard method at different concentrations of COL+RIF, COL+VAN and COL+RIF+VAN combinations. Complete synergism was defined as FIC-index (FICI) ≤0.5. The activity of COL, VAN and RIF, alone and in combination, was also inves-tigated by time-kill studies at a final inoculum of ~5x105 CFU/ml at the following concentrations: 1xMIC COL, 0.25xMIC VAN, 1xMIC RIF, 1xMIC COL+0.25xMIC VAN, 1xMIC COL+1xMIC RIF, 1xMIC COL+0.25xMIC VAN+ 1xMIC RIF. The VAN concentration used for killing stud-ies reflected the serum trough level achieved during ther-apy (16 mg/L). Bactericidal activity was defined as ≥3-log10 CFU/ml reduction of the initial bacterial count at each time point whereas synergistic activity was defined as a ≥100-fold decrease in CFU/mL between the combi-nation and its most active constituent at the same con-centration after 24 h. The detection limit was 10 CFU/mL. SBA was determined at 3th day of COL+VAN+RIF Key words:Acinetobacter baumannii, Multi-drug resistance, Colistin resistance,  Ventilator-associated pneumonia, Vancomycin, Rifampin.SUMMARYWe present the case of a patient with ventilator-associated pneumonia (VAP) caused by a pan-resistant Acinetobacter baumannii successfully treated with the combination colistin plus vancomycin plus rifamp-in, whose in vitro activity was investigated by checkerboard method and killing testing. Furthermore, the serum bactericidal activity (SBA) was assessed. Our case shows that an innovative regimen consisting of colistin plus antimicrobials active only against Gram-positive microorganisms might represent a valid therapeutic option for severe infections caused by colistin-resistant A. baumannii.Received February 16, 2017    Accepted March 26 2017L'uso personale è consentito ma la riproduzione sistematica e l’utilizzo per fini commerciali richiedonoil permesso scritto dell’editore. Per richiederlo contattare: editorial.office@newmicrobiologica.orgA. Oliva, A. Cipolla, V. Vullo, et al.206therapy by collecting patient’s blood 30 min before and 2 h after therapy administration.Throughout MBD, MICs of COL, RIF and VAN were 4, 2 and 64 mg/L, respectively. By using E-test, COL MIC was 4 mg/L. A complete synergism was observed for COL+VAN and COL+RIF. At killing experiments, COL (1xMIC, 4 mg/L) and RIF (1xMIC, 2 mg/L) alone showed only a slight decrease of CFU/mL whereas VAN (0.25xMIC, 16 mg/L) alone did not have any effect on lowering the bacterial growth (Figure 1). On the oth-er hand, when the combinations COL+VAN, COL+RIF and COL+VAN+RIF were tested, a rapid bactericidal activity was observed after 2 h. All tested combinations showed an absence of growth at 6h, which was main-tained up to 24 h. In particular, absence of growth was observed at 6 h for COL+RIF combination whereas COL+VAN and COL+VAN+RIF yielded no bacteria at 4 h and 2 h, respectively. All the tested combinations were synergic at 24 h.Infections caused by A. baumannii are associated with a high mortality rate especially in the presence of multi-drug resistant (MDR) strains since therapeutic options are severely limited (Maragakis et al., 2008; Orsi et al., 2011). Colistin-based combinations have been consid-ered the milestone of the treatment of MDR A. bauman-ni (Motaouakkil et al., 2006; Durante-Mangoni et al., 2013) whereas unconventional regimens against carbap-enem-resistant A. baumannii include the combination of COL plus rifampin (RIF) or glycopeptides (Garna-cho-Montero et al., 2013; Petrosillo et al., 2014; Ceccarelli et al., 2015). However, the emergence of COL resistance represents a real challenge and nowadays insufficient data are available for the treatment of A. baumannii in-fections due to COL-resistant strains (Leite et al., 2016).In the present case, we demonstrated that a regimen con-sisting of COL plus antimicrobials active only against Gram-positive microorganisms might represent a val-id therapeutic option for severe infections caused by COL-resistant A. baumannii. The observed clinical effec-tiveness was confirmed by both SBA (performed at the 3rd day of COL+VAN+RIF therapy) and killing studies, which showed a high and early bactericidal activity for all the tested combinations. Interestingly, COL+VAN was more rapid in reducing the bacterial load than COL+RIF, which has hitherto been considered a primary regimen against carbapenem-resistant A. baumannii (Durante-Mango-ni et al., 2013). The rationale of using COL+VAN or RIF is based on the cell-permeabilizing properties of COL, which might allow the other drug to reach its target at in-hibitory concentrations (Gordon et al., 2010; Vidaillac et al., 2012). Although preliminary in vitro data confirmed this effect even in the presence of COL resistance (Vid-aillac et al., 2012; O’Hara et al., 2013; Bae et al., 2016), the clinical experience is still limited. Thus, the favorable result of combined clinical and microbiological data in the present case might be of crucial importance for the treatment of severe infections caused by colistin-resis-tant A. baumannii.Given that both A. baumannii and MRSA were isolated from the patient’s bronchoalveolar lavage, we should consider that the use of VAN and RIF as part of triple therapy against A. baumannii might also have had a role in the containment of S. aureus infection.One of the major concerns regarding the combination COL+VAN resides in its potential nephrotoxicity. Al-though data are still controversial (Garnacho-Montero et al., 2013; Petrosillo et al., 2014), our case confirms the potential toxicity of this regimen and we were forced to reduce colistin dosages and to discontinuate VAN after 6 days of therapy. This latter aspect should be considered, especially if concomitant multiple nephrotoxic drugs are administered. If renal failure is a major concern, the combination COL+RIF is also highly effective, as con-firmed by the in vitro experiments showing a rapid and durable antibacterial killing.In conclusion, the results of our study suggest that COL, VAN and RIF used in different combinations might confer a therapeutic benefit in the treatment of severe infections caused by MDR A. baumannii, even in the presence of COL-resistant strains. Furthermore, we highlight the importance of performing in vitro synergy analyses, in order to guide treatment decisions and pre-dict the potential efficacy of the selected antimicrobial combination.ReferencesBae S., Kim M.C., Park S.J., Kim H.S., Sung H., et al. (2016). In Vitro Syn-ergistic Activity of Antimicrobial Agents in Combination against Clini-cal Isolates of Colistin-Resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 60, 6774-6779.Ceccarelli G., Oliva A., d’Ettorre G., D’Abramo A., Caresta E., et al. (2015). The role of vancomycin in addition with colistin and meropenem against colistin-sensitive multidrug resistant Acinetobacter baumannii causing severe infections in a Paediatric Intensive Care Unit. BMC In-fect Dis. 15, 393.CLSI 2012. M07-A9. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard: ninth edition In. Wayne, PA: Clinical and Laboratory Standards Institute.Durante-Mangoni E., Signoriello G., Andini R., Mattei A., De Cristoforo M., et al. (2013). Colistin and rifampicin compared with colistin alone for the treatment of serious infections due to extensively drug-resistant Acinetobacter baumannii: a multicenter, randomized clinical trial. Clin Infect Dis. 57, 349-358.Figure 1 - Killing studies eval-uating the activity of COL, VAN and RIF, alone and in combina-tion at different concentrations, against a colistin- and carbap-enem-resistant A. baumannii. COL: colistin; VAN: vancomy-cin; RIF: rifampin; GC: growth control. Dashed line represents bactericidal activity that oc-curred at any time point com-pared to the initial bacterial in-oculum.Colistin+vancomycin against colistin-resistant A. baumannii 207Garnacho-Montero J., Amaya-Villar R., Gutiérrez-Pizarraya A., Espe-jo-Gutiérrez de Tena E., Artero-González M.L., et al. (2013). Clinical efficacy and safety of the combination of colistin plus vancomycin for the treatment of severe infections caused by carbapenem-resistant Acinetobacter baumannii. Chemotherapy. 59, 225-231.Gordon N.C., Png K., Wareham D.W. (2010). Potent synergy and sustained bactericidal activity of a vancomycin-colistin combination versus mul-tidrug-resistant strains of Acinetobacter baumannii. Antimicrob Agents Chemother. 54, 5316-5322.Leite G.C., Oliveira M.S., Perdigão-Neto L.V., Dias Rocha C.K., Guimarães T., et al. (2016). Antimicrobial Combinations against Pan- Resistant Acinetobacter baumannii Isolates with Different Resistance Mecha-nisms. PloS One. doi:10.1371/journal.pone.0151270.Maragakis L.L., Perl T.M. (2008). Acinetobacter baumannii: epidemiology, antimicrobial resistance, and treatment options. Clin Infect Dis. 46, 1254-1263.Motaouakkil S., Charra B., Hachimi A., Nejmi H., Benslama A., et al. (2006). Colistin and rifampicin in the treatment of nosocomial infections from multiresistant Acinetobacter baumannii. J Infect. 53, 274-278.O’Hara J.A., Ambe L.A., Casella L.G., Townsend B.M., Pelletier M.R., et al. (2013). Activities of vancomycin-containing regimens against colistin-resistant Acinetobacter baumannii clinical strains. Antimicrob Agents Chemother. 57, 2103-2108.Orsi G.B., Falcone M., Venditti M. (2011). Surveillance and management of multidrug-resistant microorganisms. Expert Rev Anti Infect Ther. 9, 653-679.Petrosillo N., Giannella M., Antonelli M., Antonini M., Barsic B., et al. (2014). Clinical experience of colistin-glycopeptide combination in critically ill patients infected with Gram-negative bacteria. Antimicrob Agents Chemother. 58, 851-858.Vidaillac C., Benichou L., Duval R.E. (2012). In vitro synergy of colistin combinations against colistin-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae isolates. Antimi-crob Agents Chemother. 56, 4856-4861.Powered by TCPDF (www.tcpdf.org)

Clinical and in vitro efficacy of colistin plus vancomycin and rifampin against colistin-resistant Acinetobacter baumannii causing ventilator-associated pneumonia

Archivio della ricerca- Università di Roma La Sapienza

SHORT COMMUNICATIONNew Microbiologica, 40, 3, 205-207, 2017, ISN 1121-7138Clinical and in vitro efficacy of colistin plus vancomycin and rifampin against colistin-resistant Acinetobacter baumannii causing ventilator-associated pneumoniaAlessandra Oliva, Alessia Cipolla, Vincenzo Vullo, Mario Venditti,  Claudio Maria Mastroianni, Marco FalconeDepartment of Public Health and Infectious Diseases, “Sapienza” University of Rome, ItalyA 77-year-old man was admitted to the Intensive Care Unit (ICU) for an acute subarachnoid hemorrhage. His recent medical history included a diagnosis of culture negative brain abscess treated with a combination ther-apy of linezolid and meropenem six weeks prior to ICU admission. The patient underwent neurosurgery and mechanical ventilation was started. During the early post-operative period the patient had an acute worsen-ing of respiratory gas exchanges, associated with leu-kocytosis. Chest radiography showed left pneumonia and tracheal aspirate was positive for Extended Spec-trum Beta Lactamases (ESBL)-producing E. coli. Thus, therapy with meropenem 1 g every 8 hours was started, with improvement of clinical conditions. However, af-ter 12 days after intubation the patient developed fever and hypotension with sudden worsening of respiratory gases and metabolic acidosis. A CT scan of the chest revealed bilateral multiple areas of consolidation of the lungs. Bronchoalveolar lavage culture was positive for colistin- (COL) and carbapenem-resistant Acinetobacter baumannii and methicillin-resistant S. aureus (MRSA). Meropenem was discontinuated and therapy with i.v. colistin 9.000.000 UI loading dose followed by 4.500.000 UI every 12 hours plus rifampin (RIF) 600 mg/day plus vancomycin (VAN) 1g loading dose followed by 2 g/day was initiated. Aerosolized COL (1.000.000 UI every 8 hours) was also administered. The clinical conditions of the patient improved. However, a significant increase Corresponding author:Alessandra OlivaE-mail: alessandra.oliva@uniroma1.it©2017 by EDIMES - Edizioni Internazionali Srl. All rights reservedin creatinine level was observed (up to 3 mg/dL), lead-ing to the reduction of COL dosages to 2.500.000 ev-ery 12 hours and discontinuation of VAN after 6 days of therapy. Serum bactericidal activity (SBA) performed at day 3 of therapy was 1:16 (pre-dose) and 1:64 (after dose). COL and RIF were stopped after 2 weeks of ther-apy, with resolution of the infection and progressive im-provement of renal function after 4 weeks. The patient was then transferred to a rehabilitation center 7 weeks after ICU admission. Considering its challenging antimicrobial susceptibility pattern, the clinical isolate was immediately submitted to additional in vitro analyses including synergy testing by both checkerboard method and killing tests.Minimal inhibitory concentrations (MICs) of COL, VAN and RIF were determined by broth macrodilution method (BMD) in cation-adjusted Mueller Hinton broth (CAM-HB) (CLSI, 2012). Furthermore, for COL MIC determina-tion a gradient strip test (E-test) was used. Synergy tests were performed throughout the checkerboard method at different concentrations of COL+RIF, COL+VAN and COL+RIF+VAN combinations. Complete synergism was defined as FIC-index (FICI) ≤0.5. The activity of COL, VAN and RIF, alone and in combination, was also inves-tigated by time-kill studies at a final inoculum of ~5x105 CFU/ml at the following concentrations: 1xMIC COL, 0.25xMIC VAN, 1xMIC RIF, 1xMIC COL+0.25xMIC VAN, 1xMIC COL+1xMIC RIF, 1xMIC COL+0.25xMIC VAN+ 1xMIC RIF. The VAN concentration used for killing stud-ies reflected the serum trough level achieved during ther-apy (16 mg/L). Bactericidal activity was defined as ≥3-log10 CFU/ml reduction of the initial bacterial count at each time point whereas synergistic activity was defined as a ≥100-fold decrease in CFU/mL between the combi-nation and its most active constituent at the same con-centration after 24 h. The detection limit was 10 CFU/mL. SBA was determined at 3th day of COL+VAN+RIF Key words:Acinetobacter baumannii, Multi-drug resistance, Colistin resistance,  Ventilator-associated pneumonia, Vancomycin, Rifampin.SUMMARYWe present the case of a patient with ventilator-associated pneumonia (VAP) caused by a pan-resistant Acinetobacter baumannii successfully treated with the combination colistin plus vancomycin plus rifamp-in, whose in vitro activity was investigated by checkerboard method and killing testing. Furthermore, the serum bactericidal activity (SBA) was assessed. Our case shows that an innovative regimen consisting of colistin plus antimicrobials active only against Gram-positive microorganisms might represent a valid therapeutic option for severe infections caused by colistin-resistant A. baumannii.Received February 16, 2017    Accepted March 26 2017A. Oliva, A. Cipolla, V. Vullo, et al.206therapy by collecting patient’s blood 30 min before and 2 h after therapy administration.Throughout MBD, MICs of COL, RIF and VAN were 4, 2 and 64 mg/L, respectively. By using E-test, COL MIC was 4 mg/L. A complete synergism was observed for COL+VAN and COL+RIF. At killing experiments, COL (1xMIC, 4 mg/L) and RIF (1xMIC, 2 mg/L) alone showed only a slight decrease of CFU/mL whereas VAN (0.25xMIC, 16 mg/L) alone did not have any effect on lowering the bacterial growth (Figure 1). On the oth-er hand, when the combinations COL+VAN, COL+RIF and COL+VAN+RIF were tested, a rapid bactericidal activity was observed after 2 h. All tested combinations showed an absence of growth at 6h, which was main-tained up to 24 h. In particular, absence of growth was observed at 6 h for COL+RIF combination whereas COL+VAN and COL+VAN+RIF yielded no bacteria at 4 h and 2 h, respectively. All the tested combinations were synergic at 24 h.Infections caused by A. baumannii are associated with a high mortality rate especially in the presence of multi-drug resistant (MDR) strains since therapeutic options are severely limited (Maragakis et al., 2008; Orsi et al., 2011). Colistin-based combinations have been consid-ered the milestone of the treatment of MDR A. bauman-ni (Motaouakkil et al., 2006; Durante-Mangoni et al., 2013) whereas unconventional regimens against carbap-enem-resistant A. baumannii include the combination of COL plus rifampin (RIF) or glycopeptides (Garna-cho-Montero et al., 2013; Petrosillo et al., 2014; Ceccarelli et al., 2015). However, the emergence of COL resistance represents a real challenge and nowadays insufficient data are available for the treatment of A. baumannii in-fections due to COL-resistant strains (Leite et al., 2016).In the present case, we demonstrated that a regimen con-sisting of COL plus antimicrobials active only against Gram-positive microorganisms might represent a val-id therapeutic option for severe infections caused by COL-resistant A. baumannii. The observed clinical effec-tiveness was confirmed by both SBA (performed at the 3rd day of COL+VAN+RIF therapy) and killing studies, which showed a high and early bactericidal activity for all the tested combinations. Interestingly, COL+VAN was more rapid in reducing the bacterial load than COL+RIF, which has hitherto been considered a primary regimen against carbapenem-resistant A. baumannii (Durante-Mango-ni et al., 2013). The rationale of using COL+VAN or RIF is based on the cell-permeabilizing properties of COL, which might allow the other drug to reach its target at in-hibitory concentrations (Gordon et al., 2010; Vidaillac et al., 2012). Although preliminary in vitro data confirmed this effect even in the presence of COL resistance (Vid-aillac et al., 2012; O’Hara et al., 2013; Bae et al., 2016), the clinical experience is still limited. Thus, the favorable result of combined clinical and microbiological data in the present case might be of crucial importance for the treatment of severe infections caused by colistin-resis-tant A. baumannii.Given that both A. baumannii and MRSA were isolated from the patient’s bronchoalveolar lavage, we should consider that the use of VAN and RIF as part of triple therapy against A. baumannii might also have had a role in the containment of S. aureus infection.One of the major concerns regarding the combination COL+VAN resides in its potential nephrotoxicity. Al-though data are still controversial (Garnacho-Montero et al., 2013; Petrosillo et al., 2014), our case confirms the potential toxicity of this regimen and we were forced to reduce colistin dosages and to discontinuate VAN after 6 days of therapy. This latter aspect should be considered, especially if concomitant multiple nephrotoxic drugs are administered. If renal failure is a major concern, the combination COL+RIF is also highly effective, as con-firmed by the in vitro experiments showing a rapid and durable antibacterial killing.In conclusion, the results of our study suggest that COL, VAN and RIF used in different combinations might confer a therapeutic benefit in the treatment of severe infections caused by MDR A. baumannii, even in the presence of COL-resistant strains. Furthermore, we highlight the importance of performing in vitro synergy analyses, in order to guide treatment decisions and pre-dict the potential efficacy of the selected antimicrobial combination.ReferencesBae S., Kim M.C., Park S.J., Kim H.S., Sung H., et al. (2016). In Vitro Syn-ergistic Activity of Antimicrobial Agents in Combination against Clini-cal Isolates of Colistin-Resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 60, 6774-6779.Ceccarelli G., Oliva A., d’Ettorre G., D’Abramo A., Caresta E., et al. (2015). The role of vancomycin in addition with colistin and meropenem against colistin-sensitive multidrug resistant Acinetobacter baumannii causing severe infections in a Paediatric Intensive Care Unit. BMC In-fect Dis. 15, 393.CLSI 2012. M07-A9. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard: ninth edition In. Wayne, PA: Clinical and Laboratory Standards Institute.Durante-Mangoni E., Signoriello G., Andini R., Mattei A., De Cristoforo M., et al. (2013). Colistin and rifampicin compared with colistin alone for the treatment of serious infections due to extensively drug-resistant Acinetobacter baumannii: a multicenter, randomized clinical trial. Clin Infect Dis. 57, 349-358.Figure 1 - Killing studies eval-uating the activity of COL, VAN and RIF, alone and in combina-tion at different concentrations, against a colistin- and carbap-enem-resistant A. baumannii. COL: colistin; VAN: vancomy-cin; RIF: rifampin; GC: growth control. Dashed line represents bactericidal activity that oc-curred at any time point com-pared to the initial bacterial in-oculum.Colistin+vancomycin against colistin-resistant A. baumannii 207Garnacho-Montero J., Amaya-Villar R., Gutiérrez-Pizarraya A., Espe-jo-Gutiérrez de Tena E., Artero-González M.L., et al. (2013). Clinical efficacy and safety of the combination of colistin plus vancomycin for the treatment of severe infections caused by carbapenem-resistant Acinetobacter baumannii. Chemotherapy. 59, 225-231.Gordon N.C., Png K., Wareham D.W. (2010). Potent synergy and sustained bactericidal activity of a vancomycin-colistin combination versus mul-tidrug-resistant strains of Acinetobacter baumannii. Antimicrob Agents Chemother. 54, 5316-5322.Leite G.C., Oliveira M.S., Perdigão-Neto L.V., Dias Rocha C.K., Guimarães T., et al. (2016). Antimicrobial Combinations against Pan- Resistant Acinetobacter baumannii Isolates with Different Resistance Mecha-nisms. PloS One. doi:10.1371/journal.pone.0151270.Maragakis L.L., Perl T.M. (2008). Acinetobacter baumannii: epidemiology, antimicrobial resistance, and treatment options. Clin Infect Dis. 46, 1254-1263.Motaouakkil S., Charra B., Hachimi A., Nejmi H., Benslama A., et al. (2006). Colistin and rifampicin in the treatment of nosocomial infections from multiresistant Acinetobacter baumannii. J Infect. 53, 274-278.O’Hara J.A., Ambe L.A., Casella L.G., Townsend B.M., Pelletier M.R., et al. (2013). Activities of vancomycin-containing regimens against colistin-resistant Acinetobacter baumannii clinical strains. Antimicrob Agents Chemother. 57, 2103-2108.Orsi G.B., Falcone M., Venditti M. (2011). Surveillance and management of multidrug-resistant microorganisms. Expert Rev Anti Infect Ther. 9, 653-679.Petrosillo N., Giannella M., Antonelli M., Antonini M., Barsic B., et al. (2014). Clinical experience of colistin-glycopeptide combination in critically ill patients infected with Gram-negative bacteria. Antimicrob Agents Chemother. 58, 851-858.Vidaillac C., Benichou L., Duval R.E. (2012). In vitro synergy of colistin combinations against colistin-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae isolates. Antimi-crob Agents Chemother. 56, 4856-4861.

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Clinical and in vitro efficacy of colistin plus vancomycin and rifampin against colistin-resistant Acinetobacter baumannii causing ventilator-associated pneumonia

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