Activity Of Colistin In Combination Research Articles

Synergistic Activity of Colistin in Combination with Clofoctol against Colistin Resistant Gram-Negative Pathogens.

Colistin is a bactericidal antibiotic identified decades ago which is active against a number of Gram-negative pathogens. After early elimination from clinical use due to toxicity issues, colistin has been reintroduced as a last-resort treatment for antibiotic-resistant Gram-negative infections lacking other therapeutic options. Inevitably, colistin resistance has emerged among clinical isolates, making the development of colistin adjuvants extremely beneficial. Clofoctol is a synthetic antibiotic active against Gram-positive bacteria, with low toxicity and high tropism for the airways. Interestingly, clofoctol has been found to have multiple biological activities and has been proposed for the treatment of several obstructive lung diseases, including asthma, lung cancer, and SARS-CoV-2 infection. In this study, the activity of clofoctol as a colistin adjuvant was investigated in Gram-negative lung pathogens that are critical for the high prevalence of multidrug-resistant isolates, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. Clofoctol potentiated the bactericidal effect of colistin in all tested strains and reduced colistin MICs below the susceptibility breakpoint in nearly all colistin-resistant strains. Overall, this observation supports the development of inhaled clofoctol-colistin formulations for the treatment of difficult-to-treat airway infections caused by Gram-negative pathogens. IMPORTANCE Colistin is used as a last-resort antibiotic against extensively drug-resistant Gram-negative pathogens. However, colistin resistance is on the rise. Clofoctol is an antibiotic used against Gram-positive bacteria, with low toxicity and high penetration and storage in the airways. Here, a strong synergistic activity of the colistin-clofoctol combination against colistin-resistant Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii isolates is reported, supporting the development of clofoctol-colistin formulations for the therapy of difficult-to-treat airways infections caused by these Gram-negative pathogens.

Synergistic Activity of Colistin Combined With Auranofin Against Colistin-Resistant Gram-Negative Bacteria.

Colistin-resistant (Col-R) bacteria are steadily increasing, and are extremely difficult to treat. New drugs or therapies are urgently needed to treat infections caused by these pathogens. Combination therapy with colistin and other old drugs, is an important way to restore the activity of colistin. This study aimed to investigate the activity of colistin in combination with the anti-rheumatic drug auranofin against Col-R Gram-negative bacteria. The results of checkerboard analysis demonstrated that auranofin synergized with colistin against Col-R Gram-negative bacteria. Time-kill assays showed significant synergistic antimicrobial activity of colistin combined with auranofin. Electron microscopy revealed that the combination resulted in more cellular structural alterations compared to each drug alone. Auranofin enhanced the therapeutic effectiveness of colistin in mouse peritoneal infection models. These results suggested that the combination of colistin and auranofin might be a potential alternative for the treatment of Col-R Gram-negative bacterial infections.

Synergistic combination of colistin with imipenem, amikacine or ciprofloxacin against Acinetobacter baumannii and Pseudomonas aeruginosa carbapenem-resistant isolated in Annaba hospital Algeria

Objective: The aim of this study is to detect in vitro the synergetic activity of colistin in combination with imipenem, amikacin or ciprofloxacin, at sub-inhibitory concentrations, against carbapenems-resistant (CR) Acinetobacter baumannii and Pseudomonas aeruginosa strains isolated from various wards in Annaba teaching hospital in eastern Algeria. Materials and Methods: The minimal inhibitory concentrations (MIC) were determined by broth macrodilution (BMD). Carbapenemase encoding genes were screened using polymerase chain reaction (PCR). The activity of colistin in combination with second antibiotic was evaluated by the Checkerboard Technique. Results: 39 CR P. aeruginosa and 21 CR A. baumanni strains where collected. The MIC values ranging from (0.25 to 4 µg/ml) to colistin, ≥16 µg/ml for imipenem, ≥4 µg/ml to amikacin and ≥8 µg/ml ciprofloxacin. The PCR reveals the presence of the genes blaOXA23 (n = 12), blaOXA24 (n = 6), blaNDM1 (n = 3) in A. baumannii and blaVIM2 (n = 12) in P. aeruginosa. The combination of colistin with imipenem showed synergistic effect on 57.14% and 46.15% of A. baumannii and P. aeruginosa isolates, respectively. For colistin and amikacin, the synergistic effect is detected in 28.6% of A. baumannii and 30.8% of P. aeruginosa. While colistin and ciprofloxacin showed synergy on 14.29% and 15.38% of A. baumannii and P. aeruginosa isolates, respectively. Conclusion: CR A. baumannii and P. aeruginosa remain the most prevalent infection agents in patients from high-risk wards at Annaba Hospital. Colistin associated with imipenem or with amikacin at sub-inhibitory concentrations gives very encouraging results allowing better management of infections caused by this type of bacteria.

Synergistic Activities of Colistin with Tigecycline Combination Against Clinical Isolates of Carbapenem-resistant Acinetobacter baumannii

OBJECTIVES: To determine in vitro antimicrobial susceptibility and synergistic activity of colistin in combination with tigecycline against clinical strains of carbapenem- resistant Acinetobacter baumannii (CRAB).MATERIAL AND METHODS: Colistin and tigecycline minimum inhibitory concentrations (MICs) of 12-clinical CRAB isolates were determined by broth microdilution. Checkerboard testing was performed to assess the interaction of the colistin-tigecycline combination. Fractional inhibitory concentration indexes (ΣFIC) in the range of 0.5 to 1.0, > 1.0 to < 4.0 and ≥ 4.0 are considered as additive, indifferent, and antagonistic effects, respectively.RESULTS: All CRAB isolates were susceptible to colistin. Three out of 12 CRABs were susceptible to tigecycline based on a pharmacokinetic-pharmacodynamics (PK-PD) breakpoint (MICs ≤ 0.25 μg/mL). The MIC of both antimicrobials was decreased in most of the CRAB isolates in the checkerboard synergy testing. The interaction of colistin and tigecycline combination revealed both additive and indifferent effects in five and seven of the 12-CRAB isolates, respectively. Neither synergism nor antagonism of colistin and tigecycline combination was demonstrated.CONCLUSION: No synergistic effect between colistin and tigecycline against CRAB isolates was detected. However, the combination of these two drugs is likely to result in a decrease in the MIC of both drugs. Further studies with a larger sample to determine the in vitro synergistic activity of colistin and tigecycline combination are required.

Synergistic Activities of Colistin with Tigecycline Combination Against Clinical Isolates of Carbapenemresistant Acinetobacter baumannii

OBJECTIVES: To determine in vitro antimicrobial susceptibility and synergistic activity of colistin in combination with tigecycline against clinical strains of carbapenem- resistant Acinetobacter baumannii (CRAB). MATERIAL AND METHODS: Colistin and tigecycline minimum inhibitory concentrations (MICs) of 12-clinical CRAB isolates were determined by broth microdilution. Checkerboard testing was performed to assess the interaction of the colistin-tigecycline combination. Fractional inhibitory concentration indexes (ΣFIC) in the range of 0.5 to 1.0, > 1.0 to < 4.0 and ≥ 4.0 are considered as additive, indifferent, and antagonistic effects, respectively. RESULTS: All CRAB isolates were susceptible to colistin. Three out of 12 CRABs were susceptible to tigecycline based on a pharmacokinetic-pharmacodynamics (PK-PD) breakpoint (MICs ≤ 0.25 μg/mL). The MIC of both antimicrobials was decreased in most of the CRAB isolates in the checkerboard synergy testing. The interaction of colistin and tigecycline combination revealed both additive and indifferent effects in five and seven of the 12-CRAB isolates, respectively. Neither synergism nor antagonism of colistin and tigecycline combination was demonstrated. CONCLUSION: No synergistic effect between colistin and tigecycline against CRAB isolates was detected. However, the combination of these two drugs is likely to result in a decrease in the MIC of both drugs. Further studies with a larger sample to determine the in vitro synergistic activity of colistin and tigecycline combination are required. Keywords: in vitro, synergism, tigecycline, colistin, checkerboard method DOI: 10.31524/bkkmedj.2019.02.005

In vitro activity of colistin in combination with various antimicrobials against Acinetobacter baumannii species, a report from South Iran.

IntroductionAcinetobacter baumannii is a gram-negative,opportunistic pathogen responsible for resistant nosocomial infections especially in the intensive care units (ICUS).One reason for the failure in the treatment of A. baumannii is its ability of develop resistance against several antimicrobials. combination of different antimicrobials can be used to overcome such a resistance. This study was done to evaluate the in vitro synergistic activity of colistin in combination with six different antimicrobials, including ciprofloxacin, levofloxacin, imipenem, meropenem, ampicillin-sulbactam, and rifampin against A. baumannii species isolated from blood culture of patients admitted to ICUs of Nemazee hospital, Shiraz, Iran.MethodAfter performing biochemical identification assays on 20 isolates of A. baumannii, minimum inhibitory concentrations were determined by E- test method and antibiotic interactions were assessed using broth microdilution checkerboard method.ResultsCombinations of colistin with all six studied antimicrobials had some synergistic effect.Conclusionclinical studies are required to clarify the therapeutic potential of these antimicrobial combinations

Synergistic Antimicrobial Activity of Colistin in Combination with Rifampin and Azithromycin against Escherichia coli Producing MCR-1.

The lack of available antibiotics is a global public health problem due to the emergence of antimicrobial resistance. Effective therapeutic regimens are urgently needed against Escherichia coli strains that produce the colistin resistance gene mcr-1 and to inhibit the emergence of resistance. In this study, we assessed the antimicrobial activity of a series of concentrations of colistin-based combinations with rifampin and/or azithromycin against three strains of Escherichia coli, including colistin-resistant isolate MZ1501R, isolate HE1704R that produces MCR-1, and colistin-susceptible isolate MZ1509S Experiments were conducted with a medium inoculum of ∼107 CFU/ml over 48 h. Subsequently, the in vivo therapeutic effect was investigated using a neutropenic mouse thigh infection model. Almost all monotherapies showed unsatisfactory antibacterial activity against E. coli isolates producing MCR-1. In contrast, colistin in combination with rifampin or azithromycin resulted in an obvious decrease in the bacterial burden albeit with regrowth. More obviously, synergistic antimicrobial activity of colistin-based triple-combination therapy with rifampin and azithromycin was observed, resulting in a rapid and exhaustive antibacterial effect. In vivo treatments confirmed these findings, where mean decreases of 0.38 to 0.90 log10 CFU and 1.27 to 1.78 log10 CFU were noted after 24 h and 48 h of treatment, respectively, against colistin-resistant E. coli strains when 5 mg/kg of body weight of colistin was combined with rifampin and azithromycin. Colistin-based combinations with rifampin and azithromycin provide a more active therapeutic regimen than monotherapy or colistin-based double combinations against E. coli producing MCR-1.

Synergistic Activity of Colistin-Containing Combinations against Colistin-Resistant Enterobacteriaceae.

Resistance to colistin, a polypeptide drug used as an agent of last resort for the treatment of infections caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria, including carbapenem-resistant Enterobacteriaceae (CRE), severely limits treatment options and may even transform an XDR organism into one that is pan-resistant. We investigated the synergistic activity of colistin in combination with 19 antibiotics against a collection of 20 colistin-resistant Enterobacteriaceae isolates, 15 of which were also CRE. All combinations were tested against all strains using an inkjet printer-assisted digital dispensing checkerboard array, and the activities of those that demonstrated synergy by this method were evaluated against a single isolate in a time-kill synergy study. Eighteen of 19 combinations demonstrated synergy against two or more isolates, and the 4 most highly synergistic combinations (colistin combined with linezolid, rifampin, azithromycin, and fusidic acid) were synergistic against ≥90% of strains. Sixteen of 18 combinations (88.9%) that were synergistic in the checkerboard array were also synergistic in a time-kill study. Our findings demonstrate that colistin in combination with a range of antibiotics, particularly protein and RNA synthesis inhibitors, exhibits synergy against colistin-resistant strains, suggesting that colistin may exert a subinhibitory permeabilizing effect on the Gram-negative bacterial outer membrane even in isolates that are resistant to it. These findings suggest that colistin combination therapy may have promise as a treatment approach for patients infected with colistin-resistant XDR Gram-negative pathogens.

Synergistic Activity of Colistin in Combination With Resveratrol Against Colistin-Resistant Gram-Negative Pathogens.

Objectives: In this study, we investigated the antimicrobial activity of resveratrol in combination with colistin, a last-resort agent for the treatment of severe infections caused by multidrug resistant Gram-negative pathogens.Methods: The synergistic activity and the bactericidal activity of colistin in combination with resveratrol was investigated by checkerboard assays and time-kill assays, respectively. A total of 21 strains were investigated, including 16 strains of different species (Klebsiella pneumoniae, n = 6, Escherichia coli, n = 6; Citrobacter braakii, n = 1; Stenotrophomonas malthophilia, n = 1; Enterobacter cloaceae, n = 1; Acinetobacter baumannii, n = 1) with acquired colistin resistance, three colistin-susceptible K. pneumoniae precursors, and two strains of intrinsically colistin-resistant species (Serratia marcescens, n = 1; Proteus mirabilis, n = 1). Mechanisms of acquired colistin resistance included chromosomal mutations (i.e., mgrB, pmrAB) and plasmid genes (mcr-1, mcr-1.2).Results: Resveratrol did not show any significant intrinsic antimicrobial activity. Overall, a relevant synergistic antimicrobial activity of resveratrol in combination with colistin was observed with all tested strains, except for the three colistin-susceptible K. pneumoniae strains, and for two mcr-1-positive E. coli strains. In time-kill assays, performed with 15 selected strains, the combination of colistin 2 mg/L plus resveratrol 128 mg/L was bactericidal with 11 strains, and bacteriostatic for the remaining ones.Conclusions: Resveratrol was found to potentiate colistin activity against a wide panel of colistin-resistant strains, regardless of species and resistance mechanisms, which would deserve further investigation for potential clinical applications.

P085 Synergistic activity of colistin in combination with N-acetylcysteine against colistin-resistant Acinetobacter baumannii grown in biofilms

P085 Synergistic activity of colistin in combination with N-acetylcysteine against colistin-resistant Acinetobacter baumannii grown in biofilms

Colistin-daptomycin, colistin-linezolid, colistin-vancomycin combination effects on colistin in multi-resistant acinetobacter baumannii strains

Objective : The most important problem in the treatment of nosocomial Acinetobacter baumannii (A. baumannii) infections which is increasingly seen in recent years is that almost all strains are resistant to many antibiotics, including carbapenems, and that the extinction of antibiotic options to be used in treatment. This leads the clinicians to new treatment options and suggests the use of combined antibiotics to achieve success in both the treatment of multi-drug-resistant A. baumannii (MDRAB) infections as well as to prevent resistance development. We investigated the in vitro activity of colistin in combination with vancomycin, linezolid or daptomycin against MDRAB to determine whether these combinations would be considered for clinical use. . Methods: The fractional inhibitory concentration (FIC) index was used to determine the antibiotic combination effects and to evaluate the effect of antibiotic combinations on the bacteria. Results: MIC values of colistin/vancomycin, colistin/linezolid, and colistin/daptomycin in 10 strains (33.3%) gave similar results. Twenty strains gave different MIC results according to antibiotics. The colistin/daptomycin antagonistic ratio was high when the colistin/vancomycin synergy ratio was high compared to the others. Conclusion: Antibiotic combinations can be used as an alternative treatment approach in multi-drug resistant A. baumannii infections.

New therapy from old drugs: synergistic bactericidal activity of sulfadiazine with colistin against colistin-resistant bacteria, including plasmid-mediated colistin-resistant mcr-1 isolates

The recent emergence of colistin (COL) resistance, particularly mcr-1 plasmid-mediated COL resistance in Gram-negative bacteria, has led to renewed interest in antibiotic combinations to overcome clinical therapeutic impasses. The aim of this study was to evaluate the potential of the synergistic and bactericidal activity of COL in combination with sulphonamide compounds, including sulfadiazine (SDI), sulfamethoxazole (SMX) and trimethoprim/sulfamethoxazole (SXT), as well as trimethoprim (TMP) against clinical COL-resistant bacterial strains, including strains with the plasmid-encoded mcr-1 gene. A collection of 55 COL-resistant and -susceptible strains from different origins (Laos, Thailand and France) was used in this study. Several in vitro methods were used to determine the potential of the synergistic activity of these combinations, including Etest on agar pre-treated plates, the Etest cross method and the chequerboard assay. A time–kill assay was performed to evaluate the potential bactericidal activity of combinations in addition to synergistic activity. Significant synergistic activity was observed with all combinations tested. The combination of COL + SDI presented the highest synergistic effect against the various species of COL-resistant strains (92.7%). For the other combinations, a synergistic effect was also observed but with lower frequency for COL + SMX (33.3%), COL + TMP (47.3%) and COL + SXT (31.5%). Synergy was observed independently of the COL resistance mechanism. These in vitro results suggest that the combination of COL + SDI would appear to be justifiable in patients with multidrug-resistant bacterial infections that cannot be treated with COL monotherapy.

Increased activity of colistin in combination with amikacin against Escherichia coli co-producing NDM-5 and MCR-1.

Colistin and carbapenem are two lines of last-resort antibiotics against lethal infections caused by MDR Gram-negative pathogens. The emergence of carbapenemase-positive Escherichia coli with colistin resistance poses a serious threat to public health worldwide. Here we report, for the first time (to the best of our knowledge), a novel combination therapy used for the treatment of E. coli co-producing MCR-1 and NDM-5. The MICs of colistin were determined alone and with 1-4 mg/L amikacin. A 7-by-4 time-kill array of colistin (0, 0.5, 1, 2, 4, 8 and 16 mg/L) and amikacin (0, 1, 2 and 4 mg/L) over 48 h was designed to characterize the in vitro activity of these agents alone and in combination against each E. coli isolate at an inoculum of 10 6 and 10 8 cfu/mL. The sigmoid E max model was utilized for better delineation of the concentration-effect relationship of each combination. In vivo effectiveness was investigated using a mouse model (combination therapy with intraperitoneal colistin plus amikacin compared with monotherapy). For colistin-resistant isolates, the addition of amikacin demonstrated augmented susceptibility, reducing colistin MICs below the current susceptibility breakpoint. A concentration-dependent decrease in the EC 50 values of colistin was observed for all study isolates in the presence of increasing amikacin concentrations. Further in vivo treatment experiments demonstrated that this combination could achieve 1.5-2.8log 10 killing after 24 h of therapy, while monotherapy was unable to achieve such a killing effect. The combination of colistin and amikacin may be a promising therapeutic option for the treatment of lethal infections caused by NDM-5-bearing MCR-1-positive superbugs.

Activity of Colistin in Combination with Meropenem, Tigecycline, Fosfomycin, Fusidic Acid, Rifampin or Sulbactam against Extensively Drug-Resistant Acinetobacter baumannii in a Murine Thigh-Infection Model.

Few effective therapeutic options are available for treating severe infections caused by extensively drug-resistant Acinetobacter baumannii (XDR-AB). Using a murine thigh-infection model, we examined the in vivo efficacy of colistin in combination with meropenem, tigecycline, fosfomycin, fusidic acid, rifampin, or sulbactam against 12 XDR-AB strains. Colistin, tigecycline, rifampin, and sulbactam monotherapy significantly decreased bacterial counts in murine thigh infections compared with those observed in control mice receiving no treatment. Colistin was the most effective agent tested, displaying bactericidal activity against 91.7% of strains at 48 h post-treatment. With strains showing a relatively low minimum inhibitory concentration (MIC) for meropenem (MIC ≤ 32 mg/L), combination therapy with colistin plus meropenem caused synergistic inhibition at both 24 h and 48 h post-treatment. However, when the meropenem MIC was ≥64 mg/L, meropenem did not significantly alter the efficacy of colistin. The addition of rifampin and fusidic acid significantly improved the efficacy of colistin, showing a synergistic effect in 100% and 58.3% of strains after 24 h of treatment, respectively, while the addition of tigecycline, fosfomycin, or sulbactam did not show obvious synergistic activity. No clear differences in activities were observed between colistin-rifampin and colistin-fusidic acid combination therapy with most strains. Overall, our in vivo study showed that administering colistin in combination with rifampin or fusidic acid is more efficacious in treating XDR-AB infections than other combinations. The colistin-meropenem combination may be another appropriate option if the MIC is ≤32 mg/L. Further clinical studies are urgently needed to confirm the relevance of these findings.

In vitro activities of colistin combined with imipenem, tigecycline or cefoperazone-sulbactam against multidrug-resistant Acinetobacter baumannii blood-stream isolates

Acinetobacter baumannii has emerged as one of the most important nosocomial pathogens and multi-drug resistant (MDR) isolates are of great concern worldwide. The aim of the present study was to investigate the in vitro synergistic activity of colistin in combination with other antibiotics against MDR A. baumannii blood stream isolates. A total of 54 non-duplicate, MDR A. baumannii isolates from blood culture specimens obtained between June 2011 and July 2012 were included in the study. In vitro synergistic activity of colistin in combination with imipenem, tigecycline or cefoperazone-sulbactam against study isolates was investigated by Etest superimposing method and the fractional inhibitory concentration (FIC) index was calculated for each antibiotic combination. The most frequent synergistic effect of colistin was found in combination with tigecycline in only 7 isolates (13.0%). All three antibiotics were found to have synergistic effect with colistin in four isolates (7.4%). Of isolates, 46 (85.2%) showed additive effect of colistin in combination with cefoperazone-sulbactam or tigecycline, 45 (83.3%) with imipenem. We found synergistic activity of colistin with other study antibiotics in only a small number of isolates. Although Etest method is a practical method to investigate the synergistic activity, in case of choosing empirical treatment, colistin in combination with another antibiotic may be preferred.

In vitro Activity of Colistin in Combination with Tigecycline against Carbapenem-Resistant Acinetobacter baumannii Strains Isolated from Patients with Ventilator-Associated Pneumonia

Objective: This study investigated the minimum inhibitory concentration (MIC) values and in vitro activity of colistin in combination with tigecycline against carbapenem-resistant Acinetobacter baumannii strains isolated from patients with ventilator-associated pneumonia (VAP) using the E-test method.Methods: A total of 40 A. baumannii strains, identified using the Phoenix Automated Microbiology System (Becton, Dickinson and Co., Franklin Lakes, NJ, USA) by conventional methods, were included in this study. Pulsed-field gel electrophoresis was performed to examine the clonal relationships between isolates. The carbapenem resistance of the strains to colistin and tigecycline was assessed using the E-test method (Liofilchem, Roseto Degli Abruzzi, Italy). The in vitro activity of colistin in combination with tigecycline was evaluated using the fractional inhibitor concentration (FIC) index.Results: While only 1 of 40 A. baumannii strains was determined to be colistin resistant, 6 were tigecycline resistant. The MIC50, MIC90, and MIC intervals of the A. baumannii strains were 0.19, 1.5, and 0.064‒4 μg/ml for colistin and 1, 8, and 0.094‒256 μg/ml for tigecycline, respectively. No synergistic effect was observed using the FIC index; 8 strains exhibited an indifferent effect and 32 exhibited an antagonist effect. Three of the six strains that were resistant to tigecycline were indifferent; the remaining three were antagonistic. The colistin-resistant strain also exhibited an antagonist effect.Conclusion: In contrast to their synergistic effect against carbapenem-resistant A. baumannii isolates, colistin and tigecycline were highly antagonistic to carbapenem-resistant A. baumannii strains isolated from patients with VAP when the drugs were administered together. Therefore, alternative treatment options should be used during the treatment of VAP attributed to A. baumannii.

In vitro synergism of combinations of colistin with selected antibiotics against colistin-resistant Acinetobacter baumannii.

Aim: The in vitro activity of colistin in combination with sulbactam, netilmicin, and vancomycin against colistin-resistant A. baumannii strains was investigated. Furthermore, the clonal relationship of the strains was analyzed. Methods: Clonal relationship was investigated using rep-PCR. To screen for synergysm, the fractional inhibitory concentration index (FICI) was calculated using checkerboard assay. The killing kinetics of the combination of colistin with vancomycin was assessed using time-kill assay. Results: Three different clones were found among 10 clinical isolates of colistin-resistant A. baumannii strains. Thereof, 8 strains were susceptible to netilmicin. Synergistic interaction was detected in 1 strain with the combination of colistin-netilmicin, in 5 strains with colistin-sulbactam, and in 9 strains with colistin-vancomycin. None of combinations had antagonistic activity. Colistin-vancomycin combination resulted in rapid bactericidal activity. Conclusion: These results show a distinct in vitro synergism between colistin and vancomycin, which might be useful to treat infection with multiple-resistant strains, prevent emergence of resistant strains, and to lower doses for both antibiotics to be used.

Activity of colistin in combination with tigecycline or rifampicin against multidrug-resistant Stenotrophomonas maltophilia.

The antimicrobial treatment of Stenotrophomonas maltophilia infections is complicated by intrinsic multidrug resistance and a lack of reliable susceptibility data. We assessed the activity of colistin (COL), rifampicin (RIF) and tigecycline (TGC) alone and in combination using a range of in vitro susceptibility testing methodologies and a simple invertebrate model of S. maltophilia infection (Galleria mellonella). Synergy [fractional inhibitory concentration indices (FICIs) ≤0.5] between COL and either RIF or TGC was observed against 92 % and 88 % of 25 S. maltophilia isolates, respectively, despite resistance to one or another of the single agents alone. In time-kill assays, COL combined with either RIF or TGC was superior to single agents, but only the COL/RIF regimen was reliably bactericidal. The in vitro findings correlated with treatment outcomes in G. mellonella, with heightened survival observed for larvae treated with COL/RIF or COL/TGC compared with COL, RIF or TGC alone. COL combined with RIF was the most effective combination overall in both in vitro and in vivo (p < 0.05) assays. Given the difficulty in selecting appropriate therapy for S. maltophilia infections, regimens consisting of COL combined with RIF or TGC could be considered for clinical use.

In vitro activity of daptomycin in combination with low-dose colistin against a diverse collection of Gram-negative bacterial pathogens

The activity of colistin in combination with daptomycin was assessed using 30 Gram-negative type strains and multidrug-resistant isolates with defined mechanisms of resistance. Daptomycin minimum inhibitory concentrations (MICs) were determined with and without sub-inhibitory concentrations of colistin. The activity of daptomycin was not affected with respect to Escherichia coli, Klebsiella pneumoniae or Pseudomonas aeruginosa. For colistin-susceptible Acinetobacter baumannii, sensitisation factors ranged from 8 to 128 (median 32), with the daptomycin MIC being reduced to the Clinical and Laboratory Standards Institute (CLSI) enterococci susceptibility breakpoint of 4μg/ml for the ATCC 19606 type strain. A combination of daptomycin and colistin may be useful for the treatment of A. baumannii but not infections due to other Gram-negative species.

In vitro antimicrobial activity of colistin in combination with rifampicin against carbapenem-resistant Acinetobacter baumannii

Objectives: The aim of this study was to determine the antimicrobial activities of the combination between colistin and rifampicin against carbapenem-resistant Acinetobacter baumannii. Methods: Thirty carbapenem-resistant A. baumannii isolates from Bamrasnaradura Infectious Disease Hospital between April 2007 and May 2009 were included in this study. Antimicrobial susceptibility tests were performed by both Kirby-Bauer disk diffusion and Agar dilution methods. Synergy effect of the combination of colistin and rifampicin was determined by checkerboard method. In addition, the time-kill study was used to determine the bactericidal activity at 0.5 × MIC and 1 × MIC of either colistin or rifampicin alone and the combination of both agents. Morphological cell changes of the bacteria grown in the media plus antimicrobials were observed by scanning electron microscopy. Results: Susceptibility testing of 12 antimicrobial agents against carbapenem-resistant A. baumannii showed that all 30 isolates were resistant to meropenem, imipenem and rifampicin, while 96.7% of these isolates were resistant to cefepime, ceftazidime, piperacillin/tazobactam and ciprofloxacin. Ninety percent of tested isolates were resistant to amikacin, gentamicin, netilmicin and tobramycin, but 80% were still susceptible to colistin. The MIC ranges for colistin and rifampicin were 1-4 μg/ml and 8-16 μg/ml, respectively. MIC50 and MIC90 of colistin were 1, 2 μg/ml, respectively and MIC50 and MIC90 of rifampicin were 8 μg/ml. The synergy study showed the partial synergy effect of colistin when combined with rifampicin in 26.7% of the isolates. Bactericidal activity of the combination was observed at all incubation times by time-kill study. The more damaging effect of the bacterial cell lysis was clearly observed when the bacteria were grown in the combined antimicrobials as compared with the growth in each antimicrobial agent. 1Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand. 2Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand. 3Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand. Reprint request: Pintip Pongpech, Ph.D., Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand.