Combination Of Colistin Research Articles

Colistin: an update on the antibiotic of the 21st century

The emergence of multidrug-resistant Gram-negative bacteria that cause nosocomial infections is a growing problem worldwide. Colistin was first introduced in 1952 and was used until the early 1980s for the treatment of infections caused by Gram-negative bacilli. In vitro, colistin has demonstrated excellent activity against various Gram-negative rod-shaped bacteria, including multidrug-resistant Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. Recent clinical findings regarding colistin activity, pharmacokinetic properties, clinical uses, emerging resistance, toxicities and combination therapy have been reviewed. Recent approaches to the use of colistin in combination with other antibiotics hold promise for increased antibacterial efficacy. It is probable that colistin will be the ‘last-line’ therapeutic drug against multidrug-resistant Gram-negative pathogens in the 21st century.

The combination of colistin and doripenem is synergistic against Klebsiella pneumoniae at multiple inocula and suppresses colistin resistance in an in vitro pharmacokinetic/pharmacodynamic model.

Multidrug-resistant (MDR) Klebsiella pneumoniae may require combination therapy. We systematically investigated bacterial killing with colistin and doripenem mono- and combination therapy against MDR K. pneumoniae and emergence of colistin resistance. A one-compartment in vitro pharmacokinetic/pharmacodynamic model was employed over a 72-h period with two inocula (∼10(6) and ∼10(8) CFU/ml); a colistin-heteroresistant reference strain (ATCC 13883) and three clinical isolates (colistin-susceptible FADDI-KP032 [doripenem resistant], colistin-heteroresistant FADDI-KP033, and colistin-resistant FADDI-KP035) were included. Four combinations utilizing clinically achievable concentrations were investigated. Microbiological responses were examined by determining log changes and population analysis profiles (for emergence of colistin resistance) over 72 h. Against colistin-susceptible and -heteroresistant isolates, combinations of colistin (constant concentration regimens of 0.5 or 2 mg/liter) plus doripenem (steady-state peak concentration [C(max)] of 2.5 or 25 mg/liter over 8 h; half-life, 1.5 h) generally resulted in substantial improvements in bacterial killing at both inocula. Combinations were additive or synergistic against ATCC 13883, FADDI-KP032, and FADDI-KP033 in 9, 9, and 14 of 16 cases (4 combinations at 6, 24, 48, and 72 h) at the 10(6)-CFU/ml inoculum and 14, 11, and 12 of 16 cases at the 10(8)-CFU/ml inoculum, respectively. Combinations at the highest dosage regimens resulted in undetectable bacterial counts at 72 h in 5 of 8 cases (4 isolates at 2 inocula). Emergence of colistin-resistant subpopulations in colistin-susceptible and -heteroresistant isolates was virtually eliminated with combination therapy. Against the colistin-resistant isolate, colistin at 2 mg/liter plus doripenem (C(max), 25 mg/liter) at the low inoculum improved bacterial killing. This investigation provides important information for optimization of colistin-doripenem combinations.

In vitro synergy of colistin combinations against colistin-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae isolates.

Colistin resistance, although uncommon, is increasingly being reported among Gram-negative clinical pathogens, and an understanding of its impact on the activity of antimicrobials is now evolving. We evaluated the potential for synergy of colistin plus trimethoprim, trimethoprim-sulfamethoxazole (1/19 ratio), or vancomycin against 12 isolates of Acinetobacter baumannii (n = 4), Pseudomonas aeruginosa (n = 4), and Klebsiella pneumoniae (n = 4). The strains included six multidrug-resistant clinical isolates, K. pneumoniae ATCC 700603, A. baumannii ATCC 19606, P. aeruginosa ATCC 27853, and their colistin-resistant derivatives (KPm1, ABm1, and PAm1, respectively). Antimicrobial susceptibilities were assessed by broth microdilution and population analysis profiles. The potential for synergy of colistin combinations was evaluated using a checkerboard assay, as well as static time-kill experiments at 0.5× and 0.25× MIC. The MIC ranges of vancomycin, trimethoprim, and trimethoprim-sulfamethoxazole (1/19) were ≥128, 4 to ≥128, and 2/38 to >128/2,432 μg/ml, respectively. Colistin resistance demonstrated little impact on vancomycin, trimethoprim, or trimethoprim-sulfamethoxazole MIC values. Isolates with subpopulations heterogeneously resistant to colistin were observed to various degrees in all tested isolates. In time-kill assays, all tested combinations were synergistic against KPm1 at 0.25× MIC and 0.5× MIC and ABm1 and PAm1 at 0.5× MIC. In contrast, none of the tested combinations demonstrated synergy against any colistin-susceptible P. aeruginosa isolates and clinical strains of K. pneumoniae isolates. Only colistin plus trimethoprim or trimethoprim-sulfamethoxazole was synergistic and bactericidal at 0.5× MIC against K. pneumoniae ATCC 700603. Colistin resistance seems to promote the in vitro activity of unconventional colistin combinations. Additional experiments are warranted to understand the clinical significance of these observations.

Predictors of Mortality in Bloodstream Infections Caused by Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae: Importance of Combination Therapy

The spread of Klebsiella pneumoniae (Kp) strains that produce K. pneumoniae carbapenemases (KPCs) has become a significant problem, and treatment of infections caused by these pathogens is a major challenge for clinicians. In this multicenter retrospective cohort study, conducted in 3 large Italian teaching hospitals, we examined 125 patients with bloodstream infections (BSIs) caused by KPC-producing Kp isolates (KPC-Kp) diagnosed between 1 January 2010 and 30 June 2011. The outcome measured was death within 30 days of the first positive blood culture. Survivor and nonsurvivor subgroups were compared to identify predictors of mortality. The overall 30-day mortality rate was 41.6%. A significantly higher rate was observed among patients treated with monotherapy (54.3% vs 34.1% in those who received combined drug therapy; P = .02). In logistic regression analysis, 30-day mortality was independently associated with septic shock at BSI onset (odds ratio [OR]: 7.17; 95% confidence interval [CI]: 1.65-31.03; P = .008); inadequate initial antimicrobial therapy (OR: 4.17; 95% CI: 1.61-10.76; P = .003); and high APACHE III scores (OR: 1.04; 95% CI: 1.02-1.07; P < .001). Postantibiogram therapy with a combination of tigecycline, colistin, and meropenem was associated with lower mortality (OR: 0.11; 95% CI: .02-.69; P = .01). KPC-Kp BSIs are associated with high mortality. To improve survival, combined treatment with 2 or more drugs with in vitro activity against the isolate, especially those also including a carbapenem, may be more effective than active monotherapy.

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.

Effect of substitution of medium-chain organic acids for zinc bacitracin in a diet containing colistin on performance and development of intestinal lymphoid tissues in growing rabbits experimentally infected with Escherichia coli O103 and Clostridium perfringens toxinotype A

This work tested the effect of replacing zinc bacitracin with a blend of caproic and caprylic acids in a diet including colistin on growth performance, mortality, gut histology and development of intestinal lymphoid tissues in rabbits experimentally infected with Escherichia coli and Clostridium perfringens. Three experimental diets were formulated: a control non-medicated diet (diet C), diet C medicated with 150mg zinc bacitracin and 120mgcolistin/kg (diet B) and diet C supplemented with a 4-g mixture of the acids and 120mgcolistin/kg (diet A). Forty rabbits weaned at 28days of age and housed individually were assigned to each diet. At 35days of age, rabbits were orally infected with 109cfu of E. coli and 109cfu of C. perfringens. At 35 and 56days of age, five rabbits per diet and age were slaughtered to assess caecal traits, jejunal histology and follicular development in the caudal ileal Peyer's patch and the appendix. No significant differences were reported on growth performance. Mortality rate reached 60.0% for control rabbits whereas no mortality occurred in rabbits fed the supplemented diets. Caecal pH was not influenced by diet but was lower at 56 than at 35days (6.20 vs. 6.49, P<0.001). No differences were detected on villus height of control rabbits between 35 and 56days of age (average height of 597μm) but villi of rabbits fed diets B and A were, respectively, 19 and 34% (P<0.001) longer at 56days than at 35days. The average follicle area in the Peyer's patch (81,900μm2vs. 56,800μm2, P<0.001) and in the appendix (116,000μm2vs. 56,900μm2, P<0.001) increased after the infection. Besides, average follicle area of the Peyer's patch was influenced by diet (78,983μm2vs. 69,632μm2vs. 59,457μm2, P=0.011, for diets C, B and A, respectively). No significant effect of treatments was detected on the number of follicles of the appendix (37.2 follicles on average). To conclude, the substitution of caproic and caprylic acids for zinc bacitracin in a diet including colistin increased jejunal villus height and reduced follicle hypertrophy of the caudal ileal Peyer's patch in growing rabbits experimentally infected with C. perfringens A and E. coli O103. The dietary combination of colistin with both zinc bacitracin and the blend of esterified caproic and caprylic acids prevented the rise of fattening mortality, even after the infection. However, the effect of including medium-chain organic acids in a diet free of medication on challenged rabbit health is yet to be elucidated.

The Combination of Doripenem and Colistin Is Bactericidal and Synergistic against Colistin-Resistant, Carbapenemase-Producing Klebsiella pneumoniae

We tested two-drug combinations of doripenem, colistin, gentamicin, and doxycycline against 12 carbapenemase-producing Klebsiella pneumoniae (KPC) isolates by time-kill. The combination of doripenem and colistin reduced the starting inocula by 2 logs for each isolate (range, 2.02 to 6.01 log(10)) and was bactericidal and synergistic against 75 and 50%, respectively. Among colistin- and pan-drug-resistant isolates, synergy was identified in 60 and 67%, respectively. All other combinations were inferior. We are currently evaluating the combination of doripenem and colistin as a frontline therapy for KPC infection.

Bactericidal Activity of Multiple Combinations of Tigecycline and Colistin against NDM-1-Producing Enterobacteriaceae

The interaction between colistin and tigecycline against eight well-characterized NDM-1-producing Enterobacteriaceae strains was studied. Time-kill methodology was employed using a 4-by-4 exposure matrix with pharmacokinetically achievable free drug peak, trough, and average 24-h serum concentrations. Colistin sulfate and methanesulfonate alone showed good early bactericidal activity, often with subsequent regrowth. Tigecycline alone had poor activity. Addition of tigecycline to colistin does not produce increased bacterial killing; instead, it may cause antagonism at lower concentrations.

In vitro time-kill studies of antimicrobial agents against blood isolates of imipenem-resistant Acinetobacter baumannii, including colistin- or tigecycline-resistant isolates

The emergence of colistin or tigecycline resistance as well as imipenem resistance in Acinetobacter baumannii poses a great therapeutic challenge. The bactericidal and synergistic effects of several combinations of antimicrobial agents against imipenem-, colistin- or tigecycline-resistant A. baumannii isolates were investigated by in vitro time-kill experiments. Six imipenem-resistant A. baumannii blood isolates were examined in this study, including colistin- and tigecycline-susceptible, colistin-resistant but tigecycline-susceptible, and colistin-susceptible but tigecycline-resistant isolates. Time-kill studies were performed using five antimicrobial agents singly or in combinations (imipenem plus colistin, imipenem plus ampicillin-sulbactam, colistin plus rifampicin, colistin plus tigecycline, and tigecycline plus rifampicin) at concentrations of 0.5× and 1× their MICs. Only imipenem was consistently effective as a single agent against all six A. baumannii isolates. Although the effectiveness of combinations of 0.5× MIC antimicrobial agents was inconsistent, combination regimens using 1× MIC of the antimicrobial agents displayed excellent bactericidal activities against all six A. baumannii isolates. Among the combinations of 0.5× MIC antimicrobial agents, the combination of colistin and tigecycline showed synergistic or bactericidal effects against four of the isolates. This in vitro time-kill analysis suggests that antimicrobial combinations are effective for killing imipenem-resistant A. baumannii isolates, even if they are simultaneously resistant to either colistin or tigecycline. However, the finding that the combinations of 0.5× MIC antimicrobial agents were effective on only some isolates may warrant further investigation of the doses of combination agents needed to kill resistant A. baumannii.

Development of a modified selective medium to enhance the recovery rate of Brachyspira hyodysenteriae and other porcine intestinal spirochaetes from faeces

The aim of this study was to develop a modified selective medium to improve the recovery rate of Brachyspira hyodysenteriae and other clinically significant intestinal spirochaetes from porcine faeces. The susceptibility of five Brachyspira spp. type strains and five Thai field isolates of B. hyodysenteriae to the antimicrobials halquinol and flavomycin was determined by in vitro susceptibility tests in the agar dilution method, and optimal incorporation rates were confirmed by broth dilution. All the spirochaetes were susceptible to halquinol at ≤ 1 μg ml(-1), while 16 μg ml(-1) of flavomycin (F) allowed their growth, and therefore, only the latter was selected for further use. F and different combinations of colistin (C), spectinomycin (S) and rifampacin (R) were incorporated into pre-enrichment broths and/or agar plates, and growth of the spirochaetes from seeded faeces was determined. Two solid media were selected for further testing using faeces from 90 finishing pigs on 10 farms. A previously recommended method of pre-enrichment did not increase the recovery rate. The use of blood agar modified medium (BAM) containing F (16 μg ml(-1)), S (400 μg ml(-1)), R (30 μg ml(-1)) and colistin (C, 100 U ml(-1)) (assigning as BAM-CSRF) reduced the growth of contaminating intestinal microbiota and resulted in a significantly higher rate of spirochaete recovery than the previous recommended medium. BAM-CSRF is a useful new selective medium for the isolation of B. hyodysenteriae and other intestinal spirochaetes from pig faeces. The new selective medium for isolating B. hyodysenteriae and other Brachyspira spp. from pig faeces will improve their recovery and subsequent disease diagnosis.

In vitro activity of antibiotic combinations against multidrug-resistant strains of Acinetobacter baumannii and the effects of their antibiotic resistance determinants

Various combinations of antibiotics are reported to show synergy in treating nosocomial infections with multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii). Here, we studied hospital-acquired outbreak strains of MDR A. baumannii to evaluate optimal combinations of antibiotics. One hundred and twenty-one strains were grouped into one major and one minor clonal group based on repetitive PCR amplification. Twenty representative strains were tested for antibiotic synergy using Etest(®). Five strains were further analyzed by analytical isoelectric focusing and PCR to identify β-lactamase genes or other antibiotic resistance determinants. Our investigation showed that the outbreak strains of MDR A. baumannii belonged to two dominant clones. A combination of colistin and doxycycline showed the best result, being additive or synergistic against 70% of tested strains. Antibiotic additivity was observed more frequently than synergy. Strains possessing the same clonality did not necessarily demonstrate the same response to antibiotic combinations in vitro. We conclude that the effect of antibiotic combinations on our outbreak strains of MDR A. baumannii seemed strain-specific. The bacterial response to antibiotic combinations is probably a result of complex interactions between multiple concomitant antibiotic resistance determinants in each strain.

Clonal spread of multidrug-resistant Acinetobacter baumannii in eastern Taiwan

This study was conducted to investigate the molecular epidemiology and antimicrobial susceptibility of multidrug-resistant (MDR) Acinetobacter baumannii to three types of antibiotics. One hundred and thirty-four specimens of MDR A baumannii were collected from three branches (Taipei, Dalin, and Hualien branches) of Buddhist Tzu Chi Hospital, which are located in northern, southern, and eastern Taiwan, during 2007. Genotyping was performed by pulsed-field gel electrophoresis. Antibiotic susceptibilities to colistin, rifampicin, and tigecycline were determined. The synergistic effects of rifampin and colistin were also evaluated. Antibiotic susceptibility testing showed that 10.4%, 47.8% and 45.5% of the MDR A baumannii isolates are resistant to colistin, rifampicin, and tigecycline, respectively. A majority of the rifampicin-resistant isolates (62.7%) were found in the Haulien branch, whereas 62.2% of tigecycline-resistant isolates were found in the Taipei branch. The combination of colistin and rifampicin had a synergistic effect on all of the isolates. Genotyping by pulsed-field gel electrophoresis identified 17, 23, and 11 pulsotypes in the Taipei, Dalin, and Haulien branches, respectively. Furthermore, 74.5% of isolates in the Haulien branch were identified as one of three pulsotypes. Among 37 rifampicin-resistant and 22 tigecycline-resistant MDR A baumannii isolates found in the Haulien branch, 51.3% (19/37) and 50% (11/22) of the isolates belonged to the same clone, respectively. This study confirms the high prevalence of resistance to rifampicin and tigecycline in MDR A baumannii in the three hospitals that were studied, and the high proportion of identical strains that exist in eastern Taiwan.

Ascorbic acid protects against the nephrotoxicity and apoptosis caused by colistin and affects its pharmacokinetics

The use of colistin in the treatment of life-threatening Gram-negative infections is associated with a high rate of nephrotoxicity that is dose limiting. This study aimed to examine the nephroprotective effect of ascorbic acid against colistin-induced nephrotoxicity. Rats were treated intravenously twice daily with saline, colistin (cumulative dose of 36.5 mg/kg), a combination of ascorbic acid (50 or 200 mg/kg) and colistin, or ascorbic acid (200 mg/kg) over 7 days. Colistin-induced apoptosis was examined in rats over 5 days and in vitro using rat renal proximal tubular cells NRK-52E over 24 h with and without ascorbic acid. The effect of co-administered ascorbic acid on colistin pharmacokinetics was investigated. The 24 h urinary excretion of N-acetyl-β-D-glucosaminidase, a sensitive marker for tubular damage, was significantly lower (P < 0.0001) in the colistin/ascorbic acid 200 mg/kg group. Significant histological abnormalities (P < 0.01) were detected only in the kidneys of the colistin group, which also had the highest percentage (30.6 ± 7.8%) of apoptotic cells (P < 0.005). In the cell culture studies, the percentage of apoptotic cells was significantly higher in the presence of 0.1 mM colistin alone (51.8 ± 2.0%; P < 0.0001) than in the presence of ascorbic acid, which decreased the apoptotic effect in a concentration-dependent manner. Ascorbic acid (200 mg/kg) altered colistin pharmacokinetics, as the total body clearance decreased from 3.78 ± 0.36 mL/min/kg (colistin group) to 2.46 ± 0.57 mL/min/kg (P = 0.0024). This is the first study demonstrating the protective effect of ascorbic acid against colistin-induced nephrotoxicity and tubular apoptosis. Co-administration of ascorbic acid has the potential to increase the therapeutic index of colistin.

Synergistic Killing of Multidrug-Resistant Pseudomonas aeruginosa at Multiple Inocula by Colistin Combined with Doripenem in an In Vitro Pharmacokinetic/Pharmacodynamic Model

Combination therapy may be required for multidrug-resistant (MDR) Pseudomonas aeruginosa. The aim of this study was to systematically investigate bacterial killing and emergence of colistin resistance with colistin and doripenem combinations against MDR P. aeruginosa. Studies were conducted in a one-compartment in vitro pharmacokinetic/pharmacodynamic model for 96 h at two inocula (~10(6) and ~10(8) CFU/ml) against a colistin-heteroresistant reference strain (ATCC 27853) and a colistin-resistant MDR clinical isolate (19147 n/m). Four combinations utilizing clinically achievable concentrations were investigated. Microbiological response was examined by log changes and population analysis profiles. Colistin (constant concentrations of 0.5 or 2 mg/liter) plus doripenem (peaks of 2.5 or 25 mg/liter every 8 h; half-life, 1.5 h) substantially increased bacterial killing against both strains at the low inoculum, while combinations containing colistin at 2 mg/liter increased activity against ATCC 27853 at the high inoculum; only colistin at 0.5 mg/liter plus doripenem at 2.5 mg/liter failed to improve activity against 19147 n/m at the high inoculum. Combinations were additive or synergistic against ATCC 27853 in 16 and 11 of 20 cases (4 combinations across 5 sample points) at the 10(6)- and 10(8)-CFU/ml inocula, respectively; the corresponding values for 19147 n/m were 16 and 9. Combinations containing doripenem at 25 mg/liter resulted in eradication of 19147 n/m at the low inoculum and substantial reductions in regrowth (including to below the limit of detection at ∼50 h) at the high inoculum. Emergence of colistin-resistant subpopulations of ATCC 27853 was substantially reduced and delayed with combination therapy. This investigation provides important information for optimization of colistin-doripenem combinations.

Comparative in vitro antimicrobial susceptibilities and synergistic activities of antimicrobial combinations against carbapenem-resistant Acinetobacter species: Acinetobacter baumannii versus Acinetobacter genospecies 3 and 13TU

Therapeutic options for the treatment of infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) are limited. In vitro activity of amikacin, ciprofloxacin, colistin (polymyxin E), ampicillin-sulbactam, and tigecycline alone and in combination with imipenem against CRAB and carbapenem-resistant Acinetobacter genospecies 3 and 13TU was investigated. Colistin (97% susceptible) and tigecycline (88% and 44% susceptible by US Food and Drug Administration [FDA] and European Committee on Antimicrobial Susceptibility Testing [EUCAST] breakpoints for Enterobacteriaceae, respectively) were the 2 most active agents against CRAB, followed by minocycline (66%), ampicillin/sulbactam (16%), and amikacin (13%). Compared with CRAB isolates, carbapenem-resistant Acinetobacter genospecies 3 and 13TU isolates had higher antimicrobial susceptible rates to ciprofloxacin (88%), amikacin (63%), tigecycline (100% by FDA breakpoint and 88% by EUCAST breakpoint for Enterobacteriaceae, respectively), minocycline (100%), and ampicillin/sulbactam (75%). For the 12 tested CRAB isolates, the checkerboard titration method demonstrated synergy between imipenem and colistin (42%), tigecycline (25%), amikacin (16%), and ampicillin/sulbactam (16%). Time-kill assays revealed antimicrobial synergism for imipenem in combination with colistin (75%), tigecycline (50%), ampicillin/sulbactam (42%), amikacin (42%), and ciprofloxacin (16%). However, antimicrobial synergism between imipenem and combined agents was not present among CRAB isolates with an imipenem MIC ≥32 mg/L. The combination of tigecycline and colistin showed good in vitro synergy for CRAB with high imipenem resistance. Our results demonstrate accurate identification of prevalent Acinetobacter species and highlight their different antimicrobial susceptibilities. This knowledge will enable clinicians to select appropriate regimens for treating these infections.

Activities of colistin- and minocycline-based combinations against extensive drug resistant Acinetobacter baumannii isolates from intensive care unit patients

BackgroundExtensive drug resistance of Acinetobacter baumannii is a serious problem in the clinical setting. It is therefore important to find active antibiotic combinations that could be effective in the treatment of infections caused by this problematic 'superbug'. In this study, we analyzed the in vitro activities of three colistin-based combinations and a minocycline-based combination against clinically isolated extensive drug resistant Acinetobacter baumannii (XDR-AB) strains.MethodsFourteen XDR-AB clinical isolates were collected. The clonotypes were determined by polymerase chain reaction-based fingerprinting. Susceptibility testing was carried out according to the standards of the Clinical and Laboratory Standards Institute. Activities of drug combinations were investigated against four selected strains and analyzed by mean survival time over 12 hours (MST12 h) in a time-kill study.ResultsThe time-kill studies indicated that the minimum inhibitory concentration (MIC) of colistin (0.5 or 0.25 μg/mL) completely killed all strains at 2 to 4 hours, but 0.5×MIC colistin showed no bactericidal activity. Meropenem (8 μg/mL), minocycline (1 μg/mL) or rifampicin (0.06 μg/mL) did not show bactericidal activity. However, combinations of colistin at 0.5×MIC (0.25 or 0.125 μg/mL) with each of the above were synergistic and shown bactericidal activities against all test isolates. A combination of meropenem (16 μg/mL) with minocycline (0.5×MIC, 4 or 2 μg/mL) was synergitic to all test isolates, but neither showed bactericidal activity alone. The MST12 h values of drug combinations (either colistin- or minocycline-based combinations) were significantly shorter than those of the single drugs (p < 0.01).ConclusionsThis study indicates that combinations of colistin/meropenem, colistin/rifampicin, colistin/minocycline and minocycline/meropenem are synergistic in vitro against XDR-AB strains.

In vitro activity of teicoplanin combined with colistin versus multidrug-resistant strains of Acinetobacter baumannii

Antimicrobial treatment of multidrug-resistant Acinetobacter baumannii (MDRAB) remains an important therapeutic challenge. With isolates resistant to all conventional agents now reported, clinicians are increasingly forced to turn to unorthodox combination treatments in the hope that these may be efficacious. Although a potent interaction between vancomycin and colistin has been demonstrated, there are concerns regarding the inherent toxicity of combining these agents in clinical practice. As teicoplanin has less nephrotoxic potential than vancomycin, we assessed whether a colistin/teicoplanin combination would have similar antimicrobial activities in vitro. The antimicrobial activity of colistin alone and in combination with teicoplanin was assessed versus a collection of MDRAB belonging to a number of epidemic lineages present in the UK. Synergy studies were undertaken using microtitre plate chequerboard assays, an Etest agar dilution method and standard time-kill methodology. The combination of teicoplanin and colistin was bactericidal versus all of the strains tested. In chequerboard assays, fractional inhibitory concentration indices of <0.5 were obtained, consistent with significant in vitro synergy. Using the Etest method the MIC of teicoplanin fell from >256 mg/L to ≤2 mg/L in the presence of subinhibitory concentrations of colistin. Significant synergy was observed when colistin was combined with teicoplanin versus MDRAB in vitro. This may represent a useful therapeutic combination for the treatment of A. baumannii infections, especially when renal toxicity is a significant concern.

Colistin monotherapy versus therapy combination

The purpose of our study was to compare the effectiveness of colistin monotherapy and colistin combination in the treatment of nosocomial infections with multi-resistant germs.

Novel Treatment Approach to Combat an Infection with Acinetobacter

The antimicrobial resistance of gram-negative pathogens has become problematic. In some cases related to Pseudomonas spp. and Acinetobacter spp., no antimicrobials on the market can be utilized at standard doses. We report a case of resistant Acinetobacter infection in a patient in the intensive care unit. In this scenario, we successfully treated the infection with doripenem at a higher dose of 1 g with a 4-hour infusion time along with the combination of tigecycline and colistin.

Carbapenem-resistant Klebsiella pneumoniae endocarditis in a young adult : Successful treatment with gentamicin and colistin

Enterobacteriaceae are rarely the etiologic agents of endocarditis, with Klebsiella species being especially rare. From the end of 2005, isolates of carbapenem-resistant Klebsiella pneumoniae began to appear in various hospitals across Israel, sensitive only to colistin and gentamicin. We present a case of hospital-acquired endocarditis caused by carbapenem-resistant K. pneumoniae in a young adult. An 18-year-old man with 40% full thickness burns developed acute bacterial endocarditis complicated by embolic myocardial infarction. Carbapenem-resistant K. pneumoniae carrying the blaKPC3 gene was isolated from multiple blood cultures. He recovered fully after antibiotic treatment with colistin and gentamicin. To our knowledge, this is the first reported case of acute bacterial endocarditis caused by carbapenem-resistant K. pneumoniae. The combination of intravenous colistin and gentamicin was effective and resulted in the cure of this patient's endocarditis without the need for surgical intervention.