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PubMed2003

Use of high-performance liquid chromatography to study the pharmacokinetics of colistin sulfate in rats following intravenous administration.

The pharmacokinetics of colistin was investigated using specific high-performance liquid chromatography (HPLC) to measure the concentrations of colistin and colistin A and B in plasma and urine in five rats after administration of an intravenous bolus of 1 mg of colistin sulfate/kg of body weight. There were differences in the pharmacokinetic behaviors of unbound colistin A and B. This is the first report of the use of HPLC to study the pharmacokinetics of colistin and its two major components.

Animals↗

PubMed2001

Contemporary assessment of antimicrobial susceptibility testing methods for polymyxin B and colistin: review of available interpretative criteria and quality control guidelines.

The emergence of infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter spp. has necessitated the search for alternative parenteral agents such as the polymyxins. The National Committee for Clinical Laboratory Standards (NCCLS) documents do not currently provide interpretative criteria for the testing of the polymyxins, colistin and polymyxin B. Therefore, an evaluation of the antimicrobial activity of colistin and polymyxin B was initiated using 200 bloodstream infection pathogens collected through the SENTRY Antimicrobial Surveillance Program. All susceptibility tests were performed according to the NCCLS recommendations. Polymyxin B and colistin displayed a nearly identical spectrum of activity, exhibiting excellent potency against P. aeruginosa (MIC(90), 2 microg/ml) and Acinetobacter sp. (MIC(90), 2 microg/ml). In contrast, they showed limited activity against some other nonfermentative bacilli such as Burkholderia cepacia (MIC(90), >/=128 microg/ml). Excellent correlation was achieved between broth microdilution and agar dilution tests (r = 0.96 to 0.98); 94.3% of the results were +/-1 log(2) dilution between the methods used for both compounds. At a resistance breakpoint of >/=4 microg/ml for both agents, unacceptable false-susceptible or very major errors were noted for colistin (5%) and polymyxin B (6%). Modified zone criteria for colistin (</=11 and >/=14 mm) and polymyxin B (</=10 and >/=14 mm) were suggested, but some degree of error persisted (>/=3.5%). It is recommended that all susceptible disk diffusion results be confirmed by MIC tests using the preferred reference NCCLS method. The quality control (QC) ranges listed in the product package insert require an adjusted range by approximately 3 mm for both NCCLS gram-negative quality control strains. This evaluation of in vitro susceptibility test methods for the polymyxin class drugs confirmed continued serious testing error with the disk diffusion method, the possible need for breakpoint adjustments, and the recalculation of disk diffusion QC ranges. Clinical laboratories should exclusively use MIC methods to assist the therapeutic application of colistin or polymyxin B until disk diffusion test modifications are sanctioned and published by the NCCLS.

Anti-Bacterial Agents↗

PubMed1997

Intravenous colistin sulphomethate in acute respiratory exacerbations in adult patients with cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis have received more intravenous antibiotic courses as median survival has steadily increased. A number of centres have adopted a policy of regular (three monthly) rather than on demand intravenous antipseudomonal antibiotics. More widespread bacterial antibiotic resistance has resulted from this increased antibiotic use. Most Pseudomonas aeruginosa strains remain fully sensitive to colistin but its use has been resisted owing to concerns about neurotoxicity and nephrotoxicity. A study was carried out to assess the safety and efficacy of intravenous colistin in the treatment of acute respiratory exacerbations in adult patients with cystic fibrosis. METHODS: Patients with chronic Pseudomonas aeruginosa colonisation who presented with protocol defined respiratory tract exacerbations were randomised to receive treatment for 12 days with either colistin (2 MU tds intravenously) alone or with a second anti-pseudomonal antibiotic. Comparisons of the absolute values of respiratory function tests on days 1, 5, and 12 and of overnight oxygen saturation on days 1 and 12 were the primary outcome measures. Patient's weight, clinical and chest radiographic scores, and peripheral blood markers of inflammation were also documented. The effect of each treatment regimen individually was assessed by the change in clinical measurements from baseline values. Adverse renal effects were monitored by measurement of serum levels of urea and electrolytes, creatinine clearance, and ward urine testing. Neurotoxicity was monitored by direct questioning for symptoms. RESULTS: Fifty three patients, 18 of whom entered the study twice, were enrolled. The mean forced expiratory volume in one second (FEV1) increased significantly in both groups, mean forced vital capacity (FVC) only with dual therapy. Both groups showed a non-significant increase in overnight oxygen saturation. All patients showed clinical improvement. Thirty seven adverse neurological events (two severe) were reported in 33 patients in the monotherapy group and 37 (none severe) in 36 patients in the dual therapy group. One patient withdrew because of severe weakness and dizziness. All other adverse neurological events were well tolerated and resolved during or shortly after treatment. Significant changes were seen in mean serum urea levels in both groups, but in only four patients to a level above the normal range, and in creatinine clearance in the dual therapy group. At 24 month follow up no long term adverse consequences from intravenous colistin were found in patients who completed the study. CONCLUSIONS: Intravenous colistin is an effective treatment for Pseudomonas aeruginosa associated pulmonary exacerbations in patients with cystic fibrosis. Assessment of the individual effect of each treatment regimen suggests a greater efficacy when colistin is combined with a second antibiotic to which the pseudomonas shows in vitro sensitivity. Changes in renal function should be monitored.

Acute Disease↗

PubMed2003

In vitro interaction of colistin and rifampin on multidrug-resistant Pseudomonas aeruginosa.

The administration of colistin is considered as the last alternative for infections by multidrug-resistant isolates of Pseudomonas aeruginosa; however its use is limited due to its considerable toxicity and poor pharmacokinetics. In order to define the in vitro activity of colistin combined with rifampin, 28 isolates resistant to piperacillin, ceftazidime, imipenem, meropenem, ciprofloxacin, amikacin, rifampin and colistin were tested. Seventeen of them that were found by PFGE to be genetically distinct were over time exposed to 2 microg/ml of colistin, to 2 microg/ml of rifampin and to their combination. Applied concentrations were selected to correspond to the mean serum level of the tested antimicrobials. Synergy between colistin and rifampin was found in four (23.5%), six (35.3%), seven (41.7%) and two (11.8%) isolates after 2, 4, 6 and 24 hours of growth, respectively. Bacterial re-growth was detected after 24 hours of exposure to the tested interaction. It is concluded that colistin and rifampin express a considerable in vitro synergistic effect on multidrug-resistant P. aeruginosa. The reported interaction should be tested in animal studies before introduction in clinical practice.

Colistin↗

PubMed2005

Toxicity after prolonged (more than four weeks) administration of intravenous colistin.

BACKGROUND: The intravenous use of polymyxins has been considered to be associated with considerable nephrotoxicity and neurotoxicity. For this reason, the systemic administration of polymyxins had been abandoned for about 20 years in most areas of the world. However, the problem of infections due to multidrug-resistant (MDR) Gram-negative bacteria such us Pseudomonas aeruginosa and Acinetobacter baumanniii has led to the re-use of polymyxins. Our objective was to study the toxicity of prolonged intravenous administration of colistin (polymyxin E). METHODS: An observational study of a retrospective cohort at "Henry Dunant" Hospital, a 450-bed tertiary care center in Athens, Greece, was undertaken.Patients who received intravenous colistin for more than 4 weeks for the treatment of multidrug resistant Gram-negative infections were included in the study. Serum creatinine, blood urea, liver function tests, symptoms and signs of neurotoxicity were the main outcomes studied. RESULTS: We analyzed data for 19 courses of prolonged intravenous colistin [mean duration of administration (+/- SD) 43.4 (+/- 14.6) days, mean daily dosage (+/- SD) 4.4 (+/- 2.1) million IU, mean cumulative dosage (+/- SD) 190.4 (+/- 91.0) million IU] in 17 patients. The median creatinine value increased by 0.25 mg/dl during the treatment compared to the baseline (p < 0.001) but returned close to the baseline at the end of treatment (higher by 0.1 mg/dl, p = 0.67). No apnea or other evidence of neuromuscular blockade was noted in any of these patients who received prolonged treatment with colistin. CONCLUSIONS: No serious toxicity was observed in this group of patients who received prolonged intravenous colistin. Colistin should be considered as a therapeutic option in patients with infections due to multidrug resistant Gram-negative bacteria.

Adolescent↗

PubMed2005

Aerosolized colistin for the treatment of nosocomial pneumonia due to multidrug-resistant Gram-negative bacteria in patients without cystic fibrosis.

The management challenges of patients with nosocomial pneumonia are great because of resistance among the responsible pathogens. In this issue of Critical Care, Argyris Michalopoulos and colleagues describe the use of inhaled colistin in the treatment of multidrug-resistant Gram-negative nosocomial pneumonia in a small group of patients. Although seven of eight patients who received nebulized colistin showed clinical improvement, some patients also received other active antibiotics. Microbiological eradication was demonstrated in only four of the eight patients. Serum levels of colistin were not measured. In addition, although adverse events were not documented in patients receiving colistin, formal assessments for bronchoconstriction and neurological toxicity were not completed in this retrospective study. Although resistance to colistin in Gram-negative organisms has not evolved, the risk of breakthrough infection with Gram-positive and inherently resistant Gram-negative bacteria remains a concern. The results of this limited study do, however, suggest that further studies examining the use of nebulized colistin are merited.

Aerosols↗

PubMed1978

Pretreatment with colistin and Proteus sensitivity to other agents.

The effects of pretreatment with colistin (polymyxin E) on the sensitivity of Proteus mirabilis, P. vulgaris and P. morganii strains to tris and sodium deoxycholate (DOC) have been studied. Pretreatment of two P. mirabilis strains (NCTC 60 and 4199) with low concentrations (0.25 approximately 1 microgram/ml) of colistin rendered them sensitive to lysis by tris (0.05M) or DOC (250 approximately 1,000 microgram/ml) although DOC induced lysis of control (non-colistin-treated) suspensions also. In contrast, the other P. mirabilis strains, as well as the P. vulgaris and P. morganii strains were little affected by tris (0.2M) or DOC (10,000 microgram/ml) even after exposure of the cells to high colistin concentrations (up to 500 microgram/ml). Colistin-pretreated or control cells of P. mirabilis NCTC 60 rapidly lost viability when suspended in water but not when held in 0.16M sodium chloride solution. Ethylenediamine tetraacetate-pretreated cells of strains 60 and 4199 were fairly sensitive to tris, although the extent of the lysis was less than when colistin was used as pretreating agent. One strain of P. vulgaris (NCTC 4175) became sensitive to tris and to DOC following exposure of the cells to ampicillin.

Colistin↗

PubMed2004

[Multiresistant nosocomial bacterial strains and their "in vitro" susceptibility to chloramphenicol and colistin].

OBJECTIVE: A multicenter study was conducted to obtain "in vitro" chloramphenicol and colistin susceptibility data on multiresistant hospital bacterial pathogens in Slovak Republic. MATERIAL AND METHODS: During the period of April-June 2001, 628 clinical bacterial multiresistant isolates from patients with serious infections were selected in 10 hospitals and tested to a large scale of antibiotics by means of a microdilution method. The strains expressed either a significant resistance phenotype (ESBL, MRSA, CoNMRS, MLSB/c, efflux in Ps. aeruginosa), or were resistant to one or more preparations in at least half of reliable unrelated antibiotic groups (beta-lactams, aminoglycosides, quinolons, macrolides). RESULTS: Both chloramphenicol and colistin retained significant "in vitro" activity against many multiresistant hospital bacterial pathogens. The highest activity of chloramphenicol was documented for isolates of Stenotrophomonas maltophilia (76,5 % susceptible, MIC50 = 4 mg/L, MIC90 = 16 mg/L) and of Staphylococcus aureus (76,2 % susceptible, MIC50 = 8 mg/L, MIC90 = 16 mg/L). In tested Pseudomonas aeruginosa (82,5 % susceptible, MIC50 = 2 mg/L, MIC90 = 16 mg/L) and Stenotrophomonas maltophilia (88,2 % susceptible, MIC50 = 1 mg/L, MIC90 = 8 mg/L) isolates colistin represented the most "in vitro" effective antibiotic. Colistin was the only "in vitro" effective antimicrobial in four of 120 multiresistant Pseudomonas aeruginosa isolates tested in our study. CONCLUSIONS: The study confirmed a good "in vitro" susceptibility of many multiresistant hospital bacterial pathogens to chloramphenicol and colistin in Slovak Republic. The clinical application of chloramphenicol and colistin might be reconsidered in infections caused by extremely resistant bacteria with prooved susceptibility to these antibiotics. It is important to consider, that the infection danger has to exceed the risk of antibiotic toxicity.

Anti-Bacterial Agents↗

PubMed1982

Effect of colistin on reduction of biliary flow induced by endotoxin in E. coli.

In order to evaluate whether an antiendotoxin agent can inhibit the action of endotoxin of Escherichia coli on biliary flow, we used 18 models of isolated perfused pig liver divided into four groups: (A) five perfused livers (control), (B) five perfused livers with 2 mg/100 ml of endotoxin added, (C) five perfused livers with 2 mg/100 ml of endotoxin added and treated with 1,500,000 IU of colistin, and (D) three perfused livers with 1,500,000 IU of colistin with no endotoxin. The livers were isolated and perfused according to a technique previously described by our laboratory. The viability of the perfusions was controlled by means of the mitochondrial respiration test. Transaminase and LDH levels were measured in the perfused circuit. A significant reduction of the biliary flow was found in the group with endotoxin of Escherichia coli (P less than 0.002). There was no reduction of biliary flow after addition of 1,500,000 IU of colistin (P less than 0.001). No significant changes were observed in the other parameters measured, and no increase of the bile flow was observed in the colistin group. From our results we conclude that colistin is an inhibitor in vitro of the diminished biliary flow induced by endotoxin of Escherichia coli.

Alkaline Phosphatase↗

PubMedDate not supplied

Colistin and trimethoprim-sulfamethoxazole for the prevention of infection in patients with acute non-lymphocytic leukaemia. Decrease in the emergence of resistant bacteria.

In a previous study we demonstrated that trimethoprim-sulfamethoxazole decreases the prevalence of infection in patients with severe granulocytopenia. However, treatment was accompanied by a relatively high incidence of multiresistant microorganisms. We therefore conducted this study to determine whether the addition of colistin to the trimethoprim-sulfamethoxazole regimen prevents the emergence of these resistant bacteria. Thirty consecutive adult patients with acute non-lymphocytic leukaemia received trimethoprim-sulfamethoxazole plus colistin p.o. prophylactically. The results of this study were compared with the results of our previously published controlled study. Trimethoprim-sulfamethoxazole plus colistin was as effective as trimethoprim-sulfamethoxazole in preventing infection. However, the addition of colistin significantly reduced the acquisition of and infection by gram-negative bacilli which were resistant to trimethoprim-sulfamethoxazole. Only two patients were colonized with resistant strains, and no infections with these strains were observed. We have concluded that patients with acute non-lymphocytic leukaemia should receive a combination of trimethoprim-sulfamethoxazole plus colistin prophylactically during remission induction treatment.

Acute Disease↗

PubMed2002

Cerebrospinal fluid penetration and pharmacokinetic/pharmacodynamic parameters of intravenously administered colistin in a case of multidrug-resistant Acinetobacter baumannii meningitis.

Described here is a case of meningitis caused by multidrug-resistant Acinetobacter baumannii susceptible only to colistin, which was treated successfully with intravenous colistin sulfomethate sodium (5 mg/kg/day). The levels of colistin in serum and cerebrospinal fluid and the pharmacokinetic/pharmacodynamic parameters of colistin were determined. In this case, intravenously administered colistin penetrated cerebrospinal fluid (25% of serum levels) at levels sustaining bactericidal concentrations.

Acinetobacter↗

PubMed1988

Further studies on colistin (polymyxin E)-induced cell leakage in mycobacteria: Mg++ efflux in Mycobacterium avium and its effects on drug-susceptibility.

Action of colistin (polymyxin E) was investigated on the opportunistic pathogenic species Mycobacterium avium ATCC 15769 (resistant strain, MIC greater than 100 micrograms/ml). Mycobacterium intracellulare ATCC 13950: a colistin-susceptible strain (MIC 25 micrograms/ml), was used as a parallel control for Mg++ efflux experiments. After the addition of 100 micrograms/ml of colistin to bacteria suspended in a buffer, both loss of viability and Mg++ efflux were followed for one week. Although there was an initial Mg++ efflux in both strains, it soon attained a plateau in case of the resistant strain without any loss of viability until 48 h, whereas in case of the susceptible strain, Mg++ efflux was about 3 times higher than former, a plateau was attained only 24 h after the drug addition, and the loss of viability started only 6 h after the drug addition. Consequently, the loss of viability of M. avium with later incubation times (6 days) was not due to the action of colistin on the cytoplasmic Mg++ efflux solely, but some additional effect was implicated. The drug-susceptibility of extracellularly-growing and intracellularly-growing (in the J-774 macrophage cell line) M. avium to the antibiotics tested could not be potentiated when they were used in combination with 5 micrograms/ml of colistin (maximal obtainable serum level in man) or the polymyxin B nonapeptide (PMBN), nor in the case of bacteria pretreated with these molecules.

Amoxicillin↗

PubMed1987

Colistin inhalation therapy in cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infection.

Forty patients with cystic fibrosis and chronic broncho-pulmonary Pseudomonas aeruginosa infection entered a prospective double-blind placebo-controlled study of colistin inhalation. Active treatment consisted of inhalation of colistin one million units twice daily for three months and was compared to placebo inhalations of isotonic saline. Significantly more patients in the colistin inhalation group completed the study as compared to the placebo group (18 versus 11). Colistin treatment was superior to placebo treatment in terms of a significantly better clinical symptom score, maintenance of pulmonary function and inflammatory parameters. We recommend colistin inhalation therapy for cystic fibrosis patients with chronic P. aeruginosa lung infection as a supplementary treatment to frequent courses of intravenous anti-pseudomonas chemotherapy.

Administration, Inhalation↗

PubMed2006

Studies on the antimicrobial activity of cecropin A-melittin hybrid peptides in colistin-resistant clinical isolates of Acinetobacter baumannii.

OBJECTIVES: Acinetobacter baumannii has successfully developed resistance against all common antibiotics, including colistin, one of the last active drugs against this pathogen. We have tested whether the differences in lethal mechanism between polymyxin B and the cecropin A-melittin hybrid peptide CA(1-8)M(1-18), shown previously with a colistin-susceptible strain, can be exploited as a new chemotherapeutic alternative against colistin-resistant clinical isolates. Furthermore, the effect of capsule on the bactericidal activity of cecropin A-melittin analogues (CAMs) was tested. METHODS: MICs and MBCs of the four CAMs were determined for 13 clinical isolates. The bactericidal activity of the antimicrobial peptides was measured using time-kill curves. The presence or absence of capsule was determined using Indian ink stain. RESULTS: The MIC ranges of CA(1-8)M(1-18) and three of its shortened analogues, namely CA(1-7)M(2-9), its Nalpha-terminal octanoylated analogue and CA(1-7)M(5-9), for A. baumannii strains were 2-8, 2-4, 2-8 and 4-4 mg/L, respectively. MBCs differed by a factor of two at the most. All of the cecropin A-melittin peptides showed bactericidal activity in time-kill curves against four A. baumannii strains. The bactericidal activity of CAMs was not affected by the presence of capsule. CONCLUSIONS: These results indicate that this class of peptides has a fast microbicidal effect on the colistin-resistant A. baumannii isolates, regardless of considerable structural variation among the four peptides and varying colistin MIC for the strains included in the study. Overall, the cecropin A-melittin peptides appear to be a promising alternative to overcome polymyxin resistance in A. baumannii.

Acinetobacter baumannii↗

PubMed2005

[Usefulness of parenteral colistin in treating of lower respiratory infection due to multidrug-resistant Pseudomonas aeruginosa].

We report a case of cystic fibrosis in a 19-year-old woman who suffered from frequent exacerbations of lower respiratory infection due to multidrug-resistant Pseudomonas aeruginosa and who was successfully treated with parenteral colistin. Multidrug-resistant Pseudomonas aeruginosa isolated from sputum had become resistant to all parenteral antibiotics commercially available in Japan. She did not show clinical improvement despite treatment with several different combinations of available antibiotics. We therefore obtained parenteral colistin from a pharmacy outside Japan. She responded well to parenteral colistin without apparent side effects such as serious nephrotoxicity or neurotoxicity. Colistin is therefore an important alternative antibiotic for treating multidrug-resistant Pseudomonas aeruginosa and its use should be considered in severe infection. We hope that parenteral colistin will become available in Japan in the near future.

Adult↗

PubMed1973

Natural colistin resistance in Edwardsiella tarda.

All of 37 recent human isolates of Edwardsiella tarda were resistant to colistin. All strains were resistant to 6.3 mug of sodium colistimethate per ml; 82% of them were resistant to 100 mug/ml. With 34 Salmonella strains, the average minimal inhibitory concentration (MIC) was 1.6 mug of sodium colistimethate per ml. There was virtually no overlapping of MIC values between both groups of bacteria. Using the Kirby-Bauer method and 10-mug colistin disks, inhibition zone diameters were less than 11 mm for all Edwardsiella strains, and larger for all Salmonella strains. An atypical, mannitol-fermenting strain of E. tarda was resistant to colistin. It is concluded that E. tarda is naturally resistant to colistin, that this property may be helpful in differentiation, and that colistin should be tried in enrichment and selective media for the isolation of E. tarda. It was also observed that, under conditions as described, all strains of E. tarda were susceptible to streptomycin and to novobiocin, whereas all strains of Salmonella were resistant.

Anti-Bacterial Agents↗

PubMed2002

Efficacy of colistin versus beta-lactams, aminoglycosides, and rifampin as monotherapy in a mouse model of pneumonia caused by multiresistant Acinetobacter baumannii.

The treatment of life-threatening infections due to carbapenem-resistant Acinetobacter baumannii has become a serious challenge for physicians worldwide. Often, only colistin shows in general good in vitro activity against these carbapenem-resistant strains, but its antibacterial efficacy in comparison with the antibiotics most used in clinical practice is not well known. We studied the efficacy of colistin versus those of imipenem, sulbactam, tobramycin, and rifampin in an experimental pneumonia model with immunocompetent mice. We used three strains of A. baumannii corresponding to the main clones (A, D, and E) involved in the outbreaks of our hospital, with different grades of resistance to imipenem (imipenem MICs of 1, 8, and 512 microg/ml, respectively) and to the other antibiotics. The MIC of colistin was 0.5 microg/ml for the three strains. Reduction of log(10) CFU/g in lung bacterial counts, clearance of bacteremia, and survival versus results with controls were used as parameters of efficacy. Imipenem and sulbactam (Deltalung counts: -5.38 and -4.64 log(10) CFU/ml) showed the highest level of bactericidal efficacy in infections by susceptible and even intermediate strains. Tobramycin and rifampin (-4.16 and -5.15 log(10) CFU/ml) provided good results against intermediate or moderately resistant strains, in agreement with killing curves and pharmacodynamics. On the contrary, colistin showed the weakest antibacterial effect among the antibiotics tested, both in killing curves and in the in vivo model (-2.39 log(10) CFU/ml; P < 0.05). We conclude that colistin did not appear as a good option for treatment of patients with pneumonia due to carbapenem-resistant A. baumannii strains. Other alternatives, including combinations with rifampin, may offer better therapeutic profiles and thus should be studied.

Acinetobacter↗

PubMed1984

Growth of coagulase-negative staphylococci on colistin-nalidixic acid agar and susceptibility to polymyxins.

Colistin-nalidixic acid agar, although recently recommended as a replacement for blood agar for primary plating of urine specimens ( Fung et al., J. Clin. Microbiol. 16:632-636, 1982), has also been reported to suppress the growth of some strains of staphylococci that are susceptible to colistin (polymyxin E). The susceptibility of 11 species of staphylococci to polymyxins was determined, and the ability of these species to grow on colistin-nalidixic acid agar was examined. Although the MICs for most of the strains tested were 8 micrograms/ml or less, only a few coagulase-negative staphylococci grew on or were inhibited by colistin-nalidixic acid agar. This descrepancy was explained by the antagonistic effects that medium components, such as physiological concentrations of magnesium and calcium and 5% sheep blood, had on the activity of polymyxin. Colistin-nalidixic acid agar is still recommended for routine urine processing; however, the poor growth of 13% of the Staphylococcus saprophyticus strains tested suggests that blood agar should be included in the primary plating battery of urine specimens obtained from female outpatients.

Agar↗