Polymyxin B: similarities to and differences from colistin (polymyxin E).

Hospital-acquired infections due to multidrug-resistant gram-negative bacteria constitute major health problems, since the medical community is continuously running out of available effective antibiotics and no new agents are in the pipeline. Polymyxins, a group of antibacterials that were discovered during the late 1940s, represent some of the last treatment options for these infections. Only two polymyxins are available commercially, polymyxin E (colistin) and polymyxin B. Although several reviews have been published recently regarding colistin, no review has focused on the similarities and differences between polymyxin B and colistin. These two medications have many similarities with respect to mechanism of action, antimicrobial spectrum, clinical uses and toxicity. However, they also differ in several aspects, including chemical structure, formulation, potency, dosage and pharmacokinetic properties.

The use of intravenous and aerosolized polymyxins for the treatment of infections in critically ill patients: a review of the recent literature.

Intravenous and aerosolized polymyxins are being used increasingly, especially in the critical care setting, for treating patients with infections due to multidrug-resistant Gram-negative bacteria, mainly Acinetobacter baumannii and Pseudomonas aeruginosa. Recent literature suggests that intravenous colistin and polymyxin B have acceptable effectiveness for the treatment of patients with bacteremia, as well as infections of various systems and organs, including pneumonia, bacteremia, skin and soft tissue, and urinary tract infections. Although data from recent studies have suggested that the toxicity of intravenous polymyxins is probably less than reported in the older literature, caution should be taken to monitor the renal function of patients who receive these antibiotics.

Secular trends of antimicrobial resistance of blood isolates in a newly founded Greek hospital.

BACKGROUND: Antimicrobial resistance is one of the most challenging issues in modern medicine. METHODS: We evaluated the secular trends of the relative frequency of blood isolates and of the pattern of their in vitro antimicrobial susceptibility in our hospital during the last four and a half years. RESULTS: Overall, the data regarding the relative frequency of blood isolates in our newly founded hospital do not differ significantly from those of hospitals that are functioning for a much longer period of time. A noteworthy emerging problem is the increasing antimicrobial resistance of Gram-negative bacteria, mainly Acinetobacter baumannii and Klebsiella pneumoniae to various classes of antibiotics. Acinetobacter baumannii isolates showed an increase of resistance to amikacin (p = 0.019), ciprofloxacin (p = 0.001), imipenem (p < 0.001), and piperacillin/tazobactam (p = 0.01) between the first and second period of the study. CONCLUSION: An alarming increase of the antimicrobial resistance of Acinetobacter baumannii isolates has been noted during our study.

Limitations in the management of aortic graft infections.

The use of aortic allografts has emerged as a management option in patients with aortic graft infections. We present a patient with a history of Takayasu's disease whose aortic graft infection was controlled with replacement of the excised infected aortic graft with an allograft. However, the patient died 9 months later after the rupture of a large anastomotic aortic aneurysm. Our report emphasizes the limitations in the management of aortic graft infections in patients with extensive vascular disease such as Takayasu's disease. This is the result of difficulties in performing extra-anatomical bypass as well as a possibly increased risk of formation of anastomotic aneurysms in these patients.

Comparison of mortality of patients with Acinetobacter baumannii bacteraemia receiving appropriate and inappropriate empirical therapy.

OBJECTIVES: To evaluate the effect of inappropriate empirical antimicrobial treatment on the mortality of patients with Acinetobacter baumannii bacteraemia. METHODS: Retrospective cohort study of patients with A. baumannii bacteraemia hospitalized at the Henry Dunant hospital from January 2002 to December 2004. RESULTS: Among 40 patients with A. baumannii bacteraemia, 22 (55%) and 18 (45%) received inappropriate and appropriate antibiotic therapy, respectively, during the 3 day period after obtaining the blood culture(s) from which the pathogen was isolated. Failure to cure the infection was more common in the first group [16/22 patients (72.7%) versus 5/18 (27.8%), P = 0.005]. Although without statistical significance, probably due to the small number of studied patients, considerably increased mortality was noted in the first group compared with the second group [13/22 patients (59.1%) versus 6/18 (33.3%), P = 0.10]. CONCLUSIONS: A. baumannii bacteraemia was associated with worse outcome regarding the cure of infection in patients who received inappropriate empirical antimicrobial treatment compared with those who received appropriate treatment.

Toxicity of polymyxins: a systematic review of the evidence from old and recent studies.

BACKGROUND: The increasing problem of multidrug-resistant gram-negative bacteria causing severe infections and the shortage of new antibiotics to combat them has led to the re-evaluation of polymyxins. These antibiotics were discovered from different species of Bacillus polymyxa in 1947; only two of them, polymyxin B and E (colistin), have been used in clinical practice. Their effectiveness in the treatment of infections due to susceptible gram-negative bacteria, including Pseudomonas aeruginosa and Acinetobacter baumannii, has not been generally questioned. However, their use was abandoned, except in patients with cystic fibrosis, because of concerns related to toxicity. METHODS: We reviewed old and recent evidence regarding polymyxin-induced toxicity by searching Pubmed (from 1950 until May 2005). RESULTS: It was reported in the old literature that the use of polymyxins was associated with considerable toxicity, mainly nephrotoxicity and neurotoxicity, including neuromuscular blockade. However, recent studies showed that the incidence of nephrotoxicity is less common and severe compared to the old studies. In addition, neurotoxic effects of polymyxins are usually mild and resolve after prompt discontinuation of the antibiotics. Furthermore, cases of neuromuscular blockade and apnea have not been reported in the recent literature. CONCLUSION: New evidence shows that polymyxins have less toxicity than previously reported. The avoidance of concurrent administration of nephrotoxic and/or neurotoxic drugs, careful dosing, as well as more meticulous management of fluid and electrolyte abnormalities and use of critical care services may be some of the reasons for the discrepancy between data reported in the old and recent literature.

Continuous versus intermittent intravenous administration of antibacterials with time-dependent action: a systematic review of pharmacokinetic and pharmacodynamic parameters.

We performed a systematic review of randomised clinical trials to evaluate the comparative pharmacokinetic and pharmacodynamic properties of the continuous versus intermittent mode of intravenous administration of various antibacterials. Data were identified from PubMed (January 1950 to January 2005), Current Contents, the Cochrane central register of controlled trials, and references from relevant articles and reviews. Seventeen randomised clinical trials comparing continuous with intermittent intravenous administration of the same antibacterial regimen and examining the pharmacokinetic and pharmacodynamic properties were included in this systematic review. We reviewed data regarding the clinical setting, number of participants, antibacterial agents and dosages used, as well as maximum serum concentration (Cmax), trough serum concentration (Cmin), steady-state or plateau serum concentration (Css), area under the concentration-time curve (AUC), time above the minimum inhibitory concentration (MIC) [T>MIC], AUC: MIC, elimination rate constant, elimination half-life, volume of distribution and systematic clearance. The mean Cmax of the intermittently administered antibacterials was higher compared with Css achieved by the continuous infusion of the same antibacterial in all eligible studies (Cmax was on average 5.5 times higher than Css, range 1.9-11.2). Css was on average 5.8 times higher than the Cmin of the intermittently administered antibacterials (range 1.2-15.6). In three of six studies the length of time that the drug concentration was above the MIC of the responsible pathogens was longer in patients receiving the antibacterials continuously. In conclusion, the reviewed data suggest that the continuous intravenous infusion of antibacterials with time-dependent bacterial killing seems to be superior than the intermittent intravenous administration, from a pharmacodynamic point of view, at least when treating bacteria with high MIC values for the studied antibacterials.

Nephrotoxicity of intravenous colistin: a prospective evaluation.

Twenty-one patients who received intravenous colistimethate sodium (CMS) for at least 7 days for the treatment of multidrug-resistant Gram-negative bacterial infections were included in a prospective cohort study at 'Henry Dunant' Hospital in Athens, Greece. The mean (+/- standard deviation) and median daily doses, cumulative doses and duration of treatment of intravenous CMS were, respectively, 5.5 (+/- 1.9) and 6 million IU, 90.2 (+/- 52.0) and 72 million IU, and 17.7 (+/- 11.7) and 15 days (range 7-54 days). Three patients (14.3%) developed nephrotoxicity during treatment with CMS. The cumulative dose of administered CMS was statistically correlated with the difference in values of serum creatinine between the end and start of CMS treatment (r = 0.6, P = 0.004 by Spearman's test).

Cure of multidrug-resistant Acinetobacter baumannii fixation device-related orthopedic infections in two patients with intravenous colistin.

We report our experience with two cases of fixation device-related orthopedic infections due to multidrug-resistant Acinetobacter baumannii strains. Both patients were successfully treated with intravenous administration of colistin, despite the reported poor penetration of this medication to these tissues, in the old literature. No serious colistin-associated toxicity developed and no recurrence of the infection occurred on follow up.

Ciprofloxacin vs an aminoglycoside in combination with a beta-lactam for the treatment of febrile neutropenia: a meta-analysis of randomized controlled trials.

OBJECTIVE: To compare the effectiveness and toxicity of ciprofloxacin vs an aminoglycoside, both in combination with a beta-lactam, for the treatment of febrile neutropenia in the inpatient setting. METHODS: For this meta-analysis of randomized controlled trials (RCTs) that compared the ciprofloxacin/beta-lactam combination vs an aminoglycoside/beta-lactam combination for the treatment of febrile neutropenia and reported data on effectiveness, mortality, and/or toxicity, we searched PubMed (1950-2004), Current Contents, Cochrane Central Register of Controlled Trials, and reference lists of retrieved articles, including review articles, as well as abstracts presented at international conferences. Data for 3 primary and 2 secondary outcomes were extracted by 2 investigators. RESULTS: Eight RCTs were included in the analysis. Comparable or better outcomes were observed with the ciprofloxacin/beta-lactam combination vs an aminoglycoside/beta-lactam combination: clinical cure without modification of the initial regimen (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.00-1.74; P=.05), clinical cure in the subset of patients with documented Infections (OR, 1.56; 95% CI, 1.05-2.31; P=.03), all-cause mortality (OR, 0.85; 95% CI, 0.54-1.35; P=.49), withdrawal of the study drugs due to toxicity (OR, 0.87; 95% CI, 0.57-1.32; P-.51), and nephrotoxicity (OR, 0.30; 95% CI, 0.16-0.59; P<.001). The ciprofloxacin/beta-lactam combination was also associated with better clinical cure compared to the aminoglycoside/beta-actam combination in the subset of RCTs with non-low-risk patients (OR, 1.38; 95% CI, 1.01-1.88; P=-.04), as well as in the subset of studies that included the same beta-lactam in both treatment arms (OR, 1.47; 95% CI, 1.06-2.05; P=.02). CONCLUSION: The combination of ciprofloxacin with a beta-actam antibiotic should be considered an important therapeutic option in hospitalized febrile neutropenic patients who have not received a quinolone for prevention of infections and in settings in which quinolone resistance is not common.

Continuous versus intermittent intravenous administration of antibiotics: a meta-analysis of randomised controlled trials.

Intermittent intravenous administration of antibiotics is the first-line approach in the management of severe infections worldwide. However, the potential benefits of alternate modes of administration of antibiotics, including continuous intravenous infusion, deserve further evaluation. We did a meta-analysis of randomised controlled trials comparing continuous intravenous infusion with intermittent intravenous administration of the same antibiotic regimen. Nine randomised controlled trials studying beta-lactams, aminoglycosides, and vancomycin were included. Clinical failure was lower, although without statistical significance, in patients receiving continuous infusion of antibiotics (pooled OR 0.73, 95% CI 0.53-1.01); the difference was statistically significant in a subset of randomised controlled trials that used the same total daily antibiotic dose for both intervention arms (0.70, 0.50-0.98, fixed and random effects models). Regarding mortality and nephrotoxicity, no differences were found (mortality 0.89, 0.48-1.64; nephrotoxicity 0.91, 0.56-1.47). In conclusion, the data suggest that the administration of the same total antibiotic dose by continuous intravenous infusion may be more efficient, with regard to clinical effectiveness, compared with the intermittent mode. In an era of gradually increasing resistance among most pathogens, the potential advantages of continuous intravenous administration of antibiotics on several clinical outcomes should be further investigated.

Combination therapy with intravenous colistin for management of infections due to multidrug-resistant Gram-negative bacteria in patients without cystic fibrosis.

Colistin, an antibiotic almost abandoned for intravenous administration for many years due to its reported toxicity, has been recently reintroduced in clinical practice due to the emergence of multidrug-resistant gram-negative bacteria and the lack of development of new antibiotics to combat them. To assess the safety and effectiveness of intravenous colistin, in combination with other antimicrobial agents, in the treatment of serious infections in patients without cystic fibrosis, a retrospective cohort study in a 450-bed tertiary-care hospital in Athens, Greece, was performed. Patients who were hospitalized from 1 October 2000 to 31 January 2004 and received intravenous colistin for more than 72 h were further analyzed. The primary outcome measure was the in-hospital mortality; secondary end points were the clinical outcome of the infections and the occurrence of colistin toxicity. Fifty patients received intravenous colistin with a median (mean) daily dose of 3 (4.5) million IU for 16.5 (21.3) days for the management of 54 episodes of infections due to multidrug-resistant gram-negative bacteria. The predominant infections were pneumonia (33.3%), bacteremia (27.8%), urinary tract infection (11.1%), and intra-abdominal infection (11.1%). The responsible pathogens were Acinetobacter baumannii (51.9%), Pseudomonas aeruginosa (42.6%), and Klebsiella pneumoniae (3.7%) strains (no pathogen was isolated from one case). In-hospital mortality was 24% (12/50 patients). Clinical response (cure or improvement) of the infection was observed in 66.7% of episodes (36/54). In the studied group, serum creatinine levels were decreased, at the end of colistin treatment, by an average of 0.2 +/- 1.3 mg/dl compared to baseline levels. Deterioration of renal function during colistin therapy was observed in 4/50 patients (8%). Coadministration of other antimicrobial agents with spectrum against gram-negative microorganisms and the absence of a control group constitute the major limitations of this study. The use of intravenous colistin for the treatment of infections due to multidrug-resistant gram-negative bacteria appears to be safe and effective.

Regression of skin lesions of Kyrle's disease with clindamycin: implications for an infectious component in the etiology of the disease.

We report our experience with the management of a 44-year-old man with manifestations of Kyrle's disease. The patient presented to us with skin lesions of two different types. The old lesions were large hyperkeratotic plaques with burrows without signs of inflammation. The newer lesions were also hyperkeratotic plaques but they clearly had signs of inflammation. The patient was successfully managed with combined surgical and medical management; removal of the large hyperkeratotic skin lesions combined with administration of clindamycin, which led to regression of the smaller skin lesions. The regression of the lesions of the initial stage of Kyrle's disease with clindamycin suggests that infectious agents (probably anaerobic bacteria) may play a role in the pathogenesis of the disease.

Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections.

The emergence of multidrug-resistant gram-negative bacteria and the lack of new antibiotics to combat them have led to the revival of polymyxins, an old class of cationic, cyclic polypeptide antibiotics. Polymyxin B and polymyxin E (colistin) are the 2 polymyxins used in clinical practice. Most of the reintroduction of polymyxins during the last few years is related to colistin. The polymyxins are active against selected gram-negative bacteria, including Acinetobacter species, Pseudomonas aeruginosa, Klebsiella species, and Enterobacter species. These drugs have been used extensively worldwide for decades for local use. However, parenteral use of these drugs was abandoned approximately 20 years ago in most countries, except for treatment of patients with cystic fibrosis, because of reports of common and serious nephrotoxicity and neurotoxicity. Recent studies of patients who received intravenous polymyxins for the treatment of serious P. aeruginosa and Acinetobacter baumannii infections of various types, including pneumonia, bacteremia, and urinary tract infections, have led to the conclusion that these antibiotics have acceptable effectiveness and considerably less toxicity than was reported in old studies.

Effusive-constrictive calcific pericarditis associated with Streptococcus salivarius. Case report and review of the literature.

We report the case of a 40-year-old patient presenting with a 6-month history of dyspnea and edema, with significant worsening of his clinical manifestations for the 2 weeks before admission to our department. During this 14-day preadmission period, continuous positive airway pressure (CPAP) was prescribed elsewhere for management of a working diagnosis of obstructive sleep apnea. The patient presented to us hemodynamically compromised. Management of the patient included emergency cardiac surgery for tamponade caused by effusive-constrictive, calcific pericarditis in addition to antimicrobial treatment as a result of the growth of Streptococcus salivarius from the pericardial fluid. This is the first report in the literature of association of this microorganism with pericarditis. The use of CPAP made the patient's symptoms worse as a result of an increase of the intrathoracic pressure, which was a pathophysiological mechanism, added to the interference of the localized pericardial effusion and the effect of the pericardial constriction. In an era of rapidly increasing use of CPAP systems, clinicians should be aware of their possible detrimental effects on patients with some types of cardiopulmonary diseases.

Outcome of infections due to pandrug-resistant (PDR) Gram-negative bacteria.

BACKGROUND: The increasing problem of infections due to multidrug-resistant Gram-negative bacteria has led to re-use of polymyxins in several countries. However, there are already clinical isolates of Gram-negative bacteria that are resistant to all available antibiotics, including polymyxins. METHODS: We present a case series of patients with infections due to pathogens resistant to all antimicrobial agents tested, including polymyxins. An isolate was defined as pandrug-resistant (PDR) if it exhibited resistance to all 7 anti-pseudomonal antimicrobial agents, i.e. antipseudomonal penicillins, cephalosporins, carbapenems, monobactams, quinolones, aminoglycosides, and polymyxins. RESULTS: Clinical cure of the infection due to pandrug-resistant (PDR) Gram-negative bacteria, namely Pseudomonas aeruginosa or Klebsiella pneumoniae was observed in 4 out of 6 patients with combination of colistin and beta lactam antibiotics. CONCLUSION: Colistin, in combination with beta lactam antibiotics, may be a useful agent for the management of pandrug-resistant Gram-negative bacterial infections. The re-use of polymyxins, an old class of antibiotics, should be done with caution in an attempt to delay the rate of development of pandrug-resistant Gram-negative bacterial infections.