Mycobacterium kansasii cutaneous infection in a patient with sarcoidosis treated with anti-TNF agents.

We describe a Mycobacterium kansasii cutaneous infection that was diagnosed in a 52-year-old female patient with sarcoidosis receiving anti-TNF agents. The diagnosis was based on the positive culture of the foot ulcerative tissue. The isolation and identification of bacterium was based on phenotypic and molecular methods. Therapy and follow-up of the patient is discussed.

The first case of Staphylococcus aureus ST398 causing bacteremia in an immunocompromised patient in Greece.

We describe a case of catheter-related bloodstream infection, in a patient with colon cancer, caused by a methicillin-sensitive Staphylococcus aureus strain, nontypeable by pulsed field gel electrophoresis of SmaI macrorestriction fragment analysis, belonging to ST398. The patient recovered after daptomycin therapy. This is the first report that documents the emergence of ST398 in Greece.

Comparative effects of ciprofloxacin and ceftazidime on cytokine production in patients with severe sepsis caused by gram-negative bacteria.

In the present study the effect of ciprofloxacin versus ceftazidime on concentrations of pro- and anti-inflammatory cytokines in the sera of patients with severe sepsis was evaluated. The study included 58 previously healthy patients suffering from severe sepsis caused by gram-negative bacteria, treated with either ciprofloxacin or ceftazidime after thorough clinical and microbiological evaluation and followed up for clinical outcome. Levels of the proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha), interleukin-1b (IL-1b), IL-6, and IL-8 and of the anti-inflammatory cytokine IL-10, as well as of IL-1 receptor antagonist and soluble TNF receptors I and II, in serum were measured at baseline and 24 and 48 h after the first antimicrobial dose. Mean SAPS-II scores, development of septic shock, and mortality rates were similar in the two groups (43.2 +/- 9.2, 21.4%, and 14.3% in the ceftazidime group versus 49.8 +/- 11.3, 20%, and 13.3% in the ciprofloxacin group). Serum TNF-alpha and IL-6 levels at 24 and 48 h were significantly lower in the ciprofloxacin group, while the IL-10/TNF-alpha ratio was significantly higher, than those for the ceftazidime group. Among patients with high baseline TNF-alpha levels, there were significant increases in the IL-10/TNF-alpha ratio at both 24 and 48 h over that at admission for the ciprofloxacin group, while no differences were noted in the ceftazidime group. These results indicate that ciprofloxacin may have an immunomodulatory effect on septic patients by attenuating the proinflammatory response, while there is no evidence that differences in the cytokines measured have any impact on the final outcome.

Expression of the cell cycle regulatory proteins p34cdc2, p21waf1, and p53 in node negative invasive ductal breast carcinoma.

AIMS: To look for correlations between expression of cell cycle regulatory proteins p34(cdc2), p21(WAF1), and p53 in node negative invasive ductal breast carcinoma, or between these proteins and clinicopathological parameters, and to assess their prognostic value. METHODS: Immunohistochemistry using formalin fixed, paraffin wax embedded sections from 94 breast carcinomas. Adjacent benign epithelial breast tissue was available in 74 cases. Median follow up was 72 months. RESULTS: Nuclear and cytoplasmic p34(cdc2) expression was seen in 80 and 62 tumours, respectively; nuclear expression was seen in adjacent benign epithelium in 12 cases. p21(WAF1) and p53 were positive in 48 and 21 tumours, respectively. High expression of p34(cdc2) in neoplastic nuclei was associated with higher histological grade and p53 expression, but not with tumour size, steroid receptor status, patient age, menopausal status, recurrence, metastasis, disease free survival (DFS), or overall survival (OS). p34(cdc2) in tumour cytoplasm was associated with p34(cdc2) nuclear positivity, high tumour grade, and DFS in univariate but not multivariate analysis. In contrast, p34(cdc2) expression in benign tissue independently predicted DFS and OS in univariate and multivariate analysis. Expression of p53 was associated with high tumour grade and negative steroid receptors, but not with recurrence, metastasis, DFS, or OS. p21(WAF1) expression was not associated with the examined parameters. CONCLUSIONS: p34(cdc2), p21(WAF1), and p53 expression does not predict outcome in node negative breast carcinoma, although p34(cdc2) expression in benign tissue is related to prognosis. The association between p34(cdc2) and p53 implicates p53 in G2-M cell cycle checkpoint control, possibly via mediators unrelated to p21(WAF1).

Influence of adjunct azithromycin on the mortality of experimental Pseudomonas aeruginosa sepsis.

The aim of this study was to determine the in vivo influence of azithromycin subinhibitory concentrations on mortality in a peritonitis-sepsis model. One hour after an intraperitoneal injection of Pseudomonas aeruginosa, mice were randomized to receive: ceftazidime, 500 mg/kg SC q4hxtwo doses alone; azithromycin, 20 mg/kg SCxone dose alone; ceftazidime plus azithromycinxone dose; ceftazidime plus azithromycinxtwo doses (1 and 24 h); ceftazidime plus prophylactic azithromycin (three doses at -48, -24, 1 h); or no treatment (control). A significant decrease in the rate of mortality was observed in animals treated with all ceftazidime plus azithromycin groups when compared with those receiving ceftazidime alone. These data indicate a potential role for adjunctive azithromycin therapy in P. aeruginosa infection.

Influence of gentamicin dosing interval on the efficacy of penicillin-containing regimens in experimental Enterococcus faecalis endocarditis.

The influence of the gentamicin dosing regimen was studied in experimental Enterococcus faecalis endocarditis. After inoculation, animals received penicillin, or penicillin plus once-daily gentamicin, or penicillin plus thrice-daily gentamicin, or no treatment. After the treatment period, bacterial densities within the vegetations (mean +/- SEM) were 6.06 +/- 0.30, 5.42 +/- 0.29, 4.98 +/- 0.10 and 9.97 +/- 0.16 log cfu/g for the four groups. All regimens produced significant reductions in bacterial density when compared with controls; penicillin plus thrice-daily gentamicin resulted in a significant difference from penicillin alone. Although once-daily regimens have proved effective in trials involving other organisms, such regimens do not appear to be so optimal for the treatment of enterococcal endocarditis.

Comparison of the bactericidal activities of piperacillin-tazobactam, ticarcillin-clavulanate, and ampicillin-sulbactam against clinical isolates of Bacteroides fragilis, Enterococcus faecalis, Escherichia coli, and Pseudomonas aeruginosa.

Owing to the broad spectrum of activity afforded by beta-lactam-beta-lactamase inhibitor preparations, these agents are frequently selected as empiric therapy for the treatment of mixed infections such as intra-abdominal and diabetic foot infections, either alone or in combination with an aminoglycoside. Twelve healthy volunteers were enrolled in a randomized, open-label, four-way crossover trial comparing the bactericidal activities of piperacillin-tazobactam, ticarcillin-clavulanate, and ampicillin-sulbactam against microorganisms commonly isolated from mixed infections. Subjects received the following regimes: (i) 3.375 g of piperacillin-tazobactam intravenously (i.v.) every 6 h (q6h) (ii) 4.5 g of piperacillin-tazobactam i.v. q8h, (iii) 3.1 g of ticarcillin-clavulanate i.v. q6h, and (iv) 3.0 g of ampicillin-sulbactam i.v. q6h. Serum bactericidal titers were determined and used to calculate the duration of measurable bactericidal activity over the dosing interval of each of the regimens against two clinical isolates of Bacillus fragilis, Escherichia coli, Enterococcus faecalis, and Pseudomonas aeruginosa. The percentage of the dosing interval over which drug concentrations in serum remained above the MIC for each organism was determined and compared with the observed duration of bactericidal activity was noted (r = 0.78; P < 0.001). All of the regimens demonstrated good activity against B. fragilis and E. coli. Against E. faecalis and P. aeruginosa, however, all of the regimens provided bactericidal activity for less than 50% of the respective dosing intervals. These data suggest that use of shorter dosing intervals or continuous-infusion regimens should be considered in combination with an aminoglycoside to improve the bactericidal profiles of these agents for E. faecalis and P. aeruginosa.

Disposition of ofloxacin in female New Zealand white rabbits.

Limited information exists regarding the disposition of ofloxacin in rabbits. Pharmacokinetic information is necessary for the design of appropriate therapeutic regimens for the treatment of organisms (e.g. Pasteurella multocida) commonly infecting this species. This study evaluated the pharmacokinetics of ofloxacin following intravenous (i.v.) and subcutaneous (s.c.) administration. Two groups of three female New Zealand White rabbits received a single dose of 20 or 40 mg/kg by the i.v. and s.c. routes. Samples were collected prior to drug administration, then 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 h postdose. Ofloxacin concentrations in serum were determined using a validated HPLC assay. Mean maximum concentrations were 66.86 +/- 10.83 mg/L and 14.1 +/- 2.20 mg/L for the i.v. and s.c. administration of 20 mg/kg. The 40 mg/kg dose produced maximum concentrations of 154.96 +/- 35.45 mg/L and 23.83 +/- 4.01 mg/L for the i.v. and s.c. doses, respectively. The area under concentration-time curve increased proportionally with the dose, while the half-life was unaltered and ranged from 1.5-1.9 h. From these data, it appears that a 20 mg/kg dose administered every 8 h by the s.c. route would optimize the pharmacodynamic profile of ofloxacin and provide an appropriate regimen for the treatment of many susceptible organisms which commonly infect this species.

Tetanus: pathophysiology and management.

OBJECTIVE: To review the epidemiology, pathophysiology, clinical manifestations, diagnosis, and management of tetanus and its complications. DATA SOURCES: MEDLINE and Iowa Drug Information Services databases were searched for literature pertaining to tetanus. Additional literature was obtained from the references of selected articles identified in the search. Information from all articles was considered for inclusion in the manuscript. STUDY SELECTION AND DATA EXTRACTION: Articles selected were those considered by the authors to assist in providing the reader an understanding of the epidemiology, pathophysiology, clinical manifestations, diagnosis, and management of tetanus. DATA SYNTHESIS: While the number of tetanus cases has decreased markedly since data reporting for the disease began in 1947, mortality among those who acquire the disease remains high. Elderly patients are particularly susceptible to tetanus and its complications. Prevention of tetanus focuses on primary immunization and scheduled boosters. Management of tetanus involves initial stabilization of the patient and protection of the airway, prevention of tetanospasmin absorption by administration of human tetanus immune globulin 3000-6000 IU, and eradication of Clostridium tetani with antimicrobial therapy (metronidazole 500 mg q8h). Supportive measures include the administration of neuromuscular blocking agents such as pancuronium in patients requiring artificial ventilation, as well as benzodiazepines (midazolam 5-15 mg/h) for sedation and muscle relaxation. Autonomic dysfunction should be managed with beta-adrenergic blockers such as propranolol or labetalol. CONCLUSIONS: Despite the relative infrequency of tetanus cases, mortality among untreated patients remains significantly high. Clinicians should become knowledgeable in the pathophysiology, clinical manifestations, and management of this potentially fatal disease.

Efficacy of vancomycin and teicoplanin alone and in combination with streptomycin in experimental, low-level vancomycin-resistant, VanB-type Enterococcus faecalis endocarditis.

The efficacy of vancomycin (VM) and teicoplanin (TE), alone and in combination with streptomycin (SM), against enterococci that express low-level VanB-type VM resistance was investigated in experimental endocarditis using isogenic strains of Enterococcus faecalis susceptible to glycopeptides and aminoglycosides or inducibly resistant to low levels of VM (MIC = 16 micrograms/ml). VM was significantly less active against the resistant strain than against the susceptible strain, establishing that low-level VanB-type VM resistance can influence therapeutic efficacy. By contrast, TE had equally good activity against both strains. VM or TE combined with SM was synergistic and bactericidal against the resistant strain in vitro. While both combinations were efficient in reducing bacterial density in vivo, TE plus SM was significantly superior to VM plus SM if valve sterilization was considered. These data suggest that despite the presence of low-level VanB-type resistance, combination therapy with a glycopeptide and SM (and presumably other aminoglycosides to which there is not high-level resistance) will nevertheless provide effective bactericidal activity.

Absorption of ciprofloxacin in patients with diabetic gastroparesis.

The purpose of this study was to assess the pharmacokinetic profile of ciprofloxacin in 12 patients with diabetic gastroparesis. Patients received both a single 500-mg oral (p.o.) dose and a single 400-mg intravenous (i.v.) dose of ciprofloxacin separated by a 1-week washout period. Pharmacokinetic parameters (means +/- standard deviations) for the p.o. and i.v. doses were as follows: areas under the concentration-time curve from 0 h to infinity, 9.74 +/- 2.59 and 11.78 +/- 3.18 micrograms.h/ml, respectively; maximum concentrations of drug in serum, 2.13 +/- 0.67 and 4.21 +/- 1.07 micrograms/ml, respectively; and half-lives, 4.03 +/- 0.58 and 4.20 +/- 0.58 h, respectively. The ratio of the areas under the concentration-time curves from 0 h to infinity for the p.o. and i.v. doses was 0.84, with a 90% confidence interval of 0.68 to 0.98; the mean absolute bioavailability was calculated to be 67% (range, 43 to 82%). From these data it appears that ciprofloxacin is adequately absorbed in patients with diabetic gastroparesis.

Influence of aspirin on development and treatment of experimental Staphylococcus aureus endocarditis.

Previously, we have shown that a 5-mg/kg of body weight daily dose of aspirin (ASA) caused reductions in the bacterial densities and weights of aortic vegetations in a rabbit model of Staphylococcus aureus endocarditis. We sought to determine (i) whether ASA dosage influences the development of vegetations and (ii) whether ASA given with antimicrobial therapy improves the treatment outcome of infective endocarditis. To study the influence of ASA dosage, animals received either no ASA (control) or oral doses of 2.5, 10, 20, and 50 mg/kg daily. The 2.5- and 10-mg/kg groups had statistically significant reductions in vegetation weight compared with untreated controls. The 10-mg/kg dose also resulted in a significant decrease in bacterial densities compared with those of the controls. Although reductions in weight and bacterial density were observed in other ASA-treated groups, these did not achieve statistical significance. To study the influence of ASA and antimicrobial therapy, the animals received either vancomycin alone or vancomycin with ASA. When ASA was given prior to and during antimicrobial therapy, a significant reduction in vegetation weight was observed. Additionally, the rate of sterilization was directly proportional to this observed reduction in weight. ASA's impact on the reduction of both the bacterial density and the weight of aortic vegetations is a dose-dependent phenomenon. When given with antimicrobial therapy, ASA not only reduces vegetation weight but also improves the rate of sterilization. This study provides additional data regarding the role of ASA in the treatment of endocarditis.

Clinical pharmacokinetics of newer cephalosporins.

Several new cephalosporins have been developed in recent years. These agents include several oral and parenteral agents with extended activity against Gram-negative pathogens. The pharmacokinetic literature for these agents is quite extensive; therefore, we have summarised this information and presented it in tabular form for critical comparison. With a few exceptions, the newer cephalosporins share similar pharmacokinetic properties. Cefixime, cefetamet pivoxil and ceftibuten differ from the others in that they exhibit nonlinear pharmacokinetic properties. The nonlinear nature of these agents is reflected by decreasing maximal concentrations with escalating doses of cefixime and cefetamet pivoxil, decreasing area under the serum concentration-time curve with increasing doses for cefixime, and a reduced bioavailability with large doses of ceftibuten. Attention to such characteristics aid the clinician in selecting appropriate dosage regimens that will optimise drug absorption. The majority of agents are primarily renally eliminated; however, renal elimination accounts for only 20% of cefixime elimination. The pharmacokinetic parameters noted for the newer cephalosporins are not influenced by multiple-dose administration, suggesting lack of drug accumulation over time. The pharmacodynamics of antimicrobials should be considered when extrapolating pharmacokinetic information into the clinical arena. In the case of the beta-lactams, the time which drug concentrations remain above some critical threshold, such as the minimal inhibitory concentration, appears to have the greatest influence on bactericidal activity. Therefore, it is important to select dosage regimens that will optimise the time serum concentrations remain above this threshold. We present an evaluation of these agents with respect to their activity against a variety of pathogens in an effort to demonstrate a pharmacokinetically-based process of antimicrobial selection.

Disposition kinetics of aspirin in female New Zealand white rabbits.

Limited information exists on the disposition of aspirin in rabbits. Such information is of value not only for treatment but also for development of experimental protocols with human applications. We evaluated the pharmacokinetics of aspirin at different doses by monitoring serum concentrations of the major metabolite, salicylic acid (SA). Four groups of six female New Zealand white rabbits received 2.5, 10, 20, or 50 mg of aspirin/kg of body weight. Aspirin was given once daily via the oral-gastric route, and blood samples were obtained after the third dose. Samples were collected before the last dose, then at 0.25, 0.50, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 12, and 24 h after dosing. Analysis of SA was completed by a validated assay on a high-performance liquid chromatography system. Mean maximal serum SA concentration was 7.54, 22.65, 43.2, and 70 micrograms/ml for the 2.5, 10, 20, and 50 mg/kg doses respectively. The total systemic clearance of SA was not altered by increasing doses of aspirin, but statistically significant differences were noted in the volume of distribution. The SA elimination half-life also increased proportionally with the aspirin dose. Bleeding tendency was associated with the highest dose of aspirin. Results of this study suggest that the 20 and 50 mg/kg dosages produced serum SA concentrations that simulate those observed in humans after 600-mg and 1.2-g aspirin doses respectively.

Enhanced killing of methicillin-resistant Staphylococcus aureus in human macrophages by liposome-entrapped vancomycin and teicoplanin.

The antibacterial effects of liposomal vancomycin and teicoplanin against intracellular methicillin-resistant Staphylococcus aureus (MRSA) were evaluated using a macrophage infection model. Human blood-derived monocytes were cultured for 7 days to obtain adherent macrophages. Uptake of each drug by macrophages was markedly enhanced by liposomal encapsulation. Following phagocytosis and removal of residual extracellular MRSA, the infected macrophages were exposed to clinically achievable concentrations of teicoplanin and vancomycin. The free (untrapped) and liposome-entrapped forms of each drug were used at the same concentration. The number of intracellular surviving bacteria was determined by colony counts after lysis of the macrophages at different time intervals following drug treatment. Intracellular antimicrobial effect of each drug was significantly (p < 0.001) increased by entrapment in liposomes. Also, the efficacies of the free and liposomal forms of both drugs were correspondingly comparable (p > 0.05). It is, therefore, concluded that liposomal encapsulation of vancomycin and teicoplanin results in an increased availability of the antibiotics for efficient elimination of intracellular MRSA infection.