Outcome and Adequacy of Empirical Antibiotherapy in Post-Operative Peritonitis: A Retrospective Study.

Background: Empirical antibiotherapy (EA) should target all bacteria in post-operative peritonitis (PP). Nevertheless, recent studies failed to prove a link between adequacy of EA and prognosis of PP. We sought to confirm this loss of association between adequate EA and prognosis and to analyze the evolution of patients' characteristics and antimicrobial strategies. Methods: This is was retrospective study. Patients with a positive fungal culture were excluded. The cohort was divided into two time periods. Data of survivors and non-survivors were compared within each time period. Differences between the two periods were assessed. A multivariable analysis searched for parameters associated with a higher hospital mortality rate. Results: Two hundred fifty-one patients were included, with 92 patients in the first period (P1) and 152 patients in the second period (P2). Inadequate EA was associated with a worse outcome only in P1. The multivariable analysis in the whole cohort showed that inadequate EA was associated with a higher mortality rate. When the differences noticed between the two periods were entered in the model (presence of resistant gram-positive cocci and EA comprising glycopeptides), inadequate EA was no longer associated with worse outcome. In P1, the most severe patients had more resistant bacteria, hence, had a higher rate of inadequate EA. This artifact disappeared in P2, during which broader antibiotherapies with triple EA were more often prescribed for the most severe patients. Conclusion: This study showed that the link between inadequate EA and outcome of patients with PP was at least partly artifactual in older studies.

Pseudomonas aeruginosa eradication therapy and risk of acquiring Aspergillus in young children with cystic fibrosis.

BACKGROUND: While Aspergillus detection rates in adults, adolescents and older children with cystic fibrosis (CF) have increased, the risk of acquiring this fungal pathogen in young children is unknown. AIM: To determine the risk and explanatory factors of acquiring Aspergillus in children with CF by age 5 years. METHODS: Cross-sectional analysis of clinical, bronchoalveolar lavage and treatment data from the Australasian Cystic Fibrosis Bronchoalveolar Lavage study was used to identify predictive factors for detecting Aspergillus at age 5 years. A parametric repeated time-to-event model quantitatively described the risk and factors associated with acquiring Aspergillus and Pseudomonas aeruginosa from birth until age 5 years. RESULTS: Cross-sectional analysis found that the number of P. aeruginosa eradication courses increased the odds of detecting Aspergillus at age 5 years (OR 1.61, 95% CI 1.23 to 2.12). The median (IQR) age for the first P. aeruginosa positive culture was 2.38 (1.32-3.79) years and 3.69 (1.68-4.74) years for the first Aspergillus positive culture. The risk of P. aeruginosa and Aspergillus events changes with time after the first year of study entry. It also decreases for P. aeruginosa after completing P. aeruginosa eradication (HR 0.15, 95% CI 0.00 to 0.79), but increases for Aspergillus events (HR 2.75, 95% CI 1.45 to 5.41). The risk of acquiring both types of events increases after having had a previous event. CONCLUSION: In young children with CF, completing P. aeruginosa eradication therapy and previous Aspergillus events are associated with increased risk of acquiring Aspergillus.

Brainstem auditory evoked responses in 37 dogs with otitis media before and after topical therapy.

OBJECTIVES: The objective of this study was to determine whether intra-aural administration of aqueous solutions of marbofloxacin, gentamicin, tobramycin and ticarcillin (used off-licence) was associated with changes in hearing as measured by brainstem auditory evoked responses. MATERIALS AND METHODS: Dogs diagnosed with otitis media (n=37) underwent brainstem auditory evoked response testing and then were treated for their ear disease. First, the external ear canal and middle ear were flushed with sterile saline followed by EDTA tris with 0·15% chlorhexidine. Then, a combination of aqueous antibiotic mixed with an aqueous solution of EDTA tris was instilled into the middle ear. Follow-up examinations were undertaken for each dog, and treatment was continued until there were no detected infectious organisms or inflammatory infiltrate. Brainstem auditory evoked response testing was repeated after resolution of the infection and discontinuation of therapy. RESULTS: Brainstem auditory evoked responses in dogs treated with aqueous solutions of marbofloxacin or gentamicin remained unchanged or improved after therapy of otitis media but were impaired in dogs treated with ticarcillin or tobramycin. CLINICAL SIGNIFICANCE: If off-licence use of topical antibiotics is deemed necessary in cases of otitis media, aqueous solutions of marbofloxacin and gentamicin appear to be less ototoxic than aqueous solutions of ticarcillin or tobramycin.

Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: II. cephalosporins and penicillins.

Acute pulmonary exacerbations (APE) are well-described complications of cystic fibrosis (CF) and are associated with progressive morbidity and mortality. Despite aggressive management with two or more intravenous anti-pseudomonal agents, approximately 25% of exacerbations will result in a loss of lung function. The aim of this review is to provide an evidence-based summary of pharmacokinetic/pharmacodynamic (PK/PD), tolerability, and efficacy studies utilizing anti-pseudomonal cephalosporins (i.e., ceftazidime and cefepime) and penicillins (i.e., piperacillin-tazobactam and ticarcillin-clavulanate) in the treatment of APE and to identify areas where further study is warranted. The ceftazidime and cefepime dosing ranges from the literature are 200-400 mg/kg/day divided every 6-8 hr, maximum 8-12 g/day, and 150-200 mg/kg/day divided every 6-8 hr, up to 6-8 g/day, respectively. The literature supported dosing ranges for piperacillin and ticarcillin are 350-600 mg/kg/day divided every 4 hr, maximum 18-24 g/day of piperacillin component, and 400-750 mg/kg/day divided every 6 hr, up to 24-30 g/day of ticarcillin component, respectively. As a large portion of CF patients will not regain their lung function following an APE, we suggest the need to optimize antibiotic dosing and dosing regimens used to treat an APE in efforts to improve outcomes for CF patients infected with Pseudomonas aeruginosa. Future studies are needed to determine the clinical efficacy of higher than FDA-approved doses of ceftazidime, cefepime, and ticarcillin-clavulanate in APE. The usefulness of high dose piperacillin (>600 mg/kg/day) may be limited due to treatment-related adverse effects. Further understanding of these adverse effects in CF patients is needed.

Biological efficacy and stability of diluted ticarcillin-clavulanic acid in the topical treatment of Pseudomonas aeruginosa infections.

Topical compounded Timentin(®) diluted with an inactive vehicle has been reported to be effective in the treatment of otitis externa caused by Pseudomonas aeruginosa. The aims of this study were to determine the biological efficacy of Timentin(®) (ticarcillin and clavulanic acid) when diluted in the carrier vehicle Methopt(®) against P. aeruginosa and to determine the efficacy and stability of Timentin(®) aqueous stock concentrate solution. Timentin(®) stock concentrate was tested against four P. aeruginosa isolates on days 0, 7, 14, 21 and 28; then after 2, 3, 4, 5, 6, 9 and 12 months of storage at 4 or -20°C. The diluted Timentin(®)-Methopt(®) solutions were tested against all isolates after 0, 2, 4, 6, 8, 10, 12, 14, 17, 21, 24 and 28 days of storage at 24 or 4°C. Minimal inhibitory concentration (MIC) levels for all strains were determined using the broth microdilution method. The MIC of the stock solution remained relatively constant and acceptable throughout the study when stored at -20°C and was also acceptable for shorter time periods (6-9 months) when stored at 4°C. The MIC for the diluted Timentin(®)-Methopt(®) solution remained relatively constant and acceptable throughout the study for all four bacterial strains, with no difference between the solutions stored at 4 or 24°C. The results of this study indicate that storage of the Timentin(®) stock solution at -20°C does not compromise efficacy for at least 12 months and that Timentin(®) diluted in Methopt(®) was stable for 28 days when stored at either 4 or 24°C.

The costs of treatment of early and chronic Pseudomonas aeruginosa infection in cystic fibrosis patients.

The aim of cystic fibrosis (CF) care is to improve both the life expectancy and quality of life of patients. However, rising costs and limited resources of health services must be taken into account. There are many different antibiotic strategies for therapy of Pseudomonas aeruginosa infection in CF patients. In this 5-year retrospective study we found that the cost of treatment of initial infection is considerably lower than the cost of treating chronic P. aeruginosa infections. The percentage distribution of costs of antibiotic treatment in relationship to the administration route was considerably different between outpatients and inpatients. We observed an increase in antibiotic costs with the age of the patient and the decrease in FEV(1)values. The implementation of early eradication treatment, in addition to decreasing the prevalence of patients chronically infected by P. aeruginosa, might also bring about a notable decrease in costs.

Cefepime versus ticarcillin and clavulanate potassium and aztreonam for febrile neutropenia therapy in high-dose chemotherapy patients.

An open labeled randomized trial comparing the efficacy and cost of empirically applied cefepime (C) as monotherapy versus combination therapy consisting of ticarcillin and clavulanate potassium and aztreonam (T/A) was performed in febrile neutropenic patients following high-dose chemotherapy (HDC) +/- radiation, with or without peripheral blood stem cell support. Over a 28-month period, 126 patients were screened and included in the study. Using afebrile status following 3 days of therapy as a primary endpoint, both regimens produced comparable clinical response rates (C = 55% vs. T/A = 61%). Also, the use of vancomycin for resistant gram-positive infections and alteration of gram-negative infection coverage was similar in both groups (C = 40% vs. T/A = 47% and C = 29% vs. T/A = 24%). Both treatment groups had similar needs for empirical antifungal therapy (C = 25% vs. T/A = 22%). There was a postrandomization difference between the two groups in that the "C" group had a significantly higher number of allogeneic transplants and non-stem-cell-supported patients, whereas the "T/A" group had a significantly greater number of autologous peripheral blood stem cell patients (p < 0.0001). Despite this difference, the C group had a significantly lower cost ratio than the T/A group (p = 0.016). In conclusion, we have shown that C treatment of febrile neutropenic patients following HDC results in similar efficacy and lower cost when compared to T/A, despite the inclusion of higher risk patients in the C group.

[Hepatic inflammatory pseudotumor regressing with antibiotic therapy]. / Pseudo-tumeur inflammatoire hépatique régressant sous antibiothérapie.

INTRODUCTION: Inflammatory hepatic pseudo-tumors are rare, non-neoplastic lesions, and their diagnosis is usually made on hepatectomy samples. OBSERVATION: The general health of a 77 year-old patient was suddenly altered and clinical examination (and scan) revealed a hepatic tumor. Diagnosis of inflammatory hepatic pseudo-tumor was evoked by analysis of a biopsy. In view of the age and the general state of the patient we chose prolonged antibiotic therapy rather than hepatic surgery. Nine months later, the tumor had regressed. COMMENTS: Because they are rare (100 cases described), hepatic pseudo-tumors raise two questions: can diagnosis be made simply by biopsy or should one always analyze the complete sample and, if hepatectomy is contraindicated, is non-surgical treatment effective? The progression of our patient permits us to reply positively to both questions.

Once-daily, high-dose levofloxacin versus ticarcillin-clavulanate alone or followed by amoxicillin-clavulanate for complicated skin and skin-structure infections: a randomized, open-label trial.

This study tested whether levofloxacin, at a new high dose of 750 mg, was effective for the treatment of complicated skin and skin-structure infections (SSSIs). Patients with complicated SSSIs (n=399) were randomly assigned in a ratio of 1:1 to 2 treatment arms: levofloxacin (750 mg given once per day intravenously [iv], orally, or iv/orally) or ticarcillin-clavulanate (TC; 3.1 g given iv every 4-6 hours) followed, at the investigator's discretion, by amoxicillin-clavulanate (AC; 875 mg given orally every 12 hours). In the clinically evaluable population, therapeutic equivalence was demonstrated between the levofloxacin and TC/AC regimens (success rates of 84.1% and 80.3%, respectively). In the microbiologically evaluable population, the overall rate of eradication was 83.7% in the levofloxacin treatment group and 71.4% in the TC/AC treatment group (95% confidence interval, -24.3 to -0.2). Both levofloxacin and TC/AC were well tolerated. These data demonstrate that levofloxacin (750 mg once per day) is safe and at least as effective as TC/AC for complicated SSSIs.

Effect of parenteral antibiotic administration on the establishment of colonization with vancomycin-resistant Enterococcus faecium in the mouse gastrointestinal tract.

A mouse model of intestinal colonization with vancomycin-resistant enterococci (VRE) was used to study the effect of different beta-lactam antibiotics on establishment of VRE colonization. A clinical VanB VRE isolate, Enterococcus faecium C68 (102 or 104 cfu), was inoculated by gastric gavage in conjunction with subcutaneous administration of antibiotics. The MIC of ceftriaxone and ticarcillin against VRE strain C68 is >10,000 microg/mL, and the MIC of piperacillin is 1250 microg/mL. Ceftriaxone and ticarcillin-clavulanate treatment groups developed persistently high levels of stool VRE compared with both the saline and the piperacillin-tazobactam (Pip-Taz) groups (P<.008). The level of stool VRE in the Pip-Taz group did not differ from that for the saline group. Thus, in this mouse model, beta-lactam antibiotics with minimal anti-enterococcal activity promoted establishment of high-level VRE colonization, but Pip-Taz (a beta-lactam antibiotic with more potent activity against VRE) did not.

Case of sepsis caused by Bifidobacterium longum.

We report a case of sepsis caused by Bifidobacterium longum in a 19-year-old male who had developed high fever, jaundice, and hepatomegaly after acupuncture therapy with small gold needles. Anaerobic, non-spore-forming, gram-positive bacilli were isolated from his blood and finally identified as B. longum. He recovered completely after treatment with ticarcillin and metronidazole. To our knowledge, this is the first report of incidental sepsis caused by B. longum.

Endocarditis caused by Stenotrophomonas maltophilia: case report and review.

Stenotrophomonas (Xanthomonas) maltophilia is a rare cause of endocarditis. The extensive resistance of this organism to several antibiotics leaves few options for antimicrobial therapy. In vitro synergism of the combination of trimethoprim-sulfamethoxazole (TMP-SMZ) and ticarcillin/clavulanic acid (TIC/CA) has been demonstrated. To our knowledge, we report the first case of ventriculoatrial cerebrospinal fluid shunt-associated endocarditis due to S. maltophilia. The patient was cured with combination therapy with TMP-SMZ and TIC/CA along with catheter removal. This is also the first report of S. maltophilia endocarditis successfully treated with this antibiotic combination. In a review of the medical literature, only 16 cases of S. maltophilia endocarditis were found. Most patients were intravenous drug users (43.8%) or had either prosthetic heart valves (50%) or an indwelling vascular catheter (18.8%). Although S. maltophilia is usually considered a nosocomial pathogen, about one-half of the cases were community-acquired. Twelve of sixteen patients had left-sided endocarditis. Therapy with a combination of two or more antibiotics was employed in most cases. Seven patients had been given TMP-SMZ therapy, but none had been treated with TIC/CA before. One-half of the patients required cardiac surgery. The overall mortality rate was 33%. Although the optimal antibiotic treatment for S. maltophilia endocarditis remains unknown, the case reported herein reinforces in vitro findings that the combination of TMP-SMZ and TIC/CA may be effective therapy.

Stenotrophomonas maltophilia: emergence of multidrug-resistant strains during therapy and in an in vitro pharmacodynamic chamber model.

Emergence of Stenotrophomonas maltophilia as a nosocomial pathogen is becoming increasingly apparent. Pleiotropic resistance characterizes S. maltophilia. Furthermore, a slow growth rate and an increased mutation rate generate discordance between in vitro susceptibility testing and clinical outcome. Despite original susceptibility, drug-resistant strains of S. maltophilia are often recovered from patients receiving beta-lactams, quinolones, or aminoglycosides. Given the disparity among various in vitro susceptibility methods, this study incorporated a unique pharmacodynamic model to more accurately characterize the bacterial time-kill curves and mutation rates of four clinical isolates of S. maltophilia following exposure to simulated multidose regimens of ceftazidime, ciprofloxacin, gentamicin, and ticarcillin-clavulanate. Time-kill data demonstrated regrowth of S. maltophilia with all four agents. With the exception of ticarcillin-clavulanate, viable bacterial counts at the end of 24 h exceeded the starting inoculum. Ciprofloxacin only reduced bacterial counts by less than 1.0 log prior to rapid bacterial regrowth. Resistant mutant strains, identical to their parent strain by pulsed-field gel electrophoresis, were observed following exposure to each class of antibiotic. Mutant strains also had distinct susceptibility patterns. These data are consistent with previous reports which suggest that S. maltophilia, despite susceptibility data that imply that the organism is sensitive, develops multiple forms of resistance quickly and against several classes of antimicrobial agents. Standard in vitro susceptibility methods are not completely reliable for detecting resistant S. maltophilia strains; and therefore, interpretation of these results should be done with caution. In vivo studies are needed to determine optimal therapy against S. maltophilia infections.

Piperacillin/tazobactam compared with ticarcillin/clavulanate in community-acquired bacterial lower respiratory tract infection.

The efficacy and safety of a new combination parenteral antibiotic, piperacillin/tazobactam, was compared with that of parenteral ticarcillin/clavulanate in the treatment of adult patients with community-acquired lower respiratory tract infections. A total of 299 patients were enrolled in this multicentre, double-blind, comparative study; 177 received piperacillin/tazobactam and 122 received ticarcillin/clavulanate. Of these, 119 met the evaluability criteria (69, piperacillin/tazobactam and 50, ticarcillin/clavulanate). The study drugs (piperacillin/tazobactam 3 g/375 mg or ticarcillin/clavulanate 3 g/100 mg) were given every 6 h by slow iv infusion for a minimum of 5 days. The favourable clinical response (cured and improved) rates of evaluable patients were 84% and 64% at endpoint (P < 0.01) for piperacillin/tazobactam and ticarcillin/clavulanate, respectively. The favourable bacteriological response at the early follow-up (eradicated and presumed eradicated) were 91% and 67% for piperacillin/tazobactam and ticarcillin/clavulanate, respectively (P < 0.01). At endpoint, 84% and 64%, respectively (P = 0.02) had a favourable response. The most common adverse experiences involved the gastrointestinal tract and occurred in 31.6% of the piperacillin/tazobactam group compared with 20.5% in the ticarcillin/clavulanate group (P = 0.02). These events were mild and generally did not affect therapy. Piperacillin/tazobactam appears to be more effective than ticarcillin/clavulanate in this patient population and is generally well tolerated.

Necrotizing fasciitis: a classification of necrotizing soft tissue infections.

Necrotizing fasciitis is a rare, often fatal soft tissue infection. It still remains a confusing entity because of the nomenclature and multiple subtypes described in the past. An interesting case study of a patient with necrotizing fasciitis secondary to nonclostridial gas gangrene is presented. A comprehensive review of necrotizing fasciitis, its disease process and treatment modalities will be discussed.

In vitro evaluation of newer beta-lactam antibiotics against gram negative bacilli isolated from neutropenic patients.

The in-vitro susceptibility pattern to newer beta lactams namely Ticer/Clav, Azlocillin, Piperacillin and Imipenem was determined with 50 clinical strains isolated from neutropenic patients with strains isolated from neutropenic patients with sepsis, with an objective of evolving a strategy for empirical antibiotic therapy for febrile neutropenic patients. The MIC90 value for Imipenem for the Gram negative bacilli tested, other than Pseudomonas was < 0.25 mcg/ml therapy revealing a high degree of susceptibility, while for Ps. aeruginosa and related species MIC50 and MIV90 values were 2.0 and 64.0 micrograms/ml respectively. A comparatively lower degree of susceptibility was found among Gram negative bacilli included in the study to ticar/clavu, azlocillin and piperacillin indicating a moderate degree of resistance to these antibiotics. The data from this study suggests that (i) Ureidopenicillins with an aminoglycoside should be effective therapy for proven Pseudomonas and other Gram negative sepsis in febrile neutropenic patients. (ii) Imipenem would be the antibiotic of choice in Gram negative bacterial sepsis in febrile neutropenic patients where the organism is resistant to cephalosporins and ureidopenicillins.

Efficacy and safety of piperacillin/tazobactam in skin and soft tissue infections.

Piperacillin/tazobactam has excellent in vitro activity against the most pathogens involved in skin infections. Two large multicentre studies recently evaluated the efficacy and safety of piperacillin/tazobactam in the treatment of skin and soft tissue infections in patients in hospital. The efficacy and safety of piperacillin/tazobactam (4 g/500 mg every 8 hours) have been assessed in an open study in Europe. Among 120 evaluable patients, 93% were clinically cured or improved. Only six patients were withdrawn from the study because of side effects. In another trial, piperacillin/tazobactam were compared with ticarcillin/clavulanate in a double-blinded prospective study in the United States. Of evaluable patients, 67 received piperacillin/tazobactam (3 g/375 mg every 6 hours) and 44 received ticarcillin/clavulanate (3 g/100 mg every 6 hours). At assessment, 76% of patients given piperacillin/tazobactam and 77% of patients given ticarcillin/clavulanate had responded favourably. The lower success rate in this trial may be attributed to more stringent inclusion criteria that resulted in the incorporation of a higher proportion of patients with more severe conditions including diabetic/ischaemic foot infections. The incidence of adverse reactions was similar in both groups. Piperacillin/tazobactam seems to be both effective and safe in the treatment of skin and soft tissue infections in patients confined to hospital.

Comparative efficacies of ticarcillin, ticarcillin/clavulanic acid, piperacillin and cefoxitin against polymicrobial infections in mice caused by Escherichia coli and Bacteroides fragilis.

A model of localised abscess formation was used to establish mixed infections caused by Escherichia coli and Bacteroides fragilis. The beta-lactamase producing, ticarcillin-resistant strains E. coli E96 and B. fragilis VPI 8708 were used to produce one infection, and in another infection, a beta-lactamase hyperproducing strain E. coli 41548 was combined with a ticarcillin-susceptible strain, B. fragilis B3. Treatment, at doses producing clinically achievable concentrations in mouse serum, began 1 h after inoculation, and continued three times daily for four days. Bacterial numbers in infected tissue were measured at intervals. Against both infections, ticarcillin was ineffective in preventing bacterial growth and abscess formation in all mice. Piperacillin prevented abscess formation in 60% of the mice infected with E. coli E96/B. fragilis VPI 8708, and in 40% of those in the E. coli 41548/B. fragilis B3 group. Therapy with ticarcillin/clavulanic acid or cefoxitin reduced the number of both organisms at the site of infection, and thus prevented abscess formation in 100% treated animals.

Antibiotic therapy of intra-abdominal sepsis in the elderly: experience with ticarcillin and clavulanic acid.

Age is a major factor in determining the outcome for older patients with intra-abdominal sepsis. Poor outcome in these patients may be related to a number of physiologic and immunologic changes associated with aging. The treatment of intra-abdominal sepsis can itself pose special risks for the elderly. Standard regimens containing aminoglycosides have a substantial risk of nephrotoxicity, which is magnified in elderly patients. Alternatives to standard aminoglycoside-containing regimens, therefore, are desirable. Most intra-abdominal infections involve multiple pathogens, usually both aerobic and anaerobic. The polymicrobial nature of intra-abdominal sepsis mandates antimicrobial chemotherapy effective against a broad range of organisms. In the past several years, a host of new antibiotics have been introduced that used alone or in combination with other drugs has the potential of safely avoiding aminoglycosides in many patients with intra-abdominal sepsis. One such agent, ticarcillin with clavulanate potassium, is active against a wide spectrum of aerobic and anaerobic pathogens. In a prospective, randomized, open label trial, ticarcillin and clavulanate was compared with gentamicin and clindamycin. Although the sample size was too small to allow meaningful statistical comparisons of efficacy and safety, both regimens were effective and well tolerated. In general, prolonged administration of aminoglycosides is rarely indicated for the treatment of intra-abdominal sepsis in the elderly, although initial empiric use of aminoglycosides may sometimes be warranted.