Combined Treatment of 6-Gingerol Analog and Tobramycin for Inhibiting Pseudomonas aeruginosa Infections.

Pseudomonas aeruginosa is a ubiquitous human pathogen that causes severe infections. Although antibiotics, such as tobramycin, are currently used for infection therapy, their antibacterial activity has resulted in the emergence of multiple antibiotic-resistant bacteria. The 6-gingerol analog, a structural derivative of the main component of ginger, is a quorum sensing (QS) inhibitor. However, it has a lower biofilm inhibitory activity than antibiotics and the possibility to cause toxicity in humans. Therefore, novel and more effective approaches for decreasing dosing concentration and increasing biofilm inhibitory activity are required to alleviate P. aeruginosa infections. In this study, a 6-gingerol analog was combined with tobramycin to treat P. aeruginosa infections. The combined treatment of 6-gingerol analog and tobramycin showed strong inhibitory activities on biofilm formation and the production of QS-related virulence factors of P. aeruginosa compared to single treatments. Furthermore, the combined treatment alleviated the infectivity of P. aeruginosa in an insect model using Tenebrio molitor larvae without inducing any cytotoxic effects in human lung epithelial cells. The 6-gingerol analog showed these inhibitory activities at much lower concentrations when used in combination with tobramycin. Adjuvant effects were observed through increased QS-disrupting processes rather than through antibacterial action. In particular, improved RhlR inactivation by this combination is a possible target for therapeutic development in LasR-independent chronic infections. Therefore, the combined treatment of 6-gingerol analog and tobramycin may be considered an effective method for treating P. aeruginosa infections. IMPORTANCE Pseudomonas aeruginosa is a pathogen that causes various infectious diseases through quorum-sensing regulation. Although antibiotics are mainly used to treat P. aeruginosa infections, they cause the emergence of resistant bacteria in humans. To compensate for the disadvantages of antibiotics and increase their effectiveness, natural products were used in combination with antibiotics in this study. We discovered that combined treatment with 6-gingerol analog from naturally-derived ginger substances and tobramycin resulted in more effective reductions of biofilm formation and virulence factor production in P. aeruginosa than single treatments. Our findings support the notion that when 6-gingerol analog is combined with tobramycin, the effects of the analog can be exerted at much lower concentrations. Furthermore, its improved LasR-independent RhlR inactivation may serve as a key target for therapeutic development in chronic infections. Therefore, the combined treatment of 6-gingerol analog and tobramycin is suggested as a novel alternative for treating P. aeruginosa infections.

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.

The pharmacokinetics and toxicity of morning vs. evening tobramycin dosing for pulmonary exacerbations of cystic fibrosis: A randomised comparison.

BACKGROUND: Circadian variation in renal toxicity of aminoglycosides has been demonstrated in animal and human studies. People with CF are frequently prescribed aminoglycosides. Altered pharmacokinetics of aminoglycosides are predictive of toxicity. AIM: To investigate whether the time of day of aminoglycoside administration modulates renal excretion of tobramycin and toxicity in children with CF. To determine whether circadian rhythms are disrupted in children with CF during hospital admission. METHODS: Children (age 5-18years) with CF scheduled for tobramycin therapy were randomly allocated to receive tobramycin at 0800 or 2000h. Serum tobramycin levels were drawn at 1h and between 3.5 and 5h post-infusion between days 5 and 9 of therapy. Melatonin levels were measured serially at intervals from 1800h in the evening until 1200h on the next day. Circadian rhythm was categorised as normal when dim light melatonin onset was demonstrated between 1800 and 2200h and/or peak melatonin levels were observed during the night. Weight and spirometry were measured at the start and end of the therapy. Urinary biomarkers of kidney toxicity (KIM1, NAG, NGAL, IL-18 and CysC) were assayed at the start and end of the course of tobramycin. RESULTS: Eighteen children were recruited to the study. There were no differences in renal clearance between the morning and evening groups. The increase in urinary KIM-1 was greater in the evening dosage group compared to the morning group (mean difference, 0.73ng/mg; 95% CI, 0.14 to 1.32; p=0.018). There were no differences in the other urinary biomarkers. There was normal circadian rhythm in 7/11 participants (64%). CONCLUSIONS: Renal elimination of tobramycin was not affected by the time of day of administration. Urinary KIM-1 raises the possibility of greater nephrotoxicity with evening administration. Four children showed disturbed circadian rhythm and high melatonin levels (ClinicalTrials.gov NCT01207245).

Topical antibiotics for the management of bacterial keratitis: an evidence-based review of high quality randomised controlled trials.

BACKGROUND: Severe bacterial keratitis (BK) typically requires intensive antimicrobial therapy. Empiric therapy is usually with a topical fluoroquinolone or fortified aminoglycoside-cephalosporin combination. Trials to date have not reached any consensus as to which antibiotic regimen most effectively treats BK. METHODS: A systematic review and meta-analysis using Cochrane methodology was undertaken to evaluate the effectiveness of topical antibiotics in the management of BK. Outcomes included treatment success, time to cure, serious complications of infection and adverse effects. RESULTS: A comprehensive search for trials resulted in 27 956 abstracts for review. This eventually resulted in 16 high quality trials involving 1823 participants included in the review. Treatment success, time to cure and serious complications of infection were comparable among all antibiotic treatments included in the review. Furthermore, there was no evidence of difference in the risk of corneal perforation with any included antibiotics or antibiotic classes. Fluoroquinolones significantly reduced risk of ocular discomfort and chemical conjunctivitis but increased the risk of white precipitate formation compared with aminoglycoside-cephalosporin. Fortified tobramycin-cefazolin was approximately three times more likely to cause ocular discomfort than other topical antibiotics. CONCLUSIONS: Results of this review suggest no evidence of difference in comparative effectiveness between fluoroquinolones and aminoglycoside-cephalosporin treatment options in the management of BK. There were differences in safety profile, however. Fluoroquinolones decreased the risk of ocular discomfort and chemical conjunctivitis while ciprofloxacin increased the risk of white corneal precipitate compared with aminoglycoside-cephalosporin.

Evaluation of moxifloxacin 0.5% in treatment of nonperforated bacterial corneal ulcers: a randomized controlled trial.

PURPOSE: To compare the equivalence of moxifloxacin 0.5% with a combination of fortified cefazolin sodium 5% and tobramycin sulfate 1.3% eye drops in the treatment of moderate bacterial corneal ulcers. DESIGN: Randomized, controlled, equivalence clinical trial. PARTICIPANTS AND CONTROLS: Microbiologically proven cases of bacterial corneal ulcers were enrolled in the study and were allocated randomly to 1 of the 2 treatment groups. INTERVENTION: Group A was given combination therapy (fortified cefazolin sodium 5% and tobramycin sulfate) and group B was given monotherapy (moxifloxacin 0.5%). MAIN OUTCOME MEASURES: The primary outcome variable for the study was percentage of the ulcers healed at 3 months. The secondary outcome variables were best-corrected visual acuity and resolution of infiltrates. RESULTS: Of a total of 224 patients with bacterial keratitis, 114 patients were randomized to group A, whereas 110 patients were randomized to group B. The mean ± standard deviation ulcer size in groups A and B were 4.2 ± 2 and 4.41 ± 1.5 mm, respectively. The prevalence of coagulase-negative Staphylococcus (40.9% in group A and 48.2% in group B) was similar in both the study groups. A complete resolution of keratitis and healing of ulcers occurred in 90 patients (81.8%) in group A and 88 patients (81.4%) in group B at 3 months. The observed percentage of healing at 3 months was less than the equivalence margin of 20%. Worsening of ulcer was seen in 18.2% cases in group A and in 18.5% cases in group B. Mean time to epithelialization was similar, and there was no significant difference in the 2 groups (P = 0.065). No serious events attributable to therapy were reported. CONCLUSIONS: Corneal healing using 0.5% moxifloxacin monotherapy is equivalent to that of combination therapy using fortified cefazolin and tobramycin in the treatment of moderate bacterial corneal ulcers. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

[Efficacy and future of the aerosoltherapy in the treatment of cystic fibrosis patients infected by Pseudomonas aeruginosa]. / Efficacité et avenir de l'aérosolthérapie dans le traitement des infections à Pseudomonas aeruginosa chez les patients atteints de mucoviscidose.

Pseudomonas aeruginosa is considered as the most redoubtable pathogenic agent at cystic fibrosis patients. Its eradication is a priority to avoid the passage to chronic infection, the real turning point of the disease. For this, a wide therapeutic panel of intravenous antibiotics exists, and for some years, the research teams concentrate more and more on the inhaled way. The synthesis of the literature data presented herein focuses on both already experienced molecules (colistin and tobramycin), and on new therapeutics. This review aims at loosening advantages and inconveniences of each of these therapeutic options, while bringing to light the necessity of follow-up studies in order to prove the therapeutic interests of molecules in development.

Randomized clinical study for comparative evaluation of fourth-generation fluoroquinolones with the combination of fortified antibiotics in the treatment of bacterial corneal ulcers.

PURPOSE: Comparative evaluation of efficacy of monotherapy with moxifloxacin (0.5%) or gatifloxacin (0.3%) with combination therapy of cefazolin (5%) and tobramycin (1.3%) in treatment of bacterial corneal ulcers. METHODS: Patients diagnosed with bacterial keratitis (ulcer diameter 2-8 mm) were randomized to 1 of the 3 treatment groups (tobramycin 1.3% and cefazolin 5%, gatifloxacin 0.3%, or moxifloxacin 0.5%). After obtaining corneal scrapings, assigned study medication was instilled hourly for 48 hours and tapered as per clinical response. Healing of ulcer, duration to cure, adverse reactions, antibiogram profile, treatment failures, final visual acuity, and corneal opacity size were evaluated. RESULTS: A total of 61 patients were enrolled [cefazolin and tobramycin (n = 20), gatifloxacin (n = 21), and moxifloxacin (n = 20)]. Overall, 57 patients (93%) healed on treatment. On comparison of the mean time taken to heal, no statistically significant difference was found among all the 3 treatment groups (P = 0.98). Positive bacterial culture was obtained in only 38 patients (62%). There was no significant difference in the bacterial isolates in each treatment group. There were 4 (7%) treatment failures (perforation or nonhealing ulcer): 1 (5%) each in moxifloxacin and gatifloxacin group and 2 (10%) in fortified antibiotics group. All regimens were well tolerated. CONCLUSION: The study failed to find a difference in the efficacy of monotherapy with fourth-generation fluoroquinolones in the treatment of bacterial corneal ulcers of 2-8 mm size when compared with combination therapy of fortified antibiotics.

Exploratory study of the prevalence and clinical significance of tobramycin-mediated biofilm induction in Pseudomonas aeruginosa isolates from cystic fibrosis patients.

Exposure to aminoglycoside antibiotics induces biofilm formation by a laboratory strain of the cystic fibrosis (CF) pathogen Pseudomonas aeruginosa. Here, we detected this effect among about half of the clinical isolates from CF patients in a cross-sectional collection, suggesting that biofilm induction may represent a common mechanism of inducible aminoglycoside resistance in CF infections. This induction always occurred at the same tobramycin concentration regardless of MIC, suggesting that the mechanisms of killing and induction may be separable.

Early anti-pseudomonal acquisition in young patients with cystic fibrosis: rationale and design of the EPIC clinical trial and observational study'.

BACKGROUND: The primary cause of morbidity and mortality in patients with cystic fibrosis (CF) is progressive obstructive pulmonary disease due to chronic endobronchial infection, particularly with Pseudomonas aeruginosa (Pa). Risk factors for and clinical impact of early Pa infection in young CF patients are less well understood. PURPOSE: The present studies are designed to evaluate risk factors and outcomes associated with early Pa acquisition, and the benefits and harms of four anti-pseudomonal treatment regimens in young CF patients initiated after the first Pa positive respiratory culture. METHODS: The Early Pseudomonas Infection Control (EPIC) program consists of two studies, a randomized multicenter trial in CF patients ages 1-12 years at first isolation of Pa from a respiratory culture, and a longitudinal cohort study enrolling Pa-negative patients. Using a factorial design, trial participants are assigned for 18 months to either anti-pseudomonal treatment on a scheduled quarterly basis (cycled therapy) or based on recovery of Pa from quarterly respiratory cultures (culture-based therapy). The study drugs include inhaled tobramycin (300 mg BID) for 28 days, combined with either oral ciprofloxacin (15-20 mg/kg BID) or oral placebo for 14 days. The primary endpoints of the trial are the time to pulmonary exacerbation requiring IV antibiotics or hospitalization for respiratory symptoms, and the proportion of patients with new Pa-positive respiratory cultures during the study. The broad goals of the observational study are to describe the risk factors and outcomes associated with early acquisition of Pa. 306 patients were randomized in the clinical trial and 1787 were enrolled in the cohort study. CONCLUSIONS: These companion studies will provide valuable epidemiological and microbiological information on early CF lung disease and Pa acquisition, and safety and clinical efficacy data on anti-pseudomonal treatment strategies for early Pa infections in the airways of young children with CF.

Clinical efficacy of moxifloxacin in the treatment of bacterial keratitis: a randomized clinical trial.

PURPOSE: To determine the clinical efficacy and safety of moxifloxacin (1.0%) in patients with bacterial keratitis compared with patients treated with ofloxacin (0.3%) or fortified tobramycin (1.33%)/cephazolin (5%). DESIGN: Prospective randomized trial. PARTICIPANTS: A total of 229 patients diagnosed with bacterial keratitis were enrolled in the study; 78 patients were randomized to the fortified tobramycin/cephazolin group, 77 patients to the moxifloxacin group, and 74 patients to the ofloxacin group. A total of 225 patients were evaluable for safety and 198 patients were included in the efficacy analysis. INTERVENTION: After corneal specimens were obtained, the assigned study medication was instilled every hour, day and night, for 48 hours and on the third day, every hour by day and every 2 hours at night. For days 4 and 5, 1 drop every 2 hours by day and every 4 hours at night, and for days 6 and 7, 1 drop every 4 hours. After day 7, the antibiotic was tapered to every 6 hours and stopped when appropriate. MAIN OUTCOME MEASURES: Resolution of keratitis and healing of ulcer, time to cure, mean time to discharge, clinical sign score, adverse reactions to study medication, and treatment failures. RESULTS: Of the 186 nonexiting patients, resolution of the keratitis and healing of the ulcer occurred in 175 (94%) nonexiting patients. In the 175 patients in whom the corneal ulcer was cured, there were no statistically significant differences between the treatment groups for the mean time to cure (P = 0.25). There were no statistically significant differences between the 3 treatment groups in the various sign parameters including the sign score. A positive bacterial corneal culture was obtained in 190 (83%) of the 229 enrolled patients. The distribution of the species of bacterial organisms was similar in each treatment group and no significant difference in the percentage of isolates between the groups was observed. Twelve (5.2%) of the treated patients had serious complications (perforation or enucleation). No serious events attributable to therapy occurred during the study and all treatments were safe and well tolerated. CONCLUSION: No difference in healing rate, cure rate, or complications between fortified cephazolin and tobramycin, ofloxacin, or moxifloxacin was seen in this study.

Addition of inhaled tobramycin to ciprofloxacin for acute exacerbations of Pseudomonas aeruginosa infection in adult bronchiectasis.

RATIONALE: Pseudomonas aeruginosa lung infection in patients with bronchiectasis, a chronic airway disease that is characterized by episodes of exacerbation, is associated with more severe disease and a higher utilization of health-care resources. Inhaled tobramycin solution reduces the number of acute exacerbations in patients with cystic fibrosis (CF)-related bronchiectasis with P aeruginosa infection but remains untested in the treatment of exacerbations in patients with non-CF bronchiectasis. OBJECTIVES: This study tested the effect of adding inhaled tobramycin solution to oral ciprofloxacin (Cip) for the treatment of acute exacerbations of non-CF bronchiectasis in patients with P aeruginosa infection. METHODS: A double-blind, randomized, active comparator, parallel-design study conducted at 17 study centers (5 in the United Kingdom, and 12 in the United States) compared 2 weeks of therapy with Cip with either an inhaled tobramycin solution or placebo in 53 adults with known P aeruginosa infection who were having acute exacerbations of bronchiectasis. MEASUREMENTS: Clinical symptoms, pulmonary function, clinical efficacy, and sputum microbiology were investigated prospectively. MAIN RESULTS: An inhaled solution of Cip with tobramycin, compared to placebo, achieved greater microbiological response but no statistically significant difference in clinical efficacy at days 14 or 21. Clinical and microbiological outcomes at the test of cure (ie, the clinical outcome assessment at day 21) were concordant when an inhaled tobramycin solution was added to therapy with Cip and compared to placebo (p = 0.01). Both subject groups had similar overall adverse event rates, but subjects receiving therapy with an inhaled tobramycin solution reported an increased frequency of wheeze (50%; placebo group, 15%). CONCLUSIONS: The addition of an inhaled tobramycin solution to therapy with oral Cip for the treatment of acute exacerbations of bronchiectasis due to P aeruginosa improved microbiological outcome and was concordant with clinical outcome; the inability to demonstrate an additional clinical benefit may have been due to emergent wheeze resulting from treatment.

Ototoxic drugs and sensorineural hearing loss following severe neonatal respiratory failure.

AIM: To determine relationships between ototoxic drugs and 4-y sensorineural hearing loss (SNHL) in near-term and term survivors of severe neonatal respiratory failure. METHODS: All 81 survivors of the Canadian arm of the Neonatal Inhaled Nitric Oxide Study (mortality 32, loss to follow-up 9) received loop diuretics, aminoglycosides, and neuromuscular blockers (NMB), and 50 received vancomycin as neonates. Prospective, longitudinal secondary outcome using audiological tests diagnosed late-onset, progressive SNHL in 43 (53%); not flat (sloping) in 29, flat (severe to profound) in 14. Risk for SNHL was determined. RESULTS: A combination of duration of diuretic use of >14 d and average NMB dose of >0.96 mg/kg/d contributed to SNHL among survivors (odds ratio 5.2; 95% CI 1.6, 16.7). Markers of illness severity did not contribute. Dosage or duration of aminoglycosides use did not relate to SNHL. Cumulative dosages and duration of use of diuretics; NMB; use of vancomycin; and overlap of diuretics with NMB, aminoglycosides, and vancomycin individually linked to SNHL (p<0.001). CONCLUSION: Overuse of loop diuretics and/or NMB contributes to SNHL after neonatal respiratory failure; markers of illness severity or the appropriate administration of aminoglycosides do not.

A clinical comparison of two formulations of tobramycin 0.3% eyedrops in the treatment of acute bacterial conjunctivitis.

PURPOSE: To compare the safety and efficacy of a new enhanced viscosity ophthalmic formulation of tobramycin, given twice daily (BID), with the existing four times daily (QID) treatment regimen in patients with acute bacterial conjunctivitis. METHODS: This was a 12-day, multicenter, observer-masked, randomized, parallel group study. Patients received one drop of tobramycin 0.3% (3 mg/mL) enhanced viscosity ophthalmic solution BID or tobramycin 0.3% (3 mg/mL) ophthalmic solution QID in the affected eyes for 7 days. The primary efficacy variable was the percentage of patients with sustained cure/presumed bacterial eradication based on clinical judgment at the test-of-cure visit (Day 12). Pretherapy bacterial isolates were obtained and tested for susceptibility to tobramycin by determination of minimum inhibitory concentrations (MIC). RESULTS: A total of 276 patients were enrolled in the study and 203 of these were culture positive and attended all follow-up examinations. In this group, 98% of those treated with tobramycin enhanced viscosity ophthalmic solution and 99% of those treated with tobramycin 0.3% ophthalmic solution were categorized as having sustained cure/presumed eradication at the test-of-cure visit (p = 0.6037). Reported adverse events were not serious, mild to moderate in severity, and generally did not prevent continuation in the study. Several pre treatment pathogens demonstrated tobramycin resistance (MIC > 4 mg/mL). However, therapy with both treatments was effective in the majority of the cases. CONCLUSIONS: Tobramycin enhanced viscosity ophthalmic solution is well tolerated and has equivalent efficacy to the established treatment regimen with a simplified posology. The formulation provides an alternative therapy for acute bacterial conjunctivitis that should improve patient compliance and satisfaction.

Antibiotic microspheres: preliminary testing for potential treatment of osteomyelitis.

Osteomyelitis is a difficult problem for orthopaedic surgeons. The current standard of treatment requires high doses of antibiotic to be administered parenterally, which can damage vital organs. A local drug delivery system, which targets only the infected tissues, would eliminate some of the complications associated with extended courses of parenteral antibiotic treatment. In the current study, biodegradable microspheres were manufactured from a high molecular weight copolymer of 50% lactic and 50% glycolic acid and the antibiotic tobramycin. Various formulations of microspheres were tested for in vitro elution characteristics to determine the optimum formulation for linear release of antibiotic for at least 4 weeks. The optimal formulation then was implanted into a pouch created in the quadriceps muscle of mice to evaluate the in vivo elution of the antibiotic and the inflammatory response elicited by the microspheres. Results indicate that a sustained linear release of antibiotic from the microspheres is possible for a period of at least 4 weeks and that the inflammatory response was within levels required for the microspheres to be considered biocompatible.

Ciprofloxacin plus piperacillin compared with tobramycin plus piperacillin as empirical therapy in febrile neutropenic patients. A randomized, double-blind trial.

BACKGROUND: Therapy with an aminoglycoside and a beta-lactam remains common empirical therapy for febrile neutropenic patients. Concerns of aminoglycoside-induced ototoxicity and nephrotoxicity have led to studies of alternate regimens. OBJECTIVE: To determine whether ciprofloxacin-piperacillin is equivalent to tobramycin-piperacillin as empirical therapy for neutropenic fever. DESIGN: Randomized, double-blind multicenter trial. SETTING: Seven U.S. university-affiliated hospitals and one private research center. PATIENTS: Febrile (temperature >/= 38 degrees C), neutropenic (neutrophil level < 1 x 10(9) cells/L) hospitalized patients who had leukemia, lymphoma, or solid tumors, or were undergoing bone marrow transplantation. INTERVENTIONS: Patients received piperacillin, 50 mg/kg of body weight intravenously every 4 hours, and ciprofloxacin, 400 mg intravenously every 8 hours, or tobramycin, 2 mg/kg intravenously every 8 hours. MEASUREMENTS: Success was defined as resolution of infection and previously positive cultures without the need to give additional antimicrobial agents. RESULTS: 543 febrile episodes were evaluated, of which 471 were clinically evaluable (234 in the ciprofloxacin-piperacillin group and 237 in the tobramycin-piperacillin group). Success rates in the ciprofloxacin-piperacillin group (63 of 234 febrile episodes) and tobramycin-piperacillin group (52 of 237 episodes) were similar (27% vs. 22%, respectively; difference, 5.0 percentage points [95% CI, -2.3 to 12.8 percentage points]), as was survival (96.2% of patients receiving ciprofloxacin-piperacillin versus 94.1% of patients receiving tobramycin-piperacillin; difference, 2.1 percentage points [CI, -2.2 to 6.4 percentage points]). Additions to the initial antimicrobial regimen were the most common reason for treatment failure in both groups (accounting for 67% of failures in the ciprofloxacin-piperacillin group and 72% in the tobramycin-piperacillin group; difference, 5.0 percentage points [CI, -13.8 to 3.7 percentage points]). Fevers resolved faster in patients receiving ciprofloxacin-piperacillin than in patients receiving tobramycin-piperacillin (mean, 5 vs. 6 days) (P = 0.005). No significant differences in adverse events or toxicity were noted (P = 0.083). CONCLUSION: Ciprofloxacin-piperacillin is as safe and effective as tobramycin-piperacillin for empirical therapy of neutropenic fever.

Treatment With tobramycin solution for inhalation in bronchiectasis patients with Pseudomonas aeruginosa.

A randomized, placebo-controlled, multicenter trial evaluated the safety and efficacy of 300 mg aerosolized tobramycin solution for inhalation (TSI) administered twice daily for 4 weeks in 74 bronchiectasis patients colonized with Pseudomonas aeruginosa (PA). Patients were evenly divided between TSI therapy and placebo. After 2 weeks of treatment, patients treated with TSI had a mean reduction in sputum PA density of 4.8 log(10.) This reduction was maintained for the duration of treatment. The placebo group showed no change in PA density during the study. Two weeks after the end of therapy, PA had been eradicated in 13 TSI-treated patients. PA was not eradicated in any placebo patients. Among those colonized with Staphylococcus aureus at baseline, 6 of 9 patients in the TSI group and 2 of 9 patients in the placebo group were culture negative for this organism 2 weeks posttreatment. Sixty-two percent of TSI-treated patients were judged by a physician as having an improved general health status, compared with 38% of placebo-treated patients. Dyspnea, wheezing, and chest tightness were reported more frequently in the TSI-treated patient group than in the placebo-treated patient group.

Comparison of a beta-lactam alone versus beta-lactam and an aminoglycoside for pulmonary exacerbation in cystic fibrosis.

UNLABELLED: We determined whether a beta-lactam and an aminoglycoside have efficacy greater than a beta-lactam alone in the management of a pulmonary exacerbation in patients with cystic fibrosis. STUDY DESIGN: Azlocillin and placebo or azlocillin and tobramycin were administered to 76 patients with a pulmonary exacerbation caused by Pseudomonas aeruginosa in a randomized double-blind, third-party monitored protocol. Improvement was assessed by standardized clinical evaluation, pulmonary function testing, sputum bacterial density, sputum DNA content, and time to the next pulmonary exacerbation requiring hospitalization. RESULTS: No significant difference was seen between the 2 treatment groups in clinical evaluation, sputum DNA concentration, forced vital capacity, forced expiratory volume in second 1, or peak expiratory flow rate at the end of treatment (33 receiving azlocillin alone and 43 both antibiotics); adverse reactions were equivalent in each group. Sputum P. aeruginosa density decreased more with combination therapy (P =.034). On follow-up evaluation, an average of 26 days after the end of treatment, all outcome indicators had worsened in both groups. Time to readmission for a new pulmonary exacerbation was significantly longer in the group receiving azlocillin plus tobramycin (P <.001). Treatment-emergent tobramycin resistance occurred in both groups and was more frequent with combination therapy. CONCLUSION: We conclude that the combination of a beta-lactam and an aminoglycoside produces a longer clinical remission than a beta-lactam alone and slightly better initial improvement.