Susceptibility of Clostridium difficile isolates from a Phase 2 clinical trial of cadazolid and vancomycin in C. difficile infection.

OBJECTIVES: The aim of this study was to evaluate the susceptibilities of Clostridium difficile isolates to cadazolid, a novel antibiotic for the treatment of C. difficile infection. METHODS: Ribotyping and susceptibilities were determined for C. difficile isolates from a multicentre, double-blind, Phase 2 study of oral cadazolid in patients with C. difficile infection (NCT01222702, ClinicalTrials.gov; EudraCT 2010-020941-29, European Clinical Trials Database). Patients were randomized to receive 250, 500 or 1000 mg of cadazolid twice daily or 125 mg of vancomycin four times daily, for 10 days. MICs of cadazolid, vancomycin, fidaxomicin, linezolid and moxifloxacin were determined at baseline for all patients and post-baseline for patients with clinical failure or recurrence, using the agar dilution method. RESULTS: Seventy-eight of 84 patients had an evaluable toxigenic C. difficile isolate at baseline. The most frequent PCR ribotype was 027 (15.4%). Cadazolid MICs for baseline isolates (including epidemic strain 027) ranged from 0.06 to 0.25 mg/L. Baseline cadazolid MICs were similar to those of fidaxomicin and lower than those of vancomycin, linezolid and moxifloxacin. For each clinical outcome group (clinical cure, clinical failure, sustained clinical response and clinical failure or recurrence), the baseline cadazolid MIC range was 0.06-0.25 mg/L. Mean (min-max) cadazolid faecal concentration (µg/g) on day 5 was 884 (101-2710), 1706 (204-4230) and 3226 (1481-12 600) for the doses 250, 500 and 1000 mg, respectively. CONCLUSIONS: For all cadazolid doses, the faecal concentration was in excess of several thousand-fold the MIC90 for C. difficile. The MIC of cadazolid for all C. difficile isolates, including epidemic strains, was low and in the same narrow range regardless of treatment outcome.

Phase II clinical study of BC-3781, a pleuromutilin antibiotic, in treatment of patients with acute bacterial skin and skin structure infections.

This study investigated the potential of the novel systemic pleuromutilin antibiotic BC-3781 to treat patients with an acute bacterial skin and skin structure infection (ABSSSI) caused by a Gram-positive pathogen. Patients were randomized to intravenous BC-3781 100 mg, BC-3781 150 mg, or vancomycin 1 g every 12 h. Response to treatment was assessed daily and at test of cure (TOC). The primary endpoint was the clinical success rate at TOC in the modified intent-to-treat (MITT) and clinically evaluable (CE) analysis populations. Baseline characteristics, including the frequency of methicillin-resistant Staphylococcus aureus (MRSA), were comparable between the different treatment groups. Of 210 patients randomized, 186 (88.6%) patients completed the study. Clinical success at TOC in the CE population occurred in 54 (90.0%) patients in the BC-3781 100-mg group, 48 (88.9%) in the BC-3781 150-mg group, and 47 (92.2%) in the vancomycin group. At day 3, the clinical response rate was similar across the three treatment groups. Six patients discontinued study medication following an adverse event. The incidence rate for drug-related adverse events was lower for patients receiving BC-3781 (34.3% and 39.4% in the 100-mg and 150-mg groups, respectively) than those receiving vancomycin (53.0%). When BC-3781 was used to treat ABSSSIs caused by a Gram-positive pathogen, including MRSA, clinical success rates were comparable to those of the comparator, vancomycin. BC-3781 was generally well tolerated. These results provide the first proof of concept for the systemic use of a pleuromutilin antibiotic for the treatment of ABSSSIs.

Treatment of vancomycin-resistant Enterococcus faecium infections with quinupristin/dalfopristin.

Clinicians caring for patients with vancomycin-resistant Enterococcus faecium (VREF) infections face severe constraints in the selection of treatment. Quinupristin/dalfopristin (Synercid) is active in vitro against VREF, with a MIC(90) of 1.0 microg/mL. We investigated the clinical efficacy and safety of this agent in a multicenter, prospective, noncomparative, emergency-use study of 396 patients. Patients were included if they had signs and symptoms of active infection, including bacteremia of unknown origin, intra-abdominal infection, and skin and skin-structure infection, with no alternative antibiotic therapy available. The mean duration of treatment was 20 days (range, 4-40 days). The clinical response rate was 68.8% in the evaluable subset, and the overall response rate was 65.6%. The most common adverse events related to quinupristin/dalfopristin were arthralgias and myalgias. Related laboratory abnormalities were rare. In this severely ill patient population, quinupristin/dalfopristin was efficacious and demonstrated an acceptable safety profile in the treatment of VREF infection.

Rigid nasal endoscopy versus sinus puncture and aspiration for microbiologic documentation of acute bacterial maxillary sinusitis.

Sinus puncture and aspiration is an invasive procedure that hinders patient enrollment in studies of acute bacterial maxillary sinusitis (ABMS). Pain and minor bleeding also limit its potential diagnostic utility in clinical practice. Cultures obtained by rigid nasal endoscopy were compared with those from sinus puncture and aspiration in 53 patients with ABMS; 46 patients were assessable. Considering recovery of Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae from puncture and aspiration as the gold standard, endoscopy cultures demonstrated a sensitivity of 85.7% (95% confidence interval, 56.2-97.5), specificity of 90.6% (73.8-97.5), positive predictive value of 80% (51.4-94.7), negative predictive value of 93.5% (77.2-98.9), and accuracy of 89.1% (75.6-95.9). Ten adverse events related to puncture and aspiration occurred in 5 (9.6%) of 52 patients; there were no endoscopy-related adverse events. In our study, the largest to date, endoscopic sampling compared favorably with puncture and aspiration for identifying H. influenzae, M. catarrhalis, and S. pneumoniae in ABMS and produced less morbidity.

Hyperbilirubinemia during quinupristin-dalfopristin therapy in liver transplant recipients: correlation with available liver biopsy results.

STUDY OBJECTIVE: To review the liver histopathology in transplant recipients who developed hyperbilirubinemia during therapy with quinupristin-dalfopristin, a new streptogramin antibiotic, and to ascertain whether objective histologic evidence of adverse drug effect could be correlated to serum bilirubin levels. DESIGN: Retrospective analysis. SETTING: University of Pittsburgh Medical Center. PATIENTS: From a database of 34 liver recipients who received quinupristin-dalfopristin for vancomycin-resistant Enterococcus faecium infection who were prospectively enrolled in a multicenter, open-label, emergency-use protocol, the data for a subset of 25 patients who underwent one or more liver biopsies during therapy were reviewed for this study. INTERVENTIONS: Quinupristin-dalfopristin was administered intravenously at 7.5 mg/kg every 8 hours. Available serum bilirubin levels from before, during, and 1 week after therapy were tabulated. Liver biopsy results obtained within 1 week before and during therapy were retrospectively reviewed. Histopathologic results were characterized and correlated to bilirubin level. MEASUREMENTS AND MAIN RESULTS: Cholestatic changes were already present in 15 of 17 patients who underwent biopsy before therapy. During therapy, the most common findings from 40 biopsies (25 patients) were cholestasis (33 biopsies), acute rejection (10), and periportal inflammation (8). There was no evidence of drug-specific histopathologic injury. CONCLUSION: Hyperbilirubinemia in these patients was likely multifactorial and most frequently due to sepsis and prior graft injury.

Successful administration of quinupristin/dalfopristin in the outpatient setting.

Intravenous administration of quinupristin/dalfopristin outside the hospital setting has not been reported previously. We describe 37 outpatients receiving quinupristin/dalfopristin iv for infections including osteomyelitis, bacteraemia, abscesses and cellulitis. The most frequent aetiological pathogens found were Enterococcus faecium, Staphylococcus aureus and coagulase-negative staphylococci. Patients received an average of 9 days therapy as inpatients and 22 days as outpatients. Quinupristin/dalfopristin was administered using various access devices, most commonly peripherally inserted central catheters and tunnelled central catheters. The bacteriological and clinical success rates were both 89.2%. Five patients were readmitted to hospital; one patient developed catheter-related bacteraemia. The most frequently reported non-venous adverse events were nausea (18.9% of patients), myalgia (18.9%) and arthralgia (13.5%). Sixteen patients experienced venous access-related events, most commonly infusion pain, oedema and phlebitis. In this group of patients, for those who had difficult-to-treat infections, intravenous quinupristin/dalfopristin therapy was generally effective and safe outside the hospital setting.

Treatment of methicillin-resistant staphylococcus aureus infections with quinupristin-dalfopristin in patients intolerant of or failing prior therapy. For the Synercid Emergency-Use Study Group.

Safety and efficacy of quinupristin-dalfopristin (an injectable streptogramin antibiotic) were evaluated in the treatment of a variety of infections due to methicillin-resistant Staphylococcus aureus (MRSA) in patients either intolerant of or failing prior therapy. The influence of resistance phenotypes on treatment outcome was also assessed. This worldwide, multicentre, open-label, non-comparative, emergency-use clinical study enrolled patients with one or more of nine predefined, culture-confirmed infections with MRSA, who had no clinically appropriate alternative antibiotic therapy. The recommended quinupristin-dalfopristin dose was 7.5 mg/kg administered iv every 8 h for a duration judged appropriate by the investigator. There were no restrictions on prior or concomitant treatment with other antibiotics. Clinical, microbiological and laboratory assessments were performed at baseline, during study drug treatment, within 24 h after the last dose, and 7-21 days post-therapy. Ninety patients [age (mean +/- S.D.) 57.4 +/- 18.5 years] with significant underlying medical illnesses were treated at 63 centres in five countries. The most common indications were bone and joint infection (44.4% of patients) and skin and skin structure infection (16.7%). The mean (+/- S.D.) daily dose and treatment duration was 20.2 +/- 2.9 mg/kg/day for 28.5 +/- 22.3 days, most frequently administered every 8 h. The overall success rate (defined as a clinical outcome of either cure or improvement and a bacteriological outcome of eradication or presumed eradication) was 71.1% in the all-treated population (n = 90) and 66.7% in patients who were both clinically and bacteriologically evaluable (n = 27). Success rates for endocarditis, respiratory tract infection and bacteraemia of unknown source were below the population mean. The macrolide-lincosamide-streptogramin type B resistance phenotype did not appear to alter the response rate. The most common non-venous adverse events related to study medication were arthralgias (10.8%), myalgias (8.6%) and nausea (8.6%). Quinupristin-dalfopristin should be considered as a treatment option for infections caused by MRSA, especially in patients intolerant of or failing alternate therapy.

Characterization of isolates associated with emerging resistance to quinupristin/dalfopristin (Synercid) during a worldwide clinical program.

Quinupristin/dalfopristin (Synercid) is an i.v. antibiotic active against serious Gram-positive infections. Its unique dual mode of action means that the potential for resistance development is expected to be low. To determine the incidence of in vitro emerging resistance in worldwide clinical studies, susceptibility to quinupristin/dalfopristin was measured for baseline pathogens and corresponding on- or post-study isolates from 880 evaluable patients. In comparative studies of community-acquired pneumonia, complicated skin and skin structure infections, and nosocomial pneumonia, the incidence of emerging resistance was low (1 of 453; 0.22%; 95% CI: 0. 01-1.4%). Resistance development occurred in only one pathogen (methicillin-resistant Staphylococcus aureus). In noncomparative studies, six instances (1.8% of 338 evaluable cases; 95% CI: 0.7 to 4.0%) of emerging resistance (all vancomycin-resistant Enterococcus faecium) were confirmed, accompanied by therapeutic failure in four cases. Molecular typing did not confirm the identity of one pair of strains. Overall, the incidence of emerging resistance to quinupristin/dalfopristin was low.

Sparfloxacin for the treatment of acute bacterial maxillary sinusitis documented by sinus puncture.

PURPOSE: To evaluate the efficacy and safety of sparfloxacin in the treatment of patients with acute bacterial maxillary sinusitis, the microbiologic etiology of which was determined by maxillary sinus puncture. PATIENTS AND METHODS: Two hundred fifty-three patients enrolled in the open, noncomparative trial received sparfloxacin as a 400-mg loading dose followed by 200 mg once daily doses for a total of 10 days. One hundred ninety-eight patients were clinically evaluable and 82 were also bacteriologically evaluable. All treated patients were included in the safety analysis. Overall success was determined based on clinical success (resolution or reduction of signs and symptoms and sinus x-rays) and bacteriologic success (eradication and presumed eradication of baseline pathogens obtained by maxillary sinus puncture and aspiration). RESULTS: Overall success in the bacteriologically evaluable population at test-of-cure was 91.5% [75/82; 95% confidence interval (85.4%, 97.5%)]. For all pathogens, the eradication rate was 93.2% (109/117 baseline pathogens); individual pathogen eradication rates were 88.9% (16/18) for S. pneumoniae (including those strains exhibiting decreased susceptibility to penicillin); and 100% for H. influenzae (17/17), S. aureus (14/14), and M. catarrhalis (11/11). The majority of adverse events were of mild or moderate severity; the most frequently related adverse events were photosensitivity reaction, headache, nausea, and diarrhea. CONCLUSION: Sparfloxacin had an overall success rate of 91.5% for patients in this study and was generally well tolerated in the treatment of acute bacterial maxillary sinusitis.

Safety and tolerability of quinupristin/dalfopristin: administration guidelines.

The safety and tolerability of quinupristin/dalfopristin were assessed in both comparative and non-comparative trials (2298 quinupristin/dalfopristin-treated patients). In comparative clinical trials, the most frequent systemic adverse events related to quinupristin/dalfopristin were nausea (4.6%), diarrhoea (2.7%), vomiting (2.7%) and skin rash (2.5%). The comparator group showed similar rates, except that nausea was significantly more common (7.2%; P = 0.01). In non-comparative trials, arthralgia and myalgia were reported most frequently but were reversible upon treatment discontinuation. The renal, inner ear, cardiovascular and central nervous systems were not implicated as significant target organs for toxicity. The most frequent local adverse events related to infusion of quinupristin/dalfopristin were inflammation, pain, oedema, infusion site reaction and thrombophlebitis. Results of laboratory tests while on therapy were comparable for quinupristin/dalfopristin and comparator groups, except that increases in conjugated bilirubin of >5 x the upper limit of normal were reported in 5.5% of quinupristin/dalfopristin recipients; increases in total bilirubin of >5 x the upper limit of normal occurred in 1.5%. Comparator recipients more frequently had increases in alanine aminotransferase and alkaline phosphatase. Quinupristin/dalfopristin inhibits the cytochrome P450 3A4-mediated metabolism of drugs including midazolam, nifedipine, terfenadine and cyclosporin. Therefore, plasma drug monitoring and/or dosage reduction of these agents is prudent. Concomitant administration of drugs that can prolong the electrocardiographic QTc interval should be avoided. Quinupristin/dalfopristin is visually and chemically compatible with commonly used drugs of various classes, but it is not compatible with sodium chloride solution and certain other drugs, including some antimicrobials. Therefore, when prescribing quinupristin/dalfopristin, clinicians should be aware of the potential for peripheral venous intolerance, arthralgias and myalgias, increases in conjugated bilirubin, interactions with drugs metabolized by the cytochrome P450 3A4 isoenzyme and certain physico-chemical incompatibilities. However, multiple studies have shown that the safety and tolerability of quinupristin/dalfopristin are generally favourable, and that it provides clear benefits to ill patients with severe gram-positive infections.

The effect of terfenadine on the cardiac pharmacodynamics of sparfloxacin.

This double-masked, randomized, placebo-controlled study was conducted to assess the effect of concomitant administration of terfenadine and sparfloxacin on the electrocardiographic (ECG) QT(c) interval in healthy volunteers, before the removal of terfenadine from the market. Eighty-eight men (aged 18 to 49 years, weighing 60.0 to 98.6 kg) with no clinically relevant ECG abnormalities received placebo, sparfloxacin (400 mg on day 1, 200 mg daily on days 2-4), terfenadine (60 mg BID), or the combination of sparfloxacin and terfenadine. After each dose, serial blood samples and ECG measurements were collected to determine sparfloxacin pharmacokinetic and pharmacodynamic variables. The area under the concentration-time curve and maximum concentration for sparfloxacin were approximately 16% less on day 4 compared with day 1, reflecting the higher plasma level after the 400-mg loading dose compared with that after the maintenance dose of 200 mg daily. Concomitant administration of terfenadine had no effect on these pharmacokinetic variables. When compared with the placebo-adjusted increases in QTc interval in the sparfloxacin (19 milliseconds on day 1 and 14 milliseconds on day 4) and terfenadine (2 milliseconds on day 1 and 7 milliseconds on day 4) treatment groups, the placebo-adjusted increases in QTc interval in the volunteers treated with the combination of sparfloxacin and terfenadine (18 milliseconds on day 1 and 22 milliseconds on day 4) were considered to be additive (no statistically significant interaction). Thus there are no apparent pharmacokinetic or dynamic QTc interactions between terfenadine and sparfloxacin. However, sparfloxacin should be administered with caution to patients receiving concomitant medications known to prolong the QTc interval.

The efficacy and safety of quinupristin/dalfopristin for the treatment of infections caused by vancomycin-resistant Enterococcus faecium. Synercid Emergency-Use Study Group.

A progressive increase in the incidence of vancomycin resistance in strains of Enterococcus faecium (VREF) has severely constrained treatment options for patients with infection caused by this emerging pathogen. Quinupristin/dalfopristin (Synercid), the first injectable streptogramin antibiotic, is active in vitro against VREF, with an MIC90 of 1.0 mg/L. We studied the clinical efficacy and safety of quinupristin/dalfopristin in the treatment of VREF infection. Two prospective studies were conducted simultaneously. The first enrolled only patients with VREF infection; the second included patients with infection caused by other gram-positive bacterial pathogens in addition to VREF. Patients were enrolled if they had signs and symptoms of active infection and no appropriate alternative antibiotic therapy. The recommended treatment regimen of quinupristin/dalfopristin was 7.5 mg/kg i.v. every 8 h for a duration judged appropriate by the investigator. A total of 396 patients with VREF infection were enrolled. The most frequent indications for treatment included intra-abdominal infection, bacteraemia of unknown origin, urinary tract infection, catheter-related bacteraemia, and skin and skin structure infection. This patient population had a high prevalence of severe underlying illness, including a history of diabetes mellitus, transplantation, mechanical ventilation, dialysis, chronic liver disease with cirrhosis and oncological disorders. The mean (+/- S.D.) duration of treatment was 14.5 +/- 10.7 days (range: 1-108). The majority of patients (82.1%) were treated every 8 h, as assessed on day 2 of treatment, while 15.9% were treated every 12 h. The clinical success rate was 73.6% [142/193 clinically evaluable patients; 95% confidence interval (CI): 67.4%, 79.8%], the bacteriological success rate 70.5% (110/156 bacteriologically evaluable patients; 95% CI: 63.4%, 77.7%) and the overall success (both clinical and bacteriological success) rate 65.8% (102/156 bacteriologically evaluable patients; 95% CI: 57.9%, 72.9%). VREF bacteraemia at entry, mechanical ventilation and laparotomy were associated with a worse outcome. Quinupristin/dalfopristin was generally well tolerated. The most common systemic adverse events related to treatment were arthralgias (9.1%) and myalgias (6.6%). Related laboratory abnormalities were infrequent. In these severely ill patients with VREF infection and no other clinically appropriate therapeutic alternatives, quinupristin/dalfopristin demonstrated substantial efficacy and a good nervous system, cardiovascular, gastrointestinal, renal and hepatic tolerability.

The cardiac pharmacodynamics of therapeutic doses of sparfloxacin.

This double-masked, randomized, placebo-controlled study assessed the cardiac safety of sparfloxacin (as measured by the effect on corrected QT [QTc] interval) at the extremes of the expected therapeutic dosage range. Ninety healthy adult male volunteers with no clinically relevant electrocardiographic (ECG) abnormalities received either placebo or 1 of 3 sparfloxacin regimens consisting of a loading dose on day 1 followed by 3 days of daily dosing at half the loading dose (200/100 mg, 400/200 mg, or 800/400 mg). After each dose, serial blood samples and ECG measurements were obtained to determine the pharmacokinetic and pharmacodynamic variables for sparfloxacin. Increases in the area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24) for each dosing interval and in the maximum concentration (Cmax) on days 1 and 4 were dose proportional. The steady-state (day-4) values were 6% to 16% lower than the day-1 values. At steady state, the time to C ranged from 2.5 to 3.9 hours across all doses and days studied. The half-life ranged from 18.7 to 20.3 hours. Increases in the placebo-adjusted mean change and mean maximum change in QTc interval were dose related. The placebo-adjusted increases on day 1 were 9, 16, and 28 milliseconds after receipt of the 200/100-mg, 400/200-mg, and 800/400-mg regimens, respectively. The corresponding increases on day 4 were 7, 12, and 26 milliseconds. The placebo-adjusted changes in QTc interval also showed a linear relationship with the AUC0-24 and Cmax of sparfloxacin. In the majority of volunteers (>90%), these increases were within the normal range for the QTc interval (< or = 460 milliseconds).

Pharmacokinetics of sparfloxacin in patients with renal impairment.

Sparfloxacin is a fluoroquinolone antimicrobial agent with a broad spectrum of activity and long elimination half-life. Because its single-dose pharmacokinetics are altered by renal impairment, the present study was undertaken to determine the effects of moderate or severe renal insufficiency on the multidose pharmacokinetic characteristics of and tolerance to sparfloxacin. The pharmacokinetic characteristics of sparfloxacin were assessed in 32 subjects (15 men, 17 women) with (1) normal renal function (creatinine clearance [CLcr]> or = 250 mL/min per 1.73 m2) and a mean age of 52.6 years and mean weight of 70.4 kg; (2) moderate renal insufficiency (CLcr 30-49 mL/min per 1.73 m2) and a mean age of 54.4 years and mean weight of 67.8 kg; and (3) severe renal insufficiency (CLcr 10-29 mL/min per 1.73 m2) and a mean age of 50.8 years and mean weight of 73.1 kg. The first 2 groups received a 400-mg loading dose on day 1 followed by 200 mg once daily for 9 days; subjects with severe renal insufficiency received a 400-mg loading dose on day 1 followed by 200 mg every 48 hours on days 3, 5, 7, and 9. The plasma and urinary pharmacokinetics of sparfloxacin and its glucuronide metabolite were determined after the last dose. All subjects were monitored for changes in the corrected QT (QTc) interval and for adverse events. Renal insufficiency altered the steady-state pharmacokinetic variables of sparfloxacin and its glucuronide metabolite, reducing their renal clearances and increasing both maximum plasma concentration and area under the plasma concentration-time curve. Mean steady-state plasma sparfloxacin concentrations in subjects with severe renal insufficiency (48-hour dosing interval) were comparable to those in subjects with normal renal function (24-hour dosing interval). However, mean plasma sparfloxacin concentrations in patients with moderate renal insufficiency were 2 to 3 times greater than the corresponding concentrations in subjects with normal renal function receiving the same dosage regimen. The QTc interval was slightly increased in all groups (the greatest increases were 14, 14, and 6 milliseconds in the groups with normal renal function and moderately and severely impaired renal function, respectively, at 5.5 hours post-dose on day 9 or 10) but similar among subjects with normal renal function or with renal insufficiency. Sparfloxacin was well tolerated. Thus sparfloxacin clearance is reduced and plasma concentrations raised by moderate or severe renal insufficiency. These increases do not appear to augment drug effects on the QTc interval or enhance the risk for adverse events. These results suggest that alternate-day dosing (48-hour dosing interval) following a double loading dose on day 1 should be used in patients with severe renal insufficiency and may be appropriate for patients with moderate renal insufficiency.

Comparison of sparfloxacin and ciprofloxacin in the treatment of community-acquired acute uncomplicated urinary tract infection in women. Sparfloxacin Multicenter Uncomplicated Urinary Tract Infection Study Group.

Urinary tract infection (UTI) is a common illness, with > or =30% of all women experiencing a UTI during their lifetime. Less than a decade ago, the standard therapy for acute uncomplicated UTIs involved treatment with > or =7 days of an antibacterial agent, but recent studies using a variety of newly introduced antibiotics, including the fluoroquinolones, have demonstrated that a 1- to 5-day treatment regimen can be equally effective. This randomized, double-masked, multicenter study was conducted to compare the efficacy and tolerability of a single dose of sparfloxacin with those of a 3-day regimen of sparfloxacin and a 7-day regimen of ciprofloxacin in the treatment of women with community-acquired acute uncomplicated urinary tract infection. A total of 1175 women were enrolled; 395 received sparfloxacin as a single 400-mg dose on day 1, 394 received sparfloxacin as a 400-mg loading dose on day 1 followed by 200 mg once daily for 2 additional days, and 386 received ciprofloxacin 250 mg twice daily for 7 days. Patients were comparable with respect to demographic characteristics and underlying conditions. A total of 954 patients were clinically assessable; 490 of these were also bacteriologically assessable. All patients treated were included in the tolerability analysis. Escherichia coli (75.4%), Klebsiella pneumoniae (4.9%), Enterococcus faecalis (4.6%), and Staphylococcus saprophyticus (4.1%) were the most commonly isolated organisms. In the all-treated population, clinical success was achieved 5 to 9 days after therapy in 91.8%, 92.2%, and 91.6% of patients in the single-dose sparfloxacin, 3-day sparfloxacin, and 7-day ciprofloxacin groups, respectively; bacteriologic success was observed in 91.7%, 92.6%, and 96.6% of those in the 3 groups. Sustained clinical success rates 4 to 6 weeks after therapy were 76.6%, 80.2%, and 79.5% in the single-dose sparfloxacin, 3-day sparfloxacin, and 7-day ciprofloxacin groups, respectively; sustained bacteriologic success rates were 80.7%, 90.1%, and 92.6%. The most common adverse events were nausea, headache, vaginal thrush, dizziness, and diarrhea; >92% of adverse events were mild or moderate in severity. The 2 drugs had comparable frequencies of adverse events, except for photosensitivity, which occurred in 3.3% of the 3-day sparfloxacin group, 1.3% of the single-dose sparfloxacin group, and 0.3% of the ciprofloxacin group (P = 0.005). The 3-day sparfloxacin regimen was effective and well tolerated. The initial response to single-dose sparfloxacin treatment was comparable to the response to the other 2 regimens, but the single-dose regimen proved less effective over time, with higher rates of clinical recurrence and bacteriologic relapse. Sparfloxacin provides an alternative to ciprofloxacin for patients with acute uncomplicated urinary tract infection who are not at risk for photosensitivity reactions or adverse events associated with a prolonged corrected QT interval.

Treating acute bacterial exacerbations of chronic bronchitis in patients unresponsive to previous therapy: sparfloxacin versus clarithromycin.

The optimal antibiotic therapy for patients with acute bacterial exacerbations of chronic bronchitis (ABECB) who have failed to respond to previous oral antimicrobial therapy is not known; however, newer macrolide and fluoroquinolone antibiotics may be appropriate. This multicenter, randomized, double-masked, double-dummy study was undertaken to compare the efficacy and tolerability of sparfloxacin with those of clarithromycin in the treatment of ABECB. In 43 centers in the United States, 298 patients (52% male; age range, 19 to 92 years) were randomly allocated to receive a 400-mg loading dose of sparfloxacin, followed by 200 mg once daily, or clarithromycin 500 mg twice daily, for a total of 10 days. Signs and symptoms of ABECB were assessed at each of 4 visits, including a follow-up visit approximately 1 month after the completion of therapy. Efficacy was determined on the basis of the clinical and bacteriologic response rates in the clinically assessable population. Tolerability was assessed on the basis of patient reports, clinical evaluations, and laboratory tests. Of the 266 clinically assessable patients, 109 (85.2%) of 128 patients receiving sparfloxacin and 115 (83.3%) of 138 patients receiving clarithromycin had a clinically successful outcome (cure or improvement). The bacteriologic success rate (eradication of pathogen) was 88.9% (64 of 72 isolates) in the sparfloxacin group and 84.7% (83 of 98 isolates) in the clarithromycin group. Adverse events possibly or probably related to study drug included photosensitivity in 12 (8.3%) and rash in 6 (4.1%) of 145 patients in the sparfloxacin group, and diarrhea in 10 (6.5%), taste perversion in 9 (5.9%), and nausea in 8 (5.2%) of 153 patients in the clarithromycin group. Thus sparfloxacin was as well tolerated and as effective as clarithromycin in the treatment of patients with ABECB unresponsive to previous oral antimicrobial therapy. The overall rate of adverse events was comparable for the 2 study drugs, but the types of events differed.

Effects of food on the pharmacokinetics of sparfloxacin.

Sparfloxacin, a fluoroquinolone with a broad antimicrobial spectrum and long elimination half-life, is indicated for the treatment of community-acquired pneumonia and acute bacterial exacerbations of chronic bronchitis in adult patients. The present study was undertaken to determine the effects of skim milk and a high-fat breakfast without milk on the single-dose pharmacokinetic characteristics of this antibiotic. The pharmacokinetics of a single 200-mg dose of sparfloxacin were assessed in a 3-way crossover study that included 23 healthy male volunteers who had fasted, had ingested 240 mL of skim milk, or had consumed a standard high-fat breakfast. The subjects' mean age and weight were 26.5 years and 73.2 kg, respectively; 17 were white, 5 Hispanic, and 1 black. Neither skim milk nor the high-fat breakfast had a statistically significant effect on sparfloxacin absorption, as reflected in the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC). Ninety percent confidence limits for logarithmically transformed AUC from time zero to infinity and Cmax were within the 80% to 125% range, demonstrating that the rate and extent of sparfloxacin absorption with skim milk or a high-fat breakfast were not different from those under fasted conditions. As indicated by an increase in the time to Cmax from 3.6 to 5.4 hours, the high-fat breakfast slightly delayed the onset of sparfloxacin absorption. Skim milk and the high-fat breakfast did not significantly affect the elimination kinetics of sparfloxacin. Sparfloxacin was well tolerated in all 3 treatment groups. Despite the apparent delay in the onset of absorption, the bioavailability of sparfloxacin in the healthy male subjects in this study population was not affected by concomitant administration with skim milk or a high-fat meal. Accordingly, the results suggest that sparfloxacin can be administered without regard to the ingestion of milk or meals.

Comparison of the in vitro activity of and pathogen responses to sparfloxacin with those of other agents in the treatment of respiratory tract, urinary tract, and skin and skin-structure infections.

The in vitro activity of and pathogen responses to sparfloxacin were compared with those of standard therapies for the treatment of patients with community-acquired pneumonia, complicated skin or skin-structure infections, urinary tract infections, acute bacterial exacerbations of chronic bronchitis, and acute maxillary sinusitis in 7 multicenter controlled trials in North America. Sparfloxacin was administered orally as a 400-mg loading dose followed by 200 mg once daily for up to 10 days. The bacteriologic efficacy of sparfloxacin (84% to 95%) was comparable to that of comparator drugs (77% to 100%). Sparfloxacin was generally 2 to 8 times more active (minimum inhibitory concentration for 90% of strains tested [MIC90]: 0.03 to 0.5 microg/mL) than comparators against common pathogens isolated in community-acquired infections, especially Streptococcus pneumoniae, including penicillin-resistant strains; Moraxella catarrhalis; Haemophilus influenzae; Streptococcus pyogenes; and Staphylococcus aureus. Sparfloxacin was also effective against Chlamydia and Mycoplasma species. The emergence of resistance was uncommon during sparfloxacin therapy (0.3% of 1100 cases). Higher area under the plasma concentration-time curve/MIC and maximum plasma concentration/MIC ratios for sparfloxacin were associated with clinical and bacteriologic efficacy, whereas lower ratios were associated with clinical and bacteriologic failure. The clinical efficacy of sparfloxacin (80% to 95%) was comparable to that obtained with the comparator drugs (71% to 92%). In addition, sparfloxacin was well tolerated and had an overall frequency of related adverse events similar to that of the comparators. There was a higher frequency of photosensitivity reactions but a lower level of digestive adverse events with sparfloxacin compared with comparators. Sparfloxacin is a suitable therapeutic alternative for the empiric treatment of respiratory tract infections owing to its favorable pharmacokinetic profile and activity against typical and atypical respiratory tract pathogens, even in geographic areas with a high incidence of penicillin resistance.

Effect of single ascending, supratherapeutic doses of sparfloxacin on cardiac repolarization (QTc interval).

This double-masked, randomized, placebo-controlled study was conducted in healthy adult male and female volunteers with no clinically relevant baseline electrocardiographic (ECG) abnormalities to assess the cardiac tolerability margin of sparfloxacin (as measured by the effect on QTc interval) under conditions of potential overdose at up to 4 times the usual therapeutic loading dose. The 23 enrolled volunteers received a sequence of single doses of sparfloxacin (400, 800, 1200, and 1600 mg), 1 dose in each of 4 study periods. Six volunteers received placebo during each period. A 14-day washout separated the periods. Serial blood samples and ECG measurements were collected in each period to determine the pharmacokinetic and pharmacodynamic characteristics of sparfloxacin. The area under the concentration-time curve from time zero to infinity (AUC0-infinity) exhibited dose proportionality. The maximum plasma concentration (Cmax) after the 1200- and 1600-mg doses was lower than would be expected for a linear dose relationship. This was also the case with the mean increase and mean maximum increase in QTc interval. Increases in the QTc interval correlated well with Cmax but not with AUC0-infinity. The time to reach Cmax showed a slight tendency to increase with dose, as did the terminal elimination half-life. Changes in QTc-interval dispersion were similar for both placebo recipients and sparfloxacin-treated volunteers and were of no clinical consequence. At supratherapeutic doses, the extent of sparfloxacin's absorption (AUC0-infinity) was dose independent; however, the rate of absorption was dose dependent, with Cmax increasing substantially less than proportionally to the administered dose. This limited the Cmax of sparfloxacin at supratherapeutic doses and thus the increase in QTc interval. Rechallenge demonstrated that only 2 of 8 subjects had the same degree of QTc-interval prolongation, emphasizing the marked variability in the QTc interval.