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.

Invasive pulmonary aspergillosis in adult acute leukemia: clinical clues to its diagnosis.

Invasive pulmonary aspergillosis, a leading cause of morbidity and mortality in patients with acute leukemia, is difficult to diagnose antemortem because its signs and symptoms are ill-defined. To refine the clinical description of this infection, we reviewed our experience with 15 pathologically documented cases of invasive pulmonary aspergillosis in a population of 60 patients treated for acute leukemia. Findings occurring significantly more often (P less than or equal to .001) among cases than controls included pleuritic chest pain; acute sinus tenderness, and nasal discharge, epistaxis and eschar; rales; development of multilobar infiltrates after the 14th hospital day; and presence of nodular or cavitary infiltrates. In addition, patients with invasive pulmonary aspergillosis had a significantly prolonged duration of granulocytopenia, more febrile days and febrile episodes without a fever diagnosis and more febrile days on antibiotics (P less than or equal to .001 in all). This complex of findings should improve the clinician's ability to diagnose invasive pulmonary aspergillosis in patients with acute leukemia.

Risk factors for acquisition of gentamicin-resistant enterococci. A multivariate analysis.

High-level gentamicin resistance in enterococci is an increasing problem in hospitalized patients. Multiple risk factors for the acquisition of these organisms have been identified, but these risk factors are highly interrelated, and it has been unclear which of them are truly important. We performed a case-control study comparing 37 patients colonized or infected with resistant enterococci with 84 patients with susceptible strains. Crude odds ratios were significant for nosocomial acquisition, duration of hospitalization, hospitalization on the medical service or in an intensive care unit, number and duration of antibiotics received, and receipt of several individual antibiotics. By logistic regression, hospitalization longer than 2 weeks (odds ratio, 5.4; 95% confidence interval, 1.7 to 17) and receipt of five or more antibiotics (odds ratio, 26; 95% confidence interval, 2.8 to 250) were significantly associated with colonization or infection with resistant enterococci. Patients with these latter two risk factors may be targeted in infection control efforts.

Persistent fever after recovery from granulocytopenia in acute leukemia.

We reviewed the hospital admissions of 168 patients with acute leukemia to determine the incidence of persistent fever following recovery from chemotherapy-induced granulocytopenia. This phenomenon was observed during 26 (15.5%) hospital admissions. The microbiologically and/or clinically documented causes identified in 23 instances included viral infection (two patients), perirectal abscess (two patients), Hickman catheter-related bacteremia (two patients), intraabdominal infection (four patients), and nine fungal infections (five resolving pneumonia, one disseminated candidiasis, three focal hepatic and/or splenic mycosis). One patient had both cholecystitis and a pneumonia of uncertain origin and three patients had drug reactions. Although overall the source of fever was usually readily apparent, focal hepatic and/or splenic mycosis produced protracted fevers that were difficult to diagnose. Visceral fungal infection should be a leading diagnostic consideration in patients with leukemia who remain persistently febrile following recovery from chemotherapy-induced granulocytopenia.

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.

Risk factors for nosocomial candidemia: a case-control study in adults without leukemia.

PURPOSE: The purpose of this study was to define risk factors for nosocomial candidemia in adult patients without leukemia at a tertiary care medical center. PATIENTS AND METHODS: All patients with nosocomial candidemia between August 1, 1981, and October 31, 1984, were included if they met strict selection criteria and did not have acute or chronic leukemia. For each case, one control was selected from among patients admitted during the same month/year and matched for hospital service and duration of hospitalization up to the first blood culture that grew Candida species. Logistic regression was used to obtain estimates of risk after simultaneously controlling for other variables. RESULTS: Candida albicans caused 24 of the 48 fungemias studied. The risk factors identified included the presence of a central line (odds ratio, 26.4; 95% confidence interval, 1.5 to 451.1); bladder catheter (13.0 1.3 to 131.4); two or more antibiotics (25.1, 2.1 to 318); azotemia (22.1, 2.2 to 223.2); transfer from another hospital (21.3, 1.7 to 274.5); diarrhea (10.2, 1.03 to 101.4); and candiduria (27.0, 1.7 to 423.5). A prior surgical procedure was associated with lowered risk (0.1, 0.01 to 0.9), suggesting perhaps that medical service patients are at higher risk than those on surgical services. Because total parenteral nutrition was always administered by means of a central line, it could not be shown to increase the risk over that conferred by a central line alone. CONCLUSIONS: This study has defined seven major risk factors for nosocomial candidemia. These findings should facilitate development of rational approaches to preventing infection and may assist clinicians in identifying those patients in whom this life-threatening complication is likely to occur.

Role of fiberoptic bronchoscopy in the diagnosis of invasive pulmonary aspergillosis in patients with acute leukemia.

The utility and safety of fiberoptic bronchoscopy in the diagnosis of invasive pulmonary aspergillosis in patients with acute leukemia have not been examined. The results of 21 bronchoscopic procedures in 19 patients with invasive pulmonary aspergillosis and acute leukemia were reviewed. Analysis was confined to the 16 patients who had histopathologically documented infection on biopsy or at autopsy. Fiberoptic bronchoscopy established or suggested the diagnosis of invasive pulmonary aspergillosis in eight of 16 (50 percent) patients. Transbronchial or bronchial biopsy added only one diagnosis to those obtained by bronchial washing and brushing. Although fiberoptic bronchoscopy was a safe and well-tolerated procedure in our patients with invasive pulmonary aspergillosis and acute leukemia, its success rate was only 50 percent overall, and it appeared to be even less successful when performed early in the course of the disease. Fiberoptic bronchoscopy is a useful first procedure for the evaluation of patients with acute leukemia and possible invasive pulmonary aspergillosis, but a negative result does not exclude aspergillosis. Further diagnostic procedures, including repeated bronchoscopy, or institution of empiric antifungal therapy may be warranted if the clinical suspicion of invasive pulmonary aspergillosis is high.

Risk factors for Amphotericin B-associated nephrotoxicity.

PURPOSE: A case-control study was performed to identify and quantify risk factors for amphotericin B-associated nephrotoxicity. PATIENTS AND METHODS: Thirty-five patients receiving intravenous amphotericin B for treatment of proven or suspected fungal infection who developed nephrotoxicity (greater than 100% increase in baseline serum creatinine to a level above the normal range) were compared with 60 control patients receiving amphotericin B who did not develop nephrotoxicity. Amphotericin B dosing variables and other potential risk factors were analyzed in a logistic regression model. RESULTS: Cases of nephrotoxicity received a significantly higher average daily dose of amphotericin B (0.49 +/- 0.18 mg/kg/day) than did controls (0.34 +/- 0.17 mg/kg/day). In a multivariate model, the risk of nephrotoxicity increased 3.7-fold for each 50-mg increase in total dose for a fixed duration of therapy and patient weight. Risk decreased by a factor of 0.4 for each extra day of therapy for a fixed total dose and weight. An increase in weight was also protective when the two other dosage variables were held constant. Each 0.10 mg/kg/day dose increment was associated with a 1.8-fold (95% confidence interval, 1.2 to 2.7) increase in the risk of nephrotoxicity. Other significant risk factors included diuretic use during amphotericin B therapy (12.5, 1.7 to 94.7), for which a linear dose-response relationship was demonstrated, and an abnormal baseline serum creatinine level (15.4, 1.4 to 173.2). CONCLUSION: Risk factors for amphotericin B-associated nephrotoxicity include higher average daily doses (approximately a doubling for each 0.10 mg/kg/day increment), diuretic use, and abnormal baseline renal function. These data suggest possible protective interventions and will aid clinicians in assessing the risk-benefit ratio of amphotericin B therapy for deep fungal infection.

Discriminant scorecard for diagnosis of invasive pulmonary aspergillosis in patients with acute leukemia.

Invasive pulmonary aspergillosis, a serious opportunistic infection in adult patients with acute leukemia, is difficult to diagnose antemortem. To identify patients with invasive pulmonary aspergillosis without reliance on invasive diagnostic procedures, a discriminant scorecard for invasive pulmonary aspergillosis based on clinical parameters was evaluated in a three-phase study. In phase I, the records of 62 patients, including 15 with invasive pulmonary aspergillosis, were reviewed. Eleven clinical parameters distinguished patients with invasive pulmonary aspergillosis from control subjects. These parameters were combined into a discriminant scorecard. In phase II, the discriminant scorecard was validated by a blinded, retrospective review of 94 consecutive admissions. The discriminant scorecard score was highly associated with the clinical outcome (p less than 0.0005). The sensitivity of the discriminant scorecard was calculated as a range from 62.9 to 92.8 percent and the specificity as a range from 87.5 to 98.3 percent. In phase III, the clinical utility of the discriminant scorecard was determined by its prospective application to 49 consecutive patient admissions. The discriminant scorecard identified patients with invasive pulmonary aspergillosis at an average of 4.1 days prior to clinical recognition of the disease and initiation of amphotericin B therapy. The discriminant scorecard outperformed a complex function based on multiple linear regressions, was easy to use, and did not require difficult calculations. Thus, for this patient population, the discriminant scorecard was an accurate, useful noninvasive screening test for invasive pulmonary aspergillosis. The scorecard allows more rapid clinical identification of patients with this infection and could lead to improved patient survival through earlier diagnostic and therapeutic intervention.

Sparfloxacin vs ofloxacin in the treatment of acute bacterial exacerbations of chronic bronchitis: a multicenter, double-blind, randomized, comparative study. Sparfloxacin Multicenter ABECB Study Group.

STUDY OBJECTIVE: Comparison of efficacy and safety of sparfloxacin vs ofloxacin for treatment of acute bacterial exacerbations of chronic bronchitis (ABECB). DESIGN: Multicenter, double-blind, randomized study. SETTING: Sixty-eight private offices and outpatient clinics in the United States and Canada. PATIENTS: Seven hundred ninety-eight adults with ABECB, as confirmed by the acute onset of new (or worsened from the immediate premorbid state) cough and sputum production. INTERVENTIONS: Randomization 1:1 to sparfloxacin, 400 mg on day 1, then 200 mg once daily, or ofloxacin, 400 mg twice daily, with matching comparator placebos, given concurrently for 10 consecutive days. RESULTS: The primary efficacy parameter was overall response in the bacteriologically evaluable population. Overall success rates in this population were 85.3% and 89.3% for sparfloxacin and ofloxacin, respectively. The two-sided 95% confidence interval was -9.9, 1.9, indicating that sparfloxacin was statistically equivalent to ofloxacin. The all-treated population analysis was similar to that in the evaluable population. Bacterial eradication rates were similar in both treatment groups for Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, Chlamydia pneumoniae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Enterobacter cloacae, and Staphylococcus aureus. The frequency of adverse events overall was comparable in the two treatment groups. The sparfloxacin group had a lower frequency of digestive and nervous system adverse events, but a higher frequency of photosensitivity reactions than the ofloxacin group. CONCLUSIONS: Once-daily oral treatment with 200 mg sparfloxacin (after initial 400 mg dose) is as effective as twice-daily treatment with 400 mg ofloxacin in patients with ABECB.

An epidemic of adenovirus 7a infection in a neonatal nursery: course, morbidity, and management.

An epidemic of adenovirus 7a in our neonatal intensive care nursery and intermediate care nursery in July and August 1987 caused the death of two patients. Significant symptomatic infection possibly due to the virus occurred in nine patients, ten staff, and three parents, of whom three patients, three staff, and one parent were positive by culture. As a direct consequence of the outbreak, 58 staff days of work were lost; the intensive care nursery had to be closed to admissions for 19 days and the intermediate care nursery for 14 days. Seventeen newborns were transferred to other hospitals and four mothers were sent elsewhere for delivery. Control measures, which included cohorting of patients, use of gloves, gowns and goggles, and exclusion of symptomatic staff from the unit, appeared effective. Rapid immunofluorescence testing of virological specimens was of little use in monitoring the outbreak, largely because of poor specimen quality. This outbreak further underlines the ease of transmission and high morbidity of neonatal adenovirus infection.

Risk factors for Clostridium difficile toxin-associated diarrhea.

The hospital-wide attack rate for Clostridium difficile-associated diarrhea at our tertiary-care university hospital was 0.02 per 100 patient discharges (0.02%) in 1982, but 0.41% and 1.47% in 1986 and 1987, respectively, with a peak incidence of 2.25% in the fourth quarter of 1987. Hospital antibiotic usage patterns showed concurrent increased use of third-generation cephalosporins, and intravenous vancomycin and metronidazole. Thirty-seven cases selected for study were older than 37 control patients, more likely to have an underlying malignancy and less likely hospitalized on the obstetrics/gynecology service. Their mean duration of hospitalization prior to diagnosis was 21 days, versus a mean total length of stay of eight days for controls. All cases received antibiotics, compared to 24 of the controls. Cases were given more antibiotics for longer periods, and more often received clindamycin, third-generation cephalosporins, aminoglycosides and vancomycin. Gender, race, duration of hospitalization, prior surgery and antiulcer therapy were not significant by logistic regression analysis. Epidemiologic variables with significantly different adjusted odds ratios (95% confidence intervals) were age greater than 65 years (14.1, 1.4-141), intensive care unit residence (39.2, 2.2-713), gastrointestinal procedure (23.2, 2.1-255) and more than ten antibiotic days (summation of days of each antibiotic administered) (16.1, 2.2-117). Control measures included encouraging earlier isolation and treatment of suspected cases and formulary restriction of clindamycin, with use of metronidazole for therapy of anaerobic infections. By the second half of 1988, the attack rate had dropped progressively to 0.74%.

Anaerobic bacteremia in patients with acute leukemia.

We reviewed 402 hospital admissions of patients with acute leukemia to define the frequency and characteristics of anaerobic bacteremia in this patient population. Six (5.2%) of the 116 septicemia episodes documented in these patients were caused by anaerobes (Bacteroides species, 3; Fusobacterium species, 2; and Clostridium tertium, 1); two of these episodes were polymicrobial. Five patients had had prior bacteremia. All six patients were receiving broad-spectrum antibiotics, including an anti-pseudomonal penicillin, at the time of the episode. In each instance, the absolute granulocyte count was 0/mm3. Five patients had clinically apparent sources of infection, including perirectal abscess, gastrointestinal bleeding, or Clostridium difficile-associated diarrhea. Anaerobic bacteremia is an infrequent occurrence in granulocytopenic patients with acute leukemia, but may occur when there is obvious disruption of normal gastrointestinal anatomic barriers.

Urosepsis associated with videourodynamic studies.

Videourodynamic studies (VUS) of the lower urinary tract are useful in the evaluation of complicated voiding dysfunctions. These studies involve placement of urethral and rectal catheters, measurement of pressures during bladder filling and voiding, and simultaneous fluoroscopic cystourethrography. A cluster of five cases of urosepsis occurred in patients examined with VUS between November 1981 and February 1982. Pseudomonas aeruginosa was cultured from the blood and/or urine of three of these patients. P. aeruginosa was also recovered from cultures of fluid within the stopcock-tubing-syringe apparatus used to connect the urethral catheter to the pressure transducer. The temporal relationship of urosepsis to the VUS procedure and the identification of an environmental reservoir of P. aeruginosa suggest that these episodes were related to VUS.

Physiologic, microbiologic, and seasonal effects of handwashing on the skin of health care personnel.

The handwashing practices of 22 personnel on an oncology unit in an urban medical center were studied for 2 months. During 891 person-hours of observation, 986 handwashes were observed. Subjects washed a mean of 1.1 times an hour for a mean of 13.2 seconds. Reported and observed handwashing behavior was only moderately correlated (p = 0.05 for frequency, 0.30 for duration of handwashing). Physicians washed significantly less often (p less than 0.001), but more thoroughly (p less than 0.001), than did nurses. Nurses washed more often after minimal or no patient contact than did physicians (p less than 0.001). Individuals were very consistent in their handwashing technique. A total of 558 isolates were recovered from 158 hand cultures. The mean log count was 4.88, with no significant difference between physicians and nurses. Coagulase-negative staphylococci isolated from hands of physicians and nurses were significantly more resistant to antimicrobial agents than those of personnel with minimal patient contact (p less than 0.01). Subjects had more skin damage in winter than in summer, as indicated by increased shedding of skin squames (p less than 0.05). We conclude that handwashing practices vary significantly by profession and that reporting of handwashing practices by personnel is inaccurate.

Cefoxitin versus clindamycin and gentamicin in the treatment of postcesarean section infections.

Cefoxitin, a cefamycin derivative, has demonstrated activity against a broad spectrum of aerobic and anaerobic bacterial pathogens. The efficacy and safety of cefoxitin were compared with that of the combination of clindamycin and gentamicin in the treatment of postcesarean section infection. Ninety-eight patients were evaluated. Cefoxitin cured 36 of 48 patients (75%); clindamycin/gentamicin cured 38 of 50 (76%) (P greater than .05). Febrile degree hours and length of hospital stay did not differ between the two study groups. No patient experienced abscess formation or septic pelvic thrombophlebitis. Both therapies were well tolerated. In the authors' experience, cefoxitin as a single agent was as effective in the treatment of postoperative pelvic infection as the combination of clindamycin and gentamicin.

Sparfloxacin worldwide in vitro literature: isolate data available through 1994.

Sparfloxacin is a piperazinyl, cyclopropyl-fluoroquinolone with broad-spectrum antibacterial activity. Compared to other quinolones, sparfloxacin displays improved activity against a variety of pathogens including Staphylococcus, Streptococcus, Enterococcus, Chlamydia, Mycoplasma, Ureaplasma, and Mycobacteria species. Other susceptible organism group include Haemophilus, Legionella, Moraxella, Neisseria, Aeromonas, Acinetobacter, Bordetella, Brucella, Campylobacter, Gardnerella, and Helicobacter species. Most Enterobacteriaceae are also susceptible, whereas most isolates of Pseudomonas aeruginosa are not. Sparfloxacin is bactericidal. Activity is generally stable to variations of inoculum, pH, and cation concentration, and it is unchanged in the presence of 5% sodium cholate or 70% human serum. Susceptibility to the drug is diminished in urine. Cross-resistance, although incomplete, has been documented with other quinolones, but not with other antimicrobic classes.

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.