A Risk-Stratified Peri-Operative Protocol for Reducing Surgical Site Infection after Cesarean Delivery.

Background: Surgical site infections (SSI) are multifaceted. Pre-operative, intra-operative, and post-operative factors influence the risk of developing an infection. Our objective was to evaluate the effectiveness of an infection risk-stratification checklist, utilizing known SSI risk factors, and a tailored surgical protocol for SSI prevention in women undergoing cesarean delivery. Patients and Methods: A prospective project to reduce SSI was conducted for women undergoing cesarean delivery on the resident staff service at a midwestern, urban tertiary care hospital. Patients were categorized according to an SSI risk-stratification checklist as high risk or low risk. The low-risk group received the local standard of care (single prophylactic dose of pre-operative intravenous antibiotics and a standard pressure dressing). In the high-risk group, prophylactic antibiotic agents were given pre-operatively and continued for the first 24 hours post-operatively. Additionally, patients at high risk received an absorbent dressing (Mepilex Ag®; Mölnlycke Health Care AB, Gothenburg, Sweden) that was applied in the operating room and worn for one week. Results: The overall rate of SSIs decreased from 6.1% (pre-study rate) to 1.4% after initiation of the protocol, a 77% reduction (p < 0.001). The low- and high-risk groups did not differ in infection rate (0% and 1.4%, respectively; p < 0.59). Both deep incisional and organ/space SSIs decreased after initiation of the protocol (91% and 62% decrease, respectively). Conclusion: Stratifying patients into high- and low-risk groups with tailored peri-operative management strategies reduced overall SSIs. The protocol incorporates known risk factors for SSI in a surgical procedure with high rates of SSI. This approach offers a structured method that can be adopted by other hospital systems for SSI prevention in patients undergoing cesarean delivery.

Growth performance of piglets during the first two weeks of lactation affects the development of the intestinal microbiota.

The aim of this study was to evaluate the effect of newborn piglet weight gain during the first 2 weeks of lactation on the luminal and mucosal microbiota of the ileum and colon. The microbiota from high-weight-gain (HWG) and low-weight-gain (LWG) 2-week-old piglets was characterized by amplicon length heterogeneity PCR (LH-PCR) and compared using diversity indices and multivariate statistical analyses. At birth, LWG piglets weighted in average 0.26 kg less than HWG piglets (p = .002). The weight difference between LWG and HWG piglets increased with time and reached 2.1 kg after 16 days of lactation (p < .0001). Based on these growth performance differences, estimated colostrum and milk intake was greater in HWG than in LWG piglets (p < .0001). Analysis of the LH-PCR data of the microbiota using non-metric multidimensional scaling (NMS) and blocked multiresponse permutation procedure (MRBP) revealed that the microbiota of the HWG and LWG piglets tended to differ in ileal mucosa (p = .097) and differed in colonic lumen (p = .024). The microbiota of HWG piglets had higher levels of Bacteroidetes, Bacteroides and Ruminoccocaceae, and lower proportions of Actinobacillus porcinus and Lactobacillus amylovorus when compared with those of LWG piglets. As the weight gain of nursing piglets is highly correlated with the amount of ingested colostrum and milk, the results strongly suggest that colostrum and milk intake in the first 2 weeks of life influenced the development of the gut microbiota.

Effect of a post-weaning diet supplemented with functional feed additives on ileal transcriptome activity and serum cytokines in piglets challenged with lipopolysaccharide.

This study evaluated the potential of a weanling diet supplemented with trace minerals, vitamins, prebiotics, essential oils, antioxidants and bovine colostrum (BC) to modulate the inflammatory response of low-weight (LW) and high-weight (HW) piglets challenged with lipopolysaccharide (LPS). At weaning (20±1 d), litters from 32 sows were assigned to four groups: control diet (CTL), CTL plus dietary supplements (DS) or the antibiotic chlortetracycline (ATB), or DS plus BC in place of plasma proteins in the weanling diet (DS+BC). At 37 d (T0), two LW and two HW piglets were bled to evaluate ex vivo cytokine production by LPS activated peripheral blood mononuclear cells (PBMCs). In parallel, LW and HW piglets received intraperitoneal LPS and were bled at slaughter at 4h (T4) or 18h (T18) post-injection. Ileal tissues from these piglets and two unchallenged medium weight (MW) piglets per treatment were excised and analyzed by microarray. At T0, cytokine production of LPS-activated PBMCs was not affected by dietary treatments. At T4 after LPS challenge, serum concentrations of TNF-α, IL-6, IL-8, and IL-10 were increased in all piglets (P<0.01). Interestingly, the LW piglets had a higher TNF-α level than the HW piglets did (P=0.05). Dietary treatments had no effect on the piglet serum concentration of these cytokines neither at T4 nor at T18. Microarray data and QPCR analysis reveal that several genes were differentially expressed in the LPS-challenged piglets in comparison with the two control MW piglets (P<0.001). However, the dietary treatments had a slight effect on the ileal gene expression of the T4 and T18 LPS-challenged piglets when all piglets were included in the analysis. But when body weight (LW and HW) was considered as a fixed effect, the microarray analysis showed that the expression of 54 genes was differentially modulated by the dietary treatments in the T4 and T18 LPS-challenged LW piglets (P<0.05) while in HW piglets no difference was observed. QPCR analyses confirm that the level expression of several genes was reduced in LW piglets fed DS or DS+BC diet compared with ATB piglets. In conclusion, LPS challenge induced a transitional inflammation in weanling piglets that was characterized by increased blood-circulating cytokines and gut transcriptome activity. Results also suggest that the weanling diet supplemented with feed additives attenuated the ileal gene response to the LPS challenge, an effect that was more pronounced in the LW piglets.

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.

Effects of probiotics Pediococcus acidilactici strain MA18/5M and Saccharomyces cerevisiae subsp. boulardii strain SB-CNCM I-1079 on fecal and intestinal microbiota of nursing and weanling piglets.

In this study, the influence of (PA) and subsp. (SCB) on fecal and intestinal microbiota of piglets during lactation and after weaning was monitored. Forty sows and their litters were used and allocated to the following dietary treatments: 1) PA, 2) SCB, 3) a mixture of the 2 probiotics (PA+SCB), 4) antibiotics (ATB), and 5) control (CTRL). Four weeks before parturition, probiotic-treated sows started receiving a daily probiotic dose of at least 2.5 × 10 cfu mixed in 500 g of feed until the end of lactation. The other groups were fed a diet without probiotics and ATB. Two days after birth, piglets received, daily, 1 × 10 cfu of the same probiotics as their mother. At weaning (d 21), these piglets were fed a basal diet enriched with the same probiotics whereas piglets from untreated litters were fed the basal diet with or without ATB. Two piglets per litter were randomly chosen to evaluate the influence of treatments on fecal microbial composition (d 10 and 28) and on ileum and colon microbiota at d 37. The microbiota was characterized by culture on selective media and by 16S rRNA gene diversity assessment using the terminal RFLP technique and clone library analysis to evaluate diversity index and phylum affiliation. Terminal RFLP profiles were also analyzed to determine differences in microbial composition between animals receiving different treatments and to identify diet-specific terminal restriction fragments (TRF) using pairwise multiresponse permutation procedures (MRPP) and indicator species analysis. Before weaning, administration of probiotics to sows and piglets had minor effect on fecal microbiota of piglets. Most modulatory effects of probiotics on ileum and colon microbiota were observed on d 37. Results revealed that PA or ATB treatments reduced ileal microbiota diversity compared with the CTRL ( < 0.05) and promoted the establishment of Firmicutes whereas SCB consumption positively influenced the establishment of the Porphyromonadaceae and Ruminococcaceae bacterial families in the colon. Moreover, pairwise MRPP analysis indicated that ileum bacterial communities of pigs treated with PA or ATB differed from those of CTRL pigs ( < 0.05). In conclusion, PA and SCB supplements, respectively, influenced, in a strain-dependent manner, the ileum and colon microbiota of weaned piglets. Results also suggest that PA and SCB have the potential as feed additives to modulate bacterial populations associated with gut health.

Efficacy of the direct-fed microbial Enterococcus faecium alone or in combination with Saccharomyces cerevisiae or Lactococcus lactis during induced subacute ruminal acidosis.

This study aimed at investigating Enterococcus faecium alone or E. faecium in combination with Saccharomyces cerevisiae or Lactococcus lactis during a subacute ruminal acidosis (SARA) challenge. Four ruminally fistulated Holstein dairy cows were assigned to the following treatments in a 4×4 Latin square design: (1) control (CON); (2) E. faecium (EF); (3) EF + S. cerevisiae (EFSC); (4) EF + L. lactis DSM 11037 (EFLL). Each experimental period consisted of 18 d of adaptation to the respective direct-fed microbial, 3 d of SARA challenge, and 7d of rest. Rumen pH was recorded every 10 min over 24 h on d 17 of adaptation, d 2 of SARA, and d 6 of rest. On the last day of adaptation, SARA, and rest, samples of rumen content (0 and 3 h after feeding) were taken for volatile fatty acids, lactate, vitamin B12, rumen microbes, and lipopolysaccharides determination. Blood samples (0 and 6 h after feeding) were taken for the measurement of acute-phase proteins. Dry matter intake and milk yield were recorded daily. During SARA, mean rumen pH with EFSC (5.94) was not different from that of EFLL (5.95) and tended to be higher than with CON (5.82) or EF (5.82). Postfeeding vitamin B12 concentrations in the rumen were greater with EFSC (134.5ng/g) than with EF (99.6ng/g) and tended to be greater when compared with CON (101.2ng/g) or EFLL (104.9ng/g). During rest, prefeed vitamin B12 was greater with EFSC (166.5ng/g) compared with CON (132.3ng/g). The EFSC treatment did better than EF alone on pH characteristics during adaptation and SARA and on maintenance of ruminal vitamin B12 status during SARA. Milk yield drop from d 1 to 3 of SARA was smaller with EFSC (-0.8kg/d), EF (-0.9kg/d), or EFLL (-0.9kg/d) compared with CON (-7.5kg/d).

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.

Evaluation of molecular methods used for establishing the interactions and functions of microorganisms in anaerobic bioreactors.

Molecular techniques have unveiled the complexity of the microbial consortium in anaerobic bioreactors and revealed the presence of several uncultivated species. This paper presents a review of the panoply of classical and recent molecular approaches and multivariate analyses that have been, or might be used to establish the interactions and functions of these anaerobic microorganisms. Most of the molecular approaches used so far are based on the analysis of small subunit ribosomal RNA but recent studies also use quantification of functional gene expressions. There are now several studies that have developed quantitative real-time PCR assays to investigate methanogens. With a view to improving the stability and performance of bioreactors, monitoring with molecular methods is also discussed. Advances in metagenomics and proteomics will lead to the development of promising lab-on chip technologies for cost-effective monitoring.

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).