Real-life experience with ceftolozane/tazobactam in Canada: results from the CLEAR (Canadian LEadership on Antimicrobial Real-life usage) registry.

OBJECTIVES: Ceftolozane/tazobactam is a cephalosporin/ß-lactamase inhibitor combination with activity against Gram-negative bacilli. Here we report the use of ceftolozane/tazobactam in Canada using a national registry. METHODS: The CLEAR registry uses a REDCapTM online survey to capture details associated with clinical use of ceftolozane/tazobactam. RESULTS: Data from 51 patients treated in 2020 with ceftolozane/tazobactam are available. Infections treated included hospital-acquired bacterial pneumonia (37.3% of patients), ventilator-associated bacterial pneumonia (15.7%), bone and joint infection (11.8%), complicated intra-abdominal infection (7.8%) and complicated skin and skin-structure infection (7.8%). Moreover, 17.6% of patients had bacteraemia and 47.1% were in intensive care. Ceftolozane/tazobactam was primarily used as directed therapy for Pseudomonas aeruginosa infections (92.2% of patients). Ceftolozane/tazobactam was used because of resistance to (86.3%), failure of (11.8%) or adverse effects from (2.0%) previously prescribed antimicrobials. Ceftolozane/tazobactam susceptibility testing was performed on isolates from 88.2% of patients. Ceftolozane/tazobactam was used in combination with another antimicrobial active against Gram-negative bacilli in 39.2% of patients [aminoglycosides (15.7%), fluoroquinolones (9.8%) and colistin/polymyxin B (7.8%)]. The dosage regimen was customised in all patients based on creatinine clearance. The treatment duration was primarily >10 days (60.8% of patients), with microbiological success in 60.5% and clinical success in 64.4% of patients. Moreover, 7.8% of patients had adverse effects not requiring drug discontinuation. CONCLUSION: In Canada, ceftolozane/tazobactam is used as directed therapy to treat a variety of severe infections caused by multidrug-resistant P. aeruginosa. It is commonly used in combination with other antimicrobials with relatively high microbiological/clinical cure rates and an excellent safety profile.

Randomized Clinical Trial of Sodium Polystyrene Sulfonate for the Treatment of Mild Hyperkalemia in CKD.

BACKGROUND AND OBJECTIVES: Hyperkalemia affects up to 10% of patients with CKD. Sodium polystyrene sulfonate has long been prescribed for this condition, although evidence is lacking on its efficacy for the treatment of mild hyperkalemia over several days. This study aimed to evaluate the efficacy of sodium polystyrene sulfonate in the treatment of mild hyperkalemia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In total, 33 outpatients with CKD and mild hyperkalemia (5.0-5.9 mEq/L) in a single teaching hospital were included in this double-blind randomized clinical trial. We randomly assigned these patients to receive either placebo or sodium polystyrene sulfonate of 30 g orally one time per day for 7 days. The primary outcome was the comparison between study groups of the mean difference of serum potassium levels between the day after the last dose of treatment and baseline. RESULTS: The mean duration of treatment was 6.9 days. Sodium polystyrene sulfonate was superior to placebo in the reduction of serum potassium levels (mean difference between groups, -1.04 mEq/L; 95% confidence interval, -1.37 to -0.71). A higher proportion of patients in the sodium polystyrene sulfonate group attained normokalemia at the end of their treatment compared with those in the placebo group, but the difference did not reach statistical significance (73% versus 38%; P=0.07). There was a trend toward higher rates of electrolytic disturbances and an increase in gastrointestinal side effects in the group receiving sodium polystyrene sulfonate. CONCLUSIONS: Sodium polystyrene sulfonate was superior to placebo in reducing serum potassium over 7 days in patients with mild hyperkalemia and CKD.

Pharmacokinetics of an extended 4-hour infusion of piperacillin-tazobactam in critically ill patients undergoing continuous renal replacement therapy.

STUDY OBJECTIVE: To evaluate the pharmacokinetic and pharmacodynamic profiles of piperacillin-tazobactam administered as a 4-hour infusion in critically ill patients undergoing continuous renal replacement therapy (CRRT). DESIGN: Prospective, observational, pharmacokinetic study. SETTING: Intensive care unit of a tertiary care hospital in Montréal, Canada. PATIENTS: Twenty critically ill adults who were undergoing continuous venovenous hemodiafiltration and receiving a 4-hour infusion of piperacillin 4 g-tazobactam 0.5 g every 8 hours for a documented or suspected infection. INTERVENTION: Blood samples were collected every hour over an 8-hour dosing interval. Prefilter and postfilter blood samples, and effluent and urine samples were also collected. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the proportion of patients who achieved an unbound piperacillin plasma concentration above a target minimum inhibitory concentration (MIC) of 64 mg/L (MIC that inhibits 90% of isolates for Pseudomonas aeruginosa) for at least 50% of the dosing interval; 18 (90%) of the 20 patients achieved this outcome. In all patients, the free piperacillin concentrations were above the Pseudomonas aeruginosa breakpoint of 16 mg/L for the entire time interval. Regarding piperacillin pharmacokinetic parameters, the median (interquartile range) minimum unbound plasma concentration was 65.15 mg/L (51.30-89.30), maximum unbound plasma concentration was 141.3 mg/L (116.75-173.90), sieving coefficient was 0.809 (0.738-0.938), total clearance was 65.82 ml/minute (53.79-102.87), and renal clearance was 0.16 ml/minute (0.05-3.04). The median CRRT dose was 32.0 ml/kg/h (25.0-39.8). CONCLUSIONS: Administration of a 4-hour infusion of piperacillin-tazobactam was associated with a favorable pharmacodynamic profile in patients undergoing CRRT. Concentrations associated with maximal activity were attained in our patients.

Oral ferrous sulfate does not increase preoperative hemoglobin in patients scheduled for hip or knee arthroplasty.

BACKGROUND: Low hemoglobin (Hb) concentrations before lower limb joint replacement are associated with the need for blood transfusions and increased mortality. To optimize preoperative Hb, blood conservation protocols often recommend oral iron supplements, even in nonanemic patients. OBJECTIVE: To investigate the impact of ferrous sulfate on the change in Hb prior to hip or knee arthroplasty and evaluate the effect of oral iron on hematocrit, mean corpuscular volume (MCV), ferritin, and transferrin saturation, as well as its tolerability and treatment adherence. METHODS: We conducted a prospective, observational cohort study of adults with Hb concentrations between 10 and 15 g/dL who received iron supplementation prior to hip or knee arthroplasty. Systemic inflammatory diseases, vitamin B(12) or folate deficiency, and current use of iron supplements, intravenous iron, or erythropoietin were exclusion criteria. All participants were prescribed ferrous sulfate 300 mg 3 times daily for a minimum of 3 weeks. Complete blood cell counts and iron studies were performed before therapy and surgery. RESULTS: Eighty-seven patients with a mean (SD) Hb of 13.47 (0.84) g/dL were included in the study. Preoperative Hb decreased after treatment with iron (-0.14 [0.53] g/dL, p = 0.015). Hematocrit also declined (-0.6% [1.8%], p = 0.002), whereas ferritin increased (25.8 [38.6] ng/mL, p < 0.001). No significant change was seen in MCV and transferrin saturation. The most common adverse effects were constipation (33.3%), heartburn (13.8%), and abdominal pain (12.6%). The adherence rate was 67.1%. CONCLUSIONS: Oral ferrous sulfate supplementation is not an effective method to increase preoperative Hb in patients scheduled for hip or knee arthroplasty, and its use is associated with adverse effects.

Multipronged intervention strategy to control an outbreak of Clostridium difficile infection (CDI) and its impact on the rates of CDI from 2002 to 2007.

OBJECTIVE: At the end of 2002, a new, more virulent strain of Clostridium difficile, designated BI/NAP1, was the cause of a massive outbreak of infection in the province of Quebec. This particular strain was associated with a dramatic increase in morbidity and mortality among affected patients in 2003-2004. We tested and implemented a multipronged infection control approach to curtail the rate of C. difficile infection (CDI). DESIGN: Five-year observational study. SETTING: A 554-bed, acute care tertiary hospital, the largest single medical center in Quebec, Canada. METHODS: To curtail the magnitude of the outbreak, we implemented a global strategy consisting of rapid C. difficile testing for all hospitalized patients who had at least 1 occurrence of liquid stool, the rapid isolation of patients infected with C. difficile in a dedicated ward with a specially trained housekeeping team, a global hand hygiene program, and the hiring of infection control practitioners. Antibiotic consumption at the institutional level was also monitored during the 5-year surveillance period. Cases of hospital-acquired CDI per 1,000 admissions were continuously monitored on a monthly basis during the entire surveillance period. RESULTS: The highest recorded CDI rate was 42 cases per 1,000 admissions in January 2004. Once additional infection control resources were put in place, the rate decreased significantly during the period from April 2005 to March 2007. During the 2003-2004 period, there were 762 cases of CDI (mean annual rate, 37.28 cases per 1,000 admissions) recorded in our study, compared with 292 cases of CDI (14.48 cases per 1,000 admissions) during the 2006-2007 period (OR, 0.379 [95% CI, 0.331-0.435]; p< .001), a 61% reduction. In March 2007, the equivalent of 4 full-time equivalent infection control practitioners were in place, which gave a ratio of 0.96 infection control practitioners per 133 beds in use, compared with the ratio of 0.24 infection control practitioners per 133 beds in use in 2003, and the total number of hours dedicated to cleaning and housekeeping increased by 26.2%. The total amount of antibiotics used in the hospital did not vary significantly from 2002 to 2007, although there were changes in the classes antibiotic used. CONCLUSION: The implementation of a multipronged intervention strategy to control the outbreak of CDI significantly improved the overall situation at the hospital and underlined the importance of investing in stringent infection control practices.

Clostridium difficile infections in a Canadian tertiary care hospital before and during a regional epidemic associated with the BI/NAP1/027 strain.

Since 2002, an epidemic of Clostridium difficile infections has occurred in southern Quebec, Canada. At Hôpital Maisonneuve-Rosemont, Montreal, Quebec, Canada, the incidence of C. difficile infections increased from 11/1,000 admissions (1999 to 2002) to 27/1,000 admissions (2003 to 2005). We compared the exposures and outcomes for patients infected with strains with different ribopatterns isolated before (n = 55) and during (n = 175) the epidemic, as well as the in vitro activities of antibiotics against those isolates. During the preepidemic period, 46 isolates (84%) were of ribotype 001, 1 was of ribotype 027, and 8 were of other ribopattern types. During the epidemic period, ribotype 027 strains accounted for 140 (80%) isolates; 26 (15%) were of ribotype 001, and 7 were of other ribopattern types. Ribotype 027 strains were highly resistant to fluoroquinolones (FQs) but were susceptible to clindamycin. A pattern of prior specific antibiotic exposure that selected for antibiotic-resistant ribotype C. difficile infections was observed for FQs (ribotype 027) and clindamycin (ribotype 001). The rate of mortality was higher among older patients, those with a high Charlson comorbidity index, and those with longer previous hospitalizations. By multivariate analysis, patients infected with ribotype 027 were twice as likely to die within 30 days of diagnosis than patients infected with other ribotypes (adjusted odds ratio, 2.06; 95% confidence interval, 1.00 to 4.22). The observations from this study support the notion that continued selective antibiotic pressure resulted in the superimposition of the hypertoxigenic ribotype 027 clone on top of the prior dominant ribotype 001 clone in a setting of preexisting high endemicity, thus leading to the high rates of morbidity and mortality seen in the Quebec outbreak. Stringent antibiotic stewardship measures, combined with aggressive infection control, are required to curtail the epidemic of C. difficile infections.

Clostridium difficile-associated diarrhoea rates and global antibiotic consumption in five Quebec institutions from 2001 to 2004.

A massive outbreak of a new Clostridium difficile clone affected the province of Quebec between 2002 and 2004. There are several theories as to the exact cause of the emergence of this new clone, including the overuse of some classes of antibiotics. Antibiotic prescription is associated with C. difficile-associated diarrhoea (CDAD), but which class has the highest risk is still the subject of debate. We analysed the global antibiotic consumption patterns in five institutions in Quebec, three in the area affected by the 2002-2004 CDAD outbreak and two in non-affected areas. We showed that there is no correlation between the type and amount of antibiotics used at the institution level and the magnitude of the outbreak. Deficient infection control measures likely led to the rapid spread and dissemination of this newly characterised clone within some parts of Quebec.