Celia Cardozo

Clinical experience with ceftazidime/avibactam in patients with severe infections, including meningitis and lung abscesses, caused by extensively drug-resistant Pseudomonas aeruginosa

In the last few years, the growing incidence of infections caused by extensively drug-resistant Pseudomonas aeruginosa (XDR-PA) worldwide has become a major health problem owing to their high rates of morbidity andmortality and the toxicity of the current treatments [1,2]. Ceftazidime/avibactam is a novel cephalosporin and β-lactamase inhibitor combination with activity against Enterobacteriaceae producing extended-spectrum β-lactamases (classes A, C and some D), some carbapenemases and P. aeruginosa. The INFORM global surveillance programme tested ceftazidime/avibactam and comparators against 7062 clinical isolates of P. aeruginosa [3]. The rate of susceptibility to ceftazidime/avibactam was 92.0% (range, 88.7– 93.2%), surpassing the susceptibilities to all other tested β-lactams, including carbapenems (57.2–78.5%), and comparable with or greater than amikacin (81.8–94.4%) [3]. Nevertheless, clinical studies are scarce and are focused on complicated intra-abdominal or urinary tract infections, and do not specify the rate of resistance of the strains tested, thus the activity of ceftazidime/avibactam against themost resistant strains cannot be inferred [4]. Here we present the characteristics and outcome of two patients with severe XDR-PA infections treated with ceftazidime/avibactam. The first case was a 69-year-old male with a brain abscess due to Escherichia coli, for which he was treated with metronidazole, ampicillin and ceftriaxone for 1 month. During hospitalisation, he presented an episode of fever without evident source. Blood cultures were obtained from the catheter line and were positive for XDR-PA susceptible only to colistin. The central venous catheter was removed and its culture was positive for the same bacteria. Intravenous therapy with meropenem 2 g every 8 h (q8h) and colistin 2 MU q8h was initiated, but nevertheless the patient remained febrile and respiratory symptoms appeared. Repeated blood cultures remained negative. Computed tomography (CT) revealed seven necrotic lesions in both lungs highly suggestive of septic embolisms. Bronchoalveolar lavage was performed and the culture was also positive for XDR-PA. Antibiotic treatment was switched to ceftazidime/avibactam 2.5 g q8h, administered as a 2-h infusion, and colistin 2 MU q8h and 1 MU q8h inhaled during 18 days. The clinical and radiological evolution demonstrated a complete response (Fig. 1). The second case was a 56-year-old female who underwent renal transplantation because of diabetic nephropathy. Despite having received thymoglobulin induction and being started on immunosuppressionmaintenancewith tacrolimus, sirolimus and prednisone, she suffered an allograft rejection confirmed by biopsy, for which she received rituximab and plasma exchange. After 6 months, she presented progressive headache and facial pain. CT displayed pansinusitis with bone necrosis. Cerebrospinal fluid (CSF) analysis was normal. A surgical approach was needed and XDR-PA was isolated in surgical samples resulting from sinus debridement performed by the otolaryngologist. Meropenem 2 g q8h and colistin 2MU q8hwere started, without clinical improvement. In fact, the patient showed a progressive decrease of consciousness. A new lumbar puncture was performed and the CSF was highly suggestive of meningitis [3200 nuclear cells/mm3 (89% polymorphonuclear cells), 43 mg/ dL glucose (normal range, 40–80 mg/dL) and 285 mg/dL proteins (normal range, 15–45mg/dL)]. Cytology analysis was performed and was negative for atypical cells. Culture of the CSF was negative, but PCR sequencing of 16S rRNA identified P. aeruginosa. Treatment was

Time to Positivity and Detection of Growth in Anaerobic Blood Culture Vials Predict the Presence of Candida glabrata in Candidemia: a Two-Center European Cohort Study

ABSTRACT This study shows the accuracy of exclusive or earlier growth in anaerobic vials to predict Candida glabrata in a large series of candidemic patients from two European hospitals using the Bactec 9240 system. Alternatively, C. glabrata can be predicted by a time to positivity cutoff value, which should be determined for each setting.

Echinocandins Compared to Fluconazole for Candidemia of a Urinary Tract Source: A Propensity Score Analysis

Background Whether echinocandins could be used to treat candidemia of a urinary tract source (CUTS) is unknown. We aimed to provide current epidemiological information of CUTS and to compare echinocandin to fluconazole treatment on CUTS outcomes. Methods A multicenter study of adult patients with candidemia was conducted in 9 hospitals. CUTS was defined as a candidemia with concomitant candiduria by the same organism associated with significant urological comorbidity. The primary outcome assessed was clinical failure (defined by 7-day mortality or persistent candidemia) in patients treated with either an echinocandin or fluconazole. A propensity score was calculated and then entered into a regression model. Results Of 2176 episodes of candidemia, 128 were CUTS (5.88%). Most CUTS cases were caused by Candida albicans (52.7%), followed by Candida glabrata (25.6%) and Candida tropicalis (16.3%). Clinical failure occurred in 7 patients (20%) treated with an echinocandin and in 15 (17.1%) treated with fluconazole (P = .730). Acute renal failure (adjusted odds ratio [AOR], 3.01; 95% confidence interval [CI], 1.01-8.91; P = .047) was the only independent factor associated with clinical failure, whereas early urinary tract drainage procedures (surgical, percutaneous, or endoscopic) were identified as protective (AOR, 0.08; 95% CI, .02-.31; P < .001). Neither univariate nor multivariate analysis showed that echinocandin therapy altered the risk of clinical failure. Conclusions Initial echinocandin therapy was not associated with clinical failure in patients with CUTS. Notably, acute renal failure predicted worse outcomes and performing an early urologic procedure was a protective measure.

Influence of empirical double-active combination antimicrobial therapy compared with active monotherapy on mortality in patients with septic shock: a propensity score-adjusted and matched analysis—authors’ response

Objectives To evaluate the influence on mortality of empirical double-active combination antimicrobial therapy (DACT) compared with active monotherapy (AM) in septic shock patients. Methods A retrospective study was performed of monomicrobial septic shock patients admitted to a university centre during 2010-15. A propensity score (PS) was calculated using a logistic regression model taking the assigned therapy as the dependent variable, and used as a covariate in multivariate analysis predicting 7, 15 and 30 day mortality and for matching patients who received DACT or AM. Multivariate models comprising the assigned therapy group and the PS were built for specific patient subgroups. Results Five-hundred and seventy-six patients with monomicrobial septic shock who received active empirical antimicrobial therapy were included. Of these, 340 received AM and 236 DACT. No difference in 7, 15 and 30 day all-cause mortality was found between groups either in the PS-adjusted multivariate logistic regression analysis or in the PS-matched cohorts. However, in patients with neutropenia, DACT was independently associated with a better outcome at 15 (OR 0.29, 95% CI 0.09-0.92) and 30 (OR 0.25, 95% CI 0.08-0.79) days, while in patients with Pseudomonas aeruginosa infection DACT was associated with lower 7 (OR 0.12, 95% CI 0.02-0.7) and 30 day (OR 0.26, 95% CI 0.08-0.92) mortality. Conclusions All-cause mortality at 7, 15 and 30 days was similar in patients with monomicrobial septic shock receiving empirical double-active combination therapy and active monotherapy. However, a beneficial influence of empirical double-active combination on mortality in patients with neutropenia and those with P. aeruginosa infection is worthy of further study.

Evaluation of ceftazidime/avibactam for serious infections due to multidrug-resistant and extensively drug-resistant Pseudomonas aeruginosa

OBJECTIVES The steady progress in resistance of Pseudomonas aeruginosa (PA) has led to difficulties in treating infections due to multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. Ceftazidime/avibactam (CAZ/AVI) has in vitro activity against many of these strains, however clinical experience with CAZ/AVI is limited. This study aimed to evaluate the characteristics and outcomes of eight patients with infections due to MDR- or XDR-PA treated with CAZ/AVI, including four strains resistant to ceftolozane/tazobactam. METHODS This was a retrospective descriptive study of patients admitted to a teaching hospital between January 2016 and May 2017 who received CAZ/AVI as initial or continuation therapy for infection due to MDR- and XDR-PA. RESULTS The sources of infection were hospital-acquired lower respiratory tract infection in five patients (62.5%) and osteomyelitis, meningitis and catheter-related bacteraemia in one patient each. Clinical cure was achieved in 4 patients (50.0%). The 30-day and 90-day mortality rates were 12.5% and 37.5%, respectively. One patient (12.5%) developed encephalopathy that improved with discontinuation of the drug. CONCLUSIONS CAZ/AVI may be a valuable option for serious infections due to resistant PA.

Tenofovir disoproxil fumarate/emtricitabine plus ritonavir-boosted lopinavir or cobicistat-boosted elvitegravir as a single-tablet regimen for HIV post-exposure prophylaxis

Objectives To assess HIV-1 post-exposure prophylaxis (PEP) non-completion at day 28, comparing ritonavir-boosted lopinavir versus cobicistat-boosted elvitegravir as a single-tablet regimen (STR), using tenofovir disoproxil fumarate/emtricitabine with both of these therapies. Methods A prospective, open, randomized clinical trial was performed. Individuals attending the emergency room due to potential sexual exposure to HIV and who met criteria for PEP were randomized 1:3 into two groups receiving either 400/100 mg of lopinavir/ritonavir (n = 38) or 150/150 mg of elvitegravir/cobicistat (n = 119), with both groups also receiving 245/200 mg of tenofovir disoproxil fumarate/emtricitabine. Five follow-up visits were scheduled at days 1, 10, 28, 90 and 180. The primary endpoint was PEP non-completion at day 28. Secondary endpoints were adherence, adverse effects and rate of seroconversions. Clinical trials.gov number: NCT08431173. Results Median age was 32 years and 95% were males. PEP non-completion at day 28 was 36% (n = 57), with a trend to be higher in the lopinavir/ritonavir arm [lopinavir/ritonavir 47% (n = 18) versus elvitegravir/cobicistat 33% (n = 39), P = 0.10]. We performed a modified ITT analysis including only those patients who attended on day 1. PEP non-completion in this subgroup was higher in the lopinavir/ritonavir arm than in the elvitegravir/cobicistat arm (33% versus 15%, respectively, P = 0.04). Poor adherence was significantly higher in the lopinavir/ritonavir arm versus the elvitegravir/cobicistat arm (47% versus 9%, respectively, P < 0.0001). Adverse events were reported by 73 patients (59%), and were significantly more common in the lopinavir/ritonavir arm (90% versus 49%, P = 0.0001). A seroconversion was observed in the elvitegravir/cobicistat arm in a patient with multiple exposures before and after PEP. Conclusions A higher PEP non-completion, poor adherence and adverse events were observed in patients allocated to the lopinavir/ritonavir arm, suggesting that STR elvitegravir/cobicistat is a well-tolerated antiretroviral for PEP.