Real-Life Use of Ceftolozane/Tazobactam for the Treatment of Bloodstream Infection Due to Pseudomonas aeruginosa in Neutropenic Hematologic Patients: a Matched Control Study (ZENITH Study).

We sought to assess the characteristics and outcomes of neutropenic hematologic patients with Pseudomonas aeruginosa (PA) bloodstream infection (BSI) treated with ceftolozane-tazobactam (C/T). We conducted a multicenter, international, matched-cohort study of PA BSI episodes in neutropenic hematologic patients who received C/T. Controls were patients with PA BSI treated with other antibiotics. Risk factors for overall 7-day and 30-day case fatality rates were analyzed. We compared 44 cases with 88 controls. Overall, 91% of episodes were caused by multidrug-resistant (MDR) strains. An endogenous source was the most frequent BSI origin (35.6%), followed by pneumonia (25.8%). There were no significant differences in patient characteristics between groups. C/T was given empirically in 11 patients and as definitive therapy in 41 patients. Treatment with C/T was associated with less need for mechanical ventilation (13.6% versus 33.3%; P = 0.021) and reduced 7-day (6.8% versus 34.1%; P = 0.001) and 30-day (22.7% versus 48.9%; P = 0.005) mortality. In the multivariate analysis, pneumonia, profound neutropenia, and persistent BSI were independent risk factors for 30-day mortality, whereas lower mortality was found among patients treated with C/T (adjusted OR [aOR] of 0.19; confidence interval [CI] 95% of 0.07 to 0.55; P = 0.002). Therapy with C/T was associated with less need for mechanical ventilation and reduced 7-day and 30-day case fatality rates compared to alternative agents in neutropenic hematologic patients with PA BSI. IMPORTANCE Ceftolozane-tazobactam (C/T) has been shown to be a safe and effective alternative for the treatment of difficult to treat infections due to Pseudomonas aeruginosa (PA) in the general nonimmunocompromised population. However, the experience of this agent in immunosuppressed neutropenic patients is very limited. Our study is unique because it is focused on extremely immunosuppressed hematological patients with neutropenia and bloodstream infection (BSI) due to PA (mainly multidrug resistant [MDR]), a scenario which is often associated with very high mortality rates. In our study, we found that the use of C/T for the treatment of MDR PA BSI in hematological neutropenic patients was significantly associated with improved outcomes, and, in addition, it was found to be an independent risk factor associated with increased survival. To date, this is the largest series involving neutropenic hematologic patients with PA BSI treated with C/T.

Impact of ceftazidime/avibactam versus best available therapy on mortality from infections caused by carbapenemase-producing Enterobacterales (CAVICOR study).

BACKGROUND: Infections caused by carbapenemase-producing Enterobacterales (CPE) are not well represented in pivotal trials with ceftazidime/avibactam. The best strategy for the treatment of these infections is unknown. METHODS: We conducted a multicentre retrospective observational study of patients who received ≥48 h of ceftazidime/avibactam or best available therapy (BAT) for documented CPE infections. The primary outcome was 30 day crude mortality. Secondary outcomes were 21 day clinical response and microbiological response. A multivariate logistic regression model was used to identify factors predictive of 30 day crude mortality. A propensity score to receive treatment with ceftazidime/avibactam was used as a covariate in the analysis. RESULTS: The cohort included 339 patients with CPE infections. Ceftazidime/avibactam treatment was used in 189 (55.8%) patients and 150 (44.2%) received BAT at a median of 2 days after diagnosis of infection. In multivariate analysis, ceftazidime/avibactam treatment was associated with survival (OR 0.41, 95% CI 0.20-0.80; P = 0.01), whereas INCREMENT-CPE scores of >7 points (OR 2.57, 95% CI 1.18-1.5.58; P = 0.01) and SOFA score (OR 1.20, 95% CI 1.08-1.34; P = 0.001) were associated with higher mortality. In patients with INCREMENT-CPE scores of >7 points, ceftazidime/avibactam treatment was associated with lower mortality compared with BAT (16/73, 21.9% versus 23/49, 46.9%; P = 0.004). Ceftazidime/avibactam was also an independent factor of 21 day clinical response (OR 2.43, 95% CI 1.16-5.12; P = 0.02) and microbiological eradication (OR 0.40, 95% CI 0.18-0.85; P = 0.02). CONCLUSIONS: Ceftazidime/avibactam is an effective alternative for the treatment of CPE infections, especially in patients with INCREMENT-CPE scores of >7 points. A randomized controlled trial should confirm these findings.

Optimizing therapy of bloodstream infection due to extended-spectrum ß-lactamase-producing Enterobacteriaceae.

PURPOSE OF REVIEW: Infections due to extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-E) are increasing worldwide. Carbapenems are usually regarded as the antibiotics of choice for the treatment of serious ESBL infections. However, because of the alarming emergence or carbapenem resistance, interest in effective alternatives has emerged. The present review summarizes the findings published on the antibiotics currently available for treatment of patients with an ESBL-E bloodstream infection (BSI). RECENT FINDINGS: Meropenem and imipenem are the drugs recommended for treatment of ESBL BSIs in critically ill patients, and in infections with high bacterial loads or elevated ß-lactam minimum inhibitory concentrations. Ertapenem should be reserved for patients with less severe presentations, and should be used at high doses. In milder presentations or BSIs from low-risk sources, other carbapenem-sparing alternatives could be considered: cephamycins, fluoroquinolones, and particularly a ß-lactam/ß-lactam inhibitor combination (particularly piperacillin/tazobactam). Optimized dosing of piperacillin/tazobactam is recommended (high doses and extended infusion). There are few data on the use of the promising newly available drugs (e.g. ceftolozane/tazobactam, ceftazidime/avibactam, cefiderocol, and plazomicin), and it seems reasonable to reserve them as last-resort drugs. SUMMARY: Carbapenems should be used in patients with serious infections; alternatives could be used individually, particularly for definitive treatment of patients with milder presentations.

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.

Effect of a 3-step critical pathway to reduce duration of intravenous antibiotic therapy and length of stay in community-acquired pneumonia: a randomized controlled trial.

BACKGROUND: The length of hospital stay (LOS) for community-acquired pneumonia (CAP) varies considerably, even though this factor has a major impact on the cost of care. We aimed to determine whether the use of a 3-step critical pathway is safe and effective in reducing duration of intravenous antibiotic therapy and length of stay in hospitalized patients with CAP. METHODS: We randomly assigned 401 adults who required hospitalization for CAP to follow a 3-step critical pathway including early mobilization and use of objective criteria for switching to oral antibiotic therapy and for deciding on hospital discharge or usual care. The primary end point was LOS. Secondary end points were the duration of intravenous antibiotic therapy, adverse drug reactions, need for readmission, overall case-fatality rate, and patients' satisfaction. RESULTS: Median LOS was 3.9 days in the 3-step group and 6.0 days in the usual care group (difference, -2.1 days; 95% CI, -2.7 to -1.7; P < .001). Median duration of intravenous antibiotic therapy was 2.0 days in the 3-step group and 4.0 days in the usual care group (difference, -2.0 days; 95% CI, -2.0 to -1.0; P < .001). More patients assigned to usual care experienced adverse drug reactions (4.5% vs 15.9% [difference, -11.4 percentage points; 95% CI, -17.2 to -5.6 percentage points; P < .001]). No significant differences were observed regarding subsequent readmissions, case fatality rate, and patients' satisfaction with care. CONCLUSIONS: The use of a 3-step critical pathway was safe and effective in reducing the duration of intravenous antibiotic therapy and LOS for CAP and did not adversely affect patient outcomes. Such a strategy will help optimize the process of care of hospitalized patients with CAP, and hospital costs would be reduced. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN17875607.

Tratamiento de la enfermedad por citomegalovirus / Treatment of cytomegalovirus disease

Durante años, ganciclovir intravenoso ha sido el tratamiento recomendado para la enfermedad por citomegalovirus (CMV) en pacientes trasplantados. En los últimos años, valganciclovir oral ha mostrado una similar respuesta frente a CMV que ganciclovir intravenoso, por lo que puede ser utilizado alternativamente a ganciclovir en pacientes con enfermedad no grave. La terapia secuencial con ganciclovir seguido de valganciclovir, tras iniciarse la mejoría clínica, reduce costes y evita hospitalizaciones prolongadas, lo que supone un beneficio para los pacientes. La duración óptima del tratamiento irá guiada por la respuesta clínica y los controles virológicos (PCR o antigenemia), manteniéndose hasta que éstos sean negativos. Algunos grupos utilizan profilaxis secundaria ante la presencia de factores de riesgo de recidiva de la enfermedad por CMV. Reducir la intensidad de la inmunosupresión o complementar la terapia antiviral con inmunoglobulinas son medidas a considerar en casos graves o en grandes inmunodeprimidos. No hay datos firmes acerca del mejor tratamiento alternativo ante la evidencia de CMV resistente a ganciclovir. Las decisiones terapéuticas deberán sustentarse en el estudio genotípico de resistencias, el estado inmune del paciente y en la gravedad de la enfermedad. El tratamiento consiste en foscarnet solo o con ganciclovir en las formas más graves y en mutaciones de alta resistencia, o en el incremento de las dosis de ganciclovir en las formas clínicas o de resistencia más benignas. No hay datos concluyentes acerca de antivirales alternativos o de terapia complementaria con inhibidores de mTOR. Se ensayan diversas vacunas frente a CMV con resultados preclínicos esperanzadores (AU)

For years, intravenous ganciclovir has been the recommended treatment for cytomegalovirus (CMV) in transplant recipients. Recently, oral valganciclovir has been shown to induce a response to CMV similar to that produced by intravenous ganciclovir and could consequently be an alternative to ganciclovir in patients with non-severe disease. Sequential therapy with ganciclovir followed by valganciclovir, after the onset of clinical improvement, reduces costs and avoids prolonged hospital stays, thus benefitting patients. Optimal treatment duration is guided by clinical response and virological monitoring (polymerase chain reaction or antigenemia) and is maintained until the results are negative. Some groups use secondary prophylaxis in patients with risk factors for recurrence of CMV disease. Reducing the intensity of immunosuppression or complementing antiviral therapy with immunoglobulins can be considered in patients with severe disease or immunodepression. There are no conclusive data on the most effective treatment in ganciclovir-resistant CMV. Therapeutic decisions should be based on genotypic resistance studies, the patient’s immune status and disease severity. Treatment consists of foscarnet alone or in combination with ganciclovir in the most severe forms and in high-resistance mutations, or in increasing the dose of ganciclovir in clinical forms or in mild resistance. There are no conclusive data on alternative antiviral drugs or complementary therapy with mTOR inhibitors. Several CMV vaccines are under development and the preclinical results are encouraging (AU)

[Treatment of cytomegalovirus disease]. / Tratamiento de la enfermedad por citomegalovirus.

For years, intravenous ganciclovir has been the recommended treatment for cytomegalovirus (CMV) in transplant recipients. Recently, oral valganciclovir has been shown to induce a response to CMV similar to that produced by intravenous ganciclovir and could consequently be an alternative to ganciclovir in patients with non-severe disease. Sequential therapy with ganciclovir followed by valganciclovir, after the onset of clinical improvement, reduces costs and avoids prolonged hospital stays, thus benefitting patients. Optimal treatment duration is guided by clinical response and virological monitoring (polymerase chain reaction or antigenemia) and is maintained until the results are negative. Some groups use secondary prophylaxis in patients with risk factors for recurrence of CMV disease. Reducing the intensity of immunosuppression or complementing antiviral therapy with immunoglobulins can be considered in patients with severe disease or immunodepression. There are no conclusive data on the most effective treatment in ganciclovir-resistant CMV. Therapeutic decisions should be based on genotypic resistance studies, the patient's immune status and disease severity. Treatment consists of foscarnet alone or in combination with ganciclovir in the most severe forms and in high-resistance mutations, or in increasing the dose of ganciclovir in clinical forms or in mild resistance. There are no conclusive data on alternative antiviral drugs or complementary therapy with mTOR inhibitors. Several CMV vaccines are under development and the preclinical results are encouraging.

Health care-associated pneumonia requiring hospital admission: epidemiology, antibiotic therapy, and clinical outcomes.

BACKGROUND: Health care-associated pneumonia (HCAP) has been proposed as a new category of respiratory infection. However, limited data exist to validate this entity. We aimed to ascertain the epidemiology, causative organisms, antibiotic susceptibilities, and outcomes of and empirical antibiotic therapy for HCAP requiring hospitalization. METHODS: Observational analysis of a prospective cohort of nonseverely immunosuppressed hospitalized adults with pneumonia. Patients who had recent contact with the health care system through nursing homes, home health care programs, hemodialysis clinics, or prior hospitalization were considered to have HCAP. RESULTS: Of 727 cases of pneumonia, 126 (17.3%) were HCAP and 601 (82.7%) were community acquired. Compared with patients with community-acquired pneumonia, patients with HCAP were older (mean age, 69.5 vs 63.7 years; P < .001), had greater comorbidity (95.2% vs 74.7%; P < .001), and were more commonly classified into high-risk pneumonia severity index classes (67.5% vs 48.8%; P < .001). The most common causative organism was Streptococcus pneumoniae in both groups (27.8% vs 33.9%). Drug-resistant pneumococci were more frequently encountered in cases of HCAP. Legionella pneumophila was less common in patients with HCAP (2.4% vs 8.8%; P = .01). Aspiration pneumonia (20.6% vs 3.0%; P < .001), Haemophilus influenzae (11.9% vs 6.0%; P = .02), Staphylococcus aureus (2.4% vs 0%; P = .005), and gram-negative bacilli (4.0% vs 1.0%; P = .03) were more frequent in HCAP. Patients with HCAP more frequently received an initial inappropriate empirical antibiotic therapy (5.6% vs 2.0%; P = .03). The overall case-fatality rate (< 30 days) was higher in patients with HCAP (10.3% vs 4.3%; P = .007). CONCLUSIONS: At present, a substantial number of patients initially seen with pneumonia in the emergency department have HCAP. These patients require a targeted approach when selecting empirical antibiotic therapy.