Antipseudomonal Beta-lactam Research Articles

Risk factors for pneumonia due to beta-lactam-susceptible and beta-lactam-resistant Pseudomonas aeruginosa: a case-case-control study.

This case-case-control study aims to identify clinical predictors for pneumonia due to Pseudomonas aeruginosa (PA) which is (1) susceptible to all routinely tested antipseudomonal beta-lactams (APBL-S) and (2) resistant to at least one antipseudomonal beta-lactam (APBL-R). Hospitalized adults with acute bacterial pneumonia at Palmetto Health hospitals in Columbia, SC, USA from January 1, 2012 to April 15, 2014 were identified. Multivariate logistic regression was used to determine risk factors for pneumonia due to APBL-S PA and APBL-R PA. Among 326 unique patients, 119 had pneumonia due to APBL-S PA (cases), 44 due to APBL-R PA (cases) and 163 due to ceftriaxone-susceptible bacteria (controls). Bronchiectasis [odds ratio (OR) 5.7, 95% confidence intervals (CI) 1.3-39.2], interstitial lung disease (OR 6.2, 95% CI 1.5-42.6), prior airway colonization with APBL-S PA (OR 7.2, 95% CI 1.1-139.4) and recent exposure to both antipseudomonal beta-lactam (APBL; OR 2.2, 95% CI 1.1-4.5) and nonpseudomonal beta-lactams (OR 2.6, 95% CI 1.0-6.8) were independently associated with increased risk of APBL-S PA pneumonia. Bronchiectasis (OR 8.3, 95% CI 1.7-46.6), prior airway colonization with APBL-R PA (OR 14.9, 95% CI 2.0-312.9) and recent use of only APBL (OR 7.7, 95% CI 3.4-17.9) were predictors for APBL-R PA pneumonia. Stratification of hospitalized patients with pneumonia based on structural lung disease, prior airway colonization and recent antimicrobial exposure may improve empirical antimicrobial selection. Expansion of antimicrobial regimen from ceftriaxone to APBL or combination therapy is suggested in patients with risk factors for APBL-S or APBL-R PA, respectively.

Protocolo diagnóstico y tratamiento empírico de la neumonía en el paciente inmunocomprometido

Filamentous fungi, respiratory or herpes group, P. jirovecii, Nocardia and M. tuberculosis viruses can cause pneumonia in the immunosuppressed patient. These are mixed infections in 20% of cases. The type of infiltration (alveolar, interstitial or nodular pattern) and whether it is focal or diffuse can give a guide as to the aetiology of the infection. Bacterial, mycobacterial, fungal and viral stains and cultures from respiratory sampling (sputum, nasopharyngeal exudate, BAL), and detecting markers in BAL fluid (viral or fungal PCR, galactomannan, beta-D-glucan) are essential for diagnosis. Diffuse lesions usually require transbronchial biopsy and nodules require percutaneous CT-guided needle biopsy. Empirical treatment for focal involvement and alveolar pattern will include an antipseudomonal beta-lactam. ± amikacin ± vancomycin or linezolid (+ voriconazole if the image is nodular). Antipseudomonal beta-lactam ± vancomycin or linezolid + cotrimoxazole ± ganciclovir is recommended for cases of bilateral and diffuse involvement (alveolar or interstitial).

Cumulative Effect of an Antimicrobial Stewardship and Rapid Diagnostic Testing Bundle on Early Streamlining of Antimicrobial Therapy in Gram-Negative Bloodstream Infections.

The use of rapid diagnostic tests (RDTs) enhances antimicrobial stewardship program (ASP) interventions in optimization of antimicrobial therapy. This quasi-experimental cohort study evaluated the combined impact of an ASP/RDT bundle on the appropriateness of empirical antimicrobial therapy (EAT) and time to de-escalation of broad-spectrum antimicrobial agents (BSAA) in Gram-negative bloodstream infections (GNBSI). The ASP/RDT bundle consisted of system-wide GNBSI treatment guidelines, prospective stewardship monitoring, and sequential introduction of two RDTs, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and the FilmArray blood culture identification (BCID) panel. The preintervention period was January 2010 through December 2013, and the postintervention period followed from January 2014 through June 2015. The postintervention period was conducted in two phases; phase 1 followed the introduction of MALDI-TOF MS, and phase 2 followed the introduction of the FilmArray BCID panel. The interventions resulted in significantly improved appropriateness of EAT (95% versus 91%; P = 0.02). Significant reductions in median time to de-escalation from combination antimicrobial therapy (2.8 versus 1.5 days), antipseudomonal beta-lactams (4.0 versus 2.5 days), and carbapenems (4.0 versus 2.5 days) were observed in the postintervention compared to the preintervention period (P < 0.001 for all). The reduction in median time to de-escalation from combination therapy (1.0 versus 2.0 days; P = 0.03) and antipseudomonal beta-lactams (2.2 versus 2.7 days; P = 0.04) was further augmented during phase 2 compared to phase 1 of the postintervention period. Implementation of an antimicrobial stewardship program and RDT intervention bundle in a multihospital health care system is associated with improved appropriateness of EAT for GNBSI and decreased utilization of BSAA through early de-escalation.

Targeted simplification versus antipseudomonal broad-spectrum beta-lactams in patients with bloodstream infections due to Enterobacteriaceae (SIMPLIFY): a study protocol for a multicentre, open-label, phase III randomised, controlled, non-inferiority clinical trial

IntroductionWithin the context of antimicrobial stewardship programmes, de-escalation of antimicrobial therapy is one of the proposed strategies for reducing the unnecessary use of broad-spectrum antibiotics (BSA). The empirical treatment of...

Are third-generation cephalosporins unavoidable for empirical therapy of community-acquired pneumonia in adult patients who require ICU admission? A retrospective study

BackgroundThird-generation cephalosporins (3GCs) are recommended for empirical antibiotic therapy of community-acquired pneumonia (CAP) in patients requiring ICU admission. However, their extensive use could promote the emergence of extended-spectrum beta-lactamases-producing Enterobacteriaceae. Our aim was to assess whether the use of 3GCs in patients with CAP requiring ICU admission was justified.Methods We assessed all patients with CAP who required ICU admission during a 7-year period. We recorded empirical and definitive antibiotic therapies and susceptibility of causative pathogens. Amoxicillin, amoxicillin/clavulanate (A/C) susceptibilities as well as amikacin susceptibility of A/C-resistant strains were recorded.Results From January 2007 to March 2014, 391 patients were included in the study. Empirical 3GCs were used in 215 patients (55%). Among 267 patients with microbiologically documented CAP (68%), 241 received a beta-lactam as definitive therapy, and of those, 3CGs were chosen for 43 patients (18%). Amoxicillin or A/C was active against isolated pathogens in 159 patients (66%), while 39 patients (16%) required a beta-lactam with a broader spectrum than 3GCs. Ninety-four per cent of A/C-resistant strains were amikacin susceptible.Conclusions In ICU patients with CAP, 3GCs given on an empirical basis are changed, according to microbiological documentation, for another beta-lactam in 82% of cases especially to A/C in the absence of resistance risk factor. In patients evidencing risk factors for A/C-resistant strains infection, 3GCs or antipseudomonal beta-lactams including carbapenem associated with amikacin in the most severe patients seem a relevant empirical antibiotic therapy. This strategy could decrease 3GCs’ use.

Increased risk of death with recurrent Pseudomonas aeruginosa bacteremia

This study aimed to characterize recurrent Pseudomonas aeruginosa blood stream infection (BSI). Positive blood cultures for P. aeruginosa were identified over a 3-year period from seven tertiary care hospitals. Patients with recurrent BSI were identified. Extensive epidemiological, clinical and outcome data were obtained. BSI recurrence was found to be uncommon with 9% of patients having a first relapse of BSI. Fourteen percent of these patients went on to have a second relapse of BSI. Significant variables associated with recurrence were the presence of a hematological malignancy or receiving recent corticosteroid therapy. Exposure to anti-pseudomonal beta-lactam therapy in the 30days prior to the BSI was more likely in the patient with the recurrent BSI episode. Recurrence was associated with increased mortality when compared to the primary BSI episode. Knowledge of a patient's prior antibiotic therapy may be useful in ensuring effective empirical therapy in the recurrent BSI episode.

Acute kidney injury in patients treated with vancomycin and piperacillin-tazobactam: A retrospective cohort analysis.

Empiric antimicrobial therapy often consists of the combination of gram-positive coverage with vancomycin (VAN) and gram-negative coverage, specifically an antipseudomonal beta-lactam such as piperacillin-tazobactam (PTZ). Nephrotoxicity is commonly associated with VAN therapy; however, recent reports show higher nephrotoxicity rates among patients treated with the combination of VAN and PTZ. This study evaluated the effect of the VAN/PTZ combination on acute kidney injury (AKI) compared to VAN and PTZ monotherapies. This is a retrospective cohort analysis of adult patients without renal disease receiving VAN, PTZ, or the combination from September 1, 2010 through August 31, 2014 at an academic medical center. The primary outcome was AKI incidence as defined by the Risk, Injury, Failure, Loss, End-stage (RIFLE) criteria. Continuous and categorical variables were assessed with appropriate tests. Univariate and multivariate logistic regressions were performed to assess for associations between variables and AKI incidence. Subanalyses based on severity of illness were performed. Overall, 11,650 patients were analyzed, with 1647 (14.1%) developing AKI. AKI was significantly more frequent in the VAN/PTZ group (21%) compared to either monotherapy group (VAN 8.3%, PTZ 7.8%, P ⟨ 0.001 for both). Combination therapy was independently associated with higher AKI odds compared to monotherapy with either agent (adjusted odds ratio [aOR], 2.03; 95% confidence interval [CI], 1.74-2.39; aOR, 2.31; 95% CI, 1.97-2.71, for VAN and PTZ, respectively). Receipt of concomitant nephrotoxic drugs was independently associated with increased AKI rates, as were increased duration of therapy, hospital length of stay, increasing severity of illness, and increasing baseline renal function. In this study of more than 10,000 patients, VAN combined with PTZ was associated with twice the odds of AKI development compared to either agent as monotherapy. This demonstrates the need for judicious use of combination empiric therapy. Journal of Hospital Medicine 2017;12:77-82.

Nephrotoxicity during Vancomycin Therapy in Combination with Piperacillin-Tazobactam or Cefepime.

Recent reports have demonstrated that vancomycin (VAN) may lead to an increase in the incidence of acute kidney injury (AKI) when it is combined with antipseudomonal beta-lactams. This study compared the incidence of AKI associated with VAN plus piperacillin-tazobactam (TZP) or cefepime (FEP). This was a retrospective, matched cohort study that was conducted at an academic medical center between September 2010 and September 2014 and that included adult patients without severe chronic or structural kidney disease, dialysis, pregnancy, cystic fibrosis, or a hospital transfer receiving TZP-VAN or FEP-VAN for at least 48 h. The primary outcome was the difference in the AKI incidence between the TZP-VAN and FEP-VAN groups, evaluated using the risk, injury, failure, loss of kidney function, and end-stage kidney disease (RIFLE) criteria. Patients in the two groups were matched on the basis of age, sex, severity of illness, baseline creatinine clearance, hypotension, number of nephrotoxicity risk factors, and intravenous contrast exposure. In total, 4,193 patients met all inclusion criteria (3,605 received TZP-VAN and 588 received FEP-VAN). The unadjusted AKI incidence was 21.4% in patients receiving TZP-VAN, whereas it was 12.6% in patients receiving FEP-VAN (P < 0.001). After the patients were matched, 1,633 patients receiving TZP-VAN and 578 patients receiving FEP-VAN were evaluated. The AKI incidence remained higher in patients receiving TZP-VAN than in those receiving FEP-VAN (21.4% versus 12.5%, P < 0.0001). This trend remained true for all classifications of the RIFLE criteria. After controlling for remaining confounders, TZP-VAN therapy was associated with 2.18 times the odds of AKI than FEP-VAN therapy (95% confidence interval, 1.64 to 2.94 times) in logistic regression. AKI was significantly more common in patients receiving vancomycin in combination with piperacillin-tazobactam than in those receiving vancomycin in combination with cefepime. This finding reinforces the need for the judicious use of combination empirical antimicrobial therapy.

Impact of a clinical pathway on appropriate empiric vancomycin use in cancer patients with febrile neutropenia.

Objectives Febrile neutropenia management guidelines recommend the use of vancomycin as part of an empiric antimicrobial regimen when specific criteria are met. Often, vancomycin use among patients with febrile neutropenia is not indicated and may be over utilized for this indication. We sought to evaluate the impact of implementing a febrile neutropenia clinical pathway on empiric vancomycin use for febrile neutropenia and to identify predictors of vancomycin use when not indicated. Methods Adult febrile neutropenia patients who received initial therapy with an anti-pseudomonal beta-lactam with or without vancomycin were identified before (June 2008 to November 2010) and after (June 2012 to June 2013) pathway implementation. Patients were assessed for appropriateness of therapy based on whether the patient received vancomycin consistent with guideline recommendations. Using a comorbidity index used for risk assessment in high risk hematology/oncology patients, we evaluated whether specific comorbidities are associated with inappropriate vancomycin use in the setting of febrile neutropenia. Results A total of 206 patients were included in the pre-pathway time period with 35.9% of patients receiving vancomycin therapy that was inconsistent with the pathway. A total of 131 patients were included in the post-pathway time period with 11.4% of patients receiving vancomycin inconsistent with the pathway ( p = 0.001). None of the comorbidities assessed, nor the comorbidity index score were found to be predictors of vancomycin use inconsistent with guideline recommendations. Conclusion Our study has demonstrated that implementation of a febrile neutropenia pathway can significantly improve adherence to national guideline recommendations with respect to empiric vancomycin utilization for febrile neutropenia.

Breakthrough viridans streptococcal bacteremia in allogeneic hematopoietic stem cell transplant recipients receiving levofloxacin prophylaxis in a Japanese hospital.

BackgroundBreakthrough viridans streptococcal bacteremia (VSB) in patients with hematological malignancy receiving levofloxacin prophylaxis is a major blood stream infection (BSI) occurring during febrile neutropenia. However, clinical data focused on VSB in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients are lacking.MethodsThe medical records of allo-HSCT recipients who received oral levofloxacin prophylaxis between January 2011 and August 2013 at Toranomon Hospital were reviewed to evaluate breakthrough VSB. Stored viridans streptococcal (VGS) species were identified by using sodA gene sequencing, and were assessed for drug susceptibility.ResultsAmong the 184 allo-HSCT recipients on levofloxacin prophylaxis, 28 (15.2 %) experienced breakthrough VSB. All of the 28 recipients with VSB were treated with a cefepime-based or piperacillin/tazobactam-based regimen. The susceptibility rates of the VGS strains for levofloxacin, cefepime, piperacillin/tazobactam, meropenem, and vancomycin were 0 %, 95 %, 100 %, 100 %, and 100 %, respectively. Both the MIC50 (minimum inhibitory concentration) and the MIC90 of ceftazidim (0.5 μg/mL and 2 μg/mL, respectively) were higher than the MIC90 of all the other anti-pseudomonal beta-lactams (APBLs). Only 1 VGS strain had a penicillin MIC ≥ 2 μg/mL by the Etest (3.6 %). There were no cases with acute respiratory distress syndrome (ARDS) that was associated with VSB, although the rate of viridans group streptococcal shock syndrome was high (26 %). The crude 30-day mortality rate in the VSB group (10.7 %) did not differ significantly from that in the BSI without VSB group (9.3 %) or non-BSI group (7.0 %) (P = 0.77). Also, VSB was not a risk factor for all-cause mortality up to 60 days following allo-HSCT (P = 0.43).ConclusionsAPBL with increased anti-VGS activity (APBL-VA) monotherapy would typically be optimal for treating the VGS strains in this setting. Indication of adding an empiric anti-gram-positive agent to APBL-VA for treating VSB should depend on local factors, such as the susceptibility results. In addition, breakthrough VSB is probably not a major cause of death in allo-HSCT settings, where beta-lactam non-susceptible VGS and the ARDS are rare.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-016-1692-y) contains supplementary material, which is available to authorized users.

Tobramycin and Beta-Lactam Antibiotic Use in Cystic Fibrosis Exacerbations: A Pharmacist Approach.

Survey suggests that recommended doses and dosage regimens for antipseudomonal antibiotics for the treatment of acute pulmonary exacerbations in cystic fibrosis (CF) patients are not used, and one way to address these disparities is the involvement of pharmacists who are dedicated to CF. This is the first survey specifically designed for pharmacists at Cystic Fibrosis Foundation (CFF)-accredited centers to identify how tobramycin and antipseudomonal beta-lactams are being used. The purpose of this survey is to quantify this information and to promote future study to allow for implementation of tobramycin and beta-lactam dosage and monitoring standardization. An anonymous national cross-sectional survey of pharmacists that are affliated with CFF-accredited programs was performed using Qualtrics.com. The survey had a 48.5% response rate. Most pediatric pharmacists (78.6%) report using extended-interval tobramycin dosage. The most common reported starting dosage was 10 mg/kg every 24 hours; most centers aim for a maximum serum concentration (Cmax) between 20 and 40 mg/L (78.6%). A total of 26 adult pharmacists reported using extended-interval dosage (96%), using an initial dosage of 10 mg/kg/day. The most common parameters used to adjust dosage were Cmax and area under the curve (AUC; 31%); the Cmax goal was 20 to 40 mg/L (84.2%). Most respondents (79%) report using beta-lactams in combination with tobramycin. Extended-infusion and continuous-infusion beta-lactams were used more in adults than pediatric patients. Most CF pharmacists report using extended-interval tobramycin. With the information from this survey, the establishment of future consensus recommendations by pharmacists for optimal and consistent tobramycin and antipseudomonal beta-lactam dosage and monitoring strategies needs to be considered.

Impact of de-escalation of beta-lactam antibiotics on the emergence of antibiotic resistance in ICU patients: a retrospective observational study.

Antibiotic de-escalation is promoted to limit prolonged exposure to broad-spectrum antibiotics, but proof that it prevents the emergence of resistance is lacking. We evaluated determinants of antibiotic de-escalation in an attempt to assess whether the latter is associated with a lower emergence of antimicrobial resistance. Antibiotic treatments, starting with empirical beta-lactam prescriptions, were prospectively documented during 2013 and 2014 in a tertiary intensive care unit (ICU) and categorized as continuation, de-escalation or escalation of the empirical antimicrobial treatment. Determinants of the de-escalation or escalation treatments were identified by multivariate logistic regression; the continuation category was used as the reference group. Using systematically collected diagnostic and surveillance cultures, we estimated the cumulative incidence of antimicrobial resistance following de-escalation or continuation of therapy, with adjustment for ICU discharge and death as competing risks. Of 478 anti-pseudomonal antibiotic prescriptions, 42 (9%) were classified as escalation of the antimicrobial treatment and 121 (25%) were classified as de-escalation, mainly through replacement of the originally prescribed antibiotics with those having a narrower spectrum. In multivariate analysis, de-escalation was associated with the identification of etiologic pathogens (p<0.001). The duration of the antibiotic course in the ICU in de-escalated versus continued prescriptions was 8 (range 6-10) versus 5 (range 4-7) days, respectively (p<0.001). Mortality did not differ between patients in the de-escalation and continuation categories. The cumulative incidence estimates of the emergence of resistance to the initial beta-lactam antibiotic on day 14 were 30.6 and 23.5% for de-escalation and continuation, respectively (p=0.22). For the selection of multi-drug resistant pathogens, these values were 23.5 (de-escalation) and 18.6% (continuation) respectively (p=0.35). The emergence of antibiotic-resistant bacteria after exposure to anti-pseudomonal beta-lactam antibiotics was not lower following de-escalation.

Evaluation of a Mixing versus a Cycling Strategy of Antibiotic Use in Critically-Ill Medical Patients: Impact on Acquisition of Resistant Microorganisms and Clinical Outcomes.

ObjectiveTo compare the effect of two strategies of antibiotic use (mixing vs. cycling) on the acquisition of resistant microorganisms, infections and other clinical outcomes.MethodsProspective cohort study in an 8-bed intensive care unit during 35- months in which a mixing-cycling policy of antipseudomonal beta-lactams (meropenem, ceftazidime/piperacillin-tazobactam) and fluoroquinolones was operative. Nasopharyngeal and rectal swabs and respiratory secretions were obtained within 48h of admission and thrice weekly thereafter. Target microorganisms included methicillin-resistant S. aureus, vancomycin-resistant enterococci, third-generation cephalosporin-resistant Enterobacteriaceae and non-fermenters.ResultsA total of 409 (42%) patients were included in mixing and 560 (58%) in cycling. Exposure to ceftazidime/piperacillin-tazobactam and fluoroquinolones was significantly higher in mixing while exposure to meropenem was higher in cycling, although overall use of antipseudomonals was not significantly different (37.5/100 patient-days vs. 38.1/100 patient-days). There was a barely higher acquisition rate of microorganisms during mixing, but this difference lost its significance when the cases due to an exogenous Burkholderia cepacia outbreak were excluded (19.3% vs. 15.4%, OR 0.8, CI 0.5–1.1). Acquisition of Pseudomonas aeruginosa resistant to the intervention antibiotics or with multiple-drug resistance was similar. There were no significant differences between mixing and cycling in the proportion of patients acquiring any infection (16.6% vs. 14.5%, OR 0.9, CI 0.6–1.2), any infection due to target microorganisms (5.9% vs. 5.2%, OR 0.9, CI 0.5–1.5), length of stay (median 5 d for both groups) or mortality (13.9 vs. 14.3%, OR 1.03, CI 0.7–1.3).ConclusionsA cycling strategy of antibiotic use with a 6-week cycle duration is similar to mixing in terms of acquisition of resistant microorganisms, infections, length of stay and mortality.

Clinical evaluation of the need for carbapenems to treat community-acquired and healthcare-associated pneumonia.

Carbapenems have an overall broad antibacterial spectrum and should be protected against from the acquisition of drug resistance. The clinical advantages of carbapenem in cases of pneumonia have not been certified and the need for antipseudomonal antimicrobial agents to treat healthcare-associated pneumonia (HCAP) remains controversial. We introduced an antimicrobial stewardship program for carbapenem and tazobactam/piperacillin use and investigated the effects of this program on the clinical outcomes of 591 pneumonia cases that did not require intensive care unit management, mechanical ventilation or treatment with vasopressor agents [221 patients with community-acquired pneumonia (CAP) and 370 patients with HCAP]. Compared with the pre-intervention period, age, comorbidities and the severity and etiology of pneumonia did not differ during the intervention period. Carbapenems were rarely used during the intervention period in cases of pneumonia (CAP: 12% vs. 1%, HCAP: 13% vs. 1%), while antipseudomonal beta-lactam use was reduced from 33% to 8% among cases with HCAP. This reduction in the rate of carbapenem administration did not have an impact on the prognosis in the cases of CAP, and the in-hospital mortality was lower among the patients with HCAP during the intervention period (15% vs. 5%, p=0.013). The causes of death in the cases of HCAP were not directly related to pneumonia during the intervention period. The current study shows that carbapenem use can be avoided in cases of CAP or HCAP that are not in a critical condition. The frequent use of antipseudomonal beta-lactams does not improve the clinical outcomes of HCAP.

DE-ESCALATING ANTI-PSEUDOMONAL β-LACTAMS

De-escalation of broad-spectrum antibiotics such as anti-pseudomonal beta-lactams is recommended to reduce antimicrobial selection pressure.

Doripenem Versus Meropenem As the First-Line Empirical Therapy in High-Risk Febrile Neutropenic Patients with Hematological Malignancy: A Randomized, Controlled Trial

BACKGROUND: Febrile neutropenia (FN) is often observed in cases of hematological malignancy such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS). Carbapenem antibiotics having a potent and broad antimicrobial activity against both gram-positive and gram-negative bacteria including Pseudomonas aeruginosa, are good candidates as the first-line therapy drug in high-risk FN patients. In the IDSA guideline 2010 on the use of antimicrobial agents in FN, mono-therapy with an anti-pseudomonal beta-lactam, such as piperacillin-tazobactam, cefepime or carbapenem [only meropenem (MEPM) and imipenem-cilastatin], is recommended as an empirical therapy for high-risk FN patients. Doripenem (DRPM) is a newer carbapenem with few data available as for the efficacy and safety in the setting of FN patients. Therefore, we conducted a randomized, cooperative group, open-label trial comparing DRPM (1.0 g every 8 hours) with MEPM (1.0 g every 8 hours) as the first-line empirical antibacterial therapy for high-risk FN patients with hematological malignancy including AML, ALL and high-risk MDS.PATIENTS and METHODS: One hundred and forty-six hospitalized high-risk FN patients with hematological malignancy (AML 76, ALL 43, APL 13, MDS-AML 9, MDS-RAEB 5 cases) during or after chemotherapy were randomized to each drug group (DRPM: n=73, MEPM: n=73). The study drug was started to administer as a mono-therapy and continued at least for 5 days without drug toxicity, and the efficacy and safety were evaluated.RESULTS: The overall response rate at 7 days in DRPM and MEPM group were not significantly different (DRPM: 67.6%, MEPM: 52.9%, respectively, P=0.098). Both the resolution of fever by mono-therapy at day 3 to 5 (DRPM: 56.9%, MEPM: 47.0%, respectively, p=0.26), and survival at day 30 (DRPM: 98.4%, MEPM: 98.5%, respectively, p=0.312) were not significantly different in the two groups. The frequency of cases needed for anti-MRSA agent and antifungal agent were a little less often in DRPM rather than in MEPM group [DRPM: 36.9%, MEPM: 50.0% (p=0.185), DRPM: 26.1%, MEPM: 32.3% (p=0.535), respectively]. Only grade 1-2 adverse events were observed in both groups (liver dysfunction, renal dysfunction, diarrhea and rash), and they were less often in DRPM group significantly (DRPM: 29.8%, MEPM: 40.8%, respectively, p=0.046). These adverse events were clinically acceptable in the two groups, and most of patients could continue the treatment by both study drugs.CONCLUSIONS: Our clinical study suggested that DRPM had the non-inferiority of efficacy in comparison with MEPM as the first-line empirical therapy in high-risk FN patients with hematological malignancy, and both drugs could be generally well tolerated. DisclosuresNo relevant conflicts of interest to declare.

Multidrug-resistant bacteria: what is the threat?

Despite big advances in antimicrobial therapies and infection strategies, the emergence of antibiotic resistance represents an emergency situation, especially in immunocompromised hosts. Specifically, infections due to multidrug resistant, gram-negative pathogens are responsible for high mortality rates and may leave few effective antimicrobial options. Furthermore, although new compounds are available for severe methicillin-resistant staphylococcal infections, there is a paucity of novel classes of antimicrobials to target resistant gram-negatives. A careful assessment of the clinical conditions and underlying comorbidities, along with knowledge about the previous history of colonization or infections due to multidrug-resistant bacteria, represent key points in approaching the hematological patient with signs of infection. A de-escalation therapy with initial use of wide-spectrum antimicrobials followed by a reassessment after 72 hours of treatment may represent a good option in severe infections if a resistant pathogen is suspected. Prompt empiric or targeted therapy using combination regimens (ie, antipseudomonal beta-lactam plus an aminoglycoside or a quinolone) with the addition of colistin, along with increased dosage and therapeutic drug monitoring, represent options for these life-threatening infections. Continuous epidemiological surveillance of local bacteremias is necessary, along with stringent enforcement of antibiotic stewardship programs in cancer patients.

Doripenem Versus Meropenem For Empirical Antimicrobial Therapy In High Risk Febrile Neutropenic Patients With Hematological Malignancies: A Randomized, Controlled Trial

Background Febrile neutropenia (FN) is often observed in the treatment of hematological malignancies including acute leukemia (AL). The pathogens of systemic infection are frequently unknown in FN patients. Carbapenem antibiotics are good candidates with a potent and broad antimicrobial activity against gram-positive and gram-negative bacteria including Pseudomonas aeruginosa. These antimicrobial agents are recommended to use early and sufficiently as empiric therapy for high-risk FN patients accompanied with profound neutropenia anticipated to &gt; 7days. In the IDSA guideline published in 2010 on the use of antimicrobial agents in neutropenic patients, monotheapy with an anti-pseudomonal beta-lactam agent, such as cefepime (CFPM), meropenem (MEPM), imipenem-cilastatin (IPM) or piperacillin-tazobactam (TAZ/PIPC), is recommended as empiric therapy for high-risk FN patients. Several antimicrobial agents including MEPM, IPM or CFPM have been studied as empirical therapy for FN. However, limited data are available concerning the efficacy and safety of doripenem (DRPM), one of the carbapenem antibiotics, in FN with hematological malignancy. Methods We conducted a randomized, cooperative group, open-label trial comparing DRPM (1g, q8h IV) with MEPM (1g, q8h IV) as the first line empirical antimicrobial treatment for 165 hospitalized high-risk FN patients with AL (AML: n=90, APL: n=25, MDS-AML: n=13, ALL: n=35, ATL: n=2) during or after induction or consolidation chemotherapy (DRPM: n=83, MEPM: n=82). These study drugs were administered at least for 3 days without toxicity. The primary endpoint was response to treatment defined as complete defervescence by day 7 with improvement of infection-related symptoms and laboratory findings. We also evaluated the efficacy (resolution of fever by monotherapy at day 3 to 5, survival at day 30) and the safety of each drug, as a secondary endpoint. Results At the time of enrolment, there were no significant differences in the demographics or baseline characteristics, including as age, sex, body weight, underlying hematological malignancies, duration of initial antimicrobial therapy, median duration of severe neutropenia (neutrophil count &lt; 100×106/L) and MASCC score, between the two groups. The response rate at day 7 was not significantly different between the two arms (DRPM: 75.8%, MEPM: 64.5% (p=0.14)). The resolution of fever by monotherapy at day 3 to 5 (DRPM: 58.6%, MEPM: 45.2% (p=0.10)), or survival at day 30 (DRPM: 97.6%, MEPM: 98.7% (p=0.33)) was not significantly different in the two groups. Adverse events were minimal in the two groups, and most of patients could continue the treatment by study drugs for 7days. Conclusions We could prove the non-inferiority of DRPM in comparison with MEPM for the initial treatment in FN patients with hematological malignancies. Both drugs were well tolerated as the first line empiric therapy for high-risk FN patients. Disclosures: No relevant conflicts of interest to declare.

De-escalation of antimicrobial treatment in neutropenic patients with severe sepsis: results from an observational study

In severe sepsis, guidelines recommend de-escalating the empirical antimicrobial treatment as soon as the microbiological results are available. We aimed to determine the rate of de-escalation of the empirical antimicrobial treatment in neutropenic patients with severe sepsis. The characteristics of antimicrobial treatment associated with de-escalation and its impact on short- and long-term survival were also determined. In the intensive care unit (ICU) of a cancer referral center, we prospectively collected observational data related to the antimicrobial management in neutropenic patients who developed severe sepsis and were admitted to ICU for at least 48 h. De-escalation of antimicrobial therapy consisted either of deleting one of the empirical antibiotics of a combined treatment, or, whenever possible, to use a betalactam antibiotic with a narrower spectrum of activity. Multivariate logistic regression was conducted to determine the factors associated with de-escalation, while a Cox proportional hazards model with a time-dependent covariate was fitted to assess the effect of de-escalation on 30-day survival. Finally 1-year survival after ICU discharge was compared across de-escalation groups. Cumulative incidence of de-escalation of the empirical antimicrobial treatment among the 101 patients of the cohort was 44%, [95% confidence interval (CI) 38-53%], including 30 (68%) patients with ongoing neutropenia. A microbiological documentation was available in 63 (63%) patients. Factors associated with de-escalation were the adequation of the empirical antimicrobial treatment in ICU [OR = 10.8 (95% CI 1.20-96)] for adequate documented treatment versus appropriate empirical treatment, the compliance with guidelines regarding the empirical choice of the anti-pseudomonal betalactam [OR = 10.8 (95% CI 1.3-89.5)]. De-escalation did not significantly modify the hazard of death within the first 30 days [HR = 0.51 (95% CI 0.20-1.33)], nor within 1 year after ICU discharge [HR = 1.06 (95% CI 0.54-2.08)]. Our data suggest that, in ICU, de-escalation of the empirical antimicrobial treatment is frequently applied in neutropenic cancer patients with severe sepsis. No evidence of any prognostic impact of this de-escalation was found.

Continuous infusion meropenem and ticarcillin‐clavulanate in pediatric cystic fibrosis patients

Aztreonam, cefepime, and ceftazidime are anti-pseudomonal beta-lactam antibiotics which have been previously reported to be administered by continuous infusion (CI) in pediatric CF patients. We present two cases administering intravenous (IV) meropenem and ticarcillin-clavulanate by CI in pediatric CF patients. The delivery of beta-lactam antibiotics via CI should be considered in order to optimize the pharmacodynamics (PD) of beta-lactams in the treatment of acute pulmonary exacerbations (APE).