Pharmacokinetics/pharmacodynamics and therapeutic drug monitoring of ceftazidime/avibactam administered by continuous infusion in patients with MDR Gram-negative bacterial infections.

BACKGROUND: Therapeutic drug monitoring (TDM) of ß-lactams in critically ill patients has been correlated with better clinical outcomes. Evidence on TDM of newer ß-lactams such as ceftazidime/avibactam administered by continuous infusion (CI) is very limited. OBJECTIVES: To describe our experience with TDM of ceftazidime/avibactam and pharmacokinetic/pharmacodynamic (PK/PD) target attainment in patients with MDR bacterial infections. Clinical outcomes of ceftazidime/avibactam administered by CI were also assessed. METHODS: Patients treated with ceftazidime/avibactam administered by CI and undergoing TDM of ceftazidime plasma concentrations were included. Blood samples were obtained as part of the TDM program. The PK/PD therapeutic target of ceftazidime/avibactam was defined as 100%fT > 4 × MIC of the causative pathogen, and 100%fT > 10 × MIC was considered overexposure. Dose changes were made according to the TDM results. RESULTS: Thirty-one patients were included. Ceftazidime/avibactam total daily doses ranged from 1 g/0.25 g to 6 g/1.5 g. Twenty-six patients (83.9%) achieved a 100%fT > 4 × MIC, 15 (48.4%) of which were overexposed (100%fT > 10 × MIC). Dose reduction was suggested in 16/28 (57.1%) patients and dose maintenance in 12/28 (42.9%). Overall clinical cure was observed in 21 (67.7%) patients, and 18 of these (85.7%) achieved a 100%fT > 4 × MIC. CONCLUSIONS: Administering ceftazidime/avibactam by CI enabled the desired PK/PD target to be achieved in a large proportion of patients, even at lower doses than those recommended for a 2 h extended infusion. We suggest that the use of CI with TDM may be a useful tool for reducing initial doses, which could help to reduce antimicrobial-related adverse effects and treatment costs.

Dosage Individualization of Linezolid: Precision Dosing of Linezolid To Optimize Efficacy and Minimize Toxicity.

The high interindividual variability in the pharmacokinetics (PK) of linezolid has been described, which results in an unacceptably high proportion of patients with either suboptimal or potentially toxic concentrations following the administration of a fixed regimen. The aim of this study was to develop a population pharmacokinetic model of linezolid and use this to build and validate alogorithms for individualized dosing. A retrospective pharmacokinetic analysis was performed using data from 338 hospitalized patients (65.4% male, 65.5 [±14.6] years) who underwent routine therapeutic drug monitoring for linezolid. Linezolid concentrations were analyzed by using high-performance liquid chromatography. Population pharmacokinetic modeling was performed using a nonparametric methodology with Pmetrics, and Monte Carlo simulations were employed to calculate the 100% time >MIC after the administration of a fixed regimen of 600 mg administered every 12 h (q12h) intravenously (i.v.). The dose of linezolid needed to achieve a PTA ≥ 90% for all susceptible isolates classified according to EUCAST was estimated to be as high as 2,400 mg q12h, which is 4 times higher than the maximum licensed linezolid dose. The final PK model was then used to construct software for dosage individualization, and the performance of the software was assessed using 10 new patients not used to construct the original population PK model. A three-compartment model with an absorptive compartment with zero-order i.v. input and first-order clearance from the central compartment best described the data. The dose optimization software tracked patients with a high degree of accuracy. The software may be a clinically useful tool to adjust linezolid dosages in real time to achieve prespecified drug exposure targets. A further prospective study is needed to examine the potential clinical utility of individualized therapy.

Population Pharmacokinetics of Anidulafungin in Critically Ill Patients.

A two-compartment pharmacokinetic (PK) population model of anidulafungin was fitted to PK data from 23 critically ill patients (age, 65 years [range, 28 to 81 years]; total body weight [TBW], 75 kg [range, 54 to 168 kg]). TBW was associated with clearance and incorporated into a final population PK model. Simulations suggested that patients with higher TBWs had less-extensive MIC coverage. Dosage escalation may be warranted in patients with high TBWs to ensure optimal drug exposures for treatment of Candida albicans and Candida glabrata infections.

Effectiveness of sequential intravenous-to-oral antibiotic switch therapy in hospitalized patients with gram-positive infection: the SEQUENCE cohort study.

Switching from intravenous to oral antibiotic therapy may improve inpatient management and reduce hospital stays and the complications of intravenous treatment. We aimed to assess the effectiveness of intravenous-to-oral antibiotic switch therapy and an early discharge algorithm in hospitalized patients with gram-positive infection. We performed a prospective cohort study with a retrospective comparison cohort, recruited from eight tertiary, acute-care Spanish referral hospitals. All patients included had culture-confirmed methicillin-resistant gram-positive infection, or methicillin-susceptible gram-positive infection and beta-lactam allergy and had received intravenous treatment with glycopeptides, lipopeptides, or linezolid. The study comprised two cohorts: the prospective cohort to assess the effectiveness of a sequential intravenous-to-oral antibiotic switch algorithm and early discharge, and a retrospective cohort in which the algorithm had not been applied, used as the comparator. A total of 247 evaluable patients were included; 115 in the prospective and 132 in the retrospective cohort. Forty-five retrospective patients (34 %) were not changed to oral antibiotics, and 87 (66 %) were changed to oral antibiotics without following the proposed algorithm. The duration of hospitalization was significantly shorter in the prospective cohort compared to the retrospective group that did not switch to oral drugs (16.7 ± 18.7 vs 23 ± 13.4 days, P < 0.001). No differences were observed regarding the incidence of catheter-related bacteraemia (4.4 % vs 2.6 %, P = 0.621). Our results suggest that an intravenous-to-oral antibiotic switch strategy is effective for reducing the length of hospital stay in selected hospitalized patients with gram-positive infection.

Enterococcal bloodstream infection. Design and validation of a mortality prediction rule.

BACKGROUND: To develop a prediction rule to describe the risk of death as a result of enterococcal bloodstream infection. METHODS: A prediction rule was developed by analysing data collected from 122 patients diagnosed with enterococcal BSI admitted to the Clínica Universidad de Navarra (Pamplona, Spain); and validated by confirming its accuracy with the data of an external population (Hospital del Mar, Barcelona). RESULTS: According to this model, independent significant predictors for the risk of death were being diabetic, have received appropriate treatment, severe prognosis of the underlying diseases, have renal failure, received solid organ transplant, malignancy, source of the bloodstream infection and be immunosuppressed. The prediction rule showed a very good calibration (Hosmer-Lemeshow statistic, P = 0.93) and discrimination for both training and testing sets (area under ROC curve = 0.84 and 0.83 respectively). CONCLUSIONS: The predictive rule was able to predict risk of death as a result of enterococcal bloodstream infection as well as to identify patients, who being below the threshold value, will have a low risk of death with a negative predictive value of 96%.

Vertebral osteomyelitis after spine instrumentation surgery: risk factors and management.

BACKGROUND: Vertebral osteomyelitis after spine instrumentation surgery (pVOM) is a rare complication. Most cases of infection occur early after surgery that involve skin and soft tissue and can be managed with debridement, antibiotics, and implant retention (DAIR). AIM: To identify pVOM risk factors and evaluate management strategies. METHODS: From a multicentre cohort of deep infection after spine instrumentation (IASI) cases (2010-2016), pVOM cases were compared with those without vertebral involvement. Early and late infections were defined (<60 days and >60 days after surgery, respectively). Multivariate analysis was used to explore risk factors. FINDINGS: Among 410 IASI cases, 19 (4.6%) presented with pVOM, ranging from 2% (7/347) in early to 19.1% (12/63) in late IASIs. After multivariate analysis, age (adjusted odds ratio (aOR): 1.10; 95% confidence interval (CI): 1.03-1.18), interbody fusion (aOR: 6.96; 95% CI: 2-24.18) and coagulase-negative staphylococci (CoNS) infection (aOR: 3.83; 95% CI: 1.01-14.53) remained independent risk factors for pVOM. Cases with pVOM had worse prognoses than those without (failure rate; 26.3% vs 10.8%; P = 0.038). Material removal was the preferred strategy (57.9%), mainly in early cases, without better outcomes (failure rate; 33.3% vs 50% compared with DAIR). Late cases managed with removal had greater success compared with DAIR (failure rate; 0% vs 40%; P = 0.067). CONCLUSION: Risk factors for pVOM are old age, use of interbody fusion devices and CoNS aetiology. Although the diagnosis leads to a worse prognosis, material withdrawn should be reserved for late cases or when spinal fusion is achieved.

Incidence, associated disease burden and healthcare utilization due to Staphylococcus aureus prosthetic joint infection in European hospitals: the COMBACTE-NET ARTHR-IS multi-centre study.

BACKGROUND: The aim of this study was to estimate the incidence, associated disease burden and healthcare utilization due to Staphylococcus aureus prosthetic joint infections (SA-PJI) after primary hip and knee arthroplasty in European centres. METHODS: This study was conducted in patients who underwent primary hip and knee arthroplasty in 19 European hospitals between 2014 and 2016. The global incidence of PJI and SA-PJI was calculated. The associated disease burden was measured indirectly as infection-related mortality plus loss of function. For healthcare utilization, number and duration of hospitalizations, number and type of surgical procedures, duration of antibiotic treatments, and number of outpatient visits were collected. Subgroup and regression analyses were used to evaluate the impact of SA-PJI on healthcare utilization, controlling for confounding variables. RESULTS: The incidence of PJI caused by any micro-organism was 1.41%, and 0.40% for SA-PJI. Among SA-PJI, 20.7% were due to MRSA with substantial regional differences, and were more frequent in partial hip arthroplasty (PHA). Related deaths and loss of function occurred in 7.0% and 10.2% of SA-PJI cases, respectively, and were higher in patients with PHA. Compared with patients without PJI, patients with SA-PJI had a mean of 1.4 more readmissions, 25.1 more days of hospitalization, underwent 1.8 more surgical procedures, and had 5.4 more outpatient visits, controlling for confounding variables. Healthcare utilization was higher in patients who failed surgical treatment of SA-PJI. CONCLUSIONS: This study confirmed that the SA-PJI burden is high, especially in PHA, and provided a solid basis for planning interventions to prevent SA-PJI.

Use of non-nucleoside analogues together with rifampin in HIV patients with tuberculosis.

OBJECTIVE: The concomitant use of rifampin (RFP) with efavirenz (EFV) or nevirapine (NVP) is frequent in HIV patients with tuberculosis (TB). The necessity of increasing the dose of EFV remains controversial. The aim of the study was to evaluate the outcome of HIV infection in patients treated with non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART) and RFR. METHODS: Retrospective analysis of HIV patients who were simultaneously treated with RFP and NVP or EFV. The dose of EFV was considered to be adjusted in those patients receiving 600 mg when weighing <60 kg and 800 mg if >60 kg and was considered nonadjusted when the dose given was 600 mg in patients >60 kg. RESULTS: 63 patients were included: 13 received NVP and 50 received EFV-based ART (30 adjusted and 20 nonadjusted). Treatment failure was observed in 7 (53.8%) of the NVP group; 11 (55%) of the nonadjusted EFV group, and 8 (26.7%) of the adjusted EFV group (P = .04). The relative risk (RR) of treatment failure comparing nonadjusted and adjusted EFV was 3.36 (95% Cl, 1.02-11.11). The proportion of treatment failure was 9/18 (50%) in the nonadjusted and 5/27(18.5%) in the adjusted EFV group. CONCLUSIONS: The effectiveness of NVP and nonadjusted EFV was lower than adjusted EFV-based ART. It may be advisable to increase the dose of EFV to 800 mg once daily when administered with rifampin in patients weighing >60 kg.

Intra- and inter-species spread of carbapenemase genes in a non-hospitalized patient.

The purpose of this study was to report intra- and inter-species spread of carbapenemase genes between gram negative rods isolated from a non-hospitalized patient with bacteremia. The approach included chart review, antibiotic susceptibility testing and phenotypic screening for metallo-ß-lactamase (MBL) detection, PCR and sequencing of bla, aac(6')-Ib and qnr genes, and plasmid analysis by PCR-based replicon typing. The clonal relationships between the isolates were analysed by comparing PFGE profiles. A non-hospitalized patient presented bacteraemia due to wild type Enterobacter cloacae (4.08), a VIM-1-producing E. cloacae (5.08), a VIM-1- and CTX-M-9-producing E. cloacae (7.08), a VIM-2-producing Pseudomonas aeruginosa, and catheter colonization by VIM-1-producing Klebsiella oxytoca. The patient had no previous hospitalization but had recently undergone an ambulatory colonoscopy. In E. cloacae 7.08 and K. oxytoca isolates, the bla(VIM-1) gene was located on a transferable plasmid of 48.5 kb, while in E. cloacae 5.08 the bla(VIM-1) gene was encoded on a 194 kb non-transferable plasmid. The bla(CTX-M-9) gene detected in E. cloacae was encoded on an HI2 plasmid of 290 kb. To date the prevalence of VIM-1 enzymes in the community is low. This molecular finding suggests an intra-species and/or inter-species horizontal spread of the MBL gene in the same non-hospitalized patient.

Ceftolozane-tazobactam: When, how and why using it?

Ceftolozane-tazobactam is currently the most active antipseudomonal agent, including multidrug-resistant extensively drug-resistant strains. Tazobactam provides additional activity against many extended-spectrum beta-lactamases Enterobacterales. Ceftolozane-tazobactam is formally approved for complicated urinary tract infection, complicated intra-abdominal infection, and hospital-acquired and ventilator-associated bacterial pneumonia. The clinical and microbiological success is over 70-80% in many series. However, resistant mutants to ceftolozane-tazobactam have been already described. Combination therapies with colistin or meropenem could be among the strategies to avoid the resistance emergence.

Co-infections and superinfections complicating COVID-19 in cancer patients: A multicentre, international study.

BACKGROUND: We aimed to describe the epidemiology, risk factors, and clinical outcomes of co-infections and superinfections in onco-hematological patients with COVID-19. METHODS: International, multicentre cohort study of cancer patients with COVID-19. All patients were included in the analysis of co-infections at diagnosis, while only patients admitted at least 48 h were included in the analysis of superinfections. RESULTS: 684 patients were included (384 with solid tumors and 300 with hematological malignancies). Co-infections and superinfections were documented in 7.8% (54/684) and 19.1% (113/590) of patients, respectively. Lower respiratory tract infections were the most frequent infectious complications, most often caused by Streptococcus pneumoniae and Pseudomonas aeruginosa. Only seven patients developed opportunistic infections. Compared to patients without infectious complications, those with infections had worse outcomes, with high rates of acute respiratory distress syndrome, intensive care unit (ICU) admission, and case-fatality rates. Neutropenia, ICU admission and high levels of C-reactive protein (CRP) were independent risk factors for infections. CONCLUSIONS: Infectious complications in cancer patients with COVID-19 were lower than expected, affecting mainly neutropenic patients with high levels of CRP and/or ICU admission. The rate of opportunistic infections was unexpectedly low. The use of empiric antimicrobials in cancer patients with COVID-19 needs to be optimized.

Effectiveness and safety of colistin for the treatment of multidrug-resistant Pseudomonas aeruginosa infections.

PURPOSE: To describe the clinical and microbiological outcomes of patients infected with multidrug-resistant Pseudomonas aeruginosa (MDRP) treated with colistin (colistimethate sodium) and the adverse events observed with this treatment. METHODS: Retrospective study of MDRP infections treated with colistin from 1997 to 2006. RESULTS: 121 episodes were identified. The median daily intravenous dose was 240 mg/day; 28.9% of patients received intravenous and nebulized colistin. Clinical outcome was favorable in ten cases of bacteremia (62.5%, n = 16), 43 cases of bronchial infection (72.9%, n = 59), 13 cases of pneumonia (65%, n = 20), 11 cases of urinary infection (84.6%, n = 13), eight cases of skin and soft tissues (72.7%, n = 11), and in the one case of arthritis and one case of otitis. Eradication was achieved in 31 (34.8%) of the 89 patients with available bacteriologic data. Factors associated with bacteriological failure were smoking, chronic obstructive pulmonary disease (COPD), and previous infection with P. aeruginosa. Nephrotoxicity occurred in ten cases (8.3%), with the associated factors being previous chronic renal insufficiency, diabetes mellitus, and aminoglycoside use. Crude mortality was 16.5%, and related MDRP was 12.4%, and was higher in patients with pneumonia or bacteremia (36.1%) than in other types of infections (8.2%). CONCLUSIONS: Colistin is a safe option for the treatment of MDRP infections, with acceptable clinical outcomes. However, bacteriological eradication is difficult to achieve, especially in COPD patients.

Linezolid vs glycopeptides in the treatment of glycopeptide-susceptible Enterococcus faecium bacteraemia: A propensity score matched comparative study.

BACKGROUND: The incidence of ampicillin-resistant Enterococcus faecium bacteraemia is increasing. Vancomycin remains the first-line treatment in areas with a high prevalence of glycopeptide-susceptible isolates, but data comparing its clinical outcomes with other treatments are lacking. The objective of this study was to compare the effectiveness and safety of linezolid and glycopeptides for the treatment of glycopeptide-susceptible E. faecium bloodstream infection (GSEF-BSI). METHODS: This retrospective observational cohort study was conducted from January 2006 to May 2018 at the Hospital del Mar, Barcelona, Spain, and compared the clinical outcomes and safety of linezolid and glycopeptides in adult patients with GSEF-BSI. The main outcomes included clinical cure at the end of therapy, 30-day mortality, microbiological eradication and attributable length of stay (LOS). Propensity score matching was performed to reduce potential confounders among groups. RESULTS: In total, 105 patients with GSEF-BSI were included (linezolid, n=38; glycopeptides, n=67). After propensity score matched analysis, 56 (53.3%) patients, 28 in each cohort, entered the final analysis. No differences were observed in any of the main clinical outcomes among patients treated with linezolid or glycopeptides: clinical cure [16/28 (57.1%) vs 13/28 (46.4%), P=0.593], 30-day mortality [8/28 (28.6%) vs 12/28 (42.9%), P=0.403], microbiological eradication [22/28 (78.6%) vs 20/28 (71.4%), P=0.758] and median attributable LOS (18.0 vs 17.0 days, P=0.924). Adverse events were similar in both groups. CONCLUSIONS: Linezolid and glycopeptides showed similar clinical effectiveness and safety in the treatment of GSEF-BSI. Linezolid could be an alternative to glycopeptides in the treatment of GSEF-BSI.

High-dose benznidazole in a 62-year-old Bolivian kidney transplant recipient with Chagas central nervous system involvement.

There is little published data on benznidazole dosing, or levels in cerebrospinal fluid. In this report, we describe the clinical course of an immunosuppressed patient with Chagas central nervous system involvement. He was treated successfully with larger benznidazole doses than are recommended, in order to reach therapeutically effective concentrations in the brain.

Impact of an antimicrobial stewardship program on urinary tract infections caused by extended-spectrum ß-lactamase-producing Escherichia coli.

OBJECTIVE: To analyze the clinical and economic impact of an antimicrobial stewardship program (ASP) targeting urinary tract infections (UTI) caused by extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli. METHODS: An observational retrospective study that included adults with a diagnosis of UTI caused by ESBL-producing E. coli admitted to a tertiary care hospital in Barcelona, Spain, between January 2014 and December 2015. The impact of the ASP was analyzed in terms of clinical and economic outcomes. RESULTS: A total of 222 patients met the inclusion criteria and an intervention was made by the ASP team in 104 cases (47%). ASP intervention was an independent variable related to clinical cure (p = 0.008). Other variables influencing clinical outcomes were the McCabe Jackson score (p = 0.005) and outpatient status (p < 0.001). The ASP interventions in this study had no economic impact. CONCLUSIONS: Antimicrobial stewardship has a positive clinical impact on UTIs caused by ESBL-producing E. coli. Further prospective studies are needed to assess the economic impact of ASPs on UTI caused by ESBL-producing E. coli.

Frequency and severity of potential drug interactions in a cohort of HIV-infected patients Identified through a Multidisciplinary team.

OBJECTIVES: Interactions between antiretroviral treatment (ART) and comedications are a concern in HIV-infected patients. This study aimed to determine the frequency and severity of potential drug-drug interactions (PDDIs) with ART in our setting. METHODS: Observational study by a multidisciplinary team in 1259 consecutive HIV patients (March 2015-September 2016). Data on demographics, toxic habits, comorbidities, and current ART were collected. A structured questionnaire recorded concomitant medications (including occasional and over-the-counter drugs). PDDIs were classified into four categories: (1) no interactions, (2) mild (clinically non-significant), (3) moderate (requiring close monitoring or drug modification/dose adjustment), and (4) severe (contraindicated). STATISTICAL ANALYSIS: chi-square test, logistic regression analysis. RESULTS: In total, 881 (70%) patients took comedication, and 563 (44.7%) had ≥ PDDI. Forty-one comedicated patients (4.6%) had severe and 522 (59.2%) moderate PDDIs. Moderate PDDIs mainly involved cardiovascular (53.8%) and central nervous system (40.2%) drugs. Independent risk factors for PDDIs were ART containing a boosted protease inhibitor (odds ratio [OR]=9.11, 95% confidence interval [CI] 5.15-16.11; p = 0.0001) and/or non-nucleoside reverse transcriptase (NNRTI) (OR = 4.34, 95%CI 2.49-7.55; p = 0.0001), HCV co-infection (OR = 3.26, 95%CI 2.15-4.93; p = 0.0001), and use of two or more comedications (OR = 3.36, 95%CI 2.27-4.97; p = 0.0001). Adherence and effectiveness of ART were similar in patients with and without PDDIs. The team made 133 recommendations related to comedications (drug change or dose adjustment) or ART (drug switch or change in administration schedule). CONCLUSIONS: Systematic evaluation detected a significant percentage of PDDIs requiring an intervention in HIV patients on ART. Monitoring and advice about drug-drug interactions should be part of routine practice.

Ceftolozane-tazobactam for the treatment of ventilator-associated infections by colistin-resistant Pseudomonas aeruginosa.

The use of colistin for the treatment of multiresistant bacteria has led to the emergence of colistin-resistant strains of Gram-negative bacilli. Treatment of infections caused by these pan-drug-resistant bacteria is difficult owing to the paucity of effective antibiotics. We report two cases of ventilator-associated respiratory infection caused by pan-drug-resistant, colistin-resistant Pseudomonas aeruginosa that were successfully treated with ceftolozane-tazobactam.

Urinary micafungin levels are sufficient to treat urinary tract infections caused by Candida spp.

Six cases of patients diagnosed with urinary tract infection (UTI) successfully treated with micafungin are reported. Four were infected with fluconazole-resistant Candida spp. and two (with hepatic injury) were infected with fluconazole-sensitive Candida spp. Traditionally, echinocandins have not been considered for the treatment of UTIs. However, despite its low urinary excretion rate, therapeutic drug monitoring of micafungin urinary levels could be helpful in order to achieve optimal pharmacokinetic/pharmacodynamic (PK/PD) indices for treating UTIs caused by Candida spp. resistant to fluconazole.