Oral Tebipenem Pivoxil Hydrobromide in Complicated Urinary Tract Infection.

BACKGROUND: There is a need for oral antibiotic agents that are effective against multidrug-resistant gram-negative uropathogens. Tebipenem pivoxil hydrobromide is an orally bioavailable carbapenem with activity against uropathogenic Enterobacterales, including extended-spectrum beta-lactamase-producing and fluoroquinolone-resistant strains. METHODS: In this phase 3, international, double-blind, double-dummy trial, we evaluated the efficacy and safety of orally administered tebipenem pivoxil hydrobromide as compared with intravenous ertapenem in patients with complicated urinary tract infection or acute pyelonephritis. Patients were randomly assigned, in a 1:1 ratio, to receive oral tebipenem pivoxil hydrobromide (at a dose of 600 mg every 8 hours) or intravenous ertapenem (at a dose of 1 g every 24 hours) for 7 to 10 days (or up to 14 days in patients with bacteremia). The primary efficacy end point was overall response (a composite of clinical cure and favorable microbiologic response) at a test-of-cure visit (on day 19, within a ±2-day window) in the microbiologic intention-to-treat population. The noninferiority margin was 12.5%. RESULTS: A total of 1372 hospitalized adult patients were enrolled; 868 patients (63.3%) were included in the microbiologic intention-to-treat population (50.8% of whom had complicated urinary tract infections and 49.2% of whom had pyelonephritis). An overall response was seen in 264 of 449 patients (58.8%) who received tebipenem pivoxil hydrobromide, as compared with 258 of 419 patients (61.6%) who received ertapenem (weighted difference, -3.3 percentage points; 95% confidence interval [CI], -9.7 to 3.2). Clinical cure at the test-of-cure visit was observed in 93.1% of the patients in the microbiologic intention-to-treat population who received tebipenem pivoxil hydrobromide and 93.6% of patients who received ertapenem (weighted difference, -0.6 percentage point; 95% CI, -4.0 to 2.8); the majority of patients with microbiologic response failures at the test-of-cure visit were asymptomatic patients with recurrent bacteriuria. Secondary and subgroup analyses were supportive of the primary analysis. Adverse events were observed in 25.7% of patients who received tebipenem pivoxil hydrobromide and in 25.6% of patients who received ertapenem; the most common adverse events were mild diarrhea and headache. CONCLUSIONS: Oral tebipenem pivoxil hydrobromide was noninferior to intravenous ertapenem in the treatment of complicated urinary tract infection and acute pyelonephritis and had a similar safety profile. (Funded by Spero Therapeutics and the Department of Health and Human Services; ADAPT-PO ClinicalTrials.gov number, NCT03788967.).

Stewardship program on carbapenem prescriptions in a tertiary hospital for adults and children in France: a cohort study.

Antimicrobial stewardship programs aim at reducing the overuse of broad-spectrum antibiotics such as carbapenems, but their impact remains unclear. We compared the use of carbapenems between paediatric and adult subjects admitted to a French tertiary hospital and described the intervention of an antibiotic stewardship team (AST). As part of AST routine activity, all adult and paediatric patients receiving carbapenems are identified in real time using a computer-generated alert system and reviewed by the AST. Data associated with carbapenem prescriptions were extracted for 2 years (2014-2015) and were compared between paediatric and adult wards. Prescription appropriateness (i.e. no clinically suitable narrower spectrum alternative to carbapenem for de-escalation) and AST intervention were analysed. In total, 775 carbapenem prescriptions for 291 children and 262 adults were included. Most patients (95%) had a comordity and 52% had known recent carriage of extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBLE). Most carbapenem prescriptions came from intensive care units (n = 269, 35%) and were initiated for urinary tract (n = 200, 27%), sepsis (n = 181, 25%), and lung (n = 153, 21%) infections. Carbapenems were initiated empirically in 537 (70%) cases, and an organism was isolated in 523 (67%) cases. Among the isolated organisms, 47% (n = 246) were ESBLE and 90% (n = 468) were susceptible to carbapenems, but an alternative existed in 61% (n = 320) of cases according to antibiotic susceptibility testing. Among prescriptions reviewed by the AST, 39% (n = 255) were considered non-appropriate and led to either antibiotic discontinuation (n = 47, 7%) or de-escalation (n = 208, 32%). Non-appropriate prescriptions were more frequent in paediatric wards (p = 0.01) and in microbiologically documented infections (p = 0.013), and less observed in immunocompromised patients (p = 0.009) or with a known ESBLE carriage (p < 0.001). Tailored stewardship programs are essential to better control carbapenem use and subsequent antimicrobial resistance.

Use of carbapenems and glycopeptides increases risk for Clostridioides difficile infections in acute myeloid leukemia patients undergoing intensive induction chemotherapy.

Patients with acute myeloid leukemia (AML) are often exposed to broad-spectrum antibiotics and thus at high risk of Clostridioides difficile infections (CDI). As bacterial infections are a common cause for treatment-related mortality in these patients, we conducted a retrospective study to analyze the incidence of CDI and to evaluate risk factors for CDI in a large uniformly treated AML cohort. A total of 415 AML patients undergoing intensive induction chemotherapy between 2007 and 2019 were included in this retrospective analysis. Patients presenting with diarrhea and positive stool testing for toxin-producing Clostridioides difficile were defined to have CDI. CDI was diagnosed in 37 (8.9%) of 415 AML patients with decreasing CDI rates between 2013 and 2019 versus 2007 to 2012. Days with fever, exposition to carbapenems, and glycopeptides were significantly associated with CDI in AML patients. Clinical endpoints such as length of hospital stay, admission to ICU, response rates, and survival were not adversely affected. We identified febrile episodes and exposition to carbapenems and glycopeptides as risk factors for CDI in AML patients undergoing induction chemotherapy, thereby highlighting the importance of interdisciplinary antibiotic stewardship programs guiding treatment strategies in AML patients with infectious complications to carefully balance risks and benefits of anti-infective agents.

Surgery combined with antibiotics for the treatment of endogenous endophthalmitis caused by liver abscess.

BACKGROUNDS: Endogenous endophthalmitis is a serious disease caused by intraocular infection that can rapidly progress to cause blindness. This study evaluated the clinical features, surgical and antibiotics treatment strategies, and treatment outcomes in patients with endophthalmitis caused by liver abscess. METHODS: Between April 2014 and April 2019, the clinical data of 16 patients (19 eyes) with endophthalmitis associated with liver abscess who underwent surgery at Shengjing Hospital were retrospectively analyzed. Furthermore, we evaluated the final visual outcomes in the patients to determine the efficacy of surgery. RESULTS: Fifteen patients (18 eyes) underwent intravitreal injection followed by vitrectomy after admission. One patient (1 eye) only underwent intravitreal injection. Of the 16 patients, 3 patients (3 eyes) had recurrent intraocular inflammation and eventually underwent evisceration. Systemic antibiotics were administered for all patients based on the results of vitreous humor culture, blood culture, and antibiotic susceptibility tests. Outpatient follow-ups were performed until the patients were stable (6 months). Of the 19 eyes, 1 eye (5%) had visual acuity restored to 20/200, 6 eyes (31%) had visual acuity restored to counting fingers (CF), 2 eyes (11%) had visual acuity restored to hand motion (HM), 4 eyes (22%) showed only light perception (LP), and the remaining 6 eyes (31%) showed no light perception (NLP). Drug susceptibility tests suggested that the carbapenems exhibited significant effects in the inflammatory reaction. CONCLUSION: Endogenous endophthalmitis caused by liver abscess is a very serious condition, and the final visual outcome is poor. Timely surgical intervention combined with antibiotic treatment is essential, and the primary disease must be treated to control disease progression at the earliest.

Antimicrobial utilization and antimicrobial resistance in patients with haematological malignancies in Japan: a multi-centre cross-sectional study.

BACKGROUND: Infection is a major complication for patients with haematological malignancies. It is important to better understand the use of antimicrobial agents and antibiotic resistance for appropriate treatment and prevention of drug resistance. However, very few multi-centre analyses have focused on the use of antimicrobial agents and antibiotic resistance have been carried out in Japan. This study aimed to describe the characteristics of the use of antimicrobial agents and antibiotic resistance in patients with haematological malignancies. METHODS: We conducted a cross-sectional study using administrative claims data and antimicrobial susceptibility data in Japan. We included patients diagnosed with haematological malignancies, who were hospitalized in a haematology ward between 1 April 2015 and 30 September 2017 in 37 hospitals. Descriptive statistics were used to summarize patient characteristics, antimicrobial utilization, bacterial infections, and antibiotic resistance. RESULTS: In total, 8064 patients were included. Non-Hodgkin lymphoma (50.0%) was the most common malignancy. The broad-spectrum antibiotics displayed a following antimicrobial use density (AUD): cefepime (156.7), carbapenems (104.8), and piperacillin/tazobactam (28.4). In particular, patients with lymphoid leukaemia, myeloid leukaemia, or myelodysplastic syndromes presented a higher AUD than those with Hodgkin lymphoma, non-Hodgkin lymphoma, or multiple myeloma. The most frequent bacterial species in our study cohort was Escherichia coli (9.4%), and this trend was also observed in blood specimens. Fluoroquinolone-resistant E. coli (3.6%) was the most frequently observed antibiotic-resistant strain, while other antibiotic-resistant strains were rare. CONCLUSIONS: Broad-spectrum antibiotics were common in patients with haematological malignancies in Japan; however, antibiotic-resistant bacteria including carbapenem-resistant or multidrug-resistant bacteria were infrequent. Our results provide nationwide, cross-sectional insight into the use of antimicrobial agents, prevalence of bacteria, and antibiotic resistance, demonstrating differences in antimicrobial utilization among different haematological diseases.

Development of the predicted and standardized carbapenem usage metric: Analysis of the Japanese Diagnosis Procedure Combination payment system data.

This study aimed to develop a metric for standardized and predicted carbapenem consumption using the Diagnosis Procedure Combination payment system database and patients' characteristics. Based on Diagnosis Procedure Combination data analysis, the developed metric will provide useful benchmarks that stewardship programs can use to help drive improvements.

[The impact of carbapenem-resistance Pseudomonas aeruginosa infections on mortality of patients with hematological disorders].

Objective: To assess the risk factors for mortality and clinical outcome of carbapenem-resistant Pseudomonas aeruginosa (CRPA) infections in patients with hematological disorders. Methods: The data of in-patients with hematological disorders infected by CRPA or carbapenem-susceptible Pseudomonas aeruginosa (CSPA) were recorded in a seven-year retrospective cohort study. Risk factors for CRPA infections and impact of on mortality were identified. The primary end point was 30-day all-cause mortality. Results: A total of 81 patients with PA infections were included in the study, including 58 CSPA and 23 CRPA. Most of the primary diseases were acute leukemia or lymphoma (79.0%, 64/81). The median absolute neutrophil count at infection onset was 0.24×10(9)/L. Independent risk factors associated with carbapenem-resistance included longer duration of hospital stay (P=0.013, OR=1.045) and carbapenem exposure one month prior to infections (P=0.005, OR=8.132). The 30-day all-cause mortality of the whole cohort was 29.6%(24/81), and 30-day attributable mortality was 13.6%(11/81). Pulmonary infection was the leading cause of death, accounting for 41.7%(10/24). The adjusted 30-day mortality rate was significantly higher in patients with CRPA compared with CSPA [60.9%(14/23) vs. 17.2%(10/58), P<0.001, respectively]. CRPA infection was an independent prognostic factor for 30-day mortality(P=0.011, OR=5.427). Other factors included old age, longer duration of neutropenia and poor functional performance. Conclusions: Patients with hematological disorders have high mortality rate and poor prognosis caused by CRPA infections, which mainly develop in lungs.

Trends in and Predictors of Carbapenem Consumption across North American Hospitals: Results from a Multicenter Survey by the MAD-ID Research Network.

We sought to define trends in and predictors of carbapenem consumption across community, teaching, and university-affiliated hospitals in the United States and Canada. We conducted a retrospective multicenter survey of carbapenem and broad-spectrum noncarbapenem beta-lactam consumption between January 2011 and December 2013. Consumption was tabulated as defined daily doses (DDD) or as days of therapy (DOT) per 1,000 patient days (PD). Multivariate mixed-effects models were explored, and final model goodness of fit was assessed by regressions of observed versus predicted values and residual distributions. A total of 20 acute-care hospitals responded. The centers treated adult patients (n = 19/20) and pediatric/neonatal patients (n = 17/20). The majority of the centers were nonprofit (n = 17/20) and not affiliated with medical/teaching institutions (n = 11/20). The median (interquartile range [IQR]) carbapenem consumption rates were 38.8 (17.4 to 95.7) DDD/1,000 PD and 29.7 (19.2 to 40.1) DOT/1,000 PD overall. Carbapenem consumption was well described by a multivariate linear mixed-effects model (fixed effects, R2 = 0.792; fixed plus random effects, R2 = 0.974). Carbapenem consumption increased by 1.91-fold/quarter from 48.6 DDD/1,000 PD (P = 0.004) and by 0.056-fold/quarter from 45.7 DOT/1,000 PD (P = 0.93) over the study period. Noncarbapenem consumption was independently related to increasing carbapenem consumption (beta = 0.31 for increasing noncarbapenem beta-lactam consumption; P < 0.001). Regular antibiogram publication and promotion of conversion from intravenous (i.v.) to oral (p.o.) administration independently affected carbapenem consumption rates. In the final model, 58.5% of the observed variance in consumption was attributable to between-hospital differences. Rates of carbapenem consumption across 20 North American hospitals differed greatly, and the observed differences were correlated with hospital-specific demographics. Additional studies focusing on the drivers of hospital-specific carbapenem consumption are needed to determine whether these rates are justifiable.

Antibiotic Exposure Profiles in Trials Comparing Intensity of Continuous Renal Replacement Therapy.

OBJECTIVES: To determine whether the probability of target attainment over 72 hours of initial therapy with beta-lactam (cefepime, ceftazidime, piperacillin/tazobactam) and carbapenem (imipenem, meropenem) antibiotics were substantially influenced between intensive and less-intensive continuous renal replacement therapy groups in the Acute Renal Failure Trial Network trial and The RENAL Replacement Therapy Study trial. DESIGN: The probability of target attainment was calculated using pharmacodynamic targets of percentage of time that free serum concentrations (fT): 1) were above the target organism's minimum inhibitory concentration (≥ fT > 1 × minimum inhibitory concentration); 2) were above four times the minimum inhibitory concentration (≥ % fT > 4 × minimum inhibitory concentration); and 3) were always above the minimum inhibitory concentration (≥ 100% fT > minimum inhibitory concentration) for the first 72 hours of antibiotic therapy. Demographic data and effluent rates from the Acute Renal Failure Trial Network and RENAL Replacement Therapy Study trials were used. Optimal doses were defined as the dose achieving greater than or equal to 90% probability of target attainment. SETTING: Monte Carlo simulations using demographic data from Acute Renal Failure Trial Network and RENAL Replacement Therapy Study trials. PATIENTS: Virtual critically ill patients requiring continuous renal replacement therapy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The pharmacodynamic target of fT greater than 1 × minimum inhibitory concentration led to similarly high rates of predicted response with antibiotic doses often used in continuous renal replacement therapy. Achieving 100% fT greater than minimum inhibitory concentration is a more stringent benchmark compared with T greater than 4 × minimum inhibitory concentration with standard antibiotic dosing. The intensity of effluent flow rates (less intensive vs intensive) did not substantially influence the probability of target attainment of antibiotic dosing regimens regardless of pharmacodynamic target. CONCLUSIONS: Antibiotic pharmacodynamic target attainment rates likely were not meaningfully different in the low- and high-intensity treatment arms of the Acute Renal Failure Trial Network and RENAL Replacement Therapy Study Investigators trials.

A national quality incentive scheme to reduce antibiotic overuse in hospitals: evaluation of perceptions and impact.

Background: In 2016/2017, a financially linked antibiotic prescribing quality improvement initiative Commissioning for Quality and Innovation (AMR-CQUIN) was introduced across acute hospitals in England. This aimed for >1% reductions in DDDs/1000 admissions of total antibiotics, piperacillin/tazobactam and carbapenems compared with 2013/2014 and improved review of empirical antibiotic prescriptions. Objectives: To assess perceptions of staff leading antimicrobial stewardship activity regarding the AMR-CQUIN, the investments made by hospitals to achieve it and how these related to achieving reductions in antibiotic use. Methods: We invited antimicrobial stewardship leads at acute hospitals across England to complete a web-based survey. Antibiotic prescribing data were downloaded from the PHE Antimicrobial Resistance Local Indicators resource. Results: Responses were received from 116/155 (75%) acute hospitals. Owing to yearly increases in antibiotic use, most trusts needed to make >5% reductions in antibiotic consumption to achieve the AMR-CQUIN goal of 1% reduction. Additional funding was made available at 23/113 (20%) trusts and, in 18 (78%), this was <10% of the AMR-CQUIN value. Nationally, the annual trend for increased antibiotic use reversed in 2016/2017. In 2014/2015, year-on-year changes were +3.7% (IQR -0.8%, +8.4%), +9.4% (+0.2%, +19.5%) and +5.8% (-6.2%, +18.2%) for total antibiotics, piperacillin/tazobactam and carbapenems, respectively, and +0.1% (-5.4%, +4.0%), -4.8% (-16.9%, +3.2%) and -8.0% (-20.2%, +4.0%) in 2016/2017. Hospitals where staff believed they could reduce antibiotic use were more likely to do so (P < 0.001). Conclusions: Introducing the AMR-CQUIN was associated with a reduction in antibiotic use. For individual hospitals, achieving the AMR-CQUIN was associated with favourable perceptions of staff and not availability of funding.

"Double carbapenem" and oral fosfomycin for the treatment of complicated urinary tract infections caused by blaNDM -harboring Enterobacteriaceae in kidney transplantation.

Infections with carbapenemase-producing carbapenem-resistant Enterobacteriaceae represent an emergent problem worldwide. Treatment of infections caused by New Delhi metallo-beta-lactamase (NDM)-harboring Enterobacteriaceae is particularly challenging as it frequently involves the use of nephrotoxic agents, which is problematic in kidney transplant recipients and non-renal transplant patients with marginal kidney function. We present two cases of urinary tract infections caused by NDM-harboring Enterobacteriaceae successfully treated with a combination of "double carbapenem" and oral fosfomycin.

An intervention to control an ICU outbreak of carbapenem-resistant Acinetobacter baumannii: long-term impact for the ICU and hospital.

BACKGROUND: Following a fatal intensive care unit (ICU) outbreak of carbapenem-resistant Acinetobacter baumanii (CRAB) in 2015, an aggressive infection control intervention was instituted. We outline the intervention and long-term changes in the incidence and prevalence of CRAB. METHODS: The infection control intervention included unit closure (3 days), environmental cleaning, hand hygiene interventions, and environmental culturing. CRAB acquisition and prevalence and colistin use were compared for the 1 year before and 2 years after the intervention. RESULTS: Following the intervention, ICU CRAB acquisition decreased significantly from 54.6 (preintervention) to 1.9 (year 1) to 5.6 cases (year 2)/1000 admissions (p < 0.01 for comparisons with preintervention period.). Unexpectedly, ICU CRAB admission prevalence also decreased from 56.5 to 5.8 to 13 cases/1000 admissions (p < 0.001) despite the infection control intervention's being directed at the ICU alone. In parallel, hospital CRAB prevalence decreased from 4.4 to 2.4 to 2.5 cases/1000 admissions (p < 0.001), possibly as a result of decreased discharge of CRAB carriers from the ICU to the wards (58.5 to 1.9 to 7.4 cases/1000 admissions; p < 0.001). ICU colistin consumption decreased from 200 to 132 to 75 defined daily dose (DDD)/1000 patient-days (p < 0.05). Hospital colistin consumption decreased from 21.2 to 19.4 to 14.1 DDD/1000 patient-days (p < 0.05). CONCLUSIONS: The ICU infection control intervention was highly effective, long-lasting, and associated with a decrease in last-line antibiotic use. The intervention was associated with the unexpected finding that hospital CRAB prevalence also decreased.

A new carbapenem drug dosage metric for carbapenem usage and correlation with carbapenem resistance of Pseudomonas aeruginosa.

The emergence and dissemination of antimicrobial resistance is a worldwide problem. Inappropriate antimicrobial use contributes to this resistance, and several metrics of drug usage have been used to monitor their consumption and rational use. We examined several existing drug metrics, and developed a new one, dose/duration-density (D/d2), for a the best correlation between carbapenem usage and carbapenem resistance of Pseudomonas aeruginosa. The annual changes of antimicrobial use density (AUD), days of therapy (DOT), daily dose (DD) and D/d2 for meropenem, imipenem and total carbapenems was analyzed for a correlation with carbapenem susceptibility of P. aeruginosa from 2006 through 2015 at a university hospital. The substitution of meropenem for imipenem usage, and an approximate 10% increase in carbapenem susceptibility of P. aeruginosa occurred over the study period. There were significant correlations of the meropenem susceptibility of P. aeruginosa and meropenem usage as measured by the meropenem DD, of imipenem susceptibility and imipenem AUD and DOT, and overall carbapenem susceptibility and imipenem DOT. The D/d2 for meropenem, imipenem and total carbapenems had significant correlations with individual and all carbapenem susceptibility of P. aeruginosa. These D/d2 is the best single carbapenem use metric for correlating carbapenem usage with P. aeruginosa resistance. Further studies are warranted to consider the value of D/d2 for other antimicrobials and bacteria.

Sparing carbapenem usage.

Background: Carbapenem resistance in Gram-negative bacteria is increasing in many countries and use of carbapenems and antibiotics to which resistance is linked should be reduced to slow its emergence. There are no directly equivalent antibiotics and the alternatives are less well supported by clinical trials. The few new agents are expensive. Objectives: To provide guidance on strategies to reduce carbapenem usage. Methods: A literature review was performed as described in the BSAC/HIS/BIA/IPS Joint Working Party on Multiresistant Gram-negative Infection Report. Results: Older agents remain active against some of the pathogens, although expectations of broad-spectrum cover for empirical treatment have risen. Education, expert advice on treatment and antimicrobial stewardship can produce significant reductions in use. Conclusions: More agents may need to be introduced onto the antibiotic formulary of the hospital, despite the poor quality of scientific studies in some cases.

Impact of carbapenem restriction on the antimicrobial susceptibility pattern of Pseudomonas aeruginosa isolates in the ICU.

BACKGROUND: Rates of carbapenem-resistant Pseudomonas aeruginosa are increasing. Aggressive prevention strategies, including instituting antimicrobial stewardship programmes, are essential for combating antimicrobial resistance. OBJECTIVES: We conducted this study to compare the antimicrobial susceptibility pattern of P. aeruginosa before and after carbapenem restriction. METHODS: We conducted a two-phase retrospective study in an adult ICU. The first phase was from May until July 2016 (before carbapenem restriction), whereas the second phase was from September until November 2016 (while implementing carbapenem restriction). The antimicrobial susceptibility pattern of P. aeruginosa was reviewed in August and December 2016. The measure of carbapenem-resistant P. aeruginosa was the proportion of resistant isolates (percentage resistant). The measure of antibacterial consumption in the study phases was DDDs/1000 patient days. RESULTS: The overall carbapenem consumption decreased significantly in the second phase, from 28.44 to 11.67 DDDs/1000 patient days (P = 0.012). The resistance of P. aeruginosa to imipenem and meropenem decreased significantly from 76.0% to 38.5% (P = 0.019) and from 74.1% to 30.0% (P = 0.012), respectively. Susceptibility of P. aeruginosa to other antibacterials was not affected by carbapenem restriction. CONCLUSIONS: These data suggest that restricting carbapenems, even for a short duration, may be an effective strategy for managing the problem of carbapenem resistance in P. aeruginosa.

Double-carbapenem combination as salvage therapy for untreatable infections by KPC-2-producing Klebsiella pneumoniae.

We report our experience using the double-carbapenem combination as salvage therapy for patients with untreatable infections caused by KPC-2- producing Klebsiella pneumoniae. A total of 27 patients in two institutions in Athens, Greece suffering from complicated urinary tract infections (16) with or without secondary bacteraemia (four and 12 respectively), primary (six) or catheter-related bloodstream infections (two), HAP or VAP (two) and external ventricular drainage infection (one) were treated exclusively with ertapenem and high-dose prolonged infusion meropenem because in-vitro active antimicrobials were unavailable (19) or failed (four) or were contraindicated (six). Most patients presented with severe infections with median APACHE II score of 17 and 11 of those patients (40.7%) had severe sepsis (five) or septic shock (six). The clinical and microbiological success was 77.8 and 74.1% respectively. Crude mortality was 29.6% with attributable mortality of 11.1%. Adverse events, none of them severe, were reported in four patients (14.8%). The double-carbapenem combination as an exclusive regimen represents a safe and valid salvage therapy for untreatable infections by extensively- or pandrug-resistant KPC-producing K.pneumoniae.

Population Pharmacokinetics and Pharmacodynamics of Doripenem in Obese, Hospitalized Patients.

BACKGROUND: Doripenem population pharmacokinetics and dosing recommendations are limited in obesity. OBJECTIVE: To evaluate the population pharmacokinetics and pharmacodynamics of doripenem in obese patients. METHODS: Hospitalized adults with a body mass index (BMI) ≥ 40 kg/m2 or total body weight (TBW) ≥45.5 kg over their ideal body weight received doripenem 500 mg every 8 hours, infused over 1 hour. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed for 5 intermittent and prolonged infusion dosing regimens to calculate probability of target attainment (PTA) at 40% and 100% fT>MIC (free drug concentrations above the minimum inhibitory concentration). RESULTS: A total of 20 patients were studied: 10 in an intensive care unit (ICU) and 10 in a non-ICU. A 2-compartment model with first-order elimination best described the serum concentration-time data. Doripenem clearance (CL) was significantly associated with creatinine CL (CRCL), volume of the central compartment with TBW and ICU residence, and volume of the peripheral compartment with TBW ( P < 0.05). Using 40% fT>MIC, PTA was >90% for all simulated dosing regimens at MICs ≤2 mg/L. Using 100% fT>MIC, prolonged infusions of 1 g every 6 hours and 2 g every 8 hours achieved >90% PTA at MICs ≤2 mg/L. CONCLUSIONS: CRCL, ICU residence, and TBW are significantly associated with doripenem pharmacokinetics. Currently approved dosing regimens provide adequate pharmacodynamic exposures at 40% fT>MIC for susceptible bacteria in obese patients. However, prolonged infusions of larger doses are needed if a higher pharmacodynamic target is desired.

Triple combination antibiotic therapy for carbapenemase-producing Klebsiella pneumoniae: a systematic review.

BACKGROUND: The spread of carbapenemase-producing K. pneumoniae (CPKP) has become a significant problem worldwide. Combination therapy for CPKP is encouraging, but polymyxin resistance to many antibiotics is hampering effective treatment. Combination therapy with three or more antibiotics is being increasingly reported, therefore we performed a systematic review of triple combination cases in an effort to evaluate their clinical effectiveness for CPKP infections. METHODS: The PubMed database was searched to identify all published clinical outcomes of CPKP infections treated with triple combination therapy. Articles were stratified into two tiers depending on the level of clinical detail provided. A tier 1 study included: antibiotic regimen, regimen-specific outcome, patient status at onset of infection, and source of infection. Articles not reaching these criteria were considered tier 2. RESULTS: Thirty-three studies were eligible, 23 tier 1 and ten tier 2. Among tier 1 studies, 53 cases were included in this analysis. The most common infection was pneumonia (31%) followed by primary or catheter-related bacteremia (21%) and urinary tract infection (17%). Different combinations of antibiotic classes were utilized in triple combinations, the most common being a polymyxin (colistin or polymyxin B, 86.8%), tigecycline (73.6%), aminoglycoside (43.4%), or carbapenem (43.4%). Clinical and microbiological failure occurred in 14/39 patients (35.9%) and 22/42 patients (52.4%), respectively. Overall mortality for patients treated with triple combination therapy was 35.8% (19/53 patients). CONCLUSIONS: Triple combination therapy is being considered as a treatment option for CPKP. Polymyxin-based therapy is the backbone antibiotic in these regimens, but its effectiveness needs establishing in prospective clinical trials.

Pharmacokinetic/Pharmacodynamic Analysis for Doripenem Regimens in Intensive Care Unit Patient.

Doripenem (DRPM) is a broad-spectrum antibacterial agent often used as empirical therapy for critically ill patients, although there is a lack of studies validating the recommended dosage regimen for patients admitted to intensive care unit (ICU), based on pharmacokinetic (PK)/pharmacodynamic (PD) index. In this study, we estimated the free time above minimum inhibitory concentration (fT>MIC (%)) of DRPM using population PK analysis of 12 patients in ICU, and evaluated the validity of the dosage regimen stratified by creatinine clearance. Using a 2-compartment population PK model reported previously, the mean total clearance or distribution volume of DRPM estimated by Bayesian estimation was significantly lower or higher than that of based on population PK model. The estimated fT>MIC (%) of the recommended standard (normal renal function: 0.5 g every 8 h, moderate: 0.25 g every 8 h, severe renal impairment: 0.25 g every 12 h) and higher doses (normal: 1.0 g every 8 h, moderate: 0.5 g every 8 h, severe: 0.25 g every 8 h) against MICs of 0.5, 1 and 2 µg/mL exceeded 40% in all patients. When stratified by creatinine clearance, the PK/PD breakpoints estimated by Monte Carlo simulation in three grades of renal function tended to be higher than the previously reported PK/PD breakpoints for patients with urinary tract infection, an infection of lesser severity than ICU patients. These results suggest that the dosage regimen stratified by renal function derived from Japanese package insert may be sufficient to achieve effective treatment in ICU patients.

Evaluation of antimicrobial stewardship (AS) for appropriate use of antimicrobial agents.

We implemented an antimicrobial stewardship (AS) program whereby pharmacists sought appropriate use of antimicrobial agents in January 2012. At that time, we targeted anti-methicillin-resistant Staphylococcus aureus (MRSA) agents and carbapenems; however, in January 2014, we added tazobactam/piperacillin (TAZ/PIPC). We evaluated outcomes using multilateral analyses. The average one-day dosage of carbapenems increased; however, the duration of administration and number of recipient patients decreased significantly (P < 0.01). Moreover, the percentage of patients receiving meropenem (MEPM), for whom the time above minimal inhibitory concentration (MIC) was 40% or higher increased (P < 0.01). In contrast, patient utilization of TAZ/PIPC increased significantly after targeting of carbapenems as specific antibacterial agents. However, after TAZ/PIPC was targeted as a specific antibacterial agent, the number of TAZ/PIPC administrations decreased significantly (P < 0.01). The duration of hospitalization and mortality rate in patients receiving specific antibacterial agents significantly decreased after implementation of the AS program (P < 0.01). In conclusion, pharmacist's interventions to provide AS and patient follow-up reduced improper use and promoted proper administration of antibacterial agents. Furthermore, AS was effective in improving patient prognoses and suppressing drug-resistant strains, as well as promoting effective treatment.