Complicated Intra-abdominal Infections Research Articles

Clinical cure rate and cost-effectiveness of carbapenem-sparing beta-lactams vs. meropenem for Gram-negative infections: A systematic review, meta-analysis, and cost-effectiveness analysis

The increasing incidence of infections caused by extended-spectrum beta-lactamase (ESBL)/AmpC-producing bacteria leads to increasing use of carbapenems and risk of carbapenem resistance. Treatment success of carbapenem-sparing beta-lactams (CSBs) for ESBL infections is unclear. The aim of this study was to appraise the clinical cure rate and estimate the cost-effectiveness of meropenem vs. CSBs (piperacillin-tazobactam, temocillin, ceftazidime-avibactam, and ceftolozane-tazobactam) for urinary tract infections (UTIs) or intra-abdominal infections (IAIs) due to ESBL/AmpC-producing bacteria. A systematic literature search of the Cochrane library, EMBASE, PubMed, and Web of Science was conducted to identify studies assessing the clinical cure rate of the antibiotics. To assess the cost-effectiveness of CSBs vs. meropenem, a combined decision analytic and Markov model was probabilistically analysed over a 5-year period. The main outcome was presented as the incremental cost-effectiveness ratio and evaluated with a threshold of €20 000 per life year gained (LYG).From 656 identified articles, 17 and 14 studies were included in the qualitative synthesis and quantitative synthesis, respectively. A clinical cure of ceftazidime-avibactam and ceftolozane-tazobactam was comparable to meropenem in patients with complicated IAIs (cIAIs) due to ESBL (Risk ratio [RR]=1·04, 95% confidence interval [CI]=0·95-1·13). Both temocillin and ceftolozane-tazobactam were deemed cost-effective compared to meropenem with €157·58 and €13 398·34 per LYG, respectively, in patients with UTIs due to ESBL. However, only ceftazidime-avibactam (plus metronidazole) was cost-effective for the treatment of IAIs, with €16 916·77 per LYG. These results show that several CSBs can be considered as viable candidates for the treatment of UTIs and IAIs caused by ESBL.

Safety and Efficacy of Tigecycline to Treat Multidrug-resistant Infections in Pediatrics: An Evidence Synthesis.

The need for antimicrobial therapies effective against multidrug resistant organisms for children remains unmet. Tigecycline shows antibacterial activity across a broad spectrum of bacteria and is approved for treating complicated skin and skin-structure infections, complicated intra-abdominal infections and, in the United States, community-acquired bacterial pneumonia for adult patients. No blinded, randomized phase 3 tigecycline clinical trials on neonates or children have been completed or planned. This review aimed to provide a comprehensive synthesis of all the existing data sources, both on-label and off-label, for tigecycline use in children. Data on tigecycline use in children were identified from published and unpublished sources including clinical trials, expanded access and compassionate use programs, databases of healthcare records and patient safety monitoring. Pharmacokinetic simulations predicted that tigecycline 1.2 mg/kg (maximum dose 50 mg) every 12 hours (q12h) in children 8-11 years and 50 mg q12h in children 12 to <18 years would achieve exposure similar to adults receiving 50 mg q12h. Available phase 2 pediatric clinical trial data and data from other sources demonstrated similar clinical efficacy between adult and pediatric patients treated with tigecycline. These data showed no new or unexpected safety concerns with tigecycline in children. Information presented here may help guide the appropriate use of tigecycline in children with multidrug resistant infections. Continued pharmacovigilance from real-world observational studies may also further refine appropriate use of tigecycline.

Ceftolozane/tazobactam for the treatment of complicated intra-abdominal and urinary tract infections: current perspectives and place in therapy.

The current prevalence of infections caused by multidrug-resistant (MDR) organisms is a global threat, and thus, the development of new antimicrobial agents with activity against these pathogens is a healthcare priority. Ceftolozane–tazobactam (C/T) is a new combination of a cephalosporin with a β-lactamase inhibitor that shows excellent in vitro activity against a broad spectrum of Enterobacteriaceae and Pseudomonas aeruginosa, including extended spectrum β-lactamase-producing (ESBL) strains and MDR or extensively drug-resistant (XDR) P. aeruginosa. In phase III randomized clinical trials, C/T demonstrated similar efficacy to meropenem for the treatment of complicated intra-abdominal infections (cIAIs) and superior efficacy to levofloxacin for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis. The drug is generally safe and well tolerated and its PK/PD profile is very favorable. Observational studies with C/T have revealed good efficacy for the treatment of different types of infection caused by MDR or XDR P. aeruginosa, including some that originated from the digestive or urinary tracts. The place of C/T in therapy is not well defined, but its use could be recommended in a carbapenem-sparing approach for the treatment of infections caused by ESBL-producing strains or for the treatment of infections caused by P. aeruginosa if there are no other more favorable therapeutic options. Further clinical experience is needed to position this new antimicrobial drug for the empirical treatment of cIAIs or cUTIs.

The Efficacy and Safety of Eravacycline in the Treatment of Complicated Intra-Abdominal Infections: A Systemic Review and Meta-Analysis of Randomized Controlled Trials.

This study aims to assess the clinical efficacy and safety of eravacycline for treating complicated intra-abdominal infection (cIAI) in adult patients. The PubMed, Web of Science, EBSCO, Cochrane databases, Ovid Medline, Embase, and ClinicalTrials.gov were searched up to May 2019. Only randomized controlled trials (RCTs) that evaluated eravacycline and other comparators for the treatment of cIAI were included. The primary outcome was the clinical cure rate at the test-of-cure visit based on modified intent-to-treat population, microbiological intent-to-treat population, clinically evaluable population, and microbiological evaluable population, and the secondary outcomes were clinical failure rate and the risk of adverse event. Three RCTs were included. Overall, eravacycline had a clinical cure rate (88.7%, 559/630) at test-of-cure in modified intent-to-treat population similar to comparators (90.1%, 492/546) in the treatment of cIAIs (risk ratio (RR), 0.99; 95% confidence interval (CI), 0.95–1.03; I2 = 0%, Figure 3). In the microbiological intent-to-treat, clinically evaluable, and microbiological evaluable populations, no difference was found between eravacycline and comparators in terms of clinical cure rate at test-of-cure (microbiological intent-to-treat population, RR, 0.99; 95% CI, 0.95–1.04; I2 = 0%, clinically evaluable population, RR, 1.00; 95% CI, 0.97–1.03; I2 = 0%, microbiological evaluable population, RR, 0.98; 95% CI, 0.95–1.02; I2 = 0%). In addition, eravacycline had clinical failure rate similar to comparators at test-of-cure in modified intent-to-treat population (RR, 1.01; 95% CI, 0.61–0.69; I2 = 0%), microbiological intent-to-treat population (RR, 1.34; 95% CI, 0.77–2.31; I2 = 16%), clinically evaluable population (RR, 1.03; 95% CI, 0.61–1.76; I2 = 0%), and microbiological evaluable population (RR, 1.32; 95% CI, 0.75–2.32; I2 = 10%). Although eravacycline was associated with higher risk of treatment-emergent adverse event than comparators (RR, 1.34; 95% CI, 1.13–1.58; I2 = 0%), no significant differences were found between eravacycline and comparators for the risk of serious adverse event (RR, 1.04; 95% CI, 0.65–1.65; I2 = 0%), discontinuation of study drug because of adverse event (RR, 0.68; 95% CI, 0.23–1.99; I2 = 13%), and all-cause mortality (RR, 1.09; 95% CI, 0.41–2.9; I2 = 28%). In conclusion, the clinical efficacy of eravacycline is as high as that of the comparator drugs in the treatment of cIAIs and this antibiotic is as well tolerated as the comparators.

Eravacycline, a newly approved fluorocycline.

Complicated intra-abdominal infections (cIAIs) are commonly associated with multimicroorganisms and treatment choices are becoming narrower due to developing resistance, especially in the gram-negative Enterobacteriaceae species. Eravacycline is a newly developed, fully synthetic tetracycline derivative that has shown potent broad-spectrum activity against a wide variety of microorganisms, including those such as extended spectrum β-lactamase producing Enterobacteriaceae and Acinetobacter. Eravacycline has shown activity against many gram-positive organisms such as methicillin-resistant S. aureus and vancomycin resistant Enterococcus faecalis and Enterococcus faecium (VRE), gram-negative organisms such as Escherichia coli, and anaerobic species of microorganisms such as Bacteroides. This fluorocycline has been compared to ertapenem and meropenem for the treatment of complicated intra-abdominal infections and levofloxacin for the treatment of complicated urinary tract infections. Eravacycline was shown to be noninferior to ertapenem but did not meet noninferiority criteria in comparison to levofloxacin. Oral and IV formulations on eravacycline were tested in clinical trials, but at this time, only the IV formulation is FDA approved. Eravacycline has been noted to have a half-life of 20h with protein binding around 80%; AUC over minimum inhibitory concentration (MIC) has also been shown to be eravacycline's best predictor of efficacy. Of note, eravacycline does not require any renal dose adjustments, as the majority of its clearance is by nonrenal pathways.

Complicated intra-abdominal infections: a prospective validation study of the WSES Sepsis Severity Score.

The World Society of Emergency Surgery (WSES) recently developed and validated a sepsis severity score for complicated intra-abdominal infections (cIAIs). We aimed to prospectively study the validity of this score in our local setting and compare it with global findings. In a prospective study of 100 consecutive adult patients with cIAIs treated at Al-Ain Hospital, United Arab Emirates, from October 2014 to January 2016, we studied patients' demographics, disease, risk factors, WSES Sepsis Severity Score, management, hospital stay and mortality. Our findings were compared with those from a recent global multicentre prospective study from 53 countries (n = 4,496). Compared with global data, our patients were more likely to be male (p < 0.0001) and younger (p < 0.0001), with more appendicitis and perforated peptic ulcers (p < 0.0001), significantly lower sepsis severity score (p < 0.0001) and more delays in surgical intervention (p = 0.001). Nevertheless, they had similar adequate source control (p = 0.54) and surgical reinterventions (p = 0.63). Overall, our patients had a significantly lower mortality rate (1.0% vs. 9.3% in global data; p = 0.001). A direct logistic regression model showed that the WSES Sepsis Severity Score significantly predicted mortality (p < 0.0001), but our hospital's setting was not predictive of mortality compared with other hospitals (p = 0.18). Although our patient demographics and hospital's setting significantly differed from those of other international hospitals, the WSES Sepsis Severity Score was very accurate in predicting mortality among our patients, which supports its generalisability for all patient populations worldwide.

Ceftolozane-Tazobactam Population Pharmacokinetics and Dose Selection for Further Clinical Evaluation in Pediatric Patients with Complicated Urinary Tract or Complicated Intra-abdominal Infections.

Ceftolozane-tazobactam, a combination of the novel antipseudomonal cephalosporin ceftolozane and the well-established extended-spectrum β-lactamase inhibitor tazobactam, is approved for treating complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI) in adults. To determine doses likely to be safe and efficacious in phase 2 pediatric trials for the same indications, single-dose ceftolozane-tazobactam plasma pharmacokinetic data from a recently completed phase 1 trial in pediatric patients (birth to <18 years old) with proven/suspected Gram-negative bacterial infections, along with pharmacokinetic data from 12 adult studies, were integrated into a population pharmacokinetic (popPK) analysis. Two-compartment linear models with first-order elimination described the concentration-time profiles of ceftolozane and tazobactam in pediatric patients well. Renal function and body weight were identified to be significant predictors of ceftolozane-tazobactam pharmacokinetics. Renal function, as measured by the estimated glomerular filtration rate (eGFR), significantly affected the clearance of both ceftolozane and tazobactam. Body weight significantly affected clearance and the distribution volume, also of both ceftolozane and tazobactam. Patients with infections had a 32.3% lower tazobactam clearance than healthy volunteers. Using the final popPK models, simulations of various dosing regimens were conducted to assess each regimen's plasma exposure and the probability of pharmacokinetic/pharmacodynamic target attainment. Based on these simulations, the following doses are recommended for further clinical evaluation in phase 2 pediatric trials for cUTI and cIAI (in patients with an eGFR of ≥50 ml/min/1.73 m2 only): for children ≥12 years old, 1.5 g ceftolozane-tazobactam (1 g ceftolozane with 0.5 g tazobactam), and for neonates/very young infants, infants, and children <12 years old, 20/10 mg/kg of body weight ceftolozane-tazobactam, both via a 1-h intravenous infusion every 8 h.

Comparison of the In Vitro Susceptibility of Ceftolozane-Tazobactam With the Cumulative Susceptibility Rates of Standard Antibiotic Combinations When Tested Against Pseudomonas aeruginosa From ICU Patients With Bloodstream Infections or Pneumonia.

Background Pseudomonas aeruginosa remains an important cause of hospital-acquired infections in the United States and is frequently multidrug-resistant (MDR). The Infectious Diseases Society of America guidelines recommend empiric combination therapy that includes an antipseudomonal β-lactam with an aminoglycoside or fluoroquinolone likely to cover ≥95% of P. aeruginosa infections in seriously ill patients at risk of having an MDR pathogen. Ceftolozane is an antipseudomonal cephalosporin, combined with the β-lactamase inhibitor tazobactam. Ceftolozane-tazobactam is approved for treatment of complicated urinary tract infections and complicated intra-abdominal infections. A phase 3 clinical trial for the treatment of hospital-acquired pneumonia including ventilator-associated pneumoniae was recently completed. We compared the in vitro susceptibility rate of ceftolozane-tazobactam with the cumulative susceptibility rates of antibiotic combinations commonly used against P. aeruginosa.MethodsIsolates were collected from intensive care unit patients hospitalized in 32 US hospitals from 2011 to 2017. The susceptibilities of 1543 P. aeruginosa isolates from bloodstream infections (198 isolates, 12.8%) or pneumonia (1345 isolates, 87.2%) were determined for ceftolozane-tazobactam and comparators.ResultsThe most active antimicrobials were colistin (99.4% susceptible), amikacin (98.1% susceptible), and ceftolozane-tazobactam (96.5% susceptible). The susceptibilities to other antipseudomonal β-lactams and fluoroquinolones were <84%. A cumulative susceptibility of ≥95% was reached for cefepime, ceftazidime, meropenem, and piperacillin-tazobactam only in combination with amikacin due to the lower susceptibilities of gentamicin, ciprofloxacin, and levofloxacin. Monotherapies that exceeded 95% were ceftolozane-tazobactam, amikacin, and colistin.ConclusionsCeftolozane-tazobactam monotherapy is likely to be active against more isolates than a combination of another β-lactam and a fluoroquinolone or gentamicin for serious P. aeruginosa infections.

The role of new antibiotics in intra-abdominal infections in the era of multi-resistant bacteria

Complicated intra-abdominal infections (cIAI) are asubstantial cause of morbidity at intensive care units. cIAI are frequently caused by multidrug-resistant strains of Enterobacteriaceae and Pseudomonas aeruginosa. In 592 cIAI patients from the First Department of Surgery, General University Hospital in Prague, we found an alarming increase in resistance of Escherichia coli to amoxicillin/clavulanic acid, piperacillin/tazobactam and third-generation cephalosporins in 2014-2017 (from 28.7% in 2014 to 37.5% in 2017, from25% to 32% and from2.3% to 5.6%, respectively). Ceftolozane/tazobactam and ceftazidime/avibactam are novel cephalosporins available for the treatment of cIAI. Ceftolozane/tazobactam is highly active against multidrug-resistant strains of P. aeruginosa, including carbapenem-resistant isolates. The new non-b-lactam b-lactamase inhibitor avibactam plus ceftazidime is active against carbapenemases-producing strains of Enterobacteriaceae. Both antibiotics are included in the new WSES guidelines for the management of cIAI.

Eravacycline: The Tetracyclines Strike Back.

Objective: To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of eravacycline, a novel fluorocycline antibiotic from the tetracycline family. Data Sources: A PubMed search was conducted for data between 1946 and March 2019 using MeSH terms eravacycline and TP-434. An internet search was conducted for unpublished clinical research. Study Selection and Data Extraction: The literature search was limited to English-language studies that described clinical efficacy, safety, and pharmacokinetics in humans and animals. Abstracts featuring prepublished data were also evaluated for inclusion. Data Synthesis: Eravacycline has in vitro activity against multidrug-resistant organisms, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus, extended-spectrum β-lactamase-producing and carbapenem-resistant Enterobacteriaceae, and Acinetobacter. It was approved for the treatment of complicated intra-abdominal infections (cIAIs) in adults following favorable results of 2 phase III trials, IGNITE 1 and IGNITE 4, compared with ertapenem and meropenem, respectively. The most common adverse drug events associated with eravacycline were infusion site reactions (7.7%), nausea (6.5%), vomiting (3.7%), and diarrhea (2.3%). Relevance to Patient Care and Clinical Practice: Eravacycline will likely be most useful for resistant infections when lack of tolerability, resistant phenotypes, or allergies prevent the use of β-lactams. Conclusions: Eravacycline is a new tetracycline antibiotic with a broad spectrum of activity that has demonstrated efficacy in the treatment of cIAIs. Although it has activity against multidrug-resistant organisms, data are limited for other indications.

Clinical Pharmacokinetics and Pharmacodynamics of Eravacycline.

On 27 August, 2018, the US Food and Drug Administration approved eravacycline, a fluorocycline antimicrobial agent within the tetracycline class of antibacterial drugs, for the treatment of complicated intra-abdominal infections in patients aged 18years and older. This decision was based on substantial clinical and pre-clinical data, including rigorous pharmacokinetic and pharmacodynamic work. This paper examines the in-vivo pharmacokinetic/pharmacodynamic work that led to the approval of eravacycline and explores how this important new antibiotic may be used to treat aggressive multidrug-resistant infections in the years ahead.

Is fixed short-course antimicrobial therapy justified for patients who are critically ill with intra-abdominal infections?

A long-course antibiotic therapy increases the risk of antibiotic resistance. A 7- to 14-day duration of therapy has been traditionally adopted in patients with intra-abdominal infections (IAIs). Prophylactic antibiotic use is warranted in uncomplicated IAIs, in which the infection involves a single organ, and the source of the infection is completely eradicated by a surgical procedure. A large, randomized clinical trial of the treatment of complicated IAIs recently demonstrated that a fixed 4-day course of antibiotic therapy was as effective as a long-course therapy in patients who underwent adequate source control. Considering the poor prognosis and lack of clear evidence available for shortening the duration of antibiotic therapy in patients who are critically ill or those with ongoing signs of sepsis, the duration of therapy for complicated IAIs should be individually determined according to the clinical course. Limiting therapy to no more than 7 days seems to be warranted in patients who are critically ill with a good clinical response.

Correction to: Eravacycline: A Review in Complicated Intra-Abdominal Infections.

The article Eravacycline: A Review in Complicated Intra-Abdominal Infections, written by Lesley J. Scott, was originally published Online First without open access.

Influence of age on the clinical efficacy of tigecycline in severely ill patients.

The aim of this study was to define the relationship between age and response to tigecycline among patients treated for complicated skin and soft-tissue infections (cSSTIs) and complicated intra-abdominal infections (cIAIs). Pooled data derived from five European observational studies on the use of tigecycline (July 2006-October 2011), either as monotherapy or in combination with other antibiotics, for the treatment of cSSTI or cIAI were used in the analysis. The total population (N=1782 patients) was divided into three age categories: <65 years (804 patients); 65-80 years (836 patients) and >80 years (139 patients) (data unknown/missing for 3 patients). The overall mean Acute Physiology and Chronic Health Evaluation (APACHE) II score for patients with cSSTI and cIAI was 15.0±7.9 and 16.9±7.6, respectively, and the overall mean Sequential Organ Failure Assessment (SOFA) score was 5.8±3.9 and 7.0±4.2, respectively. Overall, patients with cSSTI and cIAI in the three age groups showed a good response to tigecycline treatment (76.2-80.0% and 69.2-81.1%, respectively) with patients aged ≤80 years showing higher response rates. Patients with cIAI appeared to be at greater risk for all types of adverse events compared with those with cSSTI, particularly in the older age groups. In these real-life studies, tigecycline, either alone or in combination, achieved favourable clinical response rates in all age categories of patients with cSSTIs and cIAIs with a high severity of illness.

The role of the intra-abdominal view in complicated intra-abdominal infections

BackgroundThe prognostic role of what a surgeon observes in the abdomen of patients with complicated intra-abdominal infection (cIAI) is largely unknown. The aim of this prospective study was to systemically analyze components of the intra-abdominal view (IAV) and their association to severe complicated intra-abdominal sepsis (SCIAS) or mortality.MethodsThe study cohort consisted of adult patients with cIAI. The operating surgeon filled a paper form describing the intra-abdominal view. Demographics, operative details, and preoperative physiological status were collected. Descriptive, univariate, and multivariate statistical analyses were performed, and a new score was developed based on regression coefficients. The primary outcome was a composite outcome of SCIAS or 30-day mortality, in which SCIAS was defined as organ dysfunctions requiring intensive care unit admission.ResultsA total of 283 patients were analyzed. The primary outcome was encountered in 71 (25%) patients. In the IAV, independent risk factors for the primary outcome were fecal or bile as exudate (odds ratio (OR) 1.98, 95% confidence interval 1.05–3.73), diffuse peritonitis (OR 2.15, 1.02–4.55), diffuse substantial redness of the peritoneum (OR 5.73, 2.12–15.44), and a non-appendiceal source of cIAI (OR 11.20, 4.11–30.54). Based on these factors, an IAV score was developed and its performance analyzed. The area under the receiver operating characteristic for the IAV score was 0.81. The IAV score also correlated significantly with several outcomes and organ dysfunctions.ConclusionsThe extent of peritonitis, diffuse substantial redness of the peritoneum, type of exudate, and source of infection associate independently with SCIAS or mortality. A high IAV score associates with mortality and organ dysfunctions, yet it needs further external validation. Combining components of IAV into comprehensive scoring systems for cIAI patients may provide additional value compared to the current scoring systems.Trial registrationThe study protocol was retrospectively registered on April 4, 2016, right after the first enrolled patient at Clinicaltrials.gov database (NCT02726932).

The 2018 Lebanese Society of Infectious Diseases and Clinical Microbiology Guidelines for the use of antimicrobial therapy in complicated intra-abdominal infections in the era of antimicrobial resistance

BackgroundThe Lebanese Society of Infectious Diseases and Clinical Microbiology (LSIDCM) is involved in antimicrobial stewardship. In an attempt at guiding clinicians across Lebanon in regards to the proper use of antimicrobial agents, members of this society are in the process of preparing national guidelines for common infectious diseases, among which are the guidelines for empiric and targeted antimicrobial therapy of complicated intra-abdominal infections (cIAI). The aims of these guidelines are optimizing patient care based on evidence-based literature and local antimicrobial susceptibility data, together with limiting the inappropriate use of antimicrobials thus decreasing the emergence of antimicrobial resistance (AMR) and curtailing on other adverse outcomes.MethodsRecommendations in these guidelines are adapted from other international guidelines but modeled based on locally derived susceptibility data and on the availability of pharmaceutical and other resources.ResultsThese guidelines propose antimicrobial therapy of cIAI in adults based on risk factors, site of acquisition of infection, and clinical severity of illness. We recommend using antibiotic therapy targeting third-generation cephalosporin (3GC)-resistant gram negative organisms, with carbapenem sparing as much as possible, for community-acquired infections when the following risk factors exist: prior (within 90 days) exposure to antibiotics, immunocompromised state, recent history of hospitalization or of surgery and invasive procedure all within the preceding 90 days. We also recommend antimicrobial de-escalation strategy after culture results. Prompt and adequate antimicrobial therapy for cIAI reduces morbidity and mortality; however, the duration of therapy should be limited to no more than 4 days when adequate source control is achieved and the patient is clinically stable. The management of acute pancreatitis is conservative, with a role for antibiotic therapy only in specific situations and after microbiological diagnosis. The use of broad-spectrum antimicrobial agents including systemic antifungals and newly approved antibiotics is preferably restricted to infectious diseases specialists.ConclusionThese guidelines represent a major step towards initiating a Lebanese national antimicrobial stewardship program. The LSIDCM emphasizes on development of a national AMR surveillance network, in addition to a national antibiogram for cIAI stratified based on the setting (community, hospital, unit-based) that should be frequently updated.

Dose Selection and Validation for Ceftazidime-Avibactam in Adults with Complicated Intra-abdominal Infections, Complicated Urinary Tract Infections, and Nosocomial Pneumonia.

Avibactam is a non-β-lactam β-lactamase inhibitor that has been approved in combination with ceftazidime for the treatment of complicated intra-abdominal infections, complicated urinary tract infections, and nosocomial pneumonia, including ventilator-associated pneumonia. In Europe, ceftazidime-avibactam is also approved for the treatment of Gram-negative infections with limited treatment options. Selection and validation of the ceftazidime-avibactam dosage regimen was guided by an iterative process of population pharmacokinetic (PK) modelling, whereby population PK models for ceftazidime and avibactam were developed using PK data from clinical trials and updated periodically. These models were used in probability of target attainment (PTA) simulations using joint pharmacodynamic (PD) targets for ceftazidime and avibactam derived from preclinical data. Joint PTA was calculated based on the simultaneous achievement of the individual PK/PD targets (50% free time above the ceftazidime-avibactam MIC for ceftazidime and free time above a critical avibactam threshold concentration of 1 mg/liter for avibactam). The joint PTA analyses supported a ceftazidime-avibactam dosage regimen of 2,000 + 500 mg every 8 h by 2-h intravenous infusion for patients with creatinine clearance (CLCR) >50 ml/min across all approved indications and modified dosage regimens for patients with CLCR ≤50 ml/min. Subgroup simulations for individual phase 3 patients showed that the dosage regimen was robust, with high target attainment (>95%) against MICs ≤8 mg/liter achieved regardless of older age, obesity, augmented renal clearance, or severity of infection. This review summarizes how the approved ceftazidime-avibactam dosage regimens were developed and validated using PK/PD targets, population PK modeling, and PTA analyses.

New antimicrobial options for the management of complicated intra-abdominal infections.

Complicated intra-abdominal infections (cIAIs) are a common cause of morbidity and mortality in surgical patients. Optimal management of cIAI requires early source control in combination with adequate antimicrobial treatment and aggressive fluid resuscitation. cIAIs are mainly caused by Gram-negative bacilli and anaerobes. Broad-spectrum single-agent or combination drug regimens against these microorganisms are the mainstay of therapy. However, development of antimicrobial resistance has become an increasingly large concern: multidrug-resistant organisms are associated with a higher rate of inadequate antimicrobial therapy, which in turn is associated with higher mortality rate, longer hospital stay, and increased cost compared to adequate antimicrobial therapy. In this mini-review, we discuss the effectiveness of several new antimicrobial agents, recently approved or in advanced phases of clinical development, for the treatment of cIAIs, including the new beta-lactam and beta-lactamase inhibitor combinations (ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, imipenem/cilastatin/relebactam, aztreonam/avibactam), siderophore cephalosporins (cefiderocol), aminoglycosides (plazomicin), and tetracyclines (eravacycline).

Nationwide observational study of mortality from complicated intra-abdominal infections and the role of bacterial cultures.

The benefit of taking intra-abdominal cultures during source control procedures in patients with complicated intra-abdominal infection (CIAI) is unknown. The aim of this study was to evaluate whether intra-abdominal cultures reduce the mortality rate of CIAI. The Japanese Diagnosis Procedure Combination database was used to identify adult patients with CIAI who had undergone source control procedures on the first day of admission to hospital between April 2014 and March 2016. In-hospital mortality was compared between patients who did and those who did not have intra-abdominal cultures taken. A generalized linear mixed-effect logistic regression model and a random intercept per hospital were used to adjust for baseline confounders and institutional differences. Subgroup analyses were also performed according to disease cause, site of onset and severity of CIAI. Intra-abdominal cultures were taken from 16 303 of 41 495 included patients. Multivariable logistic regression analysis showed that patients with intra-abdominal cultures had a significantly lower mortality than those without (odds ratio 0·85, 95 per cent c.i. 0·77 to 0·95). Subgroup analyses revealed statistically significant differences in mortality between patients with and without cultures among those with lower intestinal perforation, biliary tract infection/perforation, healthcare-associated CIAI and high-risk community-acquired CIAI. Intra-abdominal cultures obtained during source control procedures may reduce in-hospital mortality, especially in patients with lower intestinal perforation, biliary tract infection/perforation, or healthcare-associated or high-risk community-acquired CIAI.

Mass Balance and Drug Interaction Potential of Intravenous Eravacycline Administered to Healthy Subjects.

Eravacycline is a novel, fully synthetic fluorocycline that is approved for the treatment of complicated intra-abdominal infections (cIAI) in adult patients. We report results from three studies in healthy subjects that investigated the distribution, metabolism, and excretion of intravenous (i.v.) eravacycline and the effect of a CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on the pharmacokinetics (PK) of i.v. eravacycline. In the mass balance study, the majority of total radioactivity from [14C]eravacycline was recovered in the feces, suggesting biliary/fecal elimination is the major route of excretion for eravacycline and its metabolites after IV administration. The volume of distribution (217 liters) was greater than that of extracellular fluid, which suggests distribution beyond the central compartment. In the drug-drug interaction studies, mean area under the concentration-time curve from 0 h to the last time point (AUC0-t ) and half-life were increased approximately 30% to 40% after a concomitant dose of i.v. eravacycline and itraconazole and clearance (CL) was decreased. A reduction in total eravacycline exposure (AUC) of approximately 25% to 35% and an increase in CL of approximately 50% occurred with concomitant eravacycline and rifampin treatment. The dose of eravacycline should be increased to 1.5 mg/kg of body weight every 12 h when coadministered with a strong CYP3A inducer.