Cefepime-Taniborbactam in Complicated Urinary Tract Infection.

BACKGROUND: Carbapenem-resistant Enterobacterales species and multidrug-resistant Pseudomonas aeruginosa are global health threats. Cefepime-taniborbactam is an investigational ß-lactam and ß-lactamase inhibitor combination with activity against Enterobacterales species and P. aeruginosa expressing serine and metallo-ß-lactamases. METHODS: In this phase 3, double-blind, randomized trial, we assigned hospitalized adults with complicated urinary tract infection (UTI), including acute pyelonephritis, in a 2:1 ratio to receive intravenous cefepime-taniborbactam (2.5 g) or meropenem (1 g) every 8 hours for 7 days; this duration could be extended up to 14 days in case of bacteremia. The primary outcome was both microbiologic and clinical success (composite success) on trial days 19 to 23 in the microbiologic intention-to-treat (microITT) population (patients who had a qualifying gram-negative pathogen against which both study drugs were active). A prespecified superiority analysis of the primary outcome was performed after confirmation of noninferiority. RESULTS: Of the 661 patients who underwent randomization, 436 (66.0%) were included in the microITT population. The mean age of the patients was 56.2 years, and 38.1% were 65 years of age or older. In the microITT population, 57.8% of the patients had complicated UTI, 42.2% had acute pyelonephritis, and 13.1% had bacteremia. Composite success occurred in 207 of 293 patients (70.6%) in the cefepime-taniborbactam group and in 83 of 143 patients (58.0%) in the meropenem group. Cefepime-taniborbactam was superior to meropenem regarding the primary outcome (treatment difference, 12.6 percentage points; 95% confidence interval, 3.1 to 22.2; P = 0.009). Differences in treatment response were sustained at late follow-up (trial days 28 to 35), when cefepime-taniborbactam had higher composite success and clinical success. Adverse events occurred in 35.5% and 29.0% of patients in the cefepime-taniborbactam group and the meropenem group, respectively, with headache, diarrhea, constipation, hypertension, and nausea the most frequently reported; the frequency of serious adverse events was similar in the two groups. CONCLUSIONS: Cefepime-taniborbactam was superior to meropenem for the treatment of complicated UTI that included acute pyelonephritis, with a safety profile similar to that of meropenem. (Funded by Venatorx Pharmaceuticals and others; CERTAIN-1 ClinicalTrials.gov number, NCT03840148.).

Prophylaxis and Treatment against Klebsiella pneumoniae: Current Insights on This Emerging Anti-Microbial Resistant Global Threat.

Klebsiella pneumoniae (Kp) is an opportunistic pathogen and the leading cause of healthcare-associated infections, mostly affecting subjects with compromised immune systems or suffering from concurrent bacterial infections. However, the dramatic increase in hypervirulent strains and the emergence of new multidrug-resistant clones resulted in Kp occurrence among previously healthy people and in increased morbidity and mortality, including neonatal sepsis and death across low- and middle-income countries. As a consequence, carbapenem-resistant and extended spectrum ß-lactamase-producing Kp have been prioritized as a critical anti-microbial resistance threat by the World Health Organization and this has renewed the interest of the scientific community in developing a vaccine as well as treatments alternative to the now ineffective antibiotics. Capsule polysaccharide is the most important virulence factor of Kp and plays major roles in the pathogenesis but its high variability (more than 100 different types have been reported) makes the identification of a universal treatment or prevention strategy very challenging. However, less variable virulence factors such as the O-Antigen, outer membrane proteins as fimbriae and siderophores might also be key players in the fight against Kp infections. Here, we review elements of the current status of the epidemiology and the molecular pathogenesis of Kp and explore specific bacterial antigens as potential targets for both prophylactic and therapeutic solutions.

Antibiotic allergy.

Antibiotics are the commonest cause of life-threatening immune-mediated drug reactions that are considered off-target, including anaphylaxis, and organ-specific and severe cutaneous adverse reactions. However, many antibiotic reactions documented as allergies were unknown or not remembered by the patient, cutaneous reactions unrelated to drug hypersensitivity, drug-infection interactions, or drug intolerances. Although such reactions pose negligible risk to patients, they currently represent a global threat to public health. Antibiotic allergy labels result in displacement of first-line therapies for antibiotic prophylaxis and treatment. A penicillin allergy label, in particular, is associated with increased use of broad-spectrum and non-ß-lactam antibiotics, which results in increased adverse events and antibiotic resistance. Most patients labelled as allergic to penicillins are not allergic when appropriately stratified for risk, tested, and re-challenged. Given the public health importance of penicillin allergy, this Review provides a global update on antibiotic allergy epidemiology, classification, mechanisms, and management.

Time to appropriate antibiotic therapy is a predictor of outcome in patients with bloodstream infection caused by KPC-producing Klebsiella pneumoniae.

BACKGROUND: Bloodstream infections (BSIs) by Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (Kp) are associated with high mortality. The aim of this study is to assess the relationship between time to administration of appropriate antibiotic therapy and the outcome of patients with BSI due to KPC-Kp hospitalized in intensive care unit (ICU). METHODS: An observational study was conducted in the ICUs of two academic centers in Italy. Patients with KPC-Kp bacteremia hospitalized between January 2015 to December 2018 were included. The primary outcome was the relationship between time from blood cultures (BC) collection to appropriate antibiotic therapy and 30-day mortality. The secondary outcome was to evaluate the association of different treatment regimens with 30-day mortality and a composite endpoint (30-day mortality or nephrotoxicity). A Cox regression analysis to identify factors independently associated with 30-day mortality was performed. Hazard ratio (HR) and 95% confidence interval (CI) were calculated. RESULTS: A total of 102 patients with KPC-Kp BSI were included. The most common sources of infection were intra-abdominal (23.5%), urinary tract (20.6%), and skin and skin structure (17.6%). The 30-day mortality was 45%. Median time to appropriate antibiotic therapy was shorter in patients who survived (8.5 h [IQR 1-36]) versus those who died (48 h [IQR 5-108], p = 0.014). A propensity score matching showed that receipt of an in vitro active therapy within 24 h from BC collection was associated with lower 30-day mortality (HR = 0.36, 95% CI: 0.188-0.690, p = 0.0021). At Cox regression analysis, factors associated with 30-day mortality were primary bacteremia (HR 2.662 [95% CI 1.118-6.336], p = 0.027), cardiovascular disease (HR 2.196 [95% CI 1.082-4.457], p = 0.029), time (24-h increments) from BC collection to appropriate therapy (HR 1.382 [95% CI 1.132-1.687], p = 0.001), SOFA score (HR 1.122 [95% CI 1.036-1.216], p = 0.005), and age (HR 1.030 [95% CI 1.006-1.054], p = 0.012). Ceftazidime-avibactam-containing regimens were associated with reduced risk of composite endpoint (30-day mortality OR nephrotoxicity) (HR 0.231 [95% CI 0.071-0.745], p = 0.014) compared to colistin-containing regimens. CONCLUSIONS: Time to appropriate antibiotic therapy is an independent predictor of 30-day mortality in patients with KPC-Kp BSI. Appropriate antibiotic therapy should begin within 24 h from the collection of BC.

Is systematic fecal carriage screening of extended-spectrum beta-lactamase-producing Enterobacteriaceae still useful in intensive care unit: a systematic review.

BACKGROUND: Extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) are disseminating worldwide leading to increased hospital length of stay and mortality in intensive care units (ICU). ESBL-E dissemination was first due to outbreaks in hospital settings which led to the implementation of systematic fecal carriage screening to improve hygiene procedures by contact precautions. ESBLs have since spread in the community, and the relevance of contact precautions is questioned. ESBL-E dissemination led to an overuse of carbapenems triggering the emergence of carbapenem-resistant Enterobacteriaceae. Empirical antimicrobial therapy based on ESBL-E fecal carriage has been proposed but is debated as it could increase the consumption of carbapenems among ESBL-E carriers without any clinical benefit. Finally, selective decontamination among ESBL-E fecal carriers is evoked to decrease the risk for subsequent ESBL-E infection, but its efficacy remains debated. We propose to systematically review the evidence to recommend or not such systematic ESBL-E fecal carriage screening in adult ICU. METHODS: Every article focusing on ESBL-E and ICU available on the MEDLINE database was assessed. Articles were included if focusing on cross-transmission, efficacy of hygiene procedures, link between ESBL-E colonization and infection or guidance of empirical therapy or selective decontamination efficacy. RESULTS: Among 330 articles referenced on PubMed, 39 abstracts were selected for full-text assessment and 25 studies were included. Systematic screening of ESBL-E fecal carriage to guide contact precautions do not seem to decrease the rate of ESBL-E cross-transmission. It has a very good negative predictive value for subsequent ESBL-E infections but a positive predictive value between 40 and 50% and so does not help to spare carbapenems. Cessation of ESBL-E carriage systematic screening could decrease the use of carbapenems in ICU without any clinical harm. Nevertheless, further studies are needed to validate these results from monocentric before-after study. Selective decontamination strategy applied to ESBL-E fecal carriers could be helpful, but available data are conflicting. CONCLUSION: Current knowledge lacks of high-quality evidence to strongly recommend in favor of or against a systematic ESBL-E fecal carriage screening policy for ICU patients in a non-outbreak situation. Further evaluation of selective decontamination or fecal microbiota transplantation among ESBL-E fecal carriers is needed.

Carbapenemase-producing organisms in solid organ transplantation.

PURPOSE OF REVIEW: Carbapenem-resistant enterobacteriaceae (CRE) are a critical healthcare threat. Infections caused by CRE disproportionately affect transplant patients. Retrospective case studies suggest that up to 10% of transplant recipients develop a CRE infection. The current literature is reviewed with a particular focus on transplant-specific implications. RECENT FINDINGS: There are specific risks inherent to transplant recipients that result in an elevated risk for CRE carriage and subsequent infection. Additionally, the manifestations of these infections are dependent on the specific transplant type. The optimal treatment of CRE infections in transplant recipients has not been defined. SUMMARY: A reduction in the regional community CRE burden can lead to a secondary reduction in their occurrence within vulnerable transplant populations. Therefore, core principles of antibiotic stewardship and infection control within all levels of the healthcare system remains the most effective strategy for addressing the current health crisis. Simultaneously, an integrated approach to risk stratification and an approach to treatment is postulated for management of CRE infection within the solid-organ transplant population.

Infection related to Klebsiella pneumoniae producing carbapenemase in renal transplant patients.

OBJECTIVE: To evaluate the risk factors related to Klebsiella pneumoniae carbapenemase infection after renal transplantation. METHODS: This was a retrospective epidemiological (case-control) study, conducted from October 2011 to march 2016. Transplanted patients with infection by this bacteria during hospitalization were selected as cases. The controls were paired by age, sex, type of donor and transplant time. The proportion of cases and controls was 1:2. RESULTS: Thirty hundred and five patients were included in the study (45 cases and 90 controls). The risk factors found for infection by KPC were: time of hospitalization after the transplant (OR: 4.82; CI95% 2.46-9.44), delayed kidney function (OR: 5.60; CI95% 1.91-11.01) and previous infectious for another microorganism ( OR: 34.13 CI95% 3.52-132.00). CONCLUSION: The risk of acquisition of this bacterium was directly related to invasive procedures and exposure to the hospital environment. The findings reinforce the importance of prevention measures and control of infection by this microorganism.

Successful treatment and digestive decolonisation of a patient with osteitis caused by a carbapenemase-producing Klebsiella pneumoniae isolate harbouring both NDM-1 and OXA-48 enzymes.

OBJECTIVES: Carbapenem resistance in Klebsiella pneumoniae is an increasing problem worldwide and infections caused by this bacterium can be difficult to treat. This study reported the case of a patient from Romania, who was hospitalised in Bulgaria after an accident trauma. He then came to France for treatment of an osteitis caused by a Klebsiella pneumoniae carrying both blaNDM-1 and blaOXA-48. METHOD: The resistome of this extremely drug-resistant bacterium was analysed both with phenotypic (large antibiotic susceptibility testing) and genomic methods (genome sequencing). The genetic environment of the two carbapenemases was studied. RESULTS: Klebsiella pneumoniae ST307 carrying both a blaNDM-1 and blaOXA-48 gene was located on two different plasmids: Inc L/M and IncFII. The patient was successfully treated by a combination of intravenous colistin (9 MUI, then 4.5 MUI bd), intravenous fosfomycin (4g tds) and oral doxycycline (100mg bd) for 3 months. Faecal microbiota transplantation was successfully conducted for stool carriage. CONCLUSION: The ST307 type is becoming endemic in hospital environments and is frequently associated with carbapenem resistance. Treatment of infection caused by multidrug-resistant bacteria is a clinical challenge, and the use of old antibiotics associated with screening and decolonisation of the reservoirs can be an efficient therapeutic alternative.

Infection-related ventilator-associated complications in ICU patients colonised with extended-spectrum ß-lactamase-producing Enterobacteriaceae.

PURPOSE: To investigate the clinical significance of infection-related ventilator-associated complications (IVAC) and their impact on carbapenem consumption in mechanically ventilated (MV) patients colonised with extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBLE). METHODS: Inception cohort study from the French prospective multicenter OUTCOMEREA database (17 ICUs, 1997-2015) including all ESBLE carriers (systematic rectal swabbing at admission then weekly and/or urinary or superficial surgical site colonisation) with MV duration > 48 h and ≥ 1 episode of IVAC after carriage documentation. All ICU-acquired infections were microbiologically documented. RESULTS: The 318 enrolled ESBLE carriers (median age 68 years; males 67%; medical admission 68%; imported carriage 53%) experienced a total of 576 IVAC comprising 361 episodes (63%) without documented infection, 124 (21%) related to infections other than ventilator-associated pneumonia (VAP), 73 (13%) related to non-ESBLE VAP and 18 (3%) related to ESBLE VAP. Overall, ESBLE infections accounted for only 43 episodes (7%). Carbapenem exposure within the preceding 3 days was the sole independent predictor of ESBLE infection as the causative event of IVAC, with a protective effect (adjusted odds ratio 0.2, 95% confidence interval 0.05-0.6; P < 0.01). Carbapenems were initiated in 9% of IVAC without infection, 15% of IVAC related to non-VAP infections, 42% of IVAC related to non-ESBLE VAP, and 56% of IVAC related to ESBLE VAP (ESBLE VAP versus non-ESBLE VAP: P = 0.43). CONCLUSIONS: IVAC in ESBLE carriers mostly reflect noninfectious events but act as a strong driver of empirical carbapenem consumption. ESBLE infections are scarce yet hard to predict, strengthening the need for novel diagnostic approaches and carbapenem-sparing alternatives.

Impact and cost of infection control measures to reduce nosocomial transmission of extended-spectrum beta-lactamase-producing organisms in a non-outbreak setting.

We evaluated the impact of infection control interventions to reduce nosocomial extended-spectrum beta-lactamase (ESBL) transmission in a non-outbreak setting. This study was conducted at a tertiary 1200-bed hospital in Canada. The incidence of ESBLs was based on recovery of clinical isolates and assessed prospectively from 1999 to 2005. The incidence increased significantly from 0.28 to 0.67 per 1000 admissions during this period (P<0.001), reflecting an increase in the regional ESBL incidence from 1.32 to 9.28 per 100 000 population (P<0.001). Despite this increase, nosocomial ESBL rates increased only marginally, suggesting that infection control measures had an impact on nosocomial transmission. Infection control measures consisted of isolating all ESBL patients, as well as implementing the use of contact precautions for those with a high risk for transmission. The cost of these measures was CN$138 046.00 per year and CN$3191.83 per case admitted. A combination of control measures including active surveillance cultures, contact precautions for all colonized or infected patients and antimicrobial stewardship is required to significantly reduce the incidence of ESBLs.

Colonisation with extended-spectrum beta-lactamase (ESBL) not detected in a prevalence study.

BACKGROUND: The Mid-West of Ireland has higher than average national rates of invasive extended-spectrum beta-lactamase (ESBL) bloodstream infections and carbapenemase-producing Enterobacteriaceae (CPE), with increasing numbers of ESBL isolates detected in community-dwelling patients. AIMS: To conduct a point prevalence study in a convenience sample of the Mid-West population with the aim of determining the extent of ESBL colonisation. METHODS: Utilising anonymised community stool samples that had completed routine analysis, we conducted a point prevalence study over a 4-week period on all samples that met defined inclusion and exclusion criteria. Limited epidemiological data was recorded: (1) age of patient, (2) gender, and (3) sender location. From these stool specimens, rectal swabs were inoculated (eSwab™ 480CE, Copan, Italy), which were subsequently cultured on selective chromogenic agar (Colorex™ ESBL). Culture plates were incubated aerobically at 37 °C for 24 h. RESULTS: Of 195 samples processed, 58 % (n = 112) were from females. The median patient age was 62.4 years (range 20-94 years). 186 samples (95 %) originated from general practitioner clinics. During the study period, only nine eligible stool samples were received from LTCF (6 public). From 195 Colorex™ ESBL chromogenic agar plates cultured, no ESBL-producing organisms were detected. CONCLUSIONS: This community point prevalence study did not identify ESBL colonisation despite high numbers of patients with invasive ESBL bloodstream infections presenting for admission in our institution. We believe this may be because of our small sample size. Data regarding antimicrobial exposure and other risk factors for ESBL colonisation were also not available. We remain vigilant for ESBL-producing organisms.

The clear and present danger of carbapenemase-producing Enterobacteriaceae (CPE) in New Zealand: time for a national response plan.

Antimicrobial resistance (AMR) in general poses a threat to the sustainability of modern healthcare, but a particularly urgent and serious threat is posed by a specific group of antibiotic-resistant bacteria known as carbapenemase-producing Enterobacteriaceae (CPE). CPE are resistant to nearly all antibiotics and include common pathogens such as Escherichia coli and Klebsiella pneumoniae. In New Zealand, the incidence of CPE has increased from three isolates in 2012 to 45 in 2016. The current epidemiology of CPE in New Zealand has similarities with the extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-PE) epidemic in the early 2000s (just before ESBL-PE underwent a non-linear increase in incidence). Although to date in New Zealand, nearly all CPE have been imported from overseas, this situation appears to be changing, with evidence of secondary spread in both households and healthcare facilities over the last year. In this article, we argue that CPE should be regarded as the foremost AMR threat currently facing New Zealand, and highlight the need for a comprehensive national response plan, analogous to plans for other emerging transmissible infections, such as pandemic influenza and Ebola. We also make recommendations about the components of such a plan and advocate that CPE should be recognised as a key priority in New Zealand's national AMR strategy, due to be published in May 2017.

Formulation development of SYN-004 (ribaxamase) oral solid dosage form, a ß-lactamase to prevent intravenous antibiotic-associated dysbiosis of the colon.

SYN-004 (ribaxamase) delayed release drug product is a multi-particulate, hard capsule for oral delivery of a recombinant ß-lactamase enzyme designed to degrade ß-lactam antibiotics administered intravenously, and thus prevent colon dysbiosis. Here we describe the development of the SYN-004 enteric coated pellet formulation, which has been tested in multiple clinical trials. Since the SYN-004 drug substance is a buffered liquid, several binder excipients in different ratios were tested to facilitate binding of SYN-004 to sugar spheres. The binding systems were evaluated by droplet pre-evaluation and film casting tests. The most promising formulations were produced in small scale fluidized bed application runs and analyzed by dissolution tests and complementary analytical assays. Hydroxypropyl cellulose was selected as the preferred SYN-004 binding excipient. The formulation included a second, outer coat containing the enteric EUDRAGIT® L 30 D-55 polymer-based formulation to achieve gastric protection, and rapid SYN-004 release in the intestinal tract, when the pH rises above 5.5. Additional formulation improvements resulted in an increase in the SYN-004 load compared to a predecessor oral enzyme formulation (Ipsat P1A). Thus, a novel formulation and process for an orally administered enzyme was developed and used to manufacture drug product for clinical trials.

Tolerability and Pharmacokinetics of SYN-004, an Orally Administered ß-Lactamase for the Prevention of Clostridium difficile-Associated Disease and Antibiotic-Associated Diarrhea, in Two Phase 1 Studies.

BACKGROUND: SYN-004 is an orally administered ß-lactamase enzyme, designed to be given concurrently with certain intravenous ß-lactam antibiotics like cephalosporins. SYN-004 is intended to degrade residual antibiotics excreted into the intestine as a result of hepatobiliary excretion and to prevent the disruption of the gut microbiome by these excess antibiotics. Preserving the gut microbiome is expected to prevent secondary infections by pathogens like Clostridium difficile and protect against other antibiotic-associated diarrheas. METHODS: Two, randomized, double blind, placebo-controlled Phase 1 clinical studies were conducted in normal healthy adult volunteers to assess the tolerability and systemic absorption of single and multiple doses of SYN-004. A single-ascending dose study investigated single oral doses of 75-750 mg SYN-004 and was conducted in 40 subjects (five cohorts of six active and two placebo subjects). A multiple-ascending dose study investigated doses of 75-300 mg SYN-004, administered every 6 h for 7 days and was conducted in 24 subjects (three cohorts of six active and two placebo subjects). The safety and tolerability of SYN-004 was assessed and serial plasma and serum samples were collected to assess the pharmacokinetics and potential immunogenicity of SYN-004. RESULTS: Minimal and mild adverse events were reported in ~30 % of the subjects who received active drug and placebo and no antidrug antibodies were detected in any subject. Analysis of serial plasma samples demonstrated negligible systemic bioavailability of SYN-004 with most plasma concentrations being below the lower limit of quantitation (0.8 ng/mL) for the assay. SYN-004 was well tolerated in the 48 subjects who received active drug, and adverse events in those subjects were comparable to the 16 subjects who received placebo, up to the maximum doses administered in each study. CONCLUSION: SYN-004 was well tolerated up to a single oral dose of 750 mg and multiple doses of 300 mg every 6 h for 7 days. The pharmacokinetic results support that SYN-004 remained localized in the intestine.

Continuous versus intermittent intravenous administration of antibiotics: a meta-analysis of randomised controlled trials.

Intermittent intravenous administration of antibiotics is the first-line approach in the management of severe infections worldwide. However, the potential benefits of alternate modes of administration of antibiotics, including continuous intravenous infusion, deserve further evaluation. We did a meta-analysis of randomised controlled trials comparing continuous intravenous infusion with intermittent intravenous administration of the same antibiotic regimen. Nine randomised controlled trials studying beta-lactams, aminoglycosides, and vancomycin were included. Clinical failure was lower, although without statistical significance, in patients receiving continuous infusion of antibiotics (pooled OR 0.73, 95% CI 0.53-1.01); the difference was statistically significant in a subset of randomised controlled trials that used the same total daily antibiotic dose for both intervention arms (0.70, 0.50-0.98, fixed and random effects models). Regarding mortality and nephrotoxicity, no differences were found (mortality 0.89, 0.48-1.64; nephrotoxicity 0.91, 0.56-1.47). In conclusion, the data suggest that the administration of the same total antibiotic dose by continuous intravenous infusion may be more efficient, with regard to clinical effectiveness, compared with the intermittent mode. In an era of gradually increasing resistance among most pathogens, the potential advantages of continuous intravenous administration of antibiotics on several clinical outcomes should be further investigated.

Multidrug-resistant Escherichia coli in Asia: epidemiology and management.

Escherichia coli has become multiresistant by way of production of a variety of ß-lactamases. The prevalence of CTX-M-producing E. coli has reached 60-79% in certain parts of Asia. The acquisition of CTX-M plasmids by E. coli sequence type 131, a successful clone of E. coli, has caused further dissemination of CTX-M-producing E. coli. The prevalence of carbapenemase-producing E. coli, especially Klebsiella pneumoniae carbapenemase, and New Delhi metallo-ß-lactamase (NDM)-producing E. coli has been increasing in Asia. K. pneumoniae carbapenemase and NDM have now been found in E. coli sequence type 131. The occurrence of NDM-producing E. coli is a major concern particularly in the Indian subcontinent, but now elsewhere in Asia as well. There are multiple reasons why antibiotic resistance in E. coli in Asia has reached such extreme levels. Approaches beyond antibiotic therapy, such as prevention of antibiotic resistance by antibiotic stewardship and protecting natural microbiome, are strategies to avoid further spread of antibiotic resistance.

Implementation of sequential therapy programs--a microbiologist's view.

Sequential antimicrobial therapy is not new, but confusion about the timing and nature of the switch often negates perceived advantages. A common problem is the choice of oral antibiotic to follow empirical administration of an intravenous second or third generation cephalosporin. Where guidelines do not exist, particularly when data are lacking as the the best option, the Delphi technique of obtaining a consensus agreement by review of a series of case histories is recommended. Majority verdicts are used to determine what is acceptable practice, and as such the approach is also suitable for audit. Savings through reduced drug acquisition costs and shorter lengths of stay have been highlighted. However, other less obvious potential benefits of sequential antimicrobial therapy include reduced incidence of intravascular catheter infection because of shorter line dwell times and less endoluminal contamination. Sequential antimicrobial therapy may also be used as part of a policy to reduce the selective pressure, particularly due to cephalosporin use, for endemic hospital pathogens such as Clostridium difficile and extended spectrum producing gram-negative baccilli.