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The ability of influenza A virus to evolve, coupled with increasing antimicrobial resistance, could trigger an influenza pandemic with great morbidity and mortality. Much of the 1918 influenza pandemic mortality was likely due to bacterial coinfection, including Staphylococcus aureus pneumonia. S. aureus resists many antibiotics. The lack of new antibiotics suggests alternative antimicrobials, such as bacteriophages, are needed. Potential delivery routes for bacteriophage therapy (BT) include inhalation and intravenous injection. BT has recently been used successfully in compassionate access pulmonary infection cases. Phage lysins, enzymes that hydrolyze bacterial cell walls and which are bactericidal, are efficacious in animal pneumonia models. Clinical trials will be needed to determine whether BT can ameliorate disease in influenza and S. aureus coinfection.

Microsporum canis is a dermatophyte known to cause superficial skin infections. In immunocompromised patients, it can lead to invasive dermatophytosis. We present a case of biopsy-proven left knee mycetoma caused by M canis in a renal transplant patient. Identification of M canis was achieved via sequencing of the internal transcribed spacer regions. Treatment involved surgical debridement, oral posaconazole, and reduction in immunosuppression. In addition, we provide a review of current literature on invasive M canis infections.

Importance Methicillin-resistantStaphylococcus aureus(MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a β-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted. Objective To determine whether combining an antistaphylococcal β-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia. Design, Setting, and Participants Open-label, randomized clinical trial conducted at 27 hospital sites in 4 countries from August 2015 to July 2018 among 352 hospitalized adults with MRSA bacteremia. Follow-up was complete on October 23, 2018. Interventions Participants were randomized to standard therapy (intravenous vancomycin or daptomycin) plus an antistaphylococcal β-lactam (intravenous flucloxacillin, cloxacillin, or cefazolin) (n = 174) or standard therapy alone (n = 178). Total duration of therapy was determined by treating clinicians and the β-lactam was administered for 7 days. Main Outcomes and Measures The primary end point was a 90-day composite of mortality, persistent bacteremia at day 5, microbiological relapse, and microbiological treatment failure. Secondary outcomes included mortality at days 14, 42, and 90; persistent bacteremia at days 2 and 5; acute kidney injury (AKI); microbiological relapse; microbiological treatment failure; and duration of intravenous antibiotics. Results The data and safety monitoring board recommended early termination of the study prior to enrollment of 440 patients because of safety. Among 352 patients randomized (mean age, 62.2 [SD, 17.7] years; 121 women [34.4%]), 345 (98%) completed the trial. The primary end point was met by 59 (35%) with combination therapy and 68 (39%) with standard therapy (absolute difference, −4.2%; 95% CI, −14.3% to 6.0%). Seven of 9 prespecified secondary end points showed no significant difference. For the combination therapy vs standard therapy groups, all-cause 90-day mortality occurred in 35 (21%) vs 28 (16%) (difference, 4.5%; 95% CI, −3.7% to 12.7%); persistent bacteremia at day 5 was observed in 19 of 166 (11%) vs 35 of 172 (20%) (difference, −8.9%; 95% CI, −16.6% to −1.2%); and, excluding patients receiving dialysis at baseline, AKI occurred in 34 of 145 (23%) vs 9 of 145 (6%) (difference, 17.2%; 95% CI, 9.3%-25.2%). Conclusions and Relevance Among patients with MRSA bacteremia, addition of an antistaphylococcal β-lactam to standard antibiotic therapy with vancomycin or daptomycin did not result in significant improvement in the primary composite end point of mortality, persistent bacteremia, relapse, or treatment failure. Early trial termination for safety concerns and the possibility that the study was underpowered to detect clinically important differences in favor of the intervention should be considered when interpreting the findings. Trial Registration ClinicalTrials.gov Identifier:NCT02365493

Aim The objective was to study the long-term (lifetime) cost effectiveness of four different hepatitis C virus (HCV) treatment models of care (MOC) with directly acting antiviral drugs. Methods A cohort Markov model-based probabilistic cost-effectiveness analysis (CEA) was undertaken extrapolating to up to 30 years from cost and outcome data collected from a primary study involving a real-life Australian cohort. In this study, noncirrhotic patients treated for HCV from 1 March 2016 to 28 February 2017 at four major public hospitals and liaising sites in South Australia were studied retrospectively. The MOC were classified depending on the person providing patient workup, treatment and monitoring into MOC1 (specialist), MOC2 (mixed specialist and hepatitis nurse), MOC3 (hepatitis nurse) and MOC4 (general practitioner, GP). Incremental costs were estimated from the Medicare perspective. Incremental outcomes were estimated based on the quality-adjusted life years (QALY) gained by achieving a sustained virological response. A cost-effectiveness threshold of Australian dollar 50 000 per QALY gained, the implicit criterion used for assessing the cost-effectiveness of new pharmaceuticals and medical services in Australia was assumed. Net monetary benefit (NMB) estimates based on this threshold were calculated. Results A total of 1373 patients, 64% males, mean age 50 (SD ±11) years, were studied. In the CEA, MOC4 and MOC2 clearly dominated MOC1 over 30 years with lower costs and higher QALYs. Similarly, NMB was the highest in MOC4, followed by MOC2. Conclusion Decentralized care using GP and mixed consultant nurse models were cost-effective ways of promoting HCV treatment uptake in the setting of unrestricted access to new antivirals.

In March 2016, the Australian government offered unrestricted access to direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) to the entire population. This included prescription by any medical practitioner in consultation with specialists until sufficient experience was attained. We sought to determine the outcomes and experience over the first twelve months for the entire state of South Australia. We performed a prospective, observational study following outcomes of all treatments associated with the state's four main tertiary centres. A total of 1909 subjects initiating DAA therapy were included, representing an estimated 90% of all treatments in the state. Overall, SVR12 was 80.4% in all subjects intended for treatment and 95.7% in those completing treatment and follow-up. 14.2% were lost to follow-up (LTFU) and did not complete SVR12 testing. LTFU was independently associated with community treatment via remote consultation (OR 1.50, 95% CI 1.04-2.18, P = .03), prison-based treatment (OR 2.02, 95% CI 1.08-3.79, P = .03) and younger age (OR 0.98, 95% CI 0.97-0.99, P = .05). Of the 1534 subjects completing treatment and follow-up, decreased likelihood of SVR12 was associated with genotype 2 (OR 0.23, 95% CI 0.07-0.74, P = .01) and genotype 3 (OR 0.23, 95% CI 0.12-0.43, P ≤ .01). A significant decrease in treatment initiation was observed over the twelve-month period in conjunction with a shift from hospital to community-based treatment. Our findings support the high responses observed in clinical trials; however, a significant gap exists in SVR12 in our real-world cohort due to LTFU. A declining treatment initiation rate and shift to community-based treatment highlight the need to explore additional strategies to identify, treat and follow-up remaining patients in order to achieve elimination targets.

Background At a urology center in Australia, patients undergoing elective nonurgent urological surgery routinely receive empirical antibiotic treatment based on urinalysis (UA) prior to intervention to treat presumptive bacteriuria. Sterilization of urine with empirical antibiotics in procedures involving stone manipulation and mucosal disruption in the genitourinary system has been shown to reduce infection risks but whether this translates to low-risk urological interventions is not clear. Methods Patients undergoing outpatient elective urological procedures during a 3-month period between September and November 2017 were retrospectively reviewed. Patient demographics, results of urinalyses, empirical antibiotic use, and data surrounding post-intervention complications were collected and reviewed. Results were analyzed using SPSS v 25. Results Of 119 patients, 111 underwent a pre-procedure urinalysis. Fifty-eight percent (n = 64) of patients were treated with empiric antibiotics pre-operatively based on a positive UA (defined as the presence of urinary leukocytes or nitrites). Fifty-five percent (n = 41) of patients who received empirical antibiotics returned a positive urine culture, and only 49 percent (n = 20) of those receiving antibiotics cultured organisms susceptible to initial antibiotics prescribed. 1 Death, 3 incidences of bacteremia, and 10 incidences of bacteriuria up to 2 weeks occurred post-intervention in this cohort. There was no discernible risk of adverse events based on a composite of post-intervention death, bacteremia and bacteriuria in patients with a positive pre-procedural UA (n = 67/111, RR0.67 CI 0.49–0.91, P = 0.10). Pre-procedural sterilized urine similarly did not demonstrated any reduced risk of post-intervention adverse outcomes (n = 77/119, RR1.02 CI 0.64–1.63, P = 0.94). Conclusion This study demonstrated no increased risk of post-operative infection in patients with a positive urinalysis or urine culture with bacteriuria prior to intervention. There was a high use of broad-spectrum antibiotic as a reflex to positive urinalyses alone highlighting an avenue for improved anti-microbial stewardship. More research is needed to guide clinicians on the role of urine cultures and antibiotics prior to non-urgent urological procedures. Disclosures All authors: No reported disclosures.

Changes in the pharmacokinetics of piperacillin in febrile neutropenic patients have been reported to result in suboptimal exposures. This study aimed to develop a population pharmacokinetic model for piperacillin and perform dosing simulation to describe optimal dosing regimens for hematological malignancy patients with febrile neutropenia. Concentration-time data were obtained from previous prospective observational pharmacokinetic and interventional therapeutic drug monitoring studies. Nonparametric population pharmacokinetic analysis and Monte Carlo dosing simulations were performed with the Pmetrics package for R. A two-compartment model, with between-subject variability for clearance (CL), adequately described the data from 37 patients (21 males, age of 59 ± 12 years [means ± standard deviations] and weight of 77 ± 16 kg). Parameter estimates were CL of 18.0 ± 4.8 liters/h, volume of distribution of the central compartment of 14.3 ± 7.3 liters, rate constant for piperacillin distribution from the central to peripheral compartment of 1.40 ± 1.35 h −1 , and rate constant for piperacillin distribution from the peripheral to central compartment of 4.99 ± 7.81 h −1 . High creatinine clearance (CL CR ) was associated with reduced probability of target attainment (PTA). Extended and continuous infusion regimens achieved a high PTA of >90% for an unbound concentration of piperacillin remaining above the MIC ( fT >MIC ) of 50%. Only continuous regimens achieved >90% PTA for 100% fT >MIC when CL CR was high. The cumulative fraction of response (FTA, for fractional target attainment) was suboptimal (fT >MIC . FTA was maximized with prolonged infusions. Overall, changes in piperacillin pharmacokinetics and the consequences on therapeutic dosing requirements appear similar to those observed in intensive care patients. Guidelines should address the altered dosing needs of febrile neutropenic patients exhibiting high CL CR or with known/presumed infections from high-MIC bacteria.

A 22-year-old woman with no significant medical history preented to an Australian hospital in 2014 with a 24-h history of acute ight upper quadrant pain, fever and rigors. The pain was acute, aking her from sleep, rated 10/10 in severity and radiated to her ight shoulder tip. There were no neurological, respiratory, genital, rinary or bowel complaints. Initial observations were normal apart from fever of 39 ◦C. xamination revealed tenderness in the right upper quadrant nd a positive Murphy’s sign but was otherwise unremarkble. Blood tests showed a normal total white cell count of .43 × 109[reference range [RR] 4.0–11.0 × 109/L] with moderate ymphopenia of 0.58 × 109[RR 1.5–3.5 × 109/L]. C-reactive protein as modestly elevated at 33 mg/L [RR < 8.0 mg/L]. She had noral electrolytes, liver transaminases and lipase. Pregnancy was xcluded. Blood cultures collected prior to antibiotics were negtive. Chest X-ray demonstrated clear lung fields and no free gas. bdominal ultrasound showed a minimally thickened but tender allbladder without calculi. A sexual history was obtained and she reported having a single egular partner with whom she used condoms. She did not comlain of localized vaginal discomfort or discharge. Her pelvic and aginal examination was normal. The patient was diagnosed with acalculous cholecystitis and as charted analgesia and antibiotics. The following day a aparoscopic cholecystectomy was performed without complicaion. Histopathology of the gallbladder showed serositis with an nflammatory infiltrate composed mainly of neutrophils within he subserosal adipose tissue. There was only scant mucosal

While guidelines recommend empirical cefepime therapy in febrile neutropenia, the mortality benefit of cefepime has been controversial. In light of this, recent reports on pharmacokinetic changes for several antibiotics in febrile neutropenia and the consequent suboptimal exposure call for a pharmacokinetic/pharmacodynamic evaluation of current dosing. This study aimed to assess pharmacokinetic/pharmacodynamic target attainment from a 2-g intravenous (i.v.) every 8 h (q8h) cefepime regimen in febrile neutropenic patients with hematological malignancies. Cefepime plasma concentrations were measured in the 3rd, 6th, and 9th dosing intervals at 60% of the interval and/or trough point. The selected pharmacokinetic/pharmacodynamic targets were the proportion of the dosing interval (60% and 100%) for which the free drug concentration remains above the MIC ( f T >MIC ). Target attainment was assessed in reference to the MIC of isolated organisms if available or empirical breakpoints if not. The percentage of f T >MIC was also estimated by log-linear regression analysis. All patients achieved >60% f T >MIC in the 3rd and 6th dosing intervals. A 100% f T >MIC was not attained in 6/12, 4/10, and 4/9 patients in the 3rd, 6th, and 9th dose intervals, respectively, or in 14/31 (45%) of the dosing intervals investigated. On the other hand, 29/31 (94%) of trough concentrations were at or above 4 mg/liter. In conclusion, for patients with normal renal function, a high-dose 2-g i.v. q8h cefepime regimen appears to provide appropriate exposure if the MIC of the organism is ≤4 mg/liter but may fail to cover less susceptible organisms.

Objectives The objectives of this study were to describe piperacillin exposure in febrile neutropenia patients and determine whether therapeutic drug monitoring (TDM) can be used to increase the achievement of pharmacokinetic (PK)/pharmacodynamic (PD) targets. Methods In a prospective randomized controlled study (Australian New Zealand Registry, ACTRN12615000086561), patients were subjected to TDM for 3 consecutive days. Dose was adjusted in the intervention group to achieve a free drug concentration above the MIC for 100% of the dose interval (100% fT>MIC), which was also the primary outcome measure. The secondary PK/PD target was 50% fT>MIC. Duration of fever and days to recovery from neutropenia were recorded. Results Thirty-two patients were enrolled. Initially, patients received 4.5 g of piperacillin/tazobactam every 8 h or every 6 h along with gentamicin co-therapy in 30/32 (94%) patients. At the first TDM, 7/32 (22%) patients achieved 100% fT>MIC and 12/32 (38%) patients achieved 50% fT>MIC. Following dose adjustment, 11/16 (69%) of intervention patients versus 3/16 (19%) of control patients (P = 0.012) attained 100% fT>MIC, and 15/16 (94%) of intervention patients versus 5/16 (31%) of control patients (P = 0.001) achieved 50% fT>MIC. After the third TDM, the proportion of patients attaining 100% fT>MIC improved from a baseline 3/16 (19%) to 11/15 (73%) in the intervention group, while it declined from 4/16 (25%) to 1/15 (7%) in the control group. No difference was noted in the duration of fever and days to recovery from neutropenia. Conclusions Conventional doses of piperacillin/tazobactam may not offer adequate piperacillin exposure in febrile neutropenic patients. TDM provides useful feedback of dosing adequacy to guide dose optimization.

This study assessed the pharmacokinetics and dosing adequacy of piperacillin in febrile neutropenic patients after the first dose. Pharmacokinetic analysis was performed using noncompartmental methods. We observed an elevated volume of distribution (29.7 ± 8.0 liters [mean ± standard deviation]) and clearance (20.2 ± 7.5 liters/h) compared to data from other patient populations. Antibiotic exposure did not consistently result in therapeutic targets. We conclude that alternative dosing strategies guided by therapeutic drug monitoring may be required to optimize exposure.

Puvesh Punj, Renjy Nelson, Sarah Gardiner, Michelle Lodge, Stephen R Graves, Morgyn S Warner

Sudden and unexpected nontraumatic death in individuals with asplenia or hyposplenia is usually due to fulminant bacterial sepsis, most often involving Streptococcus pneumoniae, Neisseria meningitidis, and Hemophilus influenzae. We report a case of a previously well 40-year-old man who died 5 hours after hospital admission. At autopsy Waterhouse-Friderichsen syndrome was identified and Capnocytophaga canimorsus was subsequently isolated on antemortem blood cultures. Infection of humans with this organism is most often due to dog bite or contact. Upon specific inquiry it was ascertained that 2 days before admission the deceased had suffered a superficial bite to his hand by his pet Staffordshire Bullterrier dog. His relevant history included a previous splenectomy following blunt abdominal trauma. Asplenia and hyposplenia at autopsy should prompt microbiological testing with consideration of unusual organisms such as C. canimorsus. Although histories of animal contact or injury are often not available at the time of autopsy, this should also be considered in cases of apparent fulminant sepsis. In individuals with asplenia or hyposplenia, dog bites do not have to involve excessive tissue trauma, vascular compromise, or blood loss to be lethal. Language: en

Lemierre syndrome refers to necrotizing infections of the head due to Fusobacterium necrophorum and has been called the ‘forgotten disease’ due to its rarity in the antibiotic era. Recently, however, more cases have been documented in the literature suggesting that there has been an increase in incidence. A 10-year-old boy is reported who had a five-day history of ear infection, with the development of fever, drowsiness and ipsilateral neck swelling. Unexpected cardiac arrest occurred soon after medical assessment. At autopsy, right otitis media was demonstrated with extension of suppurative infection into subcutaneous tissues behind the ear and also into the extradural space at the lateral end of the petrous temporal bone. There was also septic thrombophlebitis of the adjacent sigmoid sinus, but no evidence of meningitis. This case demonstrates yet another infectious condition that may be associated with rapid deterioration and unexpected death in childhood. An autopsy approach to suspected sepsis in childhood is outlined.