Antibiotics / Infection

#### ANTIBIOTICS / INFECTION

Eur J Clin Pharmacol. 2019 Apr;75(4):511-517.

# Ertapenem for osteoarticular infections in obese patients: a pharmacokinetic study of plasma and bone concentrations.

Chambers J, Page-Sharp M, Salman S, Dyer J, Davis T, Batty K, Manning L

PURPOSE: Ertapenem is used off-label to treat osteoarticular infections but there are few pharmacokinetic (PK) data to guide optimal dosing strategies in patients who may be obese with multiple co-morbidities including diabetes and peripheral vascular disease.

METHODS: Participants undergoing lower limb amputation or elective joint arthroplasty received a dose of intravenous ertapenem prior to surgery. Eight plasma samples were collected over 24 h, together with at least one bone sample per patient. Ertapenem concentrations in plasma and bone were measured using liquid-chromatography/mass-spectroscopy and analysed using non-linear mixed effects PK modelling.

RESULTS: Plasma and bone concentrations were obtained from 10 participants. The final population PK model showed that a fat free body mass was the most appropriate body size adjustment. Ertapenem diffused rapidly into bone but concentrations throughout the 24 h dosing period were on average 40-fold higher in plasma, corresponding to a bone to plasma ratio of 0.025, and highly variable between individuals. Simulations demonstrated a high probability of target attainment (PTA) for free plasma concentrations when the minimum inhibitory concentrations (MIC) were ≤ 0.25 mg/L. By contrast, at MICs of 0.5 mg/L and ≥ 1 mg/L, the fractions of patients attaining this target was ~ 80% and 40%, respectively. In bone, the PTA was ≤ 45% when the MIC was ≥ 0.25 mg/L.

CONCLUSION: Local bone and free plasma concentrations appear adequate for osteoarticular infections where Enterobacteriaceae are the main causative pathogens, but for Staphylococcus aureus and other bacteria, conventional dosing may lead to inadequate PTA.

J Res Med Sci. 2018 Nov 28;23:98. doi: 10.4103/jrms.JRMS_384_18. eCollection 2018.

# Post-traumatic endophthalmitis prophylaxis with oral ciprofloxacin in comparison to intravenous cephazolin/gentamicin.

Dehghani A, Rafiemanzelat A, Ghaderi K, Pourazizi M, Feizi A

Background: Although posttraumatic endophthalmitis is an uncommon condition, it causes severe complications, so medical and pharmacological interventions for prevention of endophthalmitis after trauma are a major concern. The aim of this study was to evaluate the efficacy and clinical outcome of oral ciprofloxacin versus intravenous cefazolin/gentamicin for the prevention of endophthalmitis after penetrating ocular trauma.

Materials and Methods: This was a retrospective, descriptive single-center study, including all cases of penetrating ocular trauma seen in the Feiz Hospital, a Tertiary Referral Eye Hospital in Isfahan, Iran, between 2011 and 2017. Data systemically recorded for each patient included clinical, ophthalmological, and demographic findings by a trained medical record abstractor or ophthalmologist reviewing patient records.

Results: Six hundred and forty-five patients in cefazolin/gentamicin and 273 patients in oral ciprofloxacin groups were included in the study. Our study showed that the incidence of endophthalmitis was not significantly different between the two groups (P = 0.463). In patients with either sharp or blunt penetrating ocular trauma.

Conclusion: Oral ciprofloxacin as a prophylactic treatment could prevent posttraumatic endophthalmitis as effective as injectable cefazolin/gentamicin. Due to easier consumption of oral ciprofloxacin and lower systemic complications, in all patients with penetrating eye trauma, oral administration of ciprofloxacin is preferable to intravenous or intramuscular types of antibiotics to reduce the risk of posttraumatic endophthalmitis.

Diagn Microbiol Infect Dis. 2018 Dec 29; Epub ahead of print

# Microbiology of combat-related extremity wounds: Trauma Infectious Disease Outcomes Study.

Mende K, Stewart L, Shaikh F, Bradley W, Lu D, Krauss M, Greenberg L, Yu Q, Blyth D, Whitman T, Petfield J, Tribble D

We present extremity wound microbiology data from 250 combat casualties (2009-2012). Confirmed extremity wound infections (EWIs) were based on clinical and laboratory findings. Suspected EWIs had isolation of organisms from wound cultures with associated signs/symptoms not meeting clinical diagnostic criteria. Colonized wounds had organisms isolated without any infection suspicion. A total of 335 confirmed EWIs (131 monomicrobial and 204 polymicrobial) were assessed. Gram-negative bacteria were predominant (57% and 86% of monomicrobial and polymicrobial infections, respectively). In polymicrobial infections, 61% grew only bacteria, while 30% isolated bacteria and mold. Multidrug resistance was observed in 32% of isolates from first monomicrobial EWIs ±3 days of diagnosis, while it was 44% of isolates from polymicrobial EWIs. Approximately 96% and 52% of the suspected and colonized wounds, respectively, shared ≥1 organism in common with the confirmed EWI on the same patient. Understanding of combat-related EWIs can lead to improvements in combat casualty care.

Indian J Pharmacol. 2018 Nov-Dec;50(6):332-335

# Efficacy ratio: A tool to enhance optimal antimicrobial use for intra-abdominal infections.

Sabu P, Elangovan D, Pragasam A, Bakthavatchalam Y, Rodrigues C, Chitnis D, Chaudhuri B, Veeraraghavan B

BACKGROUND: Antimicrobial resistance and inappropriate antibiotic regimen hamper a favorable outcome in intra-abdominal infections. Clinicians rely on the minimum inhibitory concentration (MIC) value to choose from the susceptible antimicrobials. However, the MIC values cannot be directly compared between the different antibiotics because their breakpoints are different. For that reason, efficacy ratio (ER), a ratio of susceptible MIC breakpoint and MIC of isolate, can be used to choose the most appropriate antimicrobial.

MATERIALS AND METHODS: A prospective, observational study conducted during 2015 and 2016 included 356 Escherichia coli and 158 Klebsiella spp. isolates obtained from the intra-abdominal specimens. MIC was determined by microbroth dilution method, and ER of each antibiotic was calculated for all the isolates.

RESULTS: For both E. coli and Klebsiella spp., ertapenem, amikacin, and piperacillin/tazobactam had the best activities among their respective antibiotic classes.

DISCUSSION: This is the first study calculating ER for deciding empiric treatment choices. ER also has a potential additional value in choosing the use of susceptible drugs as monotherapy or combination therapy. A shift in ERs over a period of time tracks rising MIC values and predicts antimicrobial resistance development.

CONCLUSION: Estimation of ER could be a meaningful addition for the interpretation of an antimicrobial susceptibility report, thus helping the physician to choose the best among susceptible antimicrobials for patient management.

Mil Med. 2019 Mar 1;184(Suppl 1):78-82

# The Israeli Defense Forces Point of Injury Antimicrobial Treatment Protocol – A New Protocol and Review of the Literature.

Glick Y, Furer A, Glick K, Yitzhak A, Brosh T

INTRODUCTION: Combat wound infection is a common and serious complication, leading to significant morbidity and mortality. In 2005, a point of injury antimicrobial protocol was published by the Israel Defense Forces, in which Moxifloxacin was chosen. During 2016-2017, a revision of this protocol was performed and concluded with the publication of an updated protocol. The purpose of this report is to present this process and the revised protocol, together with a review of the literature.

METHODS: We searched "Medline" and "Google Scholar" for studies dealing with antimicrobial prophylaxis in trauma, for militaries' point of injury antimicrobial protocol protocols and for established surgical antimicrobial prophylaxis protocols.

RESULTS: Point of injury antimicrobial protocol is aimed at preventing early infection and its complications. The choice of Moxifloxacin for this purpose may not be optimal since Moxifloxacin spectrum might be overly broad, there is scant evidence supporting it for this indication, and the available preparation does not meet distinctive technical requirements. Contrarily, Ceftriaxone seemed to have suitable microbiological, pharmacological and technical features.

CONCLUSION: Point of injury antimicrobial protocol should be used especially when evacuation and definitive surgical treatment are delayed. According to present scientific data and operational needs, Ceftriaxone was chosen for most penetrating injuries, with Metronidazole addition for penetrating abdominal and cranial trauma.

Mil Med. 2019 Mar 1;184(Suppl 1):83-91

# Combat-Related Extremity Wounds: Injury Factors Predicting Early Onset Infections.

Stewart L, Shaikh F, Bradley W, Lu D, Blyth D, Petfield J, Whitman T, Krauss M, Greenberg L, Tribble D

We examined risk factors for combat-related extremity wound infections (CEWI) among U.S. military patients injured in Iraq and Afghanistan (2009-2012). Patients with ≥1 combat-related, open extremity wound admitted to a participating U.S. hospital (≤7 days postinjury) were retrospectively assessed. The population was classified based upon most severe injury (amputation, open fracture without amputation, or open soft-tissue injury defined as non-fracture/non-amputation wounds). Among 1271 eligible patients, 395 (31%) patients had ≥1 amputation, 457 (36%) had open fractures, and 419 (33%) had open soft-tissue wounds as their most severe injury, respectively. Among patients with traumatic amputations, 100 (47%) developed a CEWI compared to 66 (14%) and 12 (3%) patients with open fractures and open soft-tissue wounds, respectively. In a Cox proportional hazard analysis restricted to CEWIs ≤30 days postinjury among the traumatic amputation and open fracture groups, sustaining an amputation (hazard ratio: 1.79; 95% confidence interval: 1.25-2.56), blood transfusion ≤24 hours postinjury, improvised explosive device blast, first documented shock index ≥0.80, and >4 injury sites were independently associated with CEWI risk. The presence of a non-extremity infection at least 4 days prior to a CEWI diagnosis was associated with lower CEWI risk, suggesting impact of recent exposure to directed antimicrobial therapy. Further assessment of early clinical management will help to elucidate risk factor contribution. The wound classification system provides a comprehensive approach in assessment of injury and clinical factors for the risk and outcomes of an extremity wound infection.

Future Microbiol. 2019 Oct 1;Epub ahead of print

# Eravacycline: a new treatment option for complicated intra-abdominal infections in the age of multidrug resistance.

Solomkin J, Sway A, Lawrence K, Olesky M, Izmailyan S, Tsai L.

Aim: Recently approved for use in complicated intra-abdominal infection, eravacycline is a novel fluorocycline with broad spectrum of activity against resistant Gram-negative pathogens. This manuscript is a pooled analysis of two Phase III trials. Clinical efficacy: Clinical cure rates were 86.8% for eravacycline versus 87.6% for ertapenem, and 90.8% for eravacycline versus 91.2% for meropenem in the Intent to Treat (micro-ITT) populations, and 87.0% for eravacycline versus 88.8% ertapenem, and 92.4 versus 91.6% for meropenem in the Modified Intent to Treat (MITT) populations. Safety: Eravacycline is well tolerated, with lower rates of nausea, vomiting and diarrhea than other tetracyclines.

Conclusion: Eravacycline is an effective new option for use in complicated intra-abdominal infections, and in particular, for the treatment of extended-spectrum β-lactamase- and carbapenem-resistant Enterobacteriaceae-expressing organisms.