No difference in risk of revision due to infection between clindamycin and cephalosporins as antibiotic prophylaxis in cemented primary total knee replacements: a report from the Norwegian Arthroplasty Register 2005-2020.

BACKGROUND AND PURPOSE: Systemic antibiotic prophylaxis with clindamycin, which is often used in penicillin- or cephalosporin-allergic patients', has been associated with a higher risk of surgical revision for deep prosthetic joint infection (PJI) than cloxacillin in primary total knee replacement (TKR). We aimed to investigate whether clindamycin increases the risk of surgical revisions due to PJI compared with cephalosporins in primary cemented TKR. PATIENTS AND METHODS: Data from 59,081 TKRs in the Norwegian Arthroplasty Register (NAR) 2005-2020 was included. 2,655 (5%) received clindamycin and 56,426 (95%) received cephalosporins. Cox regression analyses were performed with adjustment for sex, age groups, diagnosis, and ASA score. Survival times were calculated using Kaplan-Meier estimates and compared using Cox regression with revision for PJI as endpoint. The cephalosporins cefalotin and cefazolin were also compared. RESULTS: Of the TKRs included, 1.3% (n = 743) were revised for PJI. 96% (n = 713) had received cephalosporins and 4% (n = 30) clindamycin for perioperative prophylaxis. Comparing cephalosporins (reference) and clindamycin, at 3-month follow-up the adjusted hazard ratio rate (HRR) for PJI was 0.7 (95% confidence interval [CI] 0.4-1.4), at 1 year 0.9 (CI 0.6-1.5), and at 5 years 0.9 (CI 0.6-1.4). Analysis using propensity score matching showed similar results. Furthermore, comparing cefalotin (reference) and cefazolin, HRR was 1.0 (CI 0.8-1.4) at 3 months and 1.0 (CI 0.7-1.3) at 1-year follow-up. CONCLUSION: We found no difference in risk of revision for PJI when using clindamycin compared with cephalosporins in primary cemented TKRs. It appears safe to continue the use of clindamycin in penicillin- or cephalosporin-allergic patients.

The Choice of Antibiotic Prophylaxis Influences the Infection Reoperation Rate in Primary Shoulder Arthroplasty: Analysis From the Swedish Shoulder Arthroplasty Register.

BACKGROUND: Periprosthetic joint infection is a serious complication and a major reason for revision surgery after primary shoulder arthroplasty. The prophylactic antibiotics for primary shoulder arthroplasty that have predominantly been used in Sweden are cloxacillin and clindamycin. To address Cutibacteriumacnes , benzylpenicillin has recently increasingly been added to cloxacillin, but it is unclear which antibiotic prophylaxis regimen is the most effective to prevent periprosthetic joint infection. QUESTIONS/PURPOSES: After controlling for baseline differences among patients such as age, gender, previous surgery, cement fixation, and arthroplasty type, was the risk of reoperation for infection higher in patients who received cloxacillin than in those who received clindamycin or the combination of benzylpenicillin and cloxacillin? METHODS: Data from the Swedish Shoulder Arthroplasty Register were used for this study. The inclusion criterion was registered antibiotic prophylaxis in primary arthroplasty. Between January 1, 1999, and December 31, 2019, 22,470 primary shoulder arthroplasties, including total shoulder, hemiarthroplasty, and reverse shoulder arthroplasties, were entered into the Swedish Shoulder Arthroplasty Register. Reporting of antibiotic prophylaxis to the register was introduced on January 1, 2013. Since then, the completeness of information on the type of antibiotic prophylaxis in the reports has been 85.3%. Consequently, 10,706 arthroplasties were eligible and fulfilled the inclusion criterion of reported antibiotic prophylaxis. A further 129 were excluded because of unusual prophylaxis regimens, leaving 10,577 shoulder arthroplasties for analysis. The Swedish Shoulder Arthroplasty Register gathers information from all 60 hospitals performing shoulder arthroplasty in Sweden, and through a comparison with the National Patient Register, it has been estimated that more than 90% of all primary shoulder arthroplasties and shoulder reoperations are reported to the register. The age of the study population ranged between 16 and 98 years; the mean age at the primary surgery was 70 ± 10 years for the entire cohort, with a mean age of 67 ± 10 years and 72 ± 9 years for men and women, respectively. The mean observation period was 989 ± 669 days. From 2013 to 2019, there was a clear change in prophylaxis; in particular, the use of the combination of benzylpenicillin and cloxacillin increased dramatically and the use of cloxacillin alone decreased. Clindamycin prophylaxis increased moderately. The primary study endpoint was reported reoperation for infection. In the register, this is defined as repeat procedures of any kind, including biopsy, lavage of the joint, or revision, defined as secondary surgery in which a component was exchanged, removed, or added. To compare the reoperation rate in relation to the different antibiotics used, which changed over time, we controlled for age, gender, previous surgery, cement fixation, and arthroplasty type using a Cox proportional hazards model. RESULTS: When adjusting for age, gender, previous surgery, cement fixation, and arthroplasty type, cloxacillin prophylaxis was associated with an increased relative risk of reoperation for infection compared with the combination of cloxacillin and benzylpenicillin (hazard ratio [HR] 2.40 [95% confidence interval (CI) 1.35 to 4.25]; p = 0.003) and compared with clindamycin alone (HR 1.78 [95% CI 1.11 to 2.85]; p = 0.02). No difference was found between the cloxacillin and benzylpenicillin combination and clindamycin (HR 0.74 [95% CI 0.42 to 1.32]; p = 0.31). CONCLUSION: Our results indicate that prophylaxis against C. acnes may be warranted in shoulder arthroplasty. Because the absolute number of infections was low and infections could have been underreported to the register, our results should be interpreted with caution. There is no available information about the causative microorganisms. The study lays the groundwork for further investigations of antibiotic prophylaxis regimens in shoulder arthroplasty. Because large randomized controlled trials would be impractical to perform, prospective register-based randomized controlled studies might be a viable method. LEVEL OF EVIDENCE: Level Ⅲ, therapeutic study.

Effectiveness of Single vs Multiple Doses of Prophylactic Intravenous Antibiotics in Implant-Based Breast Reconstruction: A Randomized Clinical Trial.

Importance: Multiple-dose antibiotic prophylaxis is widely used to prevent infection after implant-based breast reconstruction despite the lack of high-level evidence regarding its clinical benefit. Objective: To determine whether multiple-dose antibiotic prophylaxis is superior to single-dose antibiotic prophylaxis in preventing surgical site infection (SSI) after implant-based breast reconstruction. Design, Setting, and Participants: This prospective, multicenter, randomized clinical superiority trial was conducted at 7 hospitals (8 departments) in Sweden from April 25, 2013, to October 31, 2018. Eligible participants were women aged 18 years or older who were planned to undergo immediate or delayed implant-based breast reconstruction. Follow-up time was 12 months. Data analysis was performed from May to October 2021. Interventions: Multiple-dose intravenous antibiotic prophylaxis extending over 24 hours following surgery, compared with single-dose intravenous antibiotic. The first-choice drug was cloxacillin (2 g per dose). Clindamycin was used (600 mg per dose) for patients with penicillin allergy. Main Outcomes and Measures: The primary outcome was SSI leading to surgical removal of the implant within 6 months after surgery. Secondary outcomes were the rate of SSIs necessitating readmission and administration of intravenous antibiotics, and clinically suspected SSIs not necessitating readmission but oral antibiotics. Results: A total of 711 women were assessed for eligibility, and 698 were randomized (345 to single-dose and 353 to multiple-dose antibiotics). The median (range) age was 47 (19-78) years for those in the multiple-dose group and 46 (25-76) years for those in the single-dose group. The median (range) body mass index was 23 (18-38) for the single-dose group and 23 (17-37) for the multiple-dose group. Within 6 months of follow-up, 30 patients (4.3%) had their implant removed because of SSI. Readmission for intravenous antibiotics because of SSI occurred in 47 patients (7.0%), and 190 women (27.7%) received oral antibiotics because of clinically suspected SSI. There was no significant difference between the randomization groups for the primary outcome implant removal (odds ratio [OR], 1.26; 95% CI, 0.69-2.65; P = .53), or for the secondary outcomes readmission for intravenous antibiotics (OR, 1.18; 95% CI, 0.65-2.15; P = .58) and prescription of oral antibiotics (OR, 0.72; 95% CI, 0.51-1.02; P = .07). Adverse events associated with antibiotic treatment were more common in the multiple-dose group than in the single-dose group (16.4% [58 patients] vs 10.7% [37 patients]; OR, 1.64; 95% CI, 1.05-2.55; P = .03). Conclusions and Relevance: The findings of this randomized clinical trial suggest that multiple-dose antibiotic prophylaxis is not superior to a single-dose regimen in preventing SSI and implant removal after implant-based breast reconstruction but comes with a higher risk of adverse events associated with antibiotic treatment. Trial Registration: EudraCT 2012-004878-26.

Cloxacillin-induced acute vanishing bile duct syndrome: A case study and literature review.

Ductopenia is often regarded as a chronic process where ≥50% of portal tracts lack bile ducts, which is also known as vanishing bile duct syndrome (VBDS). One aetiology is drug-induced liver injury. Cloxacillin, an antistaphylococcal penicillin, typically causes "bland" cholestasis. We present the first case of cloxacillin-induced acute ductopenia or VBDS and a review of published cloxacillin-induced liver injuries. A 66-year-old woman with no prior liver disease, but known penicillin allergy, was treated for postcarotid angioplasty staphylococcal infection with 6 weeks of cloxacillin. She presented with a 2-week history of weakness and jaundice. Laboratory work-up showed elevated liver enzymes with a cholestatic pattern, hyperbilirubinemia and eosinophilia. She required ICU transfer for hypotension and was started empirically on prednisone. Liver biopsy revealed severe centrilobular cholestasis, mild necroinflammation and ductopenia with epithelial injury, but no ductular reaction. Two months later she was discharged on hydrocortisone and ursodiol with persistently elevated alkaline phosphatase and bilirubin. She was considered for liver transplantation but died of liver failure 4 months later. Four additional articles were found with histopathologic descriptions of cloxacillin-related liver injury. These included portal inflammation, cholestasis and mild necroinflammation. Clinical features were reported in two cases; both had mild symptoms with cholestatic liver enzymes and hyperbilirubinemia. Both patients recovered completely within 10-60 days. Cloxacillin-induced cholestasis can be secondary to acute ductopenia, which can result in worse clinical outcomes than previously described "bland" cholestasis. Liver biopsy is recommended to identify cases with acute VBDS.

Superior selectivity of high-frequency ultrasound toward chorine containing-pharmaceuticals elimination in urine: A comparative study with other oxidation processes through the elucidation of the degradation pathways.

This work considered the sonochemical degradation (using a bath-type reactor, at 375 kHz and 106.3 W L-1, 250 mL of sample) of three representative halogenated pharmaceuticals (cloxacillin, diclofenac, and losartan) in urine matrices. The action route of the process was initially established. Then, the selectivity of the sonochemical system, to degrade the target pharmaceuticals in simulated fresh urine was compared with electrochemical oxidation (using a BDD anode, at 1.88 mA cm-2), and UVC/H2O2 (at 60 W of light and 500 mol L-1 of H2O2). Also, the treatment of cloxacillin in an actual urine sample by ultrasound and UVC/H2O2 was evaluated. More than 90% of the target compounds concentration, in the simulated matrix, was removed after 60 min of sonication. However, the sono-treatment of cloxacillin in the real sample was less efficient than in the synthetic urine. The ultrasonic process achieved 43% of degradation after 90 min of treatment in the actual matrix. In the sonochemical system, hydroxyl radicals in the interfacial zone were the main degrading agents. Meanwhile, in the electrochemical process, electrogenerated HOCl was responsible for the elimination of pharmaceuticals. In turn, in UVC/H2O2 both direct photolysis and hydroxyl radicals degraded the target pollutants. Interestingly, the degradation by ultrasound of the pharmaceuticals in synthetic fresh urine was very close to the observed in distilled water. Indeed, the sonodegradation had a higher selectivity than the other two processes. Despite the sono-treatment of cloxacillin was affected by the actual matrix components, this contrasts with the UVC/H2O2, which was completely inhibited in the real urine. The sonochemical process led to 100% of antimicrobial activity (AA) elimination after 75 min sonication in the synthetic urine, and âˆ¼ 20% of AA was diminished after 90 min of treatment in the real matrix. The AA decreasing was linked to the transformations of the penicillin nucleus on cloxacillin, the region most prone to electrophilic attacks by radicals according to a density theory functional analysis. Finally, predictions of biological activity confirmed that the sono-treatment decreased the activity associated with cloxacillin, diclofenac, and losartan, highlighting the positive environmental impact of degradation of chlorinated pharmaceuticals in urine.

Rifampin combination therapy in staphylococcal prosthetic joint infections: a randomized controlled trial.

BACKGROUND: The evidence supporting rifampin combination therapy in prosthetic joint infections (PJI) is limited due to the lack of controlled studies. The aim of this study is to evaluate the effect of adding rifampin to conventional antimicrobial therapy in early staphylococcal PJIs treated with debridement and retention of the implant (DAIR). METHODS: In this multicenter randomized controlled trial, 99 patients with PJI after hip and knee arthroplasties were enrolled. They were randomly assigned to receive rifampin or not in addition to standard antimicrobial treatment with cloxacillin or vancomycin in case of methicillin resistance. The primary endpoint was no signs of infection after 2 years of follow-up. RESULTS: Forty-eight patients were included in the final analyses. There were no differences in patient characteristics or comorbidities between the two groups. There was no significant difference in remission rate between the rifampin combination group (17 of 23 (74%)) and the monotherapy group (18 of 25 (72%), relative risk 1.03, 95% confidence interval 0.73 to 1.45, p = 0.88). CONCLUSION: This trial has not proven a statistically significant advantage by adding rifampin to standard antibiotic treatment in acute staphylococcal PJIs. TRIAL REGISTRATION: The Regional Ethics Committee and the Norwegian Medicines Agency approved the study (EudraCT 2005-005494-29), and the study was registered at ClinicalTrials.gov at Jan 18, 2007 ( NCT00423982 ).

Differential interactions of the ß-lactam cloxacillin with human renal organic anion transporters (OATs).

The ß-lactam penicillin antibiotic cloxacillin (CLX) presents wide inter-individual pharmacokinetics variability. To better understand its molecular basis, the precise identification of the detoxifying actors involved in CLX disposition and elimination would be useful, notably with respect to renal secretion known to play a notable role in CLX elimination. The present study was consequently designed to analyze the interactions of CLX with the solute carrier transporters organic anion transporter (OAT) 1 and OAT3, implicated in tubular secretion through mediating drug entry at the basolateral pole of renal proximal cells. CLX was first shown to block OAT1 and OAT3 activity in cultured OAT-overexpressing HEK293 cells. Half maximal inhibitory concentration (IC50 ) value for OAT3 (13 µm) was however much lower than that for OAT1 (560 µm); clinical inhibition of OAT activity and drug-drug interactions may consequently be predicted for OAT3, but not OAT1. OAT3, unlike OAT1, was next shown to mediate CLX uptake in OAT-overexpressing HEK293 cells. Kinetic parameters for this OAT3-mediated transport of CLX (Km  = 10.7 µm) were consistent with a possible in vivo saturation of this process for high CLX plasma concentrations. OAT3 is consequently likely to play a pivotal role in renal CLX secretion and consequently in total renal CLX elimination, owing to the low plasma unbound fraction of the antibiotic. OAT3 genetic polymorphisms as well as co-administered drugs inhibiting in vivo OAT3 activity may therefore be considered as potential sources of CLX pharmacokinetics variability.

Síndrome de la piel escaldada estafilocócica en un paciente pediátrico con dermatitis atópica / Staphylococcal scalded skin syndrome in a pediatric patient with atopic dermatitis

El síndrome de la escaldadura estafilocócica es una entidad dermatológica poco frecuente que, en fases iniciales, puede ser confundida con una reagudización de un brote de dermatitis atópica. Se presenta el caso de un niño de 8 años, con antecedentes de dermatitis atópica y alergia al huevo, que acudió al Servicio de Urgencias por lesiones eritematoampollosas en la piel. La sintomatología comenzó como un eritema en áreas de flexuras, que asociaba conjuntivitis y eritema palpebral bilateral. A las 24 horas, apareció un eritema generalizado con ampollas flácidas de predominio en áreas flexurales, acompañado de hiperqueratosis y xerosis perioral. Ante la sospecha clínica de síndrome de escaldadura estafilocócica, se inició el tratamiento empírico con cloxacilina, con respuesta favorable. Con este caso, se destaca la importancia de realizar un correcto diagnóstico diferencial de las lesiones cutáneas de los pacientes con dermatitis atópica, con el objetivo de aplicar el tratamiento más adecuado.

The staphylococcal scalded skin syndrome is a rare dermatological entity that in early stages may be confused with a flare-up of a rush of atopic dermatitis. We present the case of an 8-year-old boy with a history of atopic dermatitis and egg allergy that went to the Emergency Department for erythematous-bullous lesions on the skin. Symptoms began as an erythema in areas of flexures, which associated conjunctivitis and bilateral eyelid erythema. After 24 hours, a generalized erythema appeared with flaccid blisters predominating in flexural areas, accompanied by hyperkeratosis and perioral xerosis. Due to the clinical suspicion of staphylococcal scalded skin syndrome, empirical treatment with cloxacillin with favorable response was initiated. This case highlights the importance of making a correct differential diagnosis of skin lesions of patients with atopic dermatitis in order to apply the most appropriate treatment.

Vacuum-Assisted Closure for the Treatment of Deep Sternal Wound Infection After Pediatric Cardiac Surgery.

OBJECTIVES: Vacuum-assisted closure is being increasingly used to treat deep sternal wound infection following cardiac surgery, but most of the data refer to adults. This study investigated the safety and efficacy of vacuum-assisted closure in pediatric patients. DESIGN: Retrospective file review. SETTING: Tertiary pediatric medical center. PATIENTS: All children with deep sternal wound infection treated with vacuum-assisted closure in 2003-2016. INTERVENTIONS: Epidemiological, clinical, and microbiological data were collected from the medical records. MEASUREMENTS AND MAIN RESULTS: The cohort included 50 patients (0.9% of cardiac patients operated during the study period) of median age 6.5 months (interquartile range, 2-12.75 mo; range, 1 wk to 14 yr) and median weight 5.1 kg (interquartile range, 4-9.75 kg). The most frequent heart defects were tetralogy of Fallot (22%) and ventricular septal defect (20%); 38% of patients had cyanotic heart disease. Deep sternal wound infections appeared a median of 10 days postoperatively (interquartile range, 7-14 d; range 3-100 d). Vacuum-assisted closure was applied a median of 13 days postoperatively (interquartile range, 10-18.5 d; range, 5-103 d) for a median duration of 10 days (interquartile range, 7-13.25 d; range, 1-21 d). Wound cultures were positive in 48 patients (96%); most isolates were Gram-positive (76%). The main bacterial pathogen was methicillin-susceptible Staphylococcus aureus (61%). Most patients were treated with cloxacillin for a median of 38 days (interquartile range, 28-42 d; range, 9-189 d). There were no statistically significant differences in clinical or treatment characteristics between bacteremic (56%) and nonbacteremic patients. Compared with older patients, infants less than 3 months old (36%) had a significantly longer hospitalization time (41 vs 25 d; p = 0.001) and higher Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery Mortality Category (3 vs 2; p = 0.003). All cases except one (contact dermatitis) were uneventful. In 10 patients, wounds were closed surgically after vacuum-assisted closure. Two patients required a pectoralis flap, both treated before 2005. One of the two deaths was infection-related. CONCLUSIONS: Vacuum-assisted closure is a feasible treatment option of deep sternal wound infection after pediatric cardiac surgery and was not associated with independent morbidity.

Antibiotic Prophylaxis With Trimethoprim/Sulfamethoxazole Instead of Cloxacillin/Cefotaxime Increases Inguinal Surgical Site Infection Rate After Lower Extremity Revascularization.

Due to the consistently high proportion of surgical site infections (SSI) after vascular surgery, a change of prophylactic antibiotic therapy from cloxacillin/cefotaxime to trimethoprim/sulfamethoxazole (TMP-SMX) was conducted in 2016. The study included consecutive patients undergoing lower extremity revascularization due to acute or chronic lower extremity arterial disease. The antibiotic regime was changed in between the two sampling periods (2014 -2016 versus 2016 -2017). The diagnosis of SSI was based on clinical examination and microbiological results, and severity was classified according to the Szilagyi classification. One hundred and twenty-two patients in the cloxacillin/cefotaxime and 67 patients in the TMP-SMX group were included. The SSI rates were 32.0% and 40.3%, respectively (p=0.25). The proportion of women were higher in the TMP-SMX group (32.8% versus 47.8%, respectively, p=0.043). No other differences between the two groups were found regarding patient, vascular surgery procedure characteristics or severity of SSI. Groin infection rate was higher in the TMP-SMX group (15.4% versus 30.5%, respectively, p=0.022). When adjusting for gender, groin infection was more common in the TMP-SMX group (Odds Ratio 2.5, 95% CI 1.1 -5.4). The groin SSI rate was higher after elective surgery in the TMP-SMX group (13.0% versus 27.8%, respectively, p=0.027), and also after adjusting for gender (Odds Ratio 2.6, 95% CI 1.1 -6.2). The change in antibiotic prophylaxis from Cloxacillin/Cefotaxime to TMP-SMX was associated with an increased rate of inguinal SSI in patients undergoing lower extremity revascularization, despite a possible Hawthorne effect.

Intravenously administered cloxacillin-induced neutropenia with eosinophilia in a patient with infective endocarditis: a case report.

BACKGROUND: Bacteremia following Staphylococcus aureus is a serious clinical condition which is often associated with distant metastatic infections. One of the most dreaded complications of Staphylococcus aureus bacteremia is infective endocarditis. Cloxacillin is a common antibiotic prescribed for suspected staphylococcal infections and confirmed methicillin-sensitive Staphylococcus aureus infections. Prolonged use of cloxacillin may lead to neutropenia. CASE PRESENTATION: A 38-year-old Sinhalese man presented to Teaching Hospital Kurunegala, Sri Lanka, complaining of a 3-week history of fever; he was found to have a pansystolic murmur over the apex of his heart. He had leukocytosis with predominant neutrocytosis. His C-reactive protein was 231 mg/l and erythrocyte sedimentation rate was 100 mm/first hour. Transthoracic two-dimensional echocardiography revealed prolapsed mitral valve with 7 × 13 mm vegetation over the posterior mitral valve. On the following day, three blood cultures became positive and were subsequently identified as Staphylococcus aureus. Intravenously administered cloxacillin 3 g 6 hourly was started. Following day 24 of intravenously administered cloxacillin, our patient developed high spike fever. His total white blood cells were: 990/mm3 with 34% neutrophils and 22% eosinophils. His hemoglobin concentration was 9.5 g/dL and platelet count remained normal (202 × 106/mm3). His C-reactive protein was 78 mg/l, erythrocyte sedimentation rate was 95 mm/first hour, and he was otherwise comfortable, showing no signs of sepsis beside the high grade fever. His serum was negative for filarial and Toxoplasma antibodies while stool was negative for oocytes and amoebic cysts. Further, his serum was negative for dengue virus, Epstein-Barr virus, cytomegalovirus, and hepatitis B antibodies. He was clinically well on day 6 after stopping cloxacillin with 44% neutrophils and 18% eosinophils. His C-reactive protein and erythrocyte sedimentation rate became normal, and there was no further plan for cardiothoracic intervention or administration of antimicrobials. He was discharged from hospital and remained well 6 months later. CONCLUSION: This case report signifies the potential fatal adverse effect of cloxacillin in methicillin-sensitive Staphylococcus aureus infections. Leukopenia is associated with prolonged use of high doses of cloxacillin. In addition to transthoracic two-dimensional echocardiography and inflammatory markers, sequential white blood cells and differential counts would help clinicians to assess the prognosis of patients with infective endocarditis.

Phenotypic and genetic resistance traits of Pseudomonas aeruginosa strains infecting cystic fibrosis patients: A French cohort study.

Pseudomonas aeruginosa is responsible for chronic respiratory tract colonisation and acute exacerbations in cystic fibrosis (CF) patients. This Gram-negative bacterium often develops multidrug resistance, which represents a therapeutic challenge. The objective of this study was to characterise the phenotypic and genetic ß-lactam resistance traits of P. aeruginosa strains isolated from CF patients at Grenoble Alpes University Hospital (Grenoble, France). The susceptibility to ß-lactam compounds of 123 P. aeruginosa strains collected from the lower respiratory tract of 45 CF patients between 2010-2014 was evaluated. Genetic analyses focused on characterisation of the presence of carbapenemase- and extended-spectrum ß-lactamases (ESBL)-encoding genes as well as alterations in the oprD gene encoding the OprD porin. Among the 123 P. aeruginosa strains evaluated, 25 were susceptible to both ceftazidime (CAZ) and imipenem (IPM), 9 only to IPM and 36 only to CAZ; 53 strains were resistant to both drugs. CAZ resistance could be reverted by cloxacillin in 29 strains, indicating overproduction of cephalosporinase. Genetic analyses performed for 79 P. aeruginosa strains revealed no ESBL- or carbapenemases-encoding genes. Among the 74 IPM-resistant strains, 42 (56.8%) displayed major alterations in the OprD protein sequence. This study shows that in this CF patient cohort, cephalosporinase overproduction and OprD alterations were the main resistance mechanisms of P. aeruginosa to CAZ and IPM, respectively. No genes coding for ESBLs or carbapenemases were detected, but monitoring of the emergence of such resistance genes in CF patients is warranted owing to their ability to rapidly spread by horizontal gene transfer.

Daptomycin versus placebo as an adjunct to beta-lactam therapy in the treatment of Staphylococcus aureus bacteremia: study protocol for a randomized controlled trial.

BACKGROUND: Staphylococcus aureus bacteremia is associated with significant morbidity and mortality. To treat this infection, the current standard of care includes intravenous anti-staphylococcal beta-lactam antibiotics and obtaining adequate source control. Combination therapy with an aminoglycoside or rifampin, despite early promise, can no longer be routinely recommended due to an absence of proven benefit and risk of harm. Daptomycin is a rapidly acting bactericidal antibiotic that is approved for the treatment of Staphylococcus aureus bacteremia as monotherapy but has not been shown to be superior to the current standard of care. As demonstrated in vitro, the addition of daptomycin to beta-lactam therapy may result in enhanced anti-staphylococcal activity. Our objective is to assess the efficacy and safety of prescribing the combination of daptomycin with cefazolin or cloxacillin for the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia in adults. We hypothesize that adjunctive therapy with daptomycin will reduce the duration of bacteremia in this population. METHODS: The DASH-RCT trial is a randomized, double blind, placebo-controlled trial designed per the Standard Protocol Items: Recommendation for Interventional Trials (SPIRIT) and Consolidated Standards of Reporting Trials (CONSORT) guidelines. We recruit adults with confirmed MSSA bacteremia, at the McGill University Health Center. Patients are eligible if they are 18 years or older, can receive cefazolin or cloxacillin monotherapy, and are enrolled within 72 h of the first blood culture being drawn. Exclusion criteria include anaphylaxis to study drugs, having polymicrobial bacteremia, anticipated hospital admission for < 5 days, and healthcare team refusal. While receiving standard of care, study patients are randomized to a 5-day course of adjunctive daptomycin or placebo. The trial began in December 2016 and is expected to end in December 2018, after recruiting an estimated 102 patients. DISCUSSION: The DASH-RCT will compare the use of daptomycin as an adjunct to an anti-staphylococcal beta-lactam versus placebo in the treatment of MSSA bacteremia. We believe that a short course of dual therapy will result in earlier eradication of bacteremia and that subsequent research could evaluate effects on metastatic infection, relapse, and/or mortality. Ongoing issues in the trial include a delay between presentation of infection, enrollment in the trial, and the potential for unrecognized deep foci of infection at diagnosis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02972983 . Registered on 25 November 2016. Trial protocol: http://individual.utoronto.ca/leet/dash/dashprotocol.pdf.

Gentamicin may have no effect on mortality of staphylococcal prosthetic valve endocarditis.

PURPOSE: To analyze the influence of adding gentamicin to a regimen consisting of ß-lactam or vancomycin plus rifampicin on survival in patients suffering from Staphylococcal prosthetic valve endocarditis (SPVE). METHODS: From January 2008 to September 2016, 334 patients with definite SPVE were attended in the participating hospitals. Ninety-four patients (28.1%) received treatment based on ß-lactam or vancomycin plus rifampicin and were included in the study. Variables were analyzed which related to patient survival during admission, including having received treatment with gentamicin. RESULTS: Seventy-seven (81.9%) were treated with cloxacillin (or vancomycin) plus rifampicin plus gentamicin, and 17 patients (18.1%) received the same regimen without gentamicin. The causative microorganism was Staphylococcus aureus in 40 cases (42.6%) and coagulase-negative staphylococci in 54 cases (57.4%). Overall, 40 patients (42.6%) died during hospital admission, 33 patients (42.9%) in the group receiving gentamicin and 7 patients in the group that did not (41.2%, P = 0.899). Worsening renal function was observed in 42 patients (54.5%) who received gentamicin and in 9 patients (52.9%) who did not (p = 0.904). Heart failure as a complication of endocarditis (OR: 4.58; CI 95%: 1.84-11.42) and not performing surgery when indicated (OR: 2.68; CI 95%: 1.03-6.94) increased mortality. Gentamicin administration remained unrelated to mortality (OR: 1.001; CI 95%: 0.29-3.38) in the multivariable analysis. CONCLUSIONS: The addition of gentamicin to a regimen containing vancomycin or cloxacillin plus rifampicin in SPVE was not associated to better outcome.

Higher risk of revision for infection using systemic clindamycin prophylaxis than with cloxacillin.

Background and purpose - Clindamycin has not been compared with other antibiotics for prophylaxis in arthroplasty. Since 2009, the Swedish Knee Arthroplasty Register (SKAR) has been collecting information on the prophylactic antibiotic regime used at every individual operation. In Sweden, when there is allergy to penicillin, clindamycin has been the recommended alternative. We examined whether there were differences in the rate of revision due to infection depending on which antibiotic was used as systemic prophylaxis. Patients and methods - Patients who had a total knee arthroplasty (TKA) performed due to osteoarthritis (OA) during the years 2009-2015 were included in the study. Information on which antibiotic was used was available for 80,018 operations (55,530 patients). Survival statistics were used to calculate the rate of revision due to infection until the end of 2015, comparing the group of patients who received cloxacillin with those who received clindamycin as systemic prophylaxis. Results - Cloxacillin was used in 90% of the cases, clindamycin in 7%, and cephalosporins in 2%. The risk of being revised due to infection was higher when clindamycin was used than when cloxacillin was used (RR =1.5, 95% CI: 1.2-2.0; p = 0.001). There was no significant difference in the revision rate for other causes (p = 0.2). Interpretation - We advise that patients reporting allergic reaction to penicillin should have their allergic history explored. In the absence of a clear history of type-I allergic reaction (e.g. urticaria, anaphylaxis, or bronchospasm), we suggest the use of a third-generation cephalosporin instead of clindamycin as perioperative prophylaxis when undergoing a TKR. No recommendation can be given regarding patients with type-1 allergy.

Uso de antimicrobiano nanoparticulado para o tratamento da mastite subclínica de ovelhas de corte no período seco / Use of nanoparticulated antimicrobians to treat subclinical mastitis of ewes during the dry period

A inflamação da glândula mamária é uma das principais causas de prejuízo na ovinocultura. Este estudo teve como objetivo investigar as taxas de cura do tratamento da mastite subclínica após infusão intramamária de princípio ativo antimicrobiano no momento da secagem, em formulações convencional e nanoparticulada. Os rebanhos estavam localizados em São Carlos, São Paulo, Brasil. Analisou-se um total de 584 glândulas mamárias de 307 ovelhas de aptidão para produção de carne. Triagem prévia dos casos subclínicos de mastite foi efetuada por meio do California Mastitis Test (CMT) e/ou da contagem de células somáticas (CCS). Análises microbiológicas foram realizadas para confirmação da etiologia infecciosa. As glândulas mamárias com mastite subclínica foram distribuídas em três grupos: G1 (Controle; glândulas mamárias que não receberam tratamento antimicrobiano); G2 (glândulas mamárias em que foi administrado 100 mg de cloxacilina benzatina em estrutura convencional) e G3 (glândulas mamárias em que foi administrado 50 mg de cloxacilina benzatina em estrutura nanoencapsulada). O tratamento aplicado ao G3 mostrou-se mais eficiente (P=0,047) na cura de glândulas mamárias com mastite subclínica. O uso da cloxacilina nanoencapsulada no momento da secagem de ovelhas de corte auxilia no controle da mastite subclínica infecciosa e reduz os prejuízos consequentes.(AU)

Inflammation of the mammary gland is one of the main causes of losses in sheep-rearing. This study aimed to investigate the cure rates from treating subclinical mastitis after intramammary infusion of active antimicrobial agents as conventional formulations or as nanoparticles, at the time when the ewes are being dried off. A total of 584 mammary glands in 307 ewes in meat-producing herds located in São Carlos, São Paulo, Brazil, were analyzed. Prescreening of subclinical mastitis cases was done using the California mastitis test (CMT) and/or the somatic cell count (SCC). Microbiological analyses were performed to confirm the infectious etiology. The mammary glands with subclinical mastitis were distributed into three groups: G1 (control; mammary glands that did not receive any antimicrobial treatment); G2 (mammary glands to which 100mg of benzathine cloxacillin in conventional form were administered); and G3 (mammary glands to which 50mg of benzathine cloxacillin in nanoparticulate form were administered). The treatment applied to G3 was more efficient (P=0.047) in curing mammary glands with subclinical mastitis. Use of cloxacillin nanoparticles at the time when the ewes are being dried off helps to control infectious subclinical mastitis and reduces consequential losses among meat-producing herds.(AU)

Molecularly imprinted polymer beads for clean-up and preconcentration of ß-lactamase-resistant penicillins in milk.

This work describes the development and application of class-selective molecularly imprinted polymers (MIPs) for the analysis of beta-lactamase-resistant penicillins, namely cloxacillin (CLOXA), oxacillin (OXA), and dicloxacillin (DICLOXA), in milk samples. Our method is based on molecularly imprinted solid-phase extraction (MISPE) coupled to high-performance liquid chromatography (HPLC) with diode-array detection (DAD). 2-Biphenylylpenicillin (2BPEN), a surrogate with a close resemblance to beta-lactamase-resistant penicillins in terms of size, shape, hydrophobicity, and functionality, was synthesized and used as the template for the polymer synthesis. A MIP library was prepared and screened to select the optimum functional monomer, N-(2-aminoethyl)methacrylamide, and cross-linker, trimethylolpropane trimethacrylate, that provided the best recognition for the target antibiotics. For the MISPE application, the MIPs were prepared in the form of microspheres, using porous silica beads (40-75 µm) as sacrificial scaffolds. The developed MISPE method enables efficient extraction from aqueous samples and analysis of the antimicrobials, when followed by a selective washing with 2 mL acetonitrile-water (20:80 v/v) and elution with 1 mL 0.05 mol L(-1) tetrabutylammonium in methanol. The analytical method was validated according to EU guideline 2002/657/EC. The limits of quantification (S/N = 10) were in the 5.3-6.3 µg kg(-1) range, well below the maximum residue limits (MRLs) currently established. Inter-day mean recoveries were in the range 99-102 % with RSDs below 9 %, improving on the performance of previously reported MISPE methods for the analysis of CLOXA, OXA, or DICLOXA in milk samples.

Antibiotic Prophylaxis With Trimethoprim/Sulfamethoxazole Instead of Cloxacillin Fails to Improve Inguinal Surgical Site Infection Rate After Vascular Surgery.

BACKGROUND: Surgical site infections (SSIs) and their prevention continue to be a major point of focus in all surgical specialties today. Antibiotic prophylaxis is one of the mainstays in their prevention. Due to the consistently high proportion of infections caused by intestinal flora from the start of our wound surveillance registry in 2005, we conducted a change in prophylactic antibiotic therapy from cloxacillin in 2012 to trimethoprim/sulfamethoxazole (TMP-SMX) in 2013. METHODS: The study included all patients undergoing vascular surgery with groin incisions between March 1 and June 30 in 2012 and 2013, respectively, whereby the antibiotic regime was changed in between the 2 sampling periods. The diagnosis of SSI was based on clinical examination and microbiological results. RESULTS: Two hundred nineteen patients with inguinal incisions were included in the analysis: 105 in the cloxacillin group of which 19% had SSI and 114 in the TMP-SMX group with an SSI rate of 18% (P = .77), without differences between the 2 groups regarding age, gender, proportion of emergency surgery, type of surgery, or frequency of concomitant foot ulcers. The high proportion of infections caused by intestinal flora between time periods was unchanged (67% vs 81%, P = .34). CONCLUSION: There was no difference between the 2 groups, suggesting that the choice of antibiotic prophylaxis had a limited role in preventing SSI at our center. Despite this, the lower cost and ease of the administration of TMP-SMX can be seen as convincing advantages.

Reposicionando la cloxacilina como antibioticoterapia empírica inicial de la sepsis tardía neonatal / Reinstating cloxacilin for empiric antibiotic in late-onset sepsis

Vancomycin has been used for more than 50 years in neonatal intensive care units (NICUs) as the therapy of choice for late-onset sepsis, mainly because Coagulase negative Staphylococci (CoNS) are common and mostly resistant to oxacyllin despitelow virulence and unusual association with fulminant sepsis. CUs due to several factors including its high pharmacokinetic variability, difficulty in reaching therapeutic plasmatic drug concentrations and progressively increasing minimum inhibitory concentrations (MIC). The increase of CoNS with higher MICs as well as the rise of infections caused by resistant gram-negative bacilli and candida should move to reconsider Vancomycin as first line treatment. Infections in neonates have a different behavior than in other populations and we consoder of utmost importance to consider the use of oxacyllin as first line antimicrobial therapy for late-onset sepsis.

Vancomicina se utiliza hace más de 50 años en unidades de cuidados intensivos neonatales (UCIN) como terapia de elección en sospecha de sepsis neonatal tardía; su principal indicación se fundamenta en que Staphylococcus coagulasa negativa (SCN) es el principal microorganismo que ocasiona sepsis tardía y éste es habitualmente resistente a cloxacilina; sin embargo, su virulencia es baja y la sepsis fulminante es inusual. Lamentablemente la prescripción de vancomicina se ha convertido en un grave problema en las UCIN, debido a diversas razones incluyendo: alta variabilidad farmacocinética del fármaco, dificultad en alcanzar concentraciones plasmáticas apropiadas y aumento de la concentración inhibitoria mínima (CIM), implicando además una mayor probabilidad de seleccionar cepas resistentes y aumento de otro tipo de infecciones ocasionadas por bacilos gramnegativos resistentes y candidiasis invasora. Considerando lo anteriormente señalado y a lo publicado en la literatura médica con respecto a las infecciones en neonatología, debido a su comportamiento clínico diferente a hospederos en otras etapas de la vida, resulta de suma importancia replantear el uso de vancomicina basado en fundamentos teóricos que avalen la seguridad de no utilizar este antimicrobiano como primera línea en sepsis neonatal tardía.

A randomized prospective study of prophylactic cloxacillin in breast reduction surgery.

BACKGROUND: Postoperative infection after breast reduction surgery is a common complication, with the most commonly involved pathogen being Staphylococcus aureus. Previous studies of antibiotic prophylaxis in breast reduction surgery have been inconclusive. The aim of the present study was to clarify the role of prophylactic antibiotics in breast reduction surgery. METHODS: In total, 325 women were randomized to antibiotic prophylaxis [with 2 g of cloxacillin intravenously (IV) or 600 mg of clindamycin IV] (intervention group) or no antibiotic prophylaxis (control group). Follow-up was conducted at 1 and 2 weeks postoperatively. Patients with signs of infections or other complications were followed up until resolution. Patients who received antibiotic treatment within 30 days from surgery (cloxacillin 750 mg or clindamycin 300 mg orally) were considered having an infection and this was the main outcome variable. All postoperative infections were also judged according to a graded scale. RESULTS: In the intervention group, 26 (16.0%) patients were treated with antibiotic; and in the control group, 32 (19.6%) patients were treated with antibiotics. No difference was found between the groups (relative risk, 0.82; 95% confidence interval, 0.51-1.31; P = 0.49). Twenty-two (14%) patients in the intervention group were classified to have a possible infection according to the scale compared to 27 (17%) in the control group. No statistical difference was found (relative risk, 0.81; 95% confidence interval, 0.48-1.37; P = 0.54). CONCLUSIONS: Prophylactic cloxacillin as a single-dose IV in breast reduction surgery does not reduce the incidence of postoperative infections.