Additional Antibiotic Treatment Research Articles

Exclusive oral antibiotic treatment for hospitalized community-acquired pneumonia: a post-hoc analysis of a randomized clinical trial

ObjectivesIn this study, we aimed to assess the efficacy of different ways of administration and types of beta-lactams for hospitalized community-acquired pneumonia (CAP). MethodsIn this post-hoc analysis of randomized controlled trials (RCT) on patients hospitalized for CAP (pneumonia short treatment trial) comparing 3-day vs. 8-day durations of beta-lactams, which concluded to non-inferiority, we included patients who received either amoxicillin-clavulanate (AMC) or third-generation cephalosporin (3GC) regimens, and exclusively either intravenous or oral treatment for the first 3 days (followed by either 5 days of oral placebo or AMC according to randomization). The choice of route and molecule was left to the physician in charge. The main outcome was a failure at 15 days after the first antibiotic intake, defined as temperature >37.9°C, and/or absence of resolution/improvement of respiratory symptoms, and/or additional antibiotic treatment for any cause. The primary outcome according to the route of administration was evaluated through logistic regression. Inverse probability treatment weighting with a propensity score model was used to adjust for non-randomization of treatment routes and potential confounders. The difference in failure rates was also evaluated among several sub-populations (AMC vs. 3GC treatments, intravenous vs. oral AMC, patients with multi-lobar infection, patients aged ≥65 years old, and patients with CURB65 scores of 3–4). ResultsWe included 200 patients from the original trial, with 93/200 (46.5%) patients only treated with intravenous treatment and 107/200 (53.5%) patients only treated with oral therapy. The failure rate at Day 15 was not significantly different among patients treated with initial intravenous vs. oral treatment [25/93 (26.9%) vs. 28/107 (26.2%), adjusted odds ratios (aOR) 0.973 (95% CI 0.519–1.823), p 0.932)]. Failure rates at Day 15 were not significantly different among the subgroup populations. DiscussionAmong hospitalized patients with CAP, there was no significant difference in efficacy between initial intravenous and exclusive oral treatment. Trial registrationThis trial is registered with ClinicalTrials.gov, NCT01963442.

Severe acute urticaria is associated with elevated plasma levels of D-dimer.

Evaluation of the disease severity of acute urticaria (AU) is essential for adequate treatment of patients. However, there are no reliable biomarkers for such an evaluation. In our department, we observed patients with severe AU having elevated plasma D-dimer levels. Thus, the objective of this study was to investigate the elevated D-dimer levels in patients with severe AU in more detail. One hundred and thirty-nine hospital patients diagnosed with severe AU were enrolled. Clinical laboratory data were collected from electronic medical records. One hundred and seventeen of the patients presented with elevated plasma D-dimer levels. Compared to the normal group, the elevated group had a significantly higher proportion of patients who were female, younger, febrile, and had a shorter prehospital time (P < 0.05). Univariate regression analysis showed that neutrophil percentage, C-reactive protein (CRP), and lactate dehydrogenase (LDH) levels increased as D-dimer levels increased, while prehospital time showed the opposite trend. Multiple regression analysis was used to estimate the simultaneous effects of CRP and LDH on D-dimer levels. Patients who responded to additional antibiotic treatment had higher levels of D-dimer. The group with highly elevated D-dimer levels required a higher maximum dose of daily glucocorticoids (GCs) to control the symptoms of AU. In conclusion, patients with severe AU might have elevated plasma D-dimer levels, which are positively correlated with CRP and LDH levels. Patients with severe AU with dramatically elevated D-dimer levels might need a higher dose of daily GCs and antibiotics to relieve symptoms. D-dimer may be a reasonable marker to evaluate the severity of AU and guide treatment.

Pivmecillinam with Amoxicillin/Clavulanic acid as step down oral therapy in febrile Urinary Tract Infections caused by ESBL-producing Enterobacterales (PACUTI)

BackgroundOral treatment alternatives for febrile urinary tract infections are limited in the era of increasing antimicrobial resistance. We aim to evaluate if the combination of pivmecillinam and amoxicillin/clavulanic acid is non-inferior to current alternatives for step-down therapy in adult patients with febrile urinary tract infection.MethodsWe plan to perform an investigator-initiated non-inferiority trial. Adult hospitalised patients treated with 1–5 days of intravenous antibiotics for acute febrile urinary tract infection caused by extended spectrum beta-lactamase (ESBL) producing Enterobacterales will be randomised 1:1 to either control (7–10 days of either oral ciprofloxacin 500 mg twice daily or oral trimethoprim–sulfamethoxazole 800 mg/160 mg twice daily or intravenous ertapenem 1 g once daily, depending on sex, drug allergy, glomerular filtration rate and susceptibility testing) or intervention (10 days of pivmecillinam 400 mg three times daily and amoxicillin/clavulanic acid 500/125 mg three times daily). The primary outcome will be clinical cure 10 days (+/− 2 days) after antibiotic treatment completion. Clinical cure is defined as being alive with absence of fever and return to non-infected baseline of urinary tract symptoms without additional antibiotic treatment or re-hospitalisation (for urinary tract infection) based on a centralised allocation-blinded structured telephone interview. We plan to recruit 330 patients to achieve 90% power based on a sample size simulation analysis using a two-group comparison, one-sided alpha of 2.5%, an absolute non-inferiority margin of 10% and expecting 93% clinical cure rate and 10% loss to follow-up. The primary endpoint will be analysed using generalised estimated equations and reported as risk difference for both intention-to-treat and per protocol populations. Patients are planned to be recruited from at least 10 centres in Sweden from 2023 to 2026.DiscussionIf the combination of pivmecillinam and amoxicillin/clavulanic acid is found to be non-inferior to the control drugs there are potential benefits in terms of tolerability, frequency of interactions, outpatient treatment, side effects, nosocomial infections and drive for further antimicrobial resistance compared to existing drugs.Trial registrationNCT05224401. Registered on February 4, 2022

Implications of reducing antibiotic treatment duration for antimicrobial resistance in hospital settings: A modelling study and meta-analysis.

Reducing antibiotic treatment duration is a key component of hospital antibiotic stewardship interventions. However, its effectiveness in reducing antimicrobial resistance is uncertain and a clear theoretical rationale for the approach is lacking. In this study, we sought to gain a mechanistic understanding of the relation between antibiotic treatment duration and the prevalence of colonisation with antibiotic-resistant bacteria in hospitalised patients. We constructed 3 stochastic mechanistic models that considered both between- and within-host dynamics of susceptible and resistant gram-negative bacteria, to identify circumstances under which shortening antibiotic duration would lead to reduced resistance carriage. In addition, we performed a meta-analysis of antibiotic treatment duration trials, which monitored resistant gram-negative bacteria carriage as an outcome. We searched MEDLINE and EMBASE for randomised controlled trials published from 1 January 2000 to 4 October 2022, which allocated participants to varying durations of systemic antibiotic treatments. Quality assessment was performed using the Cochrane risk-of-bias tool for randomised trials. The meta-analysis was performed using logistic regression. Duration of antibiotic treatment and time from administration of antibiotics to surveillance culture were included as independent variables. Both the mathematical modelling and meta-analysis suggested modest reductions in resistance carriage could be achieved by reducing antibiotic treatment duration. The models showed that shortening duration is most effective at reducing resistance carriage in high compared to low transmission settings. For treated individuals, shortening duration is most effective when resistant bacteria grow rapidly under antibiotic selection pressure and decline rapidly when stopping treatment. Importantly, under circumstances whereby administered antibiotics can suppress colonising bacteria, shortening antibiotic treatment may increase the carriage of a particular resistance phenotype. We identified 206 randomised trials, which investigated antibiotic duration. Of these, 5 reported resistant gram-negative bacteria carriage as an outcome and were included in the meta-analysis. The meta-analysis determined that a single additional antibiotic treatment day is associated with a 7% absolute increase in risk of resistance carriage (80% credible interval 3% to 11%). Interpretation of these estimates is limited by the low number of antibiotic duration trials that monitored carriage of resistant gram-negative bacteria, as an outcome, contributing to a large credible interval. In this study, we found both theoretical and empirical evidence that reducing antibiotic treatment duration can reduce resistance carriage, though the mechanistic models also highlighted circumstances under which reducing treatment duration can, perversely, increase resistance. Future antibiotic duration trials should monitor antibiotic-resistant bacteria colonisation as an outcome to better inform antibiotic stewardship policies.

Prevalence of Trachoma in Pre-validation Surveillance Surveys in 11 Evaluation Units (Covering 12 Districts) in Oromia Regional State, Ethiopia: Results from 2018−2020

ABSTRACT Purpose Interventions to reduce the prevalence of trachoma and transmission of ocular Chlamydia trachomatis have been implemented in Oromia Region, Ethiopia. Following an impact survey in which the trachomatous inflammation—follicular (TF) prevalence in 1–9-year-olds is <5%, a surveillance survey is recommended 2 years later, without additional antibiotic treatment. We report results of surveillance surveys in 11 evaluation units (EUs) covering 12 districts in Oromia Region, to plan whether future interventions are needed. Method We use a two-stage cluster-sampling cross-sectional survey design. In each EU, 26 clusters (villages) were systematically selected with probability proportional to size; from each cluster, 30 households were selected using compact segment sampling. Water, sanitation and hygiene (WASH) access was assessed in all selected households. All residents of selected households aged ≥1 year were examined for TF and trachomatous trichiasis (TT) by certified graders. Result Of 31,991 individuals enumerated, 29,230 (91% of) individuals were examined. Eight EUs had an age-adjusted TF prevalence in 1−9-year-olds of ≥5% and seven had a TT prevalence unknown to the health system among adults aged ≥15 years of ≥0.2%. About one-third of visited households had access to an improved water source for drinking, and 5% had access to an improved latrine. Conclusion Despite TF reductions to <5% at impact survey, prevalence recrudesced to ≥5% in all but three of the 11 EUs. Operational research is needed to understand transmission dynamics and epidemiology, in order to optimise elimination strategies in high-transmission settings like these.

Retained pregnancy tissue after miscarriage is associated with high rate of chronic endometritis

The objective of this study was to evaluate prevalence of chronic endometritis in a cohort of patients with retained pregnancy tissue (RPT) following miscarriage, with and without a history of recurrent pregnancy loss (RPL). In a cohort of our single academic fertility centre, we evaluated women with unexplained RPL (two or more losses) without evidence of RPT and women undergoing hysteroscopic resection of RPT following miscarriage. Endometrial samples underwent staining with H and E and CD138. A pathologist blinded to patient history recorded the number of plasma cells per 10 high power fields (HPF) and the presence or absence of endometrial stromal changes. Our main outcome measure was to measure the prevalence of chronic endometritis. Endometrial samples from 50 women with RPT following miscarriage and 50 women with unexplained RPL without evidence of RPT were reviewed. The prevalence of chronic endometritis was significantly higher in the RPT cohort (62% versus 30%). A multivariable regression demonstrated significantly higher odds of chronic endometritis in the RPT cohort, aOR 7.3 (95% CI 2.1, 25.5). We conclude that women with RPT following pregnancy loss have a high rate of chronic endometritis, suggesting that RPT is a risk factor for this disorder. Impact Statement What is already known on this subject? Known risk factors for chronic endometritis include a history of pelvic inflammatory disease, intrauterine polyps and fibroids. The aetiology for increased chronic endometritis among women with RPL is unknown. What do the results of this study add? The prevalence of chronic endometritis is significantly higher among women with retained pregnancy tissue (RPT) following miscarriage compared to women with RPL. These data presented suggest that RPT is associated with chronic endometritis among women with a history of miscarriage. What are the implications of these findings for clinical practice and/or further research? We suggest a pathologic evaluation for chronic endometritis be performed on all patients who undergo hysteroscopic resection of RPT following miscarriage. Our findings also suggest that a uterine cavity evaluation with hysteroscopy to evaluate for RPT may be reasonable in women with a history of miscarriage who are found to have chronic endometritis on endometrial biopsy. Further research is needed to determine if resection of retained tissue is sufficient to treat RPOC associated chronic endometritis, or if additional antibiotic treatment is necessary.

Factors Associated With Treatment Failure in Moderately Severe Community-Acquired Pneumonia

Failure of treatment is the most serious complication in community-acquired pneumonia (CAP). To assess the potential risk factors for treatment failure in clinically stable patients with CAP. This secondary analysis assesses data from a randomized clinical trial on CAP (Pneumonia Short Treatment [PTC] trial) conducted from December 19, 2013, to February 1, 2018. Data analysis was performed from July 18, 2019, to February 15, 2020. Patients hospitalized at 1 of 16 centers in France for moderately severe CAP who were clinically stable at day 3 of antibiotic treatment were included in the PTC trial and analyzed in the per-protocol trial population. Patients were randomly assigned (1:1) on day 3 of antibiotic treatment to receive β-lactam (amoxicillin-clavulanate [1 g/125 mg] 3 times daily) or placebo for 5 extra days. The main outcome was failure at 15 days after first antibiotic intake, defined as a temperature greater than 37.9 °C and/or absence of resolution or improvement of respiratory symptoms and/or additional antibiotic treatment for any cause. The association among demographic characteristics, baseline clinical and biological variables available (ie, at the first day of β-lactam treatment), and treatment failure at day 15 among the per-protocol trial population was assessed by univariate and multivariable logistic regressions. Overall, 310 patients were included in the study; this secondary analysis comprised 291 patients (174 [59.8%] male; mean [SD] age, 69.6 [18.5] years). The failure rate was 26.8%. Male sex (odds ratio [OR], 1.74; 95% CI, 1.01-3.07), age per year (OR, 1.03; 95% CI, 1.01-1.05), Pneumonia Severe Index score (OR, 1.01; 95% CI, 1.00-1.02), the presence of chronic lung disease (OR, 1.85; 95% CI, 1.03-3.30), and creatinine clearance (OR, 0.99; 95% CI, 0.98-1.00) were significantly associated with failure in the univariate analysis. When the Pneumonia Severe Index score was excluded to avoid collinearity with age and sex in the regression model, only male sex (OR, 1.92; 95% CI, 1.08-3.49) and age (OR, 1.02; 95% CI, 1.00-1.05) were associated with failure in the multivariable analysis. In this secondary analysis of a randomized clinical trial, among patients with CAP who reached clinical stability after 3 days of antibiotic treatment, only male sex and age were associated with higher risk of failure, independent of antibiotic treatment duration and biomarker levels. Another randomized clinical trial is needed to evaluate the impact of treatment duration in populations at higher risk for treatment failure.

Treatment of bone and joint infections by ceftazidime/avibactam and ceftolozane/tazobactam: a cohort study

Ceftazidime/avibactam (C/A) and ceftolozane/tazobactam (C/T) are two novel antibacterials with known efficacy against Gram-negative bacteria (GNB). We aimed to describe the efficacy and safety of surgical management combined with C/A or C/T treatment for bone and joint infections (BJIs). We conducted an observational, bicentric study of patients treated with C/A or C/T for a BJI between May 2016 and June 2019. Failure was defined as the need for unplanned additional antibiotic treatment or orthopaedic surgery, or death due to the BJI up to the patient's latest visit. Overall, 15 patients were included. Nine patients were treated with C/A, mainly for polymicrobial BJI due to multidrug-resistant (MDR) bacteria (Enterobacteriaceae, n=7). Six patients were male, the median age was 66 years and the median Charlson comorbidity index (CCI) was 5. It was the first septic episode at the site in 3/9 patients. The cure rate was 7/9 (median follow-up, 272 days). Two patients showed C/A-related confusion. Five patients were treated with C/T for BJI involving MDR Pseudomonas aeruginosa. Four patients were male, the median age was 53 years and the median CCI was 2. All patients had previous septic episodes at the infection site. The cure rate was 3/5 (median follow-up, 350 days). One patient was successfully treated by C/T then C/A for multistage spondylodiscitis. In our experience, C/A and C/T are two effective and safe options, even as salvage treatment for BJI due to MDR-GNB despite the absence of label, however more data are warranted.

Case Report: Cold Atmospheric Plasma as a Treatment Option for Superficial Wound Healing Disorders after Heart Transplantation

Introduction Superficial wound healing disorders (SWD) after heart transplantation (HTx) remain challenging due to continuous immunosuppression. Cold atmospheric plasma (CAP) is a partially ionized plasma, which has shown to have a beneficial effect on skin regeneration and microbial inactivation. The aim of this case report is to demonstrate an example of successful use of CAP as a supportive treatment for SWD after HTx. Case Report We present our single-center experience of two female patients (18 and 39 years) with SWD three and eight weeks after HTx. Both patients were transplanted due to dilatative cardiomyopathy and immunosuppression consisted of a combination of tacrolimus, mycophenolate mofetil and steroids for both patients. HTx was performed according to institutional guidelines and the early postoperative course was uneventful. Starting on the day of SWD diagnosis, CAP was performed as a standard therapy scheme of 5 minutes per treatment twice weekly for a total of three weeks. Both patients were schooled for adequate wound management including daily change of wound dressings.Both SWD presented as a superficial apical dehiscence of the midline incision and wound swabs showed no growth throughout the treatment. After three weeks of CAP treatment, the wounds were completely epithelialized and showed no more signs of infection without need for additional local or systemic antibiotic or surgical treatment. There were no adverse side effects of CAP therapy observed and the therapy was tolerated well by both patients. Summary CAP showed to be a safe and feasible treatment option for superficial SWD despite immunosuppressive therapy with no need for further surgery, anti-infective therapy or reduction of immunosuppression. Due to convincing results, CAP could be a safe treatment option for SWD after HTx and should be investigated further.

Discontinuing β-lactam treatment after 3 days for patients with community-acquired pneumonia in non-critical care wards (PTC): a double-blind, randomised, placebo-controlled, non-inferiority trial

Shortening the duration of antibiotic therapy for patients admitted to hospital with community-acquired pneumonia should help reduce antibiotic consumption and thus bacterial resistance, adverse events, and related costs. We aimed to assess the need for an additional 5-day course of β-lactam therapy among patients with community-acquired pneumonia who were stable after 3 days of treatment. We did this double-blind, randomised, placebo-controlled, non-inferiority trial (the Pneumonia Short Treatment [PTC]) in 16 centres in France. Adult patients (aged ≥18 years) admitted to hospital with moderately severe community-acquired pneumonia (defined as patients admitted to a non-critical care unit) and who met prespecified clinical stability criteria after 3 days of treatment with β-lactam therapy were randomly assigned (1:1) to receive β-lactam therapy (oral amoxicillin 1 g plus clavulanate 125 mg three times a day) or matched placebo for 5 extra days. Randomisation was done using a web-based system with permuted blocks with random sizes and stratified by randomisation site and Pneumonia Severity Index score. Participants, clinicians, and study staff were masked to treatment allocation. The primary outcome was cure 15 days after first antibiotic intake, defined by apyrexia (temperature ≤37·8°C), resolution or improvement of respiratory symptoms, and no additional antibiotic treatment for any cause. A non-inferiority margin of 10 percentage points was chosen. The primary outcome was assessed in all patients who were randomly assigned and received any treatment (intention-to-treat [ITT] population) and in all patients who received their assigned treatment (per-protocol population). Safety was assessed in the ITT population. This study is registered with ClinicalTrials.gov, NCT01963442, and is now complete. Between Dec 19, 2013, and Feb 1, 2018, 706 patients were assessed for eligibility, and after 3 days of β-lactam treatment, 310 eligible patients were randomly assigned to receive either placebo (n=157) or β-lactam treatment (n=153). Seven patients withdrew consent before taking any study drug, five in the placebo group and two in the β-lactam group. In the ITT population, median age was 73·0 years (IQR 57·0-84·0) and 123 (41%) of 303 participants were female. In the ITT analysis, cure at day 15 occurred in 117 (77%) of 152 participants in the placebo group and 102 (68%) of 151 participants in the β-lactam group (between-group difference of 9·42%, 95% CI -0·38 to 20·04), indicating non-inferiority. In the per-protocol analysis, 113 (78%) of 145 participants in the placebo treatment group and 100 (68%) of 146 participants in the β-lactam treatment group were cured at day 15 (difference of 9·44% [95% CI -0·15 to 20·34]), indicating non-inferiority. Incidence of adverse events was similar between the treatment groups (22 [14%] of 152 in the placebo group and 29 [19%] of 151 in the β-lactam group). The most common adverse events were digestive disorders, reported in 17 (11%) of 152 patients in the placebo group and 28 (19%) of 151 patients in the β-lactam group. By day 30, three (2%) patients had died in the placebo group (one due to bacteraemia due to Staphylococcus aureus, one due to cardiogenic shock after acute pulmonary oedema, and one due to heart failure associated with acute renal failure) and two (1%) in the β-lactam group (due to pneumonia recurrence and possible acute pulmonary oedema). Among patients admitted to hospital with community-acquired pneumonia who met clinical stability criteria, discontinuing β-lactam treatment after 3 days was non-inferior to 8 days of treatment. These findings could allow substantial reduction of antibiotic consumption. French Ministry of Health.

Pseudomonas aeruginosa Elastase Contributes to the Establishment of Chronic Lung Colonization and Modulates the Immune Response in a Murine Model.

Chronic infection by Pseudomonas aeruginosa in cystic fibrosis (CF) patients is a major contributor to progressive lung damage and is poorly treated by available antibiotic therapy. An alternative approach to the development of additional antibiotic treatments is to identify complementary therapies which target bacterial virulence factors necessary for the establishment and/or maintenance of the chronic infection. The P. aeruginosa elastase (LasB) has been suggested as an attractive anti-virulence target due to its extracellular location, its harmful degradative effects on host tissues and the immune system, and the potential to inhibit its activity using small molecule inhibitors. However, while the relevance of LasB in acute P. aeruginosa infection has been demonstrated, it is still unclear whether this elastase might also play a role in the early phase of chronic lung colonization. By analyzing clinical P. aeruginosa clonal isolates from a CF patient, we found that the isolate RP45, collected in the early phase of persistence, produces large amounts of active LasB, while its clonal variant RP73, collected after years of colonization, does not produce it. When a mouse model of persistent pneumonia was used, deletion of the lasB gene in RP45 resulted in a significant reduction in mean bacterial numbers and incidence of chronic lung colonization at Day 7 post-challenge compared to those mice infected with wild-type (wt) RP45. Furthermore, deletion of lasB in strain RP45 also resulted in an increase in immunomodulators associated with innate and adaptive immune responses in infected animals. In contrast, deletion of the lasB gene in RP73 did not affect the establishment of chronic infection. Overall, these results indicate that LasB contributes to the adaptation of P. aeruginosa to a persistent lifestyle. In addition, these findings support pharmacological inhibition of LasB as a potentially useful therapeutic intervention for P. aeruginosa-infected CF patients prior to the establishment of a chronic infection.

Efficacy of fosfomycin in the prevention of postoperative infection following transurethral resection of bladder tumor during periods of limited cefazolin, cefotiam, and cefmetazole supply

IntroductionIn March 2019, cefazolin availability was limited owing to the contamination of the drug substance. In addition, there was a difficulty in supplying drugs alternative to cefazolin, such as cefotiam and cefmetazole. In our Department of Nephro-urology, we used fosfomycin-based drugs to substitute cefazolin as perioperative preventive antibacterial drugs. In this study, we aimed to evaluate the usage status of perioperative prophylactic antibacterial drugs before and after the period of limited cefazolin supply and to investigate the efficacy and safety of fosfomycin sodium in preventing infections following transurethral resection of bladder tumor. MethodsWe enrolled 346 patients who underwent transurethral resection of bladder tumor in our department from April 2018 to August 2020. The patients received the following perioperative antibacterial agents: cefotiam (n = 146), fosfomycin (n = 166), and other antibacterial agents (n = 34). There was no significant difference in the median age or surgery time. ResultsThe median length of hospital stay was 6, 5, and 5 days in the cefotiam, fosfomycin, and other antibacterial groups, respectively, with significant difference. The median maximum postoperative temperature was 37.1 °C in all groups, with no significant difference. There were no differences in C-reactive protein, aspartate aminotransferase, and alanine aminotransferase levels determined by postoperative blood tests; preoperative and postoperative urinary white blood cell counts; preoperative urine bacterial counts; and surgery-related infection requiring additional antibiotic treatments among the groups. ConclusionsThe use of fosfomycin-based agents helped overcome the limited supply of cefazolin without worsening clinical outcomes.

Efficacy and safety of azithromycin maintenance therapy in primary ciliary dyskinesia (BESTCILIA): a multicentre, double-blind, randomised, placebo-controlled phase 3 trial

Use of maintenance antibiotic therapy with the macrolide azithromycin is increasing in a number of chronic respiratory disorders including primary ciliary dyskinesia (PCD). However, evidence for its efficacy in PCD is lacking. We aimed to determine the efficacy and safety of azithromycin maintenance therapy for 6 months in patients with PCD. The Better Experimental Screening and Treatment for Primary Ciliary Dyskinesia (BESTCILIA) trial was a multicentre, double-blind, parallel group, randomised, placebo-controlled phase 3 trial done at 6 European PCD clinics (tertiary paediatric care centres and university hospitals in Denmark, Germany, Netherlands, Switzerland, and UK). Patients with a confirmed diagnosis of PCD, aged 7-50 years old, and predicted FEV1 greater than 40% were recruited. Participants were randomly assigned (1:1), stratified by age and study site, via a web-based randomisation system to azithromycin 250 mg or 500 mg as tablets according to bodyweight (</≥ 40 kg) or identical placebo, three times a week for 6 months. The random allocation sequence was a permuted block randomisation, with a block size of four, generated by an external consultancy. Participants, investigators, and care providers were masked to treatment allocation. The primary endpoint was the number of respiratory exacerbations over 6 months. Analysis was by intention to treat. This study is registered in the EU Clinical Trials Register, EudraCT number 2013-004664-58. Between June 24, 2014, and Aug 23, 2016, 102 patients were screened, of whom 90 were randomly assigned to either azithromycin (n=49) or placebo (n=41). The study was ended without having included the planned number of participants due to recruitment difficulties. The mean number of respiratory exacerbations over 6 months was 0·75 (SD 1·12) in the azithromycin group compared with 1·62 (1·64) in the placebo group, and participants receiving azithromycin had significantly lower rate of exacerbations during the individual treatment periods (rate ratio 0·45 [95% CI 0·26-0·78]; p=0·004). Four serious adverse events were reported, occurring in one (2%) of 47 participants in the azithromycin group and in three (7%) of 41 participants in the placebo group. Loose stools or diarrhoea were more common in the azithromycin group than in the placebo group (11 [23%] vs two [5%]). This first multinational randomised controlled trial on pharmacotherapy in PCD showed that azithromycin maintenance therapy for 6 months was well tolerated and halved the rate of respiratory exacerbations. Azithromycin maintenance therapy is an option for patients with PCD with frequent exacerbations potentially leading to reduced need for additional antibiotic treatments and preventing irreversible lung damage. European Commission Seventh Framework Programme and Children's Lung Foundation (Denmark).

Indication for an additional postoperative antibiotic treatment after surgical incision of serious odontogenic abscesses

IntroductionSerious abscesses of an odontogenic origin occur frequently in the oral and maxillofacial surgery departments. Rapid surgical incision and drainage constitutes the most important therapeutic action. However, additional surgical therapy and supplementary administration of antibiotics is often carried out, such that the efficiency of this supplementary therapeutic option has been questioned. MethodsAll patients with severe odontogenic infections who received surgical treatment under general anaesthesia were recruited to this retrospective study. We determined whether they received additional antibiotic therapy on the ward and if it was possible to improve therapeutic outcomes using this option. ResultsA total of 258 patients with a severe odontogenic infection between January 2008 and August 2014 were included. The most frequent infection observed was a submandibular abscess (56%), followed by a perimandibular abscess (18%) and a submental abscess (9%). About 65% of the patients were treated with antibiotics in addition to surgery. The median CRP level prior to surgical treatment was 87.8 mg/l (Q1: 40.3 mg/l; Q3: 143.5 mg/l) in patients who were administered an additional antibiotic and 83.8 mg/l (Q1: 37.3 mg/l; Q3: 135.0 mg/l) in those who received no antibiotic treatment after surgery. The postoperative median CRP levels were 116.5 mg/l (Q1: 52.1 mg/l; Q3: 159.3 mg/l) and 106.5 mg/l (Q1: 40.6 mg/l; Q3: 152.6 mg/l), respectively. Neither the preoperative CRP level (p = 0.546) nor the postoperative CRP level (p = 0.450) differed significantly between the groups. But patients who received additional antibiotic therapy had a significantly longer hospital stay (median: 6 days; range: 1–22 days) than patients who had no additional antibiotic therapy (median: 4 days; range: 1–19 days) (p = 0.002). ConclusionsThis study did not show an improvement in the therapeutic outcome with administration of supplementary antibiotics in addition to surgery. Thus, surgically incising an abscess is the most important therapeutic action and administration of antibiotics must be critically scrutinised.

Sclerotherapy With OK-432 for the Treatment of Symptomatic Lymphocele After Lymph Node Dissection: A Retrospective Comparative Cohort Study.

This study aimed to determine the benefits of sclerotherapy with OK-432 for the treatment of postoperative chronic lymphocele. Postoperative chronic lymphocele formation is common and accounts for a high postoperative morbidity. Nonsurgical strategies comprise repetitive percutaneous fluid aspiration or percutaneous sclerotherapy. OK-432 has been used to treat congenital lymphatic malformations with several reports of promising results. We hypothesized that it is more beneficial than repetitive percutaneous fluid aspiration for the treatment of symptomatic lymphocele. Two cohorts of melanoma patients who developed recurrent lymphocele after lymph node dissection from January 2013 to August 2017 were compared. The first cohort was treated with repetitive percutaneous fluid aspiration (n = 20). The second cohort received OK-432 sclerotherapy (n = 20). Primary end points were overall treatment duration, number of treatment sessions, and the clinical success in both cohorts. Secondary end points were surgical site infection rate, need for additional antibiotic treatment, wound healing disorders, and the need for revision surgery. Mean overall duration of treatment with sclerotherapy was significantly shorter than with repetitive aspiration (9.4 ± 7.2 vs 47.5 ± 31.9 days, P < 0.01). Mean number of sclerotherapy treatment sessions were 2.5 ± 1.2. Clinical success with OK-432 was 19 of 20, and that with repeated aspiration was 7 of 20 (χ = 15.82, P < 0.001). No surgical site infection occurred in the sclerotherapy cohort, which was significantly lower than those treated with repetitive aspiration (P < 0.03). Surgical revision was mandatory in 12 of 20 patients who were treated with repetitive aspiration, and only 1 of 20 patients in the sclerotherapy cohort. Sclerotherapy with OK-432 for the treatment of postoperative lymphocele is highly beneficial with a significant reduction of morbidity and the overall treatment time compared with repetitive aspiration.

Local administration of the powder minocycline during surgical intervention for active infective endocarditis.

We retrospectively assessed the initial clinical impact of the locally administered bacteriostatic antibiotic, powder minocycline, during surgery for active infective endocarditis (AIE). Among 38 surgical AIE patients, 36 patients who underwent surgical intervention for AIE using local administration of powder minocycline between January 2008 and August 2017 in our institute were enrolled. During surgery, the local administration and dispersion of powder minocycline at not only the valvular annulus and perivalvular cavity, but also the prosthetic cuff and ring were performed following the complete resection and aggressive debridement of infectious tissues. Early clinical outcomes, including survival, postoperative co-morbidities, and freedom from re-intervention or significant paravalvular leakage (PVL), were assessed. Early mortality within 30days was 5.6% and hospital death was 13.9%. There was no reoperation within 30days and only one patient (3.8%) developed recurrent infection, which improved with additional antibiotic treatments. More than moderate PVL within 30days was detected in one patient only (3.8%). Over a median follow-up period of 38.3 ± 35.5months, a Kaplan-Meier analysis revealed that 1- and 5-year survival rates were 75.7 and 66.8%, respectively, and freedom from reoperation was 100% at 5years. Freedom from significant PVL at 5years was 91.0%. The local administration of powder minocycline may be a simple and effective manipulation during surgical intervention for AIE without extensive reconstruction; however, the surgical management of AIE remains challenging.

Weekly Sequential Antibioprophylaxis for Recurrent Urinary Tract Infections Among Patients With Neurogenic Bladder: A Randomized Controlled Trial

Recurrent urinary tract infections (R-UTIs) are the main cause of morbidity and hospitalizations in subjects with neurogenic bladder (NB) due to spinal cord injury (SCI). We evaluated the efficacy of weekly oral cyclic antibiotic (WOCA) prophylaxis (ie, the alternate weekly administration of 2 antibiotics) in preventing R-UTIs. Randomized (1:1), open-label, superiority-controlled trial compared WOCA prophylaxis to no prophylaxis (control) for 6 months in patients with NB due to SCI, using clean intermittent self-catheterization, and suffering from R-UTIs. Primary outcome was incidence of symptomatic antibiotic-treated UTIs. Secondary outcomes were number of febrile UTIs, number of hospitalizations, WOCA tolerance, antibiotic consumption, number of negative urine cultures, and emergence of bacterial resistance in urinary, intestinal, and nasal microbiota. Forty-five patients were either allocated to the WOCA group (n = 23) or the control group (n = 22). Median (IQR) incidence of symptomatic antibiotic-treated UTIs was 1.0 (0.5-2.5) in the WOCA group versus 2.5 (1.2-4.0) (P = .0241) in the control group. No febrile UTIs were recorded in the WOCA group versus 9 (45.0%) (P < .001) in the control group. The median number of additional antibiotic treatment was 0.0 (IQR, 0.0-2.0) versus 3.0 (2.0-5.0) (P = .004) in the WOCA and control groups, respectively. Only few adverse events were reported. No impact on emergence of bacterial resistance was observed. WOCA is efficient and well tolerated in preventing R-UTIs in SCI patients. In our study, we did not observe any emergence of antibiotic resistance in digestive and nasal microbiological cultures. NCT01388413.

Double-blind, placebo-controlled, randomized trial on low-dose azithromycin prophylaxis in patients with primary antibody deficiencies

Lacking protective antibodies, patients with primary antibody deficiencies (PADs) experience frequent respiratory tract infections, leading to chronic pulmonary damage. Macrolide prophylaxis has proved effective in patients with chronic respiratory diseases. We aimed to test the efficacy and safety of orally administered low-dose azithromycin prophylaxis in patients with PADs. We designed a 3-year, double-blind, placebo-controlled, randomized clinical trial to test whether oral azithromycin (250mg administered once daily 3 times a week for 2years) would reduce respiratory exacerbations in patients with PADs and chronic infection-related pulmonary diseases. The primary end point was the number of annual respiratory exacerbations. Secondary end points included time to first exacerbation, additional antibiotic courses, number of hospitalizations, and safety. Eighty-nine patients received azithromycin (n=44) or placebo (n=45). The number of exacerbations was 3.6 (95% CI, 2.5-4.7) per patient-year in the azithromycin arm and 5.2 (95% CI, 4.1-6.4) per patient-year in the placebo arm (P=.02). In the azithromycin group the hazard risk for having an acute exacerbation was 0.5 (95% CI, 0.3-0.9; P=.03), and the hazard risk for hospitalization was 0.5 (95% CI, 0.2-1.1; P=.04). The rate of additional antibiotic treatment per patient-year was 2.3 (95% CI, 2.1-3.4) in the intervention group and 3.6 (95% CI, 2.9-4.3) in the placebo group (P=.004). Haemophilus influenzae and Streptococcus pneumoniae were the prevalent isolates, and they were not susceptible to macrolides in 25% of patients of both arms. Azithromycin's safety profile was comparable with that of placebo. The study reached the main outcome centered on the reduction of exacerbation episodes per patient-year, with a consequent reduction in additional courses of antibiotics and risk of hospitalization.

Oral Azitromycin Prophylaxis, 250 Mg Once Daily Three-Times a Week, in Primary Antibody Deficiencies: A Multicenter, Double-Blind, Placebo-Controlled Randomized Clinical Trial

Background. Lacking protective antibodies, patients with Primary Antibody Deficiencies (PAD) suffer from frequent respiratory infections leading chronic pulmonary damage. Macrolides prophylaxis has been proven effective in chronic respiratory diseases, including chronic obstructive pulmonary disease, cystic fibrosis, and non-cystic fibrosis bronchiectasis. We aimed to test the efficacy and safety of orally administered low-dose azithromycin prophylaxis in PAD patients with chronic infection-related pulmonary diseases. Methods. A 3-year, randomized, double-blind, placebo-controlled trial was conducted in seven Italian immunology units. Eligible patients were aged 18-74 years, had a diagnosis of PAD with chronic infection-related pulmonary disease. Patients were randomly assigned (1:1) to receive azithromycin 250 mg once daily three-times a week for 2 years, or placebo. The primary outcome was the number of annual episodes of respiratory exacerbations. Secondary endpoints included time to the first exacerbation, additional doses of antibiotics to treat exacerbations, number of hospitalizations. Analysis was performed by modified intention to treat. This trial is registered with the Agenzia Italiana del Farmaco, Clinical Trials number: EUDRACT 2011-004351-39. Findings. Between November 2012 and December 2016, 90 patients were enrolled. We randomly assigned 89 patients to receive azithromycin (n=44) or placebo (n=45); 89 participants were comprised the modified intention-to-treat population. The number of exacerbations was 3·6 per patient-year (95%CI 2·5-4·7) in the azithromycin arm, and 5·2 (95%CI 4·1-6·4) in the placebo arm (p=0·02). In the azithromycin group the HR for having an acute exacerbation was 0·5 (95%CI 0·3-0·9, p=0·03) and the HR for hospitalization was 0.5 (95%CI 0·2-1·1) (p=0·04). The rate of additional antibiotic treatment per patient-year was 2·3 (95%CI 2·1-3·4) in the intervention and 3·6 (95%CI 2·9-4·3) in placebo groups (p=0·004). Four patients receiving placebo and none receiving azithromycin reported drug-related adverse events leading to treatment discontinuation. H.influenzae and S.pneumoniae were the prevalent isolates and they were non-susceptible to macrolides in 25% of patients of both arms. Interpretation. The study reached the main outcome centered in the reduction of exacerbation episodes per patient-year, leading to reduction of additional courses of antibiotics, and of risk of hospitalization. Adding azithromycin to the treatment regimen of PAD with respiratory exacerbation should be considered as a valuable option. Trial Registration Number: This trial is registered with the Agenzia Italiana del Farmaco, Clinical Trials number: EUDRACT 2011-004351-39. Funding. AIFA, Agenzia Italiana del Farmaco. Declaration of Interest: IQ and AP receipt of consultation fees and grants by Shire, CSL Behring, Octapharma and Kedrion; CA and AM receipt of consultation fees by Shire, Roche, CSL Behring, Octapharma, Novartis. CM, FP, FC, AP, MC, GL, VL, GF, BM, ST, DA, AS, GS, RMD and AV had none conflict of interest. Ethical Approval: The study protocol (EUDRACT: 2011-004351-39) was reviewed and approved by the Ethical Review Committee of Sapienza, University of Rome, Italy.

Comparison of the clinical and microbiological effects of antibiotic therapy in periodontal pockets following laser treatment: An in vivo study.

Laser technology in periodontal therapy could help in reducing total bacterial count. The aim of this study was to evaluate the effects of pocket debridement using an erbium-doped yttrium aluminium garnet laser (Er:YAG laser - ERL), scaling and root planing (SRP) with photodynamic therapy (PDT), or SRP alone. Teeth vitality and soft tissue carbonization were also assessed. This study included 1,169 single-rooted teeth from 84 patients divided into 3 groups (n = 28). The G1 group had ERL with 40 mJ of energy, a frequency of 40 Hz and a fluence of 63.66 J/cm2. The G2 group had SRP + PDT (635 nm diode laser, 12 J of energy and irradiation time of 30 s) and a Toluidine Blue photosensitizer (PS) (application time of 60 s). The G3 group was administered SRP alone. In the 42 subjects (G1: n = 11, G2: n = 14 and G3: n = 17) with high amounts of Aggregatibacter actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg), Treponema denticola (Td) and Tannerella forsythia (Tf), additional 1-week antibiotic treatments with clindamycin or amoxicillin + clavulanic acid - in doses of 600 mg/day or 1000 mg/day, respectively - were prescribed 3 months after the therapy. Microbiological and clinical analyses of the probing depth (PD), recession (RC), plaque index (PI), bleeding on probing (BOP), and attachment loss (AT) were performed at baseline and at the follow-up of 3 months, 3 months and 1 week, and 6 months. Plaque index decreased in G1 after 3 months, 3 months and 1 week, and 6 months (p < 0.05) and was lower in G1 vs G2 after 3 months (p < 0.05). The reduction in BOP in G1 after 3 months and 1 week was higher in comparison with G2 or G3 (p < 0.02). Probing depth decreased in all groups (p < 0.05). We found a reduction in the percentage of sites with some bacteria after 3 months - Prevotella intermedia (Pi) (G1 and G2), Capnocytophaga gingivalis (Cg) and Eubacterium nucleatum (En) (G3), and after 3 months and 1 week with En, Td, Tf (G1, G2 and G3), Pi (G1 and G2), Aa, Peptostreptococcus micros (Pm), and Cg (G3), and with Pi (G1 and G2), Tf (G2), Pg, En (G2 and G3), and Pm (G3) after 6 months (p < 0.05). We observed no signs of carbonization or teeth injury. Scaling and root planing + PDT and ERL may be an alternative therapy for chronic periodontitis.