Long-Term Oxygen Therapy for 24 or 15 Hours per Day in Severe Hypoxemia.

BACKGROUND: Long-term oxygen supplementation for at least 15 hours per day prolongs survival among patients with severe hypoxemia. On the basis of a nonrandomized comparison, long-term oxygen therapy has been recommended to be used for 24 hours per day, a more burdensome regimen. METHODS: To test the hypothesis that long-term oxygen therapy used for 24 hours per day does not result in a lower risk of hospitalization or death at 1 year than therapy for 15 hours per day, we conducted a multicenter, registry-based, randomized, controlled trial involving patients who were starting oxygen therapy for chronic, severe hypoxemia at rest. The patients were randomly assigned to receive long-term oxygen therapy for 24 or 15 hours per day. The primary outcome, assessed in a time-to-event analysis, was a composite of hospitalization or death from any cause within 1 year. Secondary outcomes included the individual components of the primary outcome assessed at 3 and 12 months. RESULTS: Between May 18, 2018, and April 4, 2022, a total of 241 patients were randomly assigned to receive long-term oxygen therapy for 24 hours per day (117 patients) or 15 hours per day (124 patients). No patient was lost to follow-up. At 12 months, the median patient-reported daily duration of oxygen therapy was 24.0 hours (interquartile range, 21.0 to 24.0) in the 24-hour group and 15.0 hours (interquartile range, 15.0 to 16.0) in the 15-hour group. The risk of hospitalization or death within 1 year in the 24-hour group was not lower than that in the 15-hour group (mean rate, 124.7 and 124.5 events per 100 person-years, respectively; hazard ratio, 0.99; 95% confidence interval [CI], 0.72 to 1.36; 90% CI, 0.76 to 1.29; P = 0.007 for nonsuperiority). The groups did not differ substantially in the incidence of hospitalization for any cause, death from any cause, or adverse events. CONCLUSIONS: Among patients with severe hypoxemia, long-term oxygen therapy used for 24 hours per day did not result in a lower risk of hospitalization or death within 1 year than therapy for 15 hours per day. (Funded by the Crafoord Foundation and others; REDOX ClinicalTrials.gov number, NCT03441204.).

Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease.

BACKGROUND: The combination of ibrutinib and venetoclax has been shown to improve outcomes in patients with chronic lymphocytic leukemia (CLL) as compared with chemoimmunotherapy. Whether ibrutinib-venetoclax and personalization of treatment duration according to measurable residual disease (MRD) is more effective than fludarabine-cyclophosphamide-rituximab (FCR) is unclear. METHODS: In this phase 3, multicenter, randomized, controlled, open-label platform trial involving patients with untreated CLL, we compared ibrutinib-venetoclax and ibrutinib monotherapy with FCR. In the ibrutinib-venetoclax group, after 2 months of ibrutinib, venetoclax was added for up to 6 years of therapy. The duration of ibrutinib-venetoclax therapy was defined by MRD assessed in peripheral blood and bone marrow and was double the time taken to achieve undetectable MRD. The primary end point was progression-free survival in the ibrutinib-venetoclax group as compared with the FCR group, results that are reported here. Key secondary end points were overall survival, response, MRD, and safety. RESULTS: A total of 523 patients were randomly assigned to the ibrutinib-venetoclax group or the FCR group. At a median of 43.7 months, disease progression or death had occurred in 12 patients in the ibrutinib-venetoclax group and 75 patients in the FCR group (hazard ratio, 0.13; 95% confidence interval [CI], 0.07 to 0.24; P<0.001). Death occurred in 9 patients in the ibrutinib-venetoclax group and 25 patients in the FCR group (hazard ratio, 0.31; 95% CI, 0.15 to 0.67). At 3 years, 58.0% of the patients in the ibrutinib-venetoclax group had stopped therapy owing to undetectable MRD. After 5 years of ibrutinib-venetoclax therapy, 65.9% of the patients had undetectable MRD in the bone marrow and 92.7% had undetectable MRD in the peripheral blood. The risk of infection was similar in the ibrutinib-venetoclax group and the FCR group. The percentage of patients with cardiac serious adverse events was higher in the ibrutinib-venetoclax group than in the FCR group (10.7% vs. 0.4%). CONCLUSIONS: MRD-directed ibrutinib-venetoclax improved progression-free survival as compared with FCR, and results for overall survival also favored ibrutinib-venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.).

Therapy duration and improvement of ventricular function in de novo heart failure: the Heart Failure Optimization study.

BACKGROUND AND AIMS: In patients with de novo heart failure with reduced ejection fraction (HFrEF), improvement of left ventricular ejection fraction (LVEF) is expected to occur when started on guideline-recommended medical therapy. However, improvement may not be completed within 90 days. METHODS: Patients with HFrEF and LVEF ≤ 35% prescribed a wearable cardioverter-defibrillator between 2017 and 2022 from 68 sites were enrolled, starting with a registry phase for 3 months and followed by a study phase up to 1 year. The primary endpoints were LVEF improvement > 35% between Days 90 and 180 following guideline-recommended medical therapy initiation and the percentage of target dose reached at Days 90 and 180. RESULTS: A total of 598 patients with de novo HFrEF [59 years (interquartile range 51-68), 27% female] entered the study phase. During the first 180 days, a significant increase in dosage of beta-blockers, renin-angiotensin system inhibitors, and mineralocorticoid receptor antagonists was observed (P < .001). At Day 90, 46% [95% confidence interval (CI) 41%-50%] of study phase patients had LVEF improvement > 35%; 46% (95% CI 40%-52%) of those with persistently low LVEF at Day 90 had LVEF improvement > 35% by Day 180, increasing the total rate of improvement > 35% to 68% (95% CI 63%-72%). In 392 patients followed for 360 days, improvement > 35% was observed in 77% (95% CI 72%-81%) of the patients. Until Day 90, sustained ventricular tachyarrhythmias were observed in 24 wearable cardioverter-defibrillator carriers (1.8%). After 90 days, no sustained ventricular tachyarrhythmia occurred in wearable cardioverter-defibrillator carriers. CONCLUSIONS: Continuous optimization of guideline-recommended medical therapy for at least 180 days in HFrEF is associated with additional LVEF improvement > 35%, allowing for better decision-making regarding preventive implantable cardioverter-defibrillator therapy.

Emulating a Target Trial of Shorter Compared to Longer Course of Antibiotic Therapy for Gram-Negative Bacteremia.

BACKGROUND: Despite the availability of antimicrobial therapies, gram-negative bacteremia remains a significant cause of morbidity and mortality on a global level. Recent randomized controlled trials support shorter antibiotic treatment duration for individuals with uncomplicated gram-negative bacteremia. The target trial framework using the cloning approach utilizes real-world data but eliminates the issue of immortal time bias seen in observational studies by emulating the analysis of randomized trials with full adherence. METHOD: A hypothetical target trial allocating individuals with gram-negative bacteremia to either short antibiotic treatment duration (5-7 days) or longer antibiotic treatment duration (8-14 days) was specified and emulated using the cloning, censoring, and weighting approach. The primary outcome was 90-day all-cause mortality. Secondary outcome was a composite endpoint of clinical and microbiological relapse. The emulated trial included individuals from four hospitals in Copenhagen from 2018 through 2021. RESULTS: In sum, 1040 individuals were included. The median age of the cohort was 76 years, the majority were male (54%), had community-acquired gram-negative bacteremia (86%), urinary tract infection as the source of the infection (78%), and Escherichia coli as the pathogen of the infection (73%). The adjusted 90-day risk difference in all-cause mortality was 1.3% (95% confidence interval [CI]: -.7, 3.3), and the risk ratio was 1.12 (95% CI: .89, 1.37). The adjusted 90-day risk difference in relapse was 0.7% (95% CI: -2.3, 3.8), and the risk ratio was 1.07 (95% CI: .71, 1.45). CONCLUSIONS: We found comparative outcomes for shorter treatment duration compared to longer treatment duration in patients with gram-negative bacteremia.

Prognosis of prosthetic valve infective endocarditis due to Streptococcus spp., a retrospective multi-site study to assess the impact of antibiotic treatment duration.

PURPOSE: The duration of antibiotic treatment for prosthetic valve endocarditis caused by Streptococcus spp. is largely based on clinical observations and expert opinion rather than empirical studies. Here we assess the impact of a shorter antibiotic duration. OBJECTIVES: To assess the impact of antibiotic treatment duration for streptococcal prosthetic valve endocarditis on 12-month mortality as well as subsequent morbidity resulting in additional cardiac surgical interventions, and rates of relapse and reinfection. METHODS: This retrospective multisite (N= 3) study examines two decades of data on patients with streptococcal prosthetic valve endocarditis receiving either 4 or 6 weeks of antibiotics. Overall mortality, relapse, and reinfection rates were also assessed for the entire available follow-up period. RESULTS: The sample includes 121 patients (median age 72 years, IQR [53; 81]). The majority (74%, 89/121) received a ß-lactam antibiotic combined with aminoglycoside in 74% (89/121, median bi-therapy 5 days [1; 14]). Twenty-eight patients underwent surgery guided by ESC-guidelines (23%). The 12-month mortality rate was not significantly affected by antibiotic duration (4/40, 10% in the 4-week group vs 3/81, 3.7% in the 6-week group, p=0.34) or aminoglycoside usage (p=0.1). Similarly, there were no significant differences between the 2 treatment groups for secondary surgical procedures (7/40 vs 21/81, p=0.42), relapse or reinfection (1/40 vs 2/81 and 2/40 vs 5/81 respectively). CONCLUSIONS: Our study found no increased adverse outcomes associated with a 4-week antibiotic duration compared to the recommended 6-week regimen. Further randomized trials are needed to ascertain the optimal duration of treatment for streptococcal endocarditis.

Duration of antibiotic therapy for multidrug resistant Pseudomonas aeruginosa pneumonia: is shorter truly better?

BACKGROUND: The 2016 IDSA guideline recommends a treatment duration of at least 7 days for hospital-acquired (HAP)/ventilator-associated pneumonia (VAP). The limited literature has demonstrated higher rates of recurrence for non-glucose fermenting gram-negative bacilli with short course therapy, raising the concern of optimal treatment duration for these pathogens. Therefore, we aimed to compare the outcomes for patients receiving shorter therapy treatment (≤ 8 days) versus longer regimen (> 8 days) for the treatment of multidrug resistant (MDR) Pseudomonas pneumonia. METHODS: A single-center, retrospective cohort study was conducted to evaluate adult patients receiving an antimicrobial regimen with activity against MDR Pseudomonas aeruginosa in respiratory culture between 2017 and 2020 for a minimum of 6 consecutive days. Exclusion criteria were inmates, those with polymicrobial pneumonia, community-acquired pneumonia, and infections requiring prolonged antibiotic therapy. RESULTS: Of 427 patients with MDR P. aeruginosa respiratory isolates, 85 patients were included. Baseline characteristics were similar among groups with a median age of 65.5 years and median APACHE 2 score of 20. Roughly 75% had ventilator-associated pneumonia. Compared to those who received ≤ 8 days of therapy, no difference was seen for clinical success in patients treated for more than 8 days (80% vs. 65.5%, p = 0.16). The number of 30-day and 90-day in-hospital mortality, 30-days relapse, and other secondary outcomes did not significantly differ among the treatment groups. CONCLUSIONS: Prolonging treatment duration beyond 8 days did not improve patient outcomes for MDR P. aeruginosa HAP/VAP.

Baseline characteristics may impact treatment duration of cabazitaxel in patients with mCRPC: a subanalysis of data from a post-marketing surveillance.

OBJECTIVE: Cabazitaxel has demonstrated improvements in overall survival among patients with metastatic castration-resistant prostate cancer (mCRPC) in the pivotal comparison clinical trials TROPIC, PROSELICA and CARD. However, these trials include mCRPC patients with similar characteristics, and there are limited data on how baseline characteristics affect treatment discontinuation in the patient population. METHODS: To assess individual factors that may impact the discontinuation rate of cabazitaxel treatment, we conducted a post hoc analysis of data from a nationwide all-case, post-marketing surveillance of cabazitaxel in Japan. Patients were grouped according to the number of cabazitaxel treatment cycles received (1-2 and ≥3 cycles). Predictive factors were identified through multivariate logistic regression analysis. RESULTS: Across 660 patients with metastatic castration-resistant prostate cancer, 70.2% received ≥3 cycles of cabazitaxel treatment. Those receiving 1-2 cycles of cabazitaxel had a greater proportion of patients with poorer Eastern Cooperative Oncology Group Performance Status, presence of lung and liver metastases, higher prostate-specific antigen level and prior radiation therapy at baseline. Regardless of the number of cabazitaxel cycles received, the primary reason for discontinuation was progression of disease rather than adverse events. Compared with those receiving 1-2 cycles, a lower proportion of patients receiving 3-10 and ≥11 cycles of cabazitaxel treatment experienced adverse events. Multivariate analysis showed a significant association between early discontinuation and presence of liver lesions, poorer Eastern Cooperative Oncology Group Performance Status and higher prostate-specific antigen level at baseline. CONCLUSIONS: Post-marketing surveillance data suggest physicians should individualize cabazitaxel treatment based on certain patient characteristics at baseline.

Questioning the 14-day dogma in candidemia treatment duration.

The growing threat of antimicrobial resistance (AMR) is a global concern. With AMR directly causing 1.27 million deaths in 2019 and projections of up to 10 million annual deaths by 2050, optimising infectious disease treatments is imperative. Prudent antimicrobial use, including treatment duration, can mitigate AMR emergence. This is particularly critical in candidemia, a severe condition with a 45% crude mortality rate, as the 14-day minimum treatment period has not been challenged in randomised comparison. A comprehensive literature search was conducted in August 2023, revealing seven original articles and two case series discussing treatment durations of less than 14 days for candidemia. No interventional trials or prospective observational studies assessing shorter durations were found. Historical studies showed varying candidemia treatment durations, questioning the current 14-day minimum recommendation. Recent research observed no significant survival differences between patients receiving shorter or longer treatment, emphasising the need for evidence-based guidance. Treatment duration reduction post-blood culture clearance could decrease exposure to antifungal drugs, limiting selection pressure, especially in the context of emerging multiresistant Candida species. Candidemia's complexity, emerging resistance and potential for shorter in-hospital stays underscore the urgency of refining treatment strategies. Evidence-driven candidemia treatment durations are imperative to balance efficacy with resistance prevention and ensure the longevity of antifungal therapies. Further research and clinical trials are needed to establish evidence-based guidelines for candidemia treatment duration.

Examining therapy duration in adults with induced laryngeal obstruction (ILO).

OBJECTIVE: This study examined the number of therapy sessions required to sufficiently improve (exercise) induced laryngeal obstruction (EILO/ILO) symptoms for discharge. Factors predicting therapy duration were examined as was the likelihood of patients returning for additional therapy sessions following initial discharge. METHODS: Retrospective observational cohort design. Data for 350 patients were gathered from the University of Wisconsin-Madison Voice and Swallow Clinics Outcome Database. Patients (>18 years of age) diagnosed with EILO/ILO received therapy from a Speech-Language Pathologist (SLP) and were successfully discharged. EILO/ILO treatment details, symptoms, triggers, medical comorbidities, and patient demographics were collected from initial evaluations and subsequent course of therapy. RESULTS: Patients required an average of 3.59 (SD = 3.7) therapy sessions prior to discharge. A comorbid behavioral health diagnosis (p = .026), higher Vocal Handicap Index Score (p = .009) and reduced physical activity due to EILO/ILO symptoms (p = .032) were associated with increased therapy duration. Patients with ILO or EILO with secondary environmental triggers required significantly more sessions than those with exercise-induced symptoms (p < .01). Eight percent of patients returned for additional sessions following discharge. Patients returning for additional sessions all came from affluent neighborhoods as measured by the Area Deprivation Index (ADI). CONCLUSIONS: Patients with EILO/ILO required an average of 3.59 therapy sessions prior to discharge. As such, 4 sessions is a reasonable estimate for clinicians to provide patients. Six sessions may be a more conservative estimate for patients who present with a behavioral health diagnosis, a voice complaint, or reduced physical activity from EILO/ILO symptoms.

Duration of orthodontic treatment with clear aligners versus fixed appliances in crowding cases: a systematic review.

OBJECTIVE: To critically appraise and assess the currently observed evidence about the difference in orthodontic treatment duration between clear aligners and fixed appliances in crowding cases. MATERIALS AND METHODS: An electronic search without limitations was conducted from inception to June 2023 covering nine databases: The Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Scopus, Web of Science, Google Scholar, Trip, CINAHL via EBSCO, EMBASE via OVID and ProQuest. Randomized controlled trials (RCTs) and matched non-randomized studies were included in this systematic review. Risk of Bias was assessed via Cochrane's tool (RoB 2) for RCTs and ROBINS-I tool for non-randomized studies. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was employed to evaluate the overall quality of evidence. RESULTS: Out of the 3537 articles initially identified, ten eligible studies were included in this systematic review; six were RCTs. Only one study offered extraction-based treatment, while the other nine adopted non-extraction treatments. According to the GRADE, there is low evidence that treatment duration in mild to moderate crowding cases with clear aligners is similar to that in fixed orthodontic appliances. Meta-analysis was not administered due to high inconsistency. CONCLUSIONS: Based on currently available information, there was no significant difference in the treatment duration between the CA and FA groups in mild to moderate crowding cases. Further well-performed RCTs, especially in severe cases, are required. CLINICAL RELEVANCE: Time efficiency is an essential outcome measure for clinical orthodontic practice. While the type of appliance used is a critical determinant of treatment duration, orthodontists should be aware of other factors that can significantly impact treatment time, such as patient and treatment-related factors.

Clinical outcomes of narrow- and regular-diameter implants with bone augmentation in the anterior maxilla: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the clinical outcomes of narrow-diameter implants (NDIs) and regular-diameter implants (RDIs) with bone augmentation in the anterior maxilla, with implant survival rate (ISR) as the primary outcome. Additionally, secondary outcomes such as peri-implant marginal bone loss (MBL), pocket probing depth (PPD), mechanical complications, and biological complications were also considered. MATERIALS AND METHODS: A thorough literature search was performed to identify randomized controlled trials and cohort studies comparing outcomes of NDIs and RDIs with bone augmentation in the anterior maxilla published up to February 2024. Only studies with a minimum follow-up period of 12 months were selected for analysis. Meta-analysis was performed if at least two articles with similar characteristics were available. RESULTS: Of the 288 articles initially considered, 5 were included in the analysis, involving 282 NDIs and 100 RDIs. At the 36-month follow-up, no statistically significant differences in ISR, which ranged 93.8-100% for NDIs and were 100% for RDIs, were observed between the two groups (relative risk, 0.989; 95% confidence interval, 0.839-1.165; p = 0.896). Similarly, MBL and PPD did not differ significantly between the two groups. Soft tissue dehiscence was the most common complication found in RDIs. CONCLUSION: The results indicate that NDIs yield clinical outcomes similar to those of RDIs with bone augmentation in the anterior maxilla over a 36-month follow-up period. CLINICAL RELEVANCE: Considering the similar clinical outcomes, the shortened treatment duration and more rapid esthetic improvement associated with NDIs may render them preferrable to RDIs with bone augmentation, particularly in this esthetic zone.

Is there a prospective association between psychological distress as measured by the CORE-OM and treatment attendance and treatment duration? A follow-up study at a Norwegian Community Mental Health Centre.

BACKGROUND: Feasible and reliable methods for identifying factors associated with treatment duration and treatment attendance in mental health services are needed. This study examined to what degree the Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM) at the start of treatment is associated with treatment attendance and treatment duration. METHODS: Outpatients (N = 124) at a community mental health centre in Norway completed the 34-item CORE-OM questionnaire addressing the domains of subjective well-being, problems and symptoms, functioning and risk at the start of treatment. The CORE-OM subscales and the 'all' items total scale were used as predictor variables in regression models, with treatment duration, number of consultations attended, treatment attendance (number of therapy sessions attended divided by number of sessions offered) and termination of treatment (planned versus unplanned) as outcome variables. RESULTS: Higher CORE-OM subscale scores and the 'all' scale were associated with longer treatment duration. No association was found between CORE-OM scales and number of therapy sessions, treatment attendance (sessions attended/offered) or whether the patients unexpectedly ended treatment. CONCLUSION: Higher patient-reported psychological distress as measured by the CORE-OM at the start of treatment was prospectively associated with treatment duration but not with treatment attendance or drop-out of treatment. The findings imply that patients with higher initial psychological distress need longer treatment but that treatment attendance may be related to factors other than the severity of distress.

Comparison of positional distraction with stabilisation exercises versus stabilisation exercises alone in the management of lumbar radiculopathy: A randomized controlled-trial.

OBJECTIVE: To compare the effects of positional distraction with stabilisation exercises versus stabilisation exercises alone in the management of lumbar radiculopathy. METHODS: The randomised controlled trial was conducted from July to December 2020 at the Institute of Physical Medicine and Rehabilitation, Dow University of Health Sciences, and the Neurosurgery ward of Civil Hospital, Karachi, and comprised individuals of either gender with lumbar radiculopathy pain who were randomised into positional distraction with stabilisation exercises group A and stabilisation exercise group B. The treatment duration was 3 sessions per week for 8 weeks. Intensity of pain and disability were assessed using the Visual Analogue Scale and the Roland Morris Disability Questionnaire, respectively. Data was analysed using SPSS 21. RESULTS: Of the 100 patients, 63(63%) were males and 37(37%) were females. Overall, 89(89%) were married. There were 50(50%) subjects in group A with mean age 39.42±6.36 years and 50(%) in group B with mean age 38.80±6.69 years. There was no significant difference in terms of age, gender and marital status between the groups (p>0.05). The study was completed by 96(96%) patients; 48(50%) in each of the 2 groups. Intragroup improvement post-intervention compared to baseline was significant (p<0.001) in both groups. Outcomes in group A were significantly better than in group B (p<0.05). CONCLUSIONS: Addition of positional distraction to stabilisation exercises was found to have superior effects compared to stabilisation exercise alone on pain and functional disability among patients with lumbar radiculopathy. Clinical Trial Number: NCT04427423 dated 27th April 2020.

Defining the Optimal Duration of Therapy for Hospitalized Patients With Complicated Urinary Tract Infections and Associated Bacteremia.

BACKGROUND: Limited data are available to guide effective antibiotic durations for hospitalized patients with complicated urinary tract infections (cUTIs). METHODS: We conducted an observational study of patients ≥18 years at 24 US hospitals to identify the optimal treatment duration for patients with cUTI. To increase the likelihood patients experienced true infection, eligibility was limited to those with associated bacteremia. Propensity scores were generated for an inverse probability of treatment weighted analysis. The primary outcome was recurrent infection with the same species ≤30 days of completing therapy. RESULTS: 1099 patients met eligibility criteria and received 7 (n = 265), 10 (n = 382), or 14 (n = 452) days of therapy. There was no difference in the odds of recurrent infection for patients receiving 10 days and those receiving 14 days of therapy (aOR: .99; 95% CI: .52-1.87). Increased odds of recurrence was observed in patients receiving 7 days versus 14 days of treatment (aOR: 2.54; 95% CI: 1.40-4.60). When limiting the 7-day versus 14-day analysis to the 627 patients who remained on intravenous beta-lactam therapy or were transitioned to highly bioavailable oral agents, differences in outcomes no longer persisted (aOR: .76; 95% CI: .38-1.52). Of 76 patients with recurrent infections, 2 (11%), 2 (10%), and 10 (36%) in the 7-, 10-, and 14-day groups, respectively, had drug-resistant infections (P = .10). CONCLUSIONS: Seven days of antibiotics appears effective for hospitalized patients with cUTI when antibiotics with comparable intravenous and oral bioavailability are administered; 10 days may be needed for all other patients.

Antibiotic Treatment Duration for Community-Acquired Pneumonia in Outpatient Children in High-Income Countries-A Systematic Review and Meta-Analysis.

BACKGROUND: The optimal treatment duration of community-acquired pneumonia (CAP) in children has been controversial in high-income countries. We conducted a meta-analysis to compare short antibiotic treatment (3-5 days) with longer treatment (7-10 days) among children aged ≥6 months. METHODS: On 31 January 2022, we searched PubMed, Scopus, and Web of Science databases for studies published in English from 2003 to 2022. We included randomized controlled trials focusing on antibiotic treatment duration in children with CAP treated as outpatients. We calculated risk differences (RDs) with 95% confidence intervals and used the fixed-effect model (low heterogeneity). Our main outcome was treatment failure, defined as need for retreatment or hospitalization within 1 month. Our secondary outcome was presence of antibiotic-related harms. RESULTS: A total of 541 studies were screened, and 4 studies with 1541 children were included in the review. Three studies had low risk of bias, and one had some concerns. All 4 studies assessed treatment failures, and the RD was 0.1% (95% confidence interval, -3.0% to 2.0%) with high quality of evidence. Two studies (1194 children) assessed adverse events related to antibiotic treatment, and the RD was 0.0% (-5.0% to 5.0%) with moderate quality of evidence. The diagnostic criteria varied between the included studies. CONCLUSIONS: A short antibiotic treatment duration of 3-5 days was equally effective and safe compared with the longer (current) recommendation of 7-10 days in children aged ≥6 months with CAP. We suggest that short antibiotic courses can be implemented in treatment of pediatric CAP.

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

BACKGROUND: 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. METHODS AND FINDINGS: 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. CONCLUSIONS: 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.

Amoxicillin for 3 or 5 Days for Chest-Indrawing Pneumonia in Malawian Children.

BACKGROUND: Evidence regarding the appropriate duration of treatment with antibiotic agents in children with pneumonia in low-resource settings in Africa is lacking. METHODS: We conducted a double-blind, randomized, controlled, noninferiority trial in Lilongwe, Malawi, to determine whether treatment with amoxicillin for 3 days is less effective than treatment for 5 days in children with chest-indrawing pneumonia (cough lasting <14 days or difficulty breathing, along with visible indrawing of the chest wall with or without fast breathing for age). Children not infected with human immunodeficiency virus (HIV) who were 2 to 59 months of age and had chest-indrawing pneumonia were randomly assigned to receive amoxicillin twice daily for either 3 days or 5 days. Children were followed for 14 days. The primary outcome was treatment failure by day 6; noninferiority of the 3-day regimen to the 5-day regimen would be shown if the percentage of children with treatment failure in the 3-day group was no more than 1.5 times that in the 5-day group. Prespecified secondary analyses included assessment of treatment failure or relapse by day 14. RESULTS: From March 29, 2016, to April 1, 2019, a total of 3000 children underwent randomization: 1497 children were assigned to the 3-day group, and 1503 to the 5-day group. Among children with day 6 data available, treatment failure had occurred in 5.9% in the 3-day group (85 of 1442 children) and in 5.2% (75 of 1456) in the 5-day group (adjusted difference, 0.7 percentage points; 95% confidence interval [CI], -0.9 to 2.4) - a result that satisfied the criterion for noninferiority of the 3-day regimen to the 5-day regimen. Among children with day 14 data available, 176 of 1411 children (12.5%) in the 3-day group and 154 of 1429 (10.8%) in the 5-day group had had treatment failure by day 6 or relapse by day 14 (between-group difference, 1.7 percentage points; 95% CI, -0.7 to 4.1). The percentage of children with serious adverse events was similar in the two groups (9.8% in the 3-day group and 8.8% in the 5-day group). CONCLUSIONS: In HIV-uninfected Malawian children, treatment with amoxicillin for chest-indrawing pneumonia for 3 days was noninferior to treatment for 5 days. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT02678195.).

Randomized Trial of Amoxicillin for Pneumonia in Pakistan.

BACKGROUND: The World Health Organization (WHO) recommends oral amoxicillin for patients who have pneumonia with tachypnea, yet trial data indicate that not using amoxicillin to treat this condition may be noninferior to using amoxicillin. METHODS: We conducted a double-blind, randomized, placebo-controlled noninferiority trial involving children at primary health care centers in low-income communities in Karachi, Pakistan. Children who were 2 to 59 months of age and who met WHO criteria for nonsevere pneumonia with tachypnea were randomly assigned to a 3-day course of a suspension of amoxicillin (the active control) of 50 mg per milliliter or matched volume of placebo (the test regimen), according to WHO weight bands (500 mg every 12 hours for a weight of 4 to <10 kg, 1000 mg every 12 hours for a weight of 10 to <14 kg, or 1500 mg every 12 hours for a weight of 14 to <20 kg). The primary outcome was treatment failure during the 3-day course of amoxicillin or placebo. The prespecified noninferiority margin was 1.75 percentage points. RESULTS: From November 9, 2014, through November 30, 2017, a total of 4002 children underwent randomization (1999 in the placebo group and 2003 in the amoxicillin group). In the per-protocol analysis, the incidence of treatment failure was 4.9% among placebo recipients (95 of 1927 children) and 2.6% among amoxicillin recipients (51 of 1929 children) (between-group difference, 2.3 percentage points; 95% confidence interval [CI], 0.9 to 3.7). Results were similar in the intention-to-treat analysis. The presence of fever and wheeze predicted treatment failure. The number needed to treat to prevent one treatment failure was 44 (95% CI, 31 to 80). One patient (<0.1%) in each group died. Relapse occurred in 40 children (2.2%) in the placebo group and in 58 children (3.1%) in the amoxicillin group. CONCLUSIONS: Among children younger than 5 years of age with nonsevere pneumonia, the frequency of treatment failure was higher in the placebo group than in the amoxicillin group, a difference that did not meet the noninferiority margin for placebo. (Funded by the Joint Global Health Trials Scheme [of the Department for International Development, Medical Research Council, and Wellcome] and others; RETAPP ClinicalTrials.gov number, NCT02372461.).

Extended duration of treatment using reduced-frequency dosing of anti-PD-1 therapy in patients with advanced melanoma and Merkel cell carcinoma.

BACKGROUND: Optimal duration of treatment (DoT) with immune checkpoint inhibitors (ICI) in metastatic cancers remains unclear. Many patients, especially those without radiologic complete remission, develop progressive disease after ICI discontinuation. Extending DoT with ICI may potentially improve efficacy outcomes but presents major logistical and cost challenges with standard frequency dosing (SFD). Receptor occupancy data supports reduced frequency dosing (RFD) of anti-PD-1 antibodies, which may represent a more practical and economically viable option to extend DoT. METHODS: We conducted a retrospective study of patients with metastatic melanoma and Merkel cell carcinoma (MCC), who received ICI at RFD administered every 3 months, after initial disease control at SFD. We evaluated efficacy, safety, and cost-savings of the RFD approach in this cohort. RESULTS: Between 2014 and 2021, 23 patients with advanced melanoma (N = 18) or MCC (N = 5) received anti-PD-1 therapy at RFD. Median DoT was 1.1 years at SFD and 1.2 years at RFD. The 3 year PFS after start of RFD was 73% in melanoma and 100% in MCC patients, which compare favorably to historical control rates. In the subset of 15 patients who received at least 2 years of therapy, total savings amounted to $1.1 million in drug costs and 384 h saved despite the extended DoT (median 3.4 years), as compared to the calculated cost of 2 years at SFD. CONCLUSIONS: ICI administration at RFD can allow extension of treatment duration, while preserving efficacy and reducing logistical and financial burden. RFD approach deserves further exploration in prospective clinical trials.

Short treatment duration for community-acquired pneumonia.

PURPOSE OF REVIEW: Lower respiratory tract infections are one of the most common indications for antibiotic use in community and hospital settings. Usual guidelines for adults with community-acquired pneumonia (CAP) recommend 5-7 days of antibiotic treatment. In daily practice, physicians often prescribe 9-10 days of antibiotic treatment. Among available strategies to decrease antibiotic use, possibly preventing the emergence of bacterial resistance, reducing treatment durations is the safest and the most acceptable to clinicians. We aim to review data evaluating the efficacy of short antibiotic duration in adult CAP and which criteria can help clinicians to reduce antibiotic treatment. RECENT FINDINGS: Several studies and meta-analyses demonstrated that the treatment duration of 7 days or less was sufficient for CAP. Two trials found that 3-day treatments were effective, even in hospitalized CAP.To customize and shorten duration, clinical and biological criteria have been studied and reflect patient's response. Indeed, stability criteria were recently shown to be effective to discontinue antibiotic treatment. Procalcitonin was also studied but never compared with clinical criteria. SUMMARY: Treatment duration for CAP is still under debate, but several studies support short durations. Clinical criteria could be possibly used to discontinue antibiotic treatment.