Targeted AntiBiotics for Chronic pulmonary diseases (TARGET ABC): can targeted antibiotic therapy improve the prognosis of Pseudomonas aeruginosa-infected patients with chronic pulmonary obstructive disease, non-cystic fibrosis bronchiectasis, and asthma? A multicenter, randomized, controlled, open-label trial.

BACKGROUND: Pseudomonas aeruginosa infection is seen in chronic pulmonary disease and is associated with exacerbations and poor long-term prognosis. However, evidence-based guidelines for the management and treatment of P. aeruginosa infection in chronic, non-cystic fibrosis (CF) pulmonary disease are lacking. The aim of this study is to investigate whether targeted antibiotic treatment against P. aeruginosa can reduce exacerbations and mortality in patients with chronic obstructive pulmonary disease (COPD), non-CF bronchiectasis, and asthma. METHODS: This study is an ongoing multicenter, randomized, controlled, open-label trial. A total of 150 patients with COPD, non-CF bronchiectasis or asthma, and P. aeruginosa-positive lower respiratory tract samples will be randomly assigned with a 1:1 ratio to either no antibiotic treatment or anti-pseudomonal antibiotic treatment with intravenous beta-lactam and oral ciprofloxacin for 14 days. The primary outcome, analyzed with two co-primary endpoints, is (i) time to prednisolone and/or antibiotic requiring exacerbation or death, in the primary or secondary health sector, within days 20-365 from study allocation and (ii) days alive and without exacerbation within days 20-365 from the study allocation. DISCUSSION: This trial will determine whether targeted antibiotics can benefit future patients with chronic, non-CF pulmonary disease and P. aeruginosa infection in terms of reduced morbidity and mortality, thus optimizing therapeutic approaches in this large group of chronic patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03262142 . Registered on August 25, 2017.

Rifampicin-induced fever during treatment against staphylococcal biofilm in a patient with periprosthetic joint infection.

Periprosthetic joint infection (PJI) after total knee arthroplasty remains a challenging complication. The treatment options for PJI include different procedures; however, regardless of the strategy, antibiotics are required. The combination of different antibiotics increased the rates of PJI eradication. For almost 3 decades, rifampicin has been used as part of antibiotic therapy for PJI. Drug fever, a febrile response that coincides with the onset of drug administration and disappears after drug discontinuation in the absence of other underlying conditions that could cause fever, is frequently misdiagnosed. We present the case of a 72-year-old man with PJI 6 months after total knee arthroplasty. Two-stage revision surgery was followed by culture-directed antibiotic treatment (ciprofloxacin and rifampicin) against Staphylococcus aureus isolated from the periprosthetic tissue. On the fifth day of antibiotic treatment, the patient became febrile and, in the next 5 days, he had an intermittent fever of up to 40°C, although he showed clinical improvement. The patient was normotensive without a maculopapular rash, urticaria or clotting abnormalities. A drug fever was suspected, and rifampicin was discontinued. A re-challenge test was performed, and the fever recurred. Antibiotic treatment with ciprofloxacin was continued and, after 12 months of follow-up, the patient was doing well. Clinicians should be aware that fever could be a clinical presentation of drug fever. If it occurs during an infection, drug fever could necessitate additional diagnostic procedures for further evaluation, inadequate antibiotic therapy and prolonged hospitalisation.

Long-term Antibiotic Treatment in Pouchitis-Patterns of Use and Safety.

INTRODUCTION: Pouchitis, often developing after colectomy and ileal pouch-anal anastomosis for ulcerative colitis, is highly responsive to antibiotics. Ciprofloxacin and/or metronidazole are commonly used, often for prolonged periods. We report patterns of antibiotic use, adverse events, and resistant infections in patients with pouchitis with long-term antibiotic treatment. METHODS: In a cohort of patients following pouch surgery, a retrospective nested case-control analysis was performed between 2010 and 2017. Ultra-long-term use, defined as the top 10% of users, was compared with the remaining users. Patterns of antibiotic use, adverse events, and resistant infections were analyzed. RESULTS: The cohort included 205 patients with UC, of whom 167 (81.5%) used antibiotics for pouchitis, predominantly ciprofloxacin. The long-term antibiotic use rate was 18% and 42% at 5 and 20 years postsurgery, respectively. Mean antibiotic use of at least 1, 3, and 6 months/year was noted in 54 (26.3%), 31 (15.1%), and 14 (6.8%) patients, respectively. Twenty-two (13.2%) and 4 (2.4%) patients reported mild and severe (transient) adverse events, respectively, without mortalities, tendinopathies or arrhythmias. Adverse event rates for ciprofloxacin and metronidazole were 1per 10,000 and 6 per 10,000 use-days, respectively. Longer, but not ultra-long antibiotic use, was associated with mild adverse events. There was no association between antibiotic use and resistant infections. Thirteen (6.3%) patients required ileostomy procedures-more commonly in the ultra-long-term antibiotic users. CONCLUSIONS: Patients with pouchitis may require prolonged antibiotic treatment, reflecting clinical benefit and favorable safety profile. Few adverse events and resistant infections were observed with long-term antibiotics use. However, resistant microbial strains selection, which are potentially transmittable, warrants consideration of different therapeutic alternatives.

Effect of 7 vs 14 Days of Antibiotic Therapy on Resolution of Symptoms Among Afebrile Men With Urinary Tract Infection: A Randomized Clinical Trial.

Importance: Determination of optimal treatment durations for common infectious diseases is an important strategy to preserve antibiotic effectiveness. Objective: To determine whether 7 days of treatment is noninferior to 14 days when using ciprofloxacin or trimethoprim/sulfamethoxazole to treat urinary tract infection (UTI) in afebrile men. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled noninferiority trial of afebrile men with presumed symptomatic UTI treated with ciprofloxacin or trimethoprim/sulfamethoxazole at 2 US Veterans Affairs medical centers (enrollment, April 2014 through December 2019; final follow-up, January 28, 2020). Of 1058 eligible men, 272 were randomized. Interventions: Participants continued the antibiotic prescribed by their treating clinician for 7 days of treatment and were randomized to receive continued antibiotic therapy (n = 136) or placebo (n = 136) for days 8 to 14 of treatment. Main Outcomes and Measures: The prespecified primary outcome was resolution of UTI symptoms by 14 days after completion of active antibiotic treatment. A noninferiority margin of 10% was selected. The as-treated population (participants who took ≥26 of 28 doses and missed no more than 2 consecutive doses) was used for the primary analysis, and a secondary analysis included all patients as randomized, regardless of treatment adherence. Secondary outcomes included recurrence of UTI symptoms and/or adverse events within 28 days of stopping study medication. Results: Among 272 patients (median [interquartile range] age, 69 [62-73] years) who were randomized, 100% completed the trial and 254 (93.4%) were included in the primary as-treated analysis. Symptom resolution occurred in 122/131 (93.1%) participants in the 7-day group vs 111/123 (90.2%) in the 14-day group (difference, 2.9% [1-sided 97.5% CI, -5.2% to ∞]), meeting the noninferiority criterion. In the secondary as-randomized analysis, symptom resolution occurred in 125/136 (91.9%) participants in the 7-day group vs 123/136 (90.4%) in the 14-day group (difference, 1.5% [1-sided 97.5% CI, -5.8% to ∞]) Recurrence of UTI symptoms occurred in 13/131 (9.9%) participants in the 7-day group vs 15/123 (12.9%) in the 14-day group (difference, -3.0% [95% CI, -10.8% to 6.2%]; P = .70). Adverse events occurred in 28/136 (20.6%) participants in the 7-day group vs 33/136 (24.3%) in the 14-day group. Conclusions and Relevance: Among afebrile men with suspected UTI, treatment with ciprofloxacin or trimethoprim/sulfamethoxazole for 7 days was noninferior to 14 days of treatment with regard to resolution of UTI symptoms by 14 days after antibiotic therapy. The findings support the use of a 7-day course of ciprofloxacin or trimethoprim/sulfamethoxazole as an alternative to a 14-day course for treatment of afebrile men with UTI. Trial Registration: ClinicalTrials.gov identifier: NCT01994538.

Kidney stone formation and the gut microbiome are altered by antibiotics in genetic hypercalciuric stone-forming rats.

Antibiotics can alter the gut microbiome (GMB), which may be associated with stone disease. We sought to determine the effect that antibiotics have on the GMB, urine ion excretion and stone formation in genetic hypercalciuric stone-forming (GHS) rats. 116th generation GHS rats were fed a fixed amount of a normal calcium (1.2%) and phosphate (0.65%) diet, and divided into three groups (n = 10): control (CTL) diet, or supplemented with ciprofloxacin (Cipro, 5 mg/day) or Bactrim (250 mg/day). Urine and fecal pellets were collected over 6, 12 and 18 weeks. Fecal DNA was amplified across the 16S rRNA V4 region. At 18 weeks, kidney stone formation was visualized by Faxitron and blindly assessed by three investigators. After 18 weeks, urine calcium and oxalate decreased with Bactrim compared to CTL and Cipro. Urine pH increased with Bactrim compared to CTL and Cipro. Urine citrate increased with Cipro compared to CTL and decreased by half with Bactrim. Calcification increased with Bactrim compared to CTL and Cipro. Increased microbial diversity correlated with decreased urinary oxalate in all animals (R = - 0.46, p = 0.006). A potential microbial network emerged as significantly associated with shifts in urinary pH. Bactrim and Cipro differentially altered the GMB of GHS rats. The Bactrim group experienced a decrease in urine calcium, increased CaP supersaturation and increased calcification. The GMB is likely a contributing factor to changes in urine chemistry, supersaturation and stone risk. Further investigation is required to fully understand the association between antibiotics, the GMB and kidney stone formation.

An open-label, randomized, non-inferiority trial of the efficacy and safety of ciprofloxacin versus streptomycin + ciprofloxacin in the treatment of bubonic plague (IMASOY): study protocol for a randomized control trial.

BACKGROUND: Bubonic plague is the primary manifestation of infection with Yersinia pestis, accounting for 90% of all plague cases and with 75% of global cases reported in Madagascar. All drugs in use for treating plague are registered based on experimental data and anecdotal evidence, and no regimen currently recommended is supported by a randomized clinical trial. The IMASOY trial intends to fill this knowledge gap by comparing two 10-day regimens included in the national guidelines in Madagascar. The primary objective of the trial is to test the hypothesis that ciprofloxacin monotherapy is non-inferior to streptomycin followed by ciprofloxacin for the treatment of bubonic plague, thus avoiding the need for injectable, potentially toxic, aminoglycosides. METHODS: A two-arm parallel-group randomized control trial will be conducted across peripheral health centres in Madagascar in five districts. Males and non-pregnant females of all ages with suspected bubonic or pneumonic plague will be recruited over the course of three plague 'seasons'. The primary endpoint of the trial is to assess the proportion of patients with bubonic plague who have a therapeutic response to treatment (defined as alive, resolution of fever, 25% reduction in the size of measurable buboes, has not received an alternative treatment and no clinical decision to continue antibiotics) as assessed on day 11. DISCUSSION: If successful, the trial has the potential to inform the standard of care guidelines not just in Madagascar but in other countries afflicted by plague. The trial is currently ongoing and expected to complete recruitment in 2022. TRIAL REGISTRATION: ClinicalTrials.gov NCT04110340 . Registered on 1 October 2019.

Probiotics use for antibiotic-associated diarrhea: a pragmatic participatory evaluation in nursing homes.

BACKGROUND: Antibiotic-associated diarrhea (AAD) occurs in 2-25% of nursing home residents, which may lead to dehydration, malnutrition, severe complications and hospitalizations. Research shows that probiotics can be effective and safe in reducing AAD. However, probiotics are not routinely used in Dutch nursing homes. The objectives of this evaluation were to develop a procedure for the implementation of probiotics to prevent AAD in nursing homes, to evaluate effects on AAD occurrence, and to evaluate the implementation process of probiotics in daily care. METHODS: A pragmatic participatory evaluation (PPE) design was chosen, as it seemed a suitable approach for implementation of probiotics, as well as for evaluation of its effectiveness in daily nursing home practice. Probiotics administration was implemented in three nursing homes of the Rivas Zorggroep for residents with somatic and/or psychogeriatric conditions. Ninety-three residents provided data on 167 episodes of antibiotics use, of which 84 episodes that included supplementation with probiotics and 83 episodes with no probiotics supplementation. A multispecies probiotics was administered twice daily upon start of antibiotic treatment, up to 1 week after completing the antibiotics course. The occurrence of AAD was monitored and a process evaluation was conducted to assess facilitators and barriers of probiotics implementation. RESULTS: The number of episodes with AAD when using probiotics was significantly lower than when no probiotics was used (20% vs 36%; p = 0,022, Chi-square). No significant differences in the occurrence of AAD were found between the residents taking amoxicillin/clavulanic acid or ciprofloxacin. Reported facilitators for implementation were perceived benefits of probiotics and prescription by medical staff. Reported challenges were probiotics intake by residents and individual decision-making as to which resident would benefit from it. CONCLUSION: Successful implementation of probiotics demonstrated the prevention of AAD in nursing home residents. TRIAL REGISTRATION: ISRCTN 94786163, retrospectively registered on 3 February 2020.

Cerebral effect of optimized Allium sativum oil-loaded chitosan nanorods: GC-MS analysis and in vitro/in vivo evaluation.

The chemical constituents of Allium sativum (garlic) oil were investigated using the GC/MS technique after silylation, and the presence of several fatty acids and their esters was revealed. The most dominant was 9,12-octadecadienoic acid (linoleic acid), a precursor of arachidonic acid, which is essential for brain development. Garlic oil-loaded chitosan nanoparticles (GCNs) were prepared to enhance its cerebral effects, and to mask its odor and taste. Two-level orthogonal factorial design, followed by regression analysis, was used to study the influence of different formulation variables. GCN3, the formula with the smallest particle size and the highest mucoadhesion, was selected as the optimized one. Transmission electron microscopy showed that GCN3 has a short nanorod-shape outline. We aimed to investigate the influence of orally administered GCN3 compared to the plain garlic oil (GO), on ciprofloxacin-induced (CPX) neurotoxicity in rats and the probable underlying mechanisms. The results show the significantly higher neurological curative effect of GCN3 compared to GO, and its greater antidepression-like and antianxiety-like potential via the alteration of brain neurotransmitter levels and inhibition of oxidative stress and inflammatory pathways. The histopathological examination showed the higher capability of GCN3 to repair the damage induced by CPX in the cerebral cortex, hippocampus area and substantia nigra brain sections. Similar results were proved immunohistochemically using Cox-2 antibody. The nanoencapsulation of GO represents a promising strategy for brain-targeting.

Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis.

BACKGROUND: Pouchitis occurs in approximately 50% of patients following ileal pouch-anal anastomosis (IPAA) for chronic ulcerative colitis (UC). OBJECTIVES: The primary objective was to determine the efficacy and safety of medical therapies for prevention or treatment of acute or chronic pouchitis. SEARCH METHODS: We searched MEDLINE, Embase and CENTRAL from inception to 25 July 2018. We also searched references, trials registers, and conference proceedings. SELECTION CRITERIA: Randomized controlled trials of prevention or treatment of acute or chronic pouchitis in adults who underwent IPAA for UC were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently screened studies for eligibility, extracted data and assessed the risk of bias. The certainty of the evidence was evaluated using GRADE. The primary outcome was clinical improvement or remission in participants with acute or chronic pouchitis, or the proportion of participants with no episodes of pouchitis after IPAA. Adverse events (AEs) was a secondary outcome. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for each dichotomous outcome. MAIN RESULTS: Fifteen studies (547 participants) were included. Four studies assessed treatment of acute pouchitis. Five studies assessed treatment of chronic pouchitis. Six studies assessed prevention of pouchitis. Three studies were low risk of bias. Three studies were high risk of bias and the other studies were unclear. Acute pouchitis: All ciprofloxacin participants (7/7) achieved remission at two weeks compared to 33% (3/9) of metronidazole participants (RR 2.68, 95% CI 1.13 to 6.35, very low certainty evidence). No ciprofloxacin participants (0/7) had an AE compared to 33% (3/9) of metronidazole participants (RR 0.18, 95% CI 0.01 to 2.98; very low certainty evidence). AEs included vomiting, dysgeusia or transient peripheral neuropathy. Forty-three per cent (6/14) of metronidazole participants achieved remission at 6 weeks compared to 50% (6/12) of budesonide enema participants (RR 0.86, 95% CI 0.37 to 1.96, very low certainty evidence). Fifty per cent (7/14) of metronidazole participants improved clinically at 6 weeks compared to 58% (7/12) of budesonide enema participants (RR 0.86, 95% CI 0.42 to 1.74, very low certainty evidence). Fifty-seven per cent (8/14) of metronidazole participants had an AE compared to 25% (3/12) of budesonide enema participants (RR 2.29, 95% CI 0.78 to 6.73, very low certainty evidence). AEs included anorexia, nausea, headache, asthenia, metallic taste, vomiting, paraesthesia, and depression. Twenty-five per cent (2/8) of rifaximin participants achieved remission at 4 weeks compared to 0% (0/10) of placebo participants (RR 6.11, 95% CI 0.33 to 111.71, very low certainty evidence). Thirty-eight per cent (3/8) of rifaximin participants improved clinically at 4 weeks compared to 30% (3/10) of placebo participants (RR 1.25, 95% CI 0.34 to 4.60, very low certainty evidence). Seventy-five per cent (6/8) of rifaximin participants had an AE compared to 50% (5/10) of placebo participants (RR 1.50, 95% CI 0.72 to 3.14, very low certainty evidence). AEs included diarrhea, flatulence, nausea, proctalgia, vomiting, thirst, candida, upper respiratory tract infection, increased hepatic enzyme, and cluster headache. Ten per cent (1/10) of Lactobacillus GG participants improved clinically at 12 weeks compared to 0% (0/10) of placebo participants (RR 3.00, 95% CI 0.14 to 65.90, very low certainty evidence). Chronic pouchitis: Eighty-five per cent (34/40) of De Simone Formulation (a probiotic formulation) participants maintained remission at 9 to 12 months compared to 3% (1/36) of placebo participants (RR 20.24, 95% CI 4.28 to 95.81, 2 studies; low certainty evidence). Two per cent (1/40) of De Simone Formulation participants had an AE compared to 0% (0/36) of placebo participants (RR 2.43, 95% CI 0.11 to 55.89; low certainty evidence). AEs included abdominal cramps, vomiting and diarrhea. Fifty per cent (3/6) of adalimumab patients achieved clinical improvement at 4 weeks compared to 43% (3/7) of placebo participants (RR, 1.17, 95% CI 0.36 to 3.76, low certainty evidence). Sixty per cent (6/10) of glutamine participants maintained remission at 3 weeks compared to 33% (3/9) of butyrate participants (RR 1.80, 95% CI 0.63 to 5.16, very low certainty evidence). Forty-five per cent (9/20) of patients treated with bismuth carbomer foam enema improved clinically at 3 weeks compared to 45% (9/20) of placebo participants (RR 1.00, 95% CI 0.50 to 1.98, very low certainty evidence). Twenty-five per cent (5/20) of participants in the bismuth carbomer foam enema group had an AE compared to 35% (7/20) of placebo participants (RR 0.71, 95% CI 0.27 to 1.88, very low certainty evidence). Adverse events included diarrhea, worsening symptoms, cramping, sinusitis, and abdominal pain. PREVENTION: At 12 months, 90% (18/20) of De Simone Formulation participants had no episodes of acute pouchitis compared to 60% (12/20) of placebo participants (RR 1.50, 95% CI 1.02 to 2.21, low certainty evidence). Another study found 100% (16/16) of De Simone Formulation participants had no episodes of acute pouchitis at 12 months compared to 92% (11/12) of the no treatment control group (RR 1.10, 95% 0.89 to 1.36, very low certainty evidence). Eighty-six per cent (6/7) of Bifidobacterium longum participants had no episodes of acute pouchitis at 6 months compared to 60% (3/5) of placebo participants (RR 1.43, 95% CI 0.66 to 3.11, very low certainty evidence). Eleven per cent (1/9) of Clostridium butyricum MIYAIRI participants had no episodes of acute pouchitis at 24 months compared to 50% (4/8) of placebo participants (RR 0.22, 95% CI 0.03 to 1.60, very low certainty evidence). Forty-six per cent (43/94) of allopurinol participants had no episodes of pouchitis at 24 months compared to 43% (39/90) of placebo participants (RR 1.06, 95% CI 0.76 to 1.46; low certainty evidence). Eighty-one per cent (21/26) of tinidazole participants had no episodes of pouchitis over 12 months compared to 58% (7/12) of placebo participants (RR 1.38, 95% CI 0.83 to 2.31, very low certainty evidence). AUTHORS' CONCLUSIONS: The effects of antibiotics, probiotics and other interventions for treating and preventing pouchitis are uncertain. Well designed, adequately powered studies are needed to determine the optimal therapy for the treatment and prevention of pouchitis.

ANTECEDENTES: La reservoritis ocurre en aproximadamente el 50% de los pacientes después de la anastomosis entre la bolsa ileal y el ano (IPAA, por sus siglas en inglés) para la colitis ulcerosa crónica (CU). OBJETIVOS: El objetivo primario fue determinar la eficacia y la seguridad de los tratamientos médicos para la prevención o el tratamiento de la reservoritis aguda o crónica. MÉTODOS DE BÚSQUEDA: Se hicieron búsquedas en MEDLINE, Embase y en CENTRAL, desde su inicio hasta el 25 julio 2018. También se buscó en las listas de referencias, registros de ensayos en curso y actas de congresos. CRITERIOS DE SELECCIÓN: Se consideraron para inclusión los ensayos controlados aleatorios de prevención o tratamiento de la reservoritis aguda o crónica en adultos a los que se les realiza IPAA para la CU. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión, de forma independiente, evaluaron la elegibilidad de los estudios, extrajeron los datos y analizaron el riesgo de sesgo. La calidad de la evidencia se evaluó mediante los criterios GRADE. El resultado primario la mejoría clínica o remisión en los pacientes con reservoritis aguda o crónica, o la proporción de pacientes sin episodios de reservoritis después de IPAA. Se incluyeron los eventos adversos como resultado secundario. Se calculó el cociente de riesgos (CR) y el intervalo de confianza (IC) del 95% correspondiente para los resultados dicotómicos. RESULTADOS PRINCIPALES: Se incluyeron 15 estudios (547 participantes). Cuatro estudios evaluaron el tratamiento de la reservoritis aguda. Cinco estudios evaluaron el tratamiento de la reservoritis crónica. Seis estudios evaluaron la prevención de la reservoritis. Tres estudios presentaban bajo de riesgo de sesgo. En tres estudios el riesgo fue alto y en los otros estudios fue poco claro. reservoritis aguda: Todos los pacientes que recibieron ciprofloxacina (7/7) lograron la remisión a las dos semanas en comparación con el 33% (3/9) de los pacientes que recibieron metronidazol (CR 2,68; IC del 95%: 1,13 a 6,35) (evidencia de certeza muy baja). Ninguno de los participantes que recibieron ciprofloxacina (0/7) presentó eventos adversos en comparación con el 33% (3/9) de los participantes que recibieron metronidazol (CR0,18; IC del 95%: 0,01 a 2,98; evidencia de certeza muy baja). Los eventos adversos incluyeron vómitos, disgeusia o neuropatía periférica transitoria. El 40% (6/14) de los participantes que recibieron metronidazol lograron la remisión a las 6 semanas en comparación con el 50% (6/12) de los participantes que recibieron enema de budesonida (CR 0,86; IC del 95%: 0,37 a 1,96; evidencia de certeza muy baja). El 50% (7/14) de los participantes del grupo de metronidazol mejoraron clínicamente a las 6 semanas en comparación con el 58% (7/12) de los participantes que recibieron enema de budesonida (CR 0,86; IC del 95%: 0,42 a 1,74; evidencia de certeza muy baja). El 57% (8/14) de los participantes del grupo de metronidazol presentaron eventos adversos en comparación con el 25% (3/12) de los participantes que recibieron enema de budesonida (CR 2,29; IC del 95%: 0,78 a 6,73; evidencia de certeza muy baja). Los eventos adversos incluyeron anorexia, náuseas, cefalea, astenia, sabor metálico, vómitos, parestesia y depresión. El 25% (2/8) de los participantes que recibieron rifaximina lograron la remisión a las 4semanas en comparación con el 0% (0/10) de los participantes que recibieron placebo (CR 6,11; IC del 95%: 0,33 a 111,71; evidencia de certeza muy baja). El 38% (3/8) de los participantes del grupo de rifaximina mejoraron clínicamente a las 4 semanas en comparación con el 30% (3/10) de los participantes que recibieron placebo (CR 1,25; IC del 95%: 0,34 a 4,60; evidencia de certeza muy baja). El 75% (6/8) de los participantes del grupo de rifaximina presentaron un evento adverso en comparación con el 50% (5/10) de los participantes que recibieron placebo (CR 1,50; IC del 95%: 0,72 a 3,14; evidencia de certeza muy baja). Los eventos adversos incluyeron diarrea, flatulencias, náuseas, proctalgia, vómitos, sed, cándida, infección de las vías respiratorias superiores, aumento de las enzimas hepáticas y cefalea en racimos. El 10% (1/10) de los participantes del grupo de Lactobacillus GGmejoraron clínicamente a las 12 semanas en comparación con el 0% (0/10) de los participantes que recibieron placebo (CR 3,00; IC del 95%: 0,14 a 65,90; evidencia de certeza muy baja). Reservoritis crónica: El 85% (34/40) de los pacientes que recibieron la formulación De Simone mantuvieron la remisión de nueve a 12 meses en comparación con el 3% (1/36) de los participantes que recibieron placebo (CR 20,24; IC del 95%: 4,28 a 95,81; dos estudios; evidencia de certeza baja). El 2% (1/40) de los participantes que recibieron la fórmula De Simone presentaron un evento adverso, en comparación con el 0% (0/36) de los participantes que recibieron placebo (CR 2,43; IC del 95%: 0,11 a 55,89; evidencia de certeza baja). Los efectos secundarios incluyeron cólicos abdominales, vómitos y diarrea. Cuarenta y tres por ciento (3/6) de los pacientes en el grupo de adalimumab lograron una mejoría clínica a las 4 semanas en comparación con un 43 (3/7) de los pacientes del grupo de placebo (CR 1,17, IC del 95%: 0,36 a 3,76; evidencia de certeza baja). El 60% (6/10) de los participantes del grupo de glutamina mantuvieron la remisión a las 3 semanas en comparación con el 33% (3/9) de los participantes que recibieron placebo (CR 1,80; IC del 95%: 0,63 a 5,16; evidencia de certeza muy baja). El 45% (9/20) de los participantes del grupo de enema de espuma de carbómero de bismuto mejoraron clínicamente a las 3 semanas en comparación con el 45% (9/20) de los participantes que recibieron placebo (CR 1,00; IC del 95%: 0,50 a 1,98; evidencia de certeza muy baja). El 25% (5/20) de los participantes del grupo de aceite de cannabis presentaron un evento adverso en comparación con el 35% (7/20) de los participantes que recibieron placebo (CR 0,71; IC del 95%: 0,27 a 1,88; evidencia de certeza muy baja). Los eventos adversos incluyeron diarrea, síntomas de empeoramiento, cólicos, sinusitis y dolor abdominal. Prevención: A los 12 meses, el 90% (18/20) de los pacientes que recibieron la formulación De Simone no presentaron episodios de reservoritis aguda en comparación con el 60% (12/20) de los pacientes que recibieron placebo (CR 1,50: IC del 95%: 1,02 a 2,21; evidencia de certeza baja). Otro estudio halló que el 100% (16/16) de los participantes que recibieron la fórmula De Simone no presentaron episodios de reservoritis aguda a los 12 meses en comparación con el 92% (11/12) de los pacientes del grupo control sin tratamiento (CR 1,10: IC del 95%: 0,89 a 1,36; evidencia de certeza muy baja). El 86% (6/7) de los participantes del grupo de Bifidobacterium longum no presentaron episodios de reservoritis aguda a los 6 meses en comparación con el 60% (3/5) de los participantes que recibieron placebo (CR 1,43; IC del 95%: 0,66 a 3,11; evidencia de certeza muy baja). El 11% (1/9) de los participantes del grupo de Clostridium butyricum MIYAIRI no presentaron episodios de reservoritis aguda a los 24 meses en comparación con el 50% (4/8) de los participantes que recibieron placebo (CR 0,22; IC del 95%: 0,03 a 1,60; evidencia de certeza muy baja). El 46% (43/94) de los participantes del grupo de alopurinol no presentaron episodios de reservoritis a los 24 meses en comparación con el 43% (39/90) de los participantes que recibieron placebo (CR1,06; IC del 95%: 0,76 a 1,46; evidencia de certeza baja). El 81% (21/26) de los participantes del grupo de tinidazol no presentaron episodios de reservoritis a los 12 meses en comparación con el 58% (7/12) de los participantes que recibieron placebo (CR 1,38; IC del 95%: 0,83 a 2,31; evidencia de certeza muy baja). CONCLUSIONES DE LOS AUTORES: No se conocen los efectos de los antibióticos, probióticos y otras intervenciones para el tratamiento y la prevención de la reservoritis. Se necesitan estudios bien diseñados con poder estadístico suficiente para determinar la forma óptima de tratamiento y prevención de la reservoritis.

Chromosomal and plasmid-mediated fluoroquinolone resistance in human Salmonella enterica infection in Ghana.

BACKGROUND: Salmonella infection poses significant public health threat globally, especially in resource-limited countries. Emergence and spread of antibiotic resistant strains to fluoroquinolones have led to treatment failures and increased mortality in Salmonella infection. However, there is dearth of information regarding mechanisms of resistance to fluoroquinolones in Ghana. This study therefore sought to identify chromosomal mutations and plasmid-mediated resistance as possible mechanisms of fluoroquinolone resistance from clinical isolates in Ghana. METHODS: This was a retrospective study of archived isolates biobanked at Kumasi Centre for Collaborative Research in Tropical Medicine, Ghana. Isolates were obtained from blood, stool and oropharynx samples at two hospitals, between May, 2016 and January, 2018. Salmonella identification was done using standard microbiological protocols and antibiotic susceptibility testing performed by Kirby-Bauer disc diffusion method. Isolates with intermediate susceptibility and/or resistance to nalidixic acid and/or ciprofloxacin were selected and examined for chromosomal mutations by Sanger sequencing and plasmid-mediated resistance by PCR. RESULTS: Of 133 biobanked isolates cultured, 68 (51.1%) and 16 (12%) were identified as Salmonella Typhi and non-typhoidal Salmonella (NTS), respectively. Sequence analysis of gyrA gene revealed the presence of 5 different nonsynonymous mutations, with the most frequent mutation (Ile203Ser) occurring in 12 out of 13 isolates tested. Gyrase B (gyrB) gene had 1 nonsynonymous mutation in 3 out of 13 isolates, substituting phenylalanine with leucine at codon 601 (Phe601Leu). No mutation was observed in parC and parE genes. Two NTS isolates were found to harbour qnrS plasmid-mediated resistant gene of molecular size 550 bp with high ciprofloxacin MIC of 0.5 µg/ml. CONCLUSION: This study reports for the first time in Ghana plasmid-mediated fluoroquinolone resistant gene qnrS in Salmonella clinical isolates. Nonsynonymous mutations of gyrA and gyrB genes likely to confer Salmonella reduced susceptibility to ciprofloxacin were also reported.

Risk factors and survival of patients infected with carbapenem-resistant Klebsiella pneumoniae in a KPC endemic setting: a case-control and cohort study.

BACKGROUND: Many gaps in the burden of resistant pathogens exist in endemic areas of low- and middle-income economies, especially those endemic for carbapenem resistance. The aim of this study is to evaluate risk factors for carbapenem-resistance, to estimate the association between carbapenem-resistance and all-cause 30-day mortality and to examine whether mortality is mediated by inappropriate therapy. METHODS: A case-control and a cohort study were conducted in one tertiary-care hospital in Medellín, Colombia from 2014 to 2015. Phenotypic and genotypic characterization of isolates was performed. In the case-control study, cases were defined as patients infected with carbapenem-resistant K. pneumoniae (CRKP) and controls as patients infected with carbapenem-susceptible K. pneumoniae (CSKP). A risk factor analysis was conducted using logistic regression models. In the cohort study, the exposed group was defined as patients infected with CRKP and the non-exposed group as patients infected with CSKP. A survival analysis using an accelerated failure time model with a lognormal distribution was performed to estimate the association between carbapenem resistance and all-cause 30-day-mortality and to examine whether mortality is mediated by inappropriate therapy. RESULTS: A total of 338 patients were enrolled; 49 were infected with CRKP and 289 with CSKP. Among CRKP isolates CG258 (n = 29), ST25 (n = 5) and ST307 (n = 4) were detected. Of importance, every day of meropenem (OR 1.18, 95%CI 1.10-1.28) and cefepime (OR 1.22, 95%CI 1.03-1.49) use increase the risk of carbapenem resistance. Additional risk factors were previous use of ciprofloxacin (OR 2.37, 95%CI 1.00-5.35) and urinary catheter (OR 2.60, 95%CI 1.25-5.37). Furthermore, a significant lower survival time was estimated for patients infected with CRKP compared to CSKP (Relative Times 0.44, 95%CI 0.24-0.82). The strength of association was reduced when appropriate therapy was included in the model (RT = 0.81 95%CI 0.48-1.37). CONCLUSION: Short antibiotic courses had the potential to reduce the selection and transmission of CRKP. A high burden in mortality occurred in patients infected with CRKP in a KPC endemic setting and CRKP leads to increased mortality via inappropriate antibiotic treatment. Furthermore, dissemination of recognized hypervirulent clones could add to the list of challenges for antibiotic resistance control.

Efficacy of inhaled ciprofloxacin agents for the treatment of bronchiectasis: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The efficacy of inhaled ciprofloxacin agents in the treatment of patients with bronchiectasis is controversial. The objective of the study was to review systematically the efficacy of inhaled ciprofloxacin agents in patients with bronchiectasis. METHODS: We searched PubMed, EMBASE, and Cochrane Library databases for randomized controlled trials (RCTs) evaluating inhaled ciprofloxacin agents among patients with bronchiectasis. Data were pooled using a meta-analysis technique. RESULTS: Two phase II and four phase III RCTs were included with a total of 1685 patients. Treatment durations of phase III studies were 48 weeks, while those of phase II studies were shorter. Pooled analysis of overall studies exhibited a statistically significant benefit of inhaled ciprofloxacin agents in three exacerbation outcome measures, including time to first exacerbation (hazard ratio 0.74, 95% confidence interval [CI] 0.63-0.86, I2 23%), exacerbation frequency (risk ratio [RR] 0.73, 95% CI 0.61-0.86, I2 42%), and exacerbation proportion (RR 0.85, 95% CI 0.76-0.96, I2 25%) without significant heterogeneity. Outcomes evaluating pulmonary function, quality of life, and adverse events were not significantly different between the two groups. Although eradication of respiratory pathogens was more frequently observed, the emergence of ciprofloxacin resistance was also significantly higher in the ciprofloxacin group. CONCLUSIONS: A meta-analysis of RCTs of inhaled ciprofloxacin agents showed clinical benefit in terms of pulmonary exacerbations in patients with bronchiectasis. Since a significant increase of resistance was also noticed, clinical trials with a longer study period are required for a conclusive assessment. The reviews of this paper are available via the supplemental material section.

Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis.

BACKGROUND: Pouchitis occurs in approximately 50% of patients following ileal pouch-anal anastomosis (IPAA) for chronic ulcerative colitis (UC). OBJECTIVES: The primary objective was to determine the efficacy and safety of medical therapies for prevention or treatment of acute or chronic pouchitis. SEARCH METHODS: We searched MEDLINE, Embase and CENTRAL from inception to 25 July 2018. We also searched references, trials registers, and conference proceedings. SELECTION CRITERIA: Randomized controlled trials of prevention or treatment of acute or chronic pouchitis in adults who underwent IPAA for UC were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently screened studies for eligibility, extracted data and assessed the risk of bias. The certainty of the evidence was evaluated using GRADE. The primary outcome was clinical improvement or remission in participants with acute or chronic pouchitis, or the proportion of participants with no episodes of pouchitis after IPAA. Adverse events (AEs) was a secondary outcome. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for each dichotomous outcome. MAIN RESULTS: Fifteen studies (547 participants) were included. Four studies assessed treatment of acute pouchitis. Five studies assessed treatment of chronic pouchitis. Six studies assessed prevention of pouchitis. Three studies were low risk of bias. Three studies were high risk of bias and the other studies were unclear.Acute pouchitis: All ciprofloxacin participants (7/7) achieved remission at two weeks compared to 33% (3/9) of metronidazole participants (RR 2.68, 95% CI 1.13 to 6.35, very low certainty evidence). No ciprofloxacin participants (0/7) had an AE compared to 33% (3/9) of metronidazole participants (RR 0.18, 95% CI 0.01 to 2.98; very low certainty evidence). AEs included vomiting, dysgeusia or transient peripheral neuropathy. Forty-three per cent (6/14) of metronidazole participants achieved remission at 6 weeks compared to 50% (6/12) of budesonide enema participants (RR 0.86, 95% CI 0.37 to 1.96, very low certainty evidence). Fifty per cent (7/14) of metronidazole participants improved clinically at 6 weeks compared to 58% (7/12) of budesonide enema participants (RR 0.86, 95% CI 0.42 to 1.74, very low certainty evidence). Fifty-seven per cent (8/14) of metronidazole participants had an AE compared to 25% (3/12) of budesonide enema participants (RR 2.29, 95% CI 0.78 to 6.73, very low certainty evidence). AEs included anorexia, nausea, headache, asthenia, metallic taste, vomiting, paraesthesia, and depression. Twenty-five per cent (2/8) of rifaximin participants achieved remission at 4 weeks compared to 0% (0/10) of placebo participants (RR 6.11, 95% CI 0.33 to 111.71, very low certainty evidence). Thirty-eight per cent (3/8) of rifaximin participants improved clinically at 4 weeks compared to 30% (3/10) of placebo participants (RR 1.25, 95% CI 0.34 to 4.60, very low certainty evidence). Seventy-five per cent (6/8) of rifaximin participants had an AE compared to 50% (5/10) of placebo participants (RR 1.50, 95% CI 0.72 to 3.14, very low certainty evidence). AEs included diarrhea, flatulence, nausea, proctalgia, vomiting, thirst, candida, upper respiratory tract infection, increased hepatic enzyme, and cluster headache. Ten per cent (1/10) of Lactobacillus GG participants improved clinically at 12 weeks compared to 0% (0/10) of placebo participants (RR 3.00, 95% CI 0.14 to 65.90, very low certainty evidence).Chronic pouchitis: Eighty-five per cent (34/40) of De Simone Formulation participants maintained remission at 9 to 12 months compared to 3% (1/36) of placebo participants (RR 20.24, 95% CI 4.28 to 95.81, 2 studies; low certainty evidence). Two per cent (1/40) of De Simone Formulation participants had an AE compared to 0% (0/36) of placebo participants (RR 2.43, 95% CI 0.11 to 55.89; low certainty evidence). AEs included abdominal cramps, vomiting and diarrhea. Fifty per cent (3/6) of adalimumab patients achieved clinical improvement at 4 weeks compared to 43% (3/7) of placebo participants (RR, 1.17, 95% CI 0.36 to 3.76, low certainty evidence). Sixty per cent (6/10) of glutamine participants maintained remission at 3 weeks compared to 33% (3/9) of butyrate participants (RR 1.80, 95% CI 0.63 to 5.16, very low certainty evidence). Forty-five per cent (9/20) of patients treated with bismuth carbomer foam enema improved clinically at 3 weeks compared to 45% (9/20) of placebo participants (RR 1.00, 95% CI 0.50 to 1.98, very low certainty evidence). Twenty-five per cent (5/20) of participants in the bismuth carbomer foam enema group had an AE compared to 35% (7/20) of placebo participants (RR 0.71, 95% CI 0.27 to 1.88, very low certainty evidence). Adverse events included diarrhea, worsening symptoms, cramping, sinusitis, and abdominal pain. PREVENTION: At 12 months, 90% (18/20) of De Simone Formulation participants had no episodes of acute pouchitis compared to 60% (12/20) of placebo participants (RR 1.50, 95% CI 1.02 to 2.21, low certainty evidence). Another study found 100% (16/16) of De Simone Formulation participants had no episodes of acute pouchitis at 12 months compared to 92% (11/12) of the no treatment control group (RR 1.10, 95% 0.89 to 1.36, very low certainty evidence). Eighty-six per cent (6/7) of Bifidobacterium longum participants had no episodes of acute pouchitis at 6 months compared to 60% (3/5) of placebo participants (RR 1.43, 95% CI 0.66 to 3.11, very low certainty evidence). Eleven per cent (1/9) of Clostridium butyricum MIYAIRI participants had no episodes of acute pouchitis at 24 months compared to 50% (4/8) of placebo participants (RR 0.22, 95% CI 0.03 to 1.60, very low certainty evidence). Forty-six per cent (43/94) of allopurinol participants had no episodes of pouchitis at 24 months compared to 43% (39/90) of placebo participants (RR 1.06, 95% CI 0.76 to 1.46; low certainty evidence). Eighty-one per cent (21/26) of tinidazole participants had no episodes of pouchitis over 12 months compared to 58% (7/12) of placebo participants (RR 1.38, 95% CI 0.83 to 2.31, very low certainty evidence). AUTHORS' CONCLUSIONS: The effects of antibiotics, probiotics and other interventions for treating and preventing pouchitis are uncertain. Well designed, adequately powered studies are needed to determine the optimal therapy for the treatment and prevention of pouchitis.

OTO-201 for the Treatment of Acute Otitis Externa: Results from a Phase 3 Randomized Clinical Study.

OBJECTIVES: OTO-201 is a ciprofloxacin otic suspension previously approved by the US Food and Drug Administration to treat children with bilateral otitis media with effusion requiring tympanostomy tube placement. In this phase 3, double-blind, randomized, prospective, sham-controlled, multicenter study, a single dose of OTO-201 was administered to the external auditory canal in subjects with unilateral or bilateral acute otitis externa. METHODS: Two hundred sixty-two subjects, 3 to 83 years of age, were randomized, and 260 subjects were included in the intent-to-treat analysis population: OTO-201 (0.2 mL, 12 mg, n = 130) or sham (air injection, n = 130). The primary efficacy measure was clinical cure (CC) on day 8, judged by blinded assessor for erythema, edema, otorrhea, and tenderness. Subjects were monitored over 28 days for efficacy and safety. RESULTS: OTO-201 demonstrated a significant increase in CC compared with sham at day 8 (69.2% vs 46.1%, P < .001). Higher CC was also noted on day 4 ( P = .028), day 15 ( P < .001), and day 29 ( P < .001). A similar effect was observed in the pathogen-positive population. Single OTO-201 administration in the office setting was well tolerated by subjects. CONCLUSIONS: In this study in subjects with acute otitis externa, a single administration of 12 mg OTO-201 to the external auditory canal demonstrated a significantly higher proportion of subjects with CC and bacterial eradication compared with sham starting on day 4 and on all other observation days through day 29, with no safety or tolerability concerns identified. OTO-201 is the first agent in a randomized phase 3 study to demonstrate the efficacy and safety of a single-dose, health care professional-administered topical antibiotic for the treatment of acute otitis externa.

Effects of ciprofloxacin and quercetin on fetal brain development: a biochemical and histopathological study.

PURPOSE: Teratogens cause birth defects and malformations while human development is being completed. In pregnancy, urinary tract infection (UTI) is a common health problem caused by bacteria. The fluoroquinolones such as ciprofloxacin, levofloxacin, moxifloxacin, and gemifloxacin can treat various types of bacterial infections successfully. The aim of this study is to determine whether the use of ciprofloxacin during pregnancy causes oxidative stress on brain tissues of the fetus, and whether quercetin contributes to prevent this damage if stress has already occurred. MATERIALS AND METHODS: In our study, 22 young female Wistar albino rats weighing 250 g were used. Rats were mated overnight in separate plastic cages. Female rats were regarded as pregnant when a vaginal plug was observed, and these were divided into four groups of control, ciprofloxacin, quercetin, and cipro + quercetin. Two daily i.p. 20 mg/kg doses of ciprofloxacin were administered to ciprofloxacin group between 7 and 17 d of pregnancy. Throughout the study, daily (20 d) 20 mg/kg quercetin was dissolved in corn oil and administered to the quercetin group by oral gavage. Rats were fed ad libitum throughout the study. Fetuses were taken by C-section on the 20th day of pregnancy. Thereafter, the brain tissues were subjected to histological assessments and biochemical analyzes. RESULTS: The experimental groups were compared with the control group; ciprofloxacin affected fetal development, especially caused damage to neurons in brain tissue and cause hemorrhagic defects. And also, it was determined that many parameters were affected such as antioxidant parameters, enzyme levels and levels of malondialdehyde (MDA) (a marker of lipid peroxidation). Quercetin is a member of flavonoid with strong antioxidant properties, and our results indicate that the use of ciprofloxacin in pregnancy can result damage to fetal brain tissue. CONCLUSIONS: Unlike these results when some parameters are evaluated it is understood that this harmful effects suppressed by quercetin.

Spectrophotometric analysis of discoloration and internal bleaching after use of different antibiotic pastes.

OBJECTIVES: To investigate teeth's antibiotic-induced color differences after bleaching using two different techniques. MATERIALS AND METHODS: One hundred twenty extracted maxillar human incisors were examined. The specimens were randomly divided into six groups, each receiving one of six antibiotic paste fillings: (1) triple antibiotic paste (TAP) with minocycline, (2) double antibiotic paste (DAP), (3) TAP with amoxicillin, (4) TAP with cefaclor, (5) TAP with doxycycline, and (6) no filling (control group). Spectrophotometric measurements were obtained at baseline and then during the first, second, and third weeks after paste placement. The specimens discolored by antibiotics pastes were randomly divided into two subgroups: (1) internal bleaching with hydrogen peroxide (H2O2) and (2) internal bleaching with H2O2 plus Nd-YAG laser irradiation. The ∆E value was calculated and analyzed using a two-way analysis of variance and post-hoc Tukey's test (α = 0.05). RESULTS: The ∆E for all groups showed color differences exceeding the perceptibility threshold (∆E Ëƒ 3.7) at all time points except in the control and DAP groups. Minocycline-induced TAP showed the most severe coronal discoloration (32.42). When the ∆E was examined, thermo/photo bleaching (22.01 ± 8.23) caused more bleaching than walking bleaching (19.73 ± 5.73) at every time point (P = 0.19). No group returned to the original color after bleaching (P < 0.05). CONCLUSIONS: Except for DAP, all antibiotic pastes caused discoloration. Internal bleaching with Nd-YAG laser can be useful for bleaching/removing this discoloration. CLINICAL RELEVANCE: For clinically successful final appearances, understanding the effects of bleaching procedures on antibiotic paste discoloration is important.

Spotlight on inhaled ciprofloxacin and its potential in the treatment of non-cystic fibrosis bronchiectasis.

Non-cystic fibrosis bronchiectasis (NCFB) is a severe chronic illness characterized by irreversible dilation of airways and thickening of bronchial walls, chronic inflammation, repeated infections, and progressive obstruction of the airways. In contrast to cystic fibrosis bronchiectasis (CFB), which is a well-defined genetic disorder, NCFB is a heterogeneous disease caused by many different medical entities. Inhaled antibiotics are effective for patients with CFB, but their efficacy in NCFB has not been proven. The main pathogens involved in the colonization of patients with bronchiectasis are Haemophilus influenza, Moraxella catarrhalis, Staphylococcus aureus, and Pseudomonas aeruginosa. The latter is associated with increased morbidity and mortality. In addition, in NCFB, P. aeruginosa strains are frequently more resistant than those in CFB. At present, there are no approved inhaled antibiotic therapies for NCFB patients. Inhaled ciprofloxacin has been under investigation in the last few years. In two phase II randomized, double-blind, placebo-controlled trials, the use of inhaled ciprofloxacin was significantly associated with reduction in sputum bacterial density and greater eradication rates. In four phase III randomized, double-blind, placebo-controlled trials, the results regarding the time of the first exacerbation and the rate of exacerbations were inconsistent. Specifically, ORBIT-4 and RESPIRE-1 trials showed clinical benefit (prolongation of the time of the first exacerbation and reduced rate of exacerbations in the treatment group compared to the placebo group), whereas the ORBIT-3 and RESPIRE-2 failed to achieve their primary endpoints. The RESPIRE-1 was the first trial that examined the 14-days on/off course separate from the standard 28-days on/off regimen, which is based on CFB protocol treatments. The current data on the efficacy of inhaled ciprofloxacin are encouraging, but further evaluation is needed to determine the appropriate target group and the ideal duration of treatment.