Comparative study of fibroblast growth factor 2 and ofloxacin ear drops for repairing large traumatic perforations: A randomized controlled study.

OBJECTIVE: The objective of this study was to compare the healing outcome of fibroblast growth factor 2 (FGF2), ofloxacin ear drops (OFLX) and spontaneous healing for repairing large traumatic tympanic membrane (TM) perforations. MATERIAL AND METHODS: A total of 75 traumatic large perforations with >1/4 of TM were randomly divided into FGF2 (n = 25), OFLX (n = 25), and spontaneous healing (n = 25) groups. The closure rates, closure times, and hearing gains were compared at 3 months. RESULTS: At 2 weeks after treatment, the closure rate was 95.8 % in the FGF2 group, 96.0 % in the ofloxacin ear drops group, and 14.3 % in the spontaneous healing group (P < 0.01), respectively. At 3 months after treatment, the closure rate was 100 % in the FGF2 group, 100 % in the OFLX group, and 85.7 % in the spontaneous healing group, no among-group differences were significant (P > 0.05). The mean closure time was 9.69 ± 2.46 days in the FGF2 group, 9.45 ± 2.32 days in the OFLX group, and 30.94 ± 8.95 days in the spontaneous healing group (P < 0.01). The mean ABG was 10.37 ± 2.51 dB for the FGF2 group, 11.01 ± 1.31 dB for the OFLX group, and 10.86 ± 1.94 dB for the spontaneous healing group, no significant difference was found among three groups (P > 0.05). CONCLUSIONS: This study suggested that both FGF2 and OFLX significantly shortened the mean closure time and improved the closure rate compared with spontaneous healing for repairing large traumatic perforations, while the healing outcome wasn't significantly different among FGF2 and OFLX groups.

Antimicrobial for 7 or 14 Days for Febrile Urinary Tract Infection in Men: A Multicenter Noninferiority Double-Blind, Placebo-Controlled, Randomized Clinical Trial.

BACKGROUND: The optimal duration of antimicrobial therapy for urinary tract infections (UTIs) in men remains controversial. METHODS: To compare 7 days to 14 days of total antibiotic treatment for febrile UTIs in men, this multicenter randomized, double-blind. placebo-controlled noninferiority trial enrolled 282 men from 27 centers in France. Men were eligible if they had a febrile UTI and urine culture showing a single uropathogen. Participants were treated with ofloxacin or a third-generation cephalosporin at day 1, then randomized at day 3-4 to either continue ofloxacin for 14 days total treatment, or for 7 days followed by placebo until day 14. The primary endpoint was treatment success, defined as a negative urine culture and the absence of fever and of subsequent antibiotic treatment between the end of treatment and 6 weeks after day 1. Secondary endpoints included recurrent UTI within weeks 6 and 12 after day 1, rectal carriage of antimicrobial-resistant Enterobacterales, and drug-related events. RESULTS: Two hundred forty participants were randomly assigned to receive antibiotic therapy for 7 days (115 participants) or 14 days (125 participants). In the intention-to-treat analysis, treatment success occurred in 64 participants (55.7%) in the 7-day group and in 97 participants (77.6%) in the 14-day group (risk difference, -21.9 [95% confidence interval, -33.3 to -10.1]), demonstrating inferiority. Adverse events during antibiotic therapy were reported in 4 participants in the 7-day arm and 7 in the 14-day arm. Rectal carriage of resistant Enterobacterales did not differ between both groups. CONCLUSIONS: A treatment with ofloxacin for 7 days was inferior to 14 days for febrile UTI in men and should therefore not be recommended. CLINICAL TRIALS REGISTRATION: NCT02424461; Eudra-CT: 2013-001647-32.

With and without exogenous biological scaffolds for repairing traumatic perforations of tympanic membrane: Randomized clinical trials.

OBJECTIVE: The objective of this study was to compare the efficacy of ofloxacin ear drops, vaseline gauze (VG) and dry gelfoam alone on the large traumatic perforations of tympanic membrane (TM). MATERIAL AND METHODS: A randomized prospective analysis was performed for the treatment of traumatic perforation larger than 25 % of the entire TM. The closure rate, closure time, and hearing gain between ofloxacin ear drops, VG and gelfoam alone groups were compared at 3 months. RESULTS: Final analysis was performed on 70 patients. The closure rates of perforation in the ofloxacin ear drops, VG, and dry gelfoam patch groups were 100.0 %, 92.0 %, and 87.5 %, respectively (P = 0.41).The mean closure times were 8.67 ± 3.1, 10.65 ± 4.2, and 14.33 ± 7.5 days for the ofloxacin ear drops, VG, and gelfoam patch alone groups, respectively. The closure times among the 3 groups were significantly different (P = 0.003). In addition, there was a significant difference between the ofloxacin ear drops and gelfoam patch alone groups with regard to closure time (P = 0.003), while there was no significant difference between the ofloxacin ear drops and VG groups (P = 0.080) or VG and gelfoam patch groups (P = 0.056).The mean hearing gain was 11.4 ± 2.3 dB for the ofloxacin ear drops group, 11.7 ± 4.1 dB for the VG group, and 12.2 ± 1.6 dB for the gelfoam patch group (P = 0.69). CONCLUSIONS: The repairing of traumatic perforations didn't require an exogenous biological scaffold. Ofloxacin ear drops and VG were a deal material for repairing traumatic perforation in otology clinic, which not only was readily available and inexpensive but also showed faster closure compared with dry gelfoam alone.

In Vitro Inhibitory Effects and Bioinformatic Analysis of Norfloxacin and Ofloxacin on Piroplasm.

PURPOSE: The in vitro inhibitory effect of two fluroquinolone antibiotics, norfloxacin and ofloxacin, was evaluated in this study on the growth of several Babesia and Theileria parasites with highlighting the bioinformatic analysis for both drugs with the commonly used antibabesial drug, diminazene aceturate (DA), and the recently identified antibabesial drugs, luteolin, and pyronaridine tetraphosphate (PYR). METHODS: The antipiroplasm efficacy of screened fluroquinolones in vitro and in vivo was assessed using a fluorescence-based SYBR Green I assay. Using atom Pair signatures, we investigated the structural similarity between fluroquinolones and the antibabesial drugs. RESULTS: Both fluroquinolones significantly inhibited (P < 0.05) the in vitro growths of Babesia bovis (B. bovis), B. bigemina, B. caballi, and Theileria equi (T. equi) in a dose-dependent manner. The best inhibitory effect for both drugs was observed on the growth of T. equi. Atom Pair fingerprints (APfp) results and AP Tanimoto values revealed that both fluroquinolones, norfloxacin with luteolin, and ofloxacin with PYR, showed the maximum structural similarity (MSS). Two drug interactions findings confirmed the synergetic interaction between these combination therapies against the in vitro growth of B. bovis and T. equi. CONCLUSION: This study helped in discovery novel potent antibabesial combination therapies consist of norfloxacin/ofloxacin, norfloxacin/luteolin, and ofloxacin/PYR.

A Literature-Based Review and Analysis of the Pharmacodynamics of the Dose Frequency of Topical 0.3% Ciprofloxacin and 0.3% Ofloxacin in the Day-1 Treatment of Bacterial Keratitis.

Purpose: To determine the appropriate dose frequency for the second-generation fluoroquinolones (2FQs), ciprofloxacin 0.3% and ofloxacin 0.3%, in the day-1 treatment of bacterial keratitis (BK) based on the corneal concentrations achievable and required Minimum Inhibitory Concentration90 (MIC90) of common BK isolates. Methods: Literature-based ocular MIC90 required to treat bacterial isolates of BK patients were determined for each fluoroquinolone. Published corneal concentrations for each 2FQ, and the drop regimens used to reach these concentrations, were then analyzed to determine the relationship between the corneal 2FQ concentration and the amount of drug applied per hour and the total amount applied. Results: Significant relationships were found to exist for corneal concentrations of both ciprofloxacin and ofloxacin and the amount of drug applied per hour (both P = 0.005), and the total amount of drug applied (P = 0.003 and P = 0.0004, respectively). Derived ciprofloxacin drops/hour corneal concentrations agreed well with both a literature-based regimen and the manufacturers' day-1 drop regimen for various MIC90. Derived ofloxacin drops per hour indicated a higher rate than that suggested by the manufacturer. Conclusions: Both a literature-based and the manufacturers' drop regimens for the day-1 treatment of BK using 0.3% ciprofloxacin have a pharmacodynamic basis, which is related to the required MIC90 of commonly encountered isolates in BK. Dose frequency for 0.3% ofloxacin should be in line with the manufacturers' maximum suggested drop regimen. Commonly suggested drop regimens below these recommendations for either FQ may need to be revised in view of these findings.

Treatment of enteric fever (typhoid and paratyphoid fever) with cephalosporins.

BACKGROUND: Typhoid and paratyphoid (enteric fever) are febrile bacterial illnesses common in many low- and middle-income countries. The World Health Organization (WHO) currently recommends treatment with azithromycin, ciprofloxacin, or ceftriaxone due to widespread resistance to older, first-line antimicrobials. Resistance patterns vary in different locations and are changing over time. Fluoroquinolone resistance in South Asia often precludes the use of ciprofloxacin. Extensively drug-resistant strains of enteric fever have emerged in Pakistan. In some areas of the world, susceptibility to old first-line antimicrobials, such as chloramphenicol, has re-appeared. A Cochrane Review of the use of fluoroquinolones and azithromycin in the treatment of enteric fever has previously been undertaken, but the use of cephalosporins has not been systematically investigated and the optimal choice of drug and duration of treatment are uncertain. OBJECTIVES: To evaluate the effectiveness of cephalosporins for treating enteric fever in children and adults compared to other antimicrobials. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, LILACS, the WHO ICTRP and ClinicalTrials.gov up to 24 November 2021. We also searched reference lists of included trials, contacted researchers working in the field, and contacted relevant organizations. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in adults and children with enteric fever that compared a cephalosporin to another antimicrobial, a different cephalosporin, or a different treatment duration of the intervention cephalosporin. Enteric fever was diagnosed on the basis of blood culture, bone marrow culture, or molecular tests. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were clinical failure, microbiological failure and relapse. Our secondary outcomes were time to defervescence, duration of hospital admission, convalescent faecal carriage, and adverse effects. We used the GRADE approach to assess certainty of evidence for each outcome. MAIN RESULTS: We included 27 RCTs with 2231 total participants published between 1986 and 2016 across Africa, Asia, Europe, the Middle East and the Caribbean, with comparisons between cephalosporins and other antimicrobials used for the treatment of enteric fever in children and adults. The main comparisons are between antimicrobials in most common clinical use, namely cephalosporins compared to a fluoroquinolone and cephalosporins compared to azithromycin. Cephalosporin (cefixime) versus fluoroquinolones Clinical failure, microbiological failure and relapse may be increased in patients treated with cefixime compared to fluoroquinolones in three small trials published over 14 years ago: clinical failure (risk ratio (RR) 13.39, 95% confidence interval (CI) 3.24 to 55.39; 2 trials, 240 participants; low-certainty evidence); microbiological failure (RR 4.07, 95% CI 0.46 to 36.41; 2 trials, 240 participants; low-certainty evidence); relapse (RR 4.45, 95% CI 1.11 to 17.84; 2 trials, 220 participants; low-certainty evidence). Time to defervescence in participants treated with cefixime may be longer compared to participants treated with fluoroquinolones (mean difference (MD) 1.74 days, 95% CI 0.50 to 2.98, 3 trials, 425 participants; low-certainty evidence). Cephalosporin (ceftriaxone) versus azithromycin Ceftriaxone may result in a decrease in clinical failure compared to azithromycin, and it is unclear whether ceftriaxone has an effect on microbiological failure compared to azithromycin in two small trials published over 18 years ago and in one more recent trial, all conducted in participants under 18 years of age: clinical failure (RR 0.42, 95% CI 0.11 to 1.57; 3 trials, 196 participants; low-certainty evidence); microbiological failure (RR 1.95, 95% CI 0.36 to 10.64, 3 trials, 196 participants; very low-certainty evidence). It is unclear whether ceftriaxone increases or decreases relapse compared to azithromycin (RR 10.05, 95% CI 1.93 to 52.38; 3 trials, 185 participants; very low-certainty evidence). Time to defervescence in participants treated with ceftriaxone may be shorter compared to participants treated with azithromycin (mean difference of -0.52 days, 95% CI -0.91 to -0.12; 3 trials, 196 participants; low-certainty evidence). Cephalosporin (ceftriaxone) versus fluoroquinolones It is unclear whether ceftriaxone has an effect on clinical failure, microbiological failure, relapse, and time to defervescence compared to fluoroquinolones in three trials published over 28 years ago and two more recent trials: clinical failure (RR 3.77, 95% CI 0.72 to 19.81; 4 trials, 359 participants; very low-certainty evidence); microbiological failure (RR 1.65, 95% CI 0.40 to 6.83; 3 trials, 316 participants; very low-certainty evidence); relapse (RR 0.95, 95% CI 0.31 to 2.92; 3 trials, 297 participants; very low-certainty evidence) and time to defervescence (MD 2.73 days, 95% CI -0.37 to 5.84; 3 trials, 285 participants; very low-certainty evidence). It is unclear whether ceftriaxone decreases convalescent faecal carriage compared to the fluoroquinolone gatifloxacin (RR 0.18, 95% CI 0.01 to 3.72; 1 trial, 73 participants; very low-certainty evidence) and length of hospital stay may be longer in participants treated with ceftriaxone compared to participants treated with the fluoroquinolone ofloxacin (mean of 12 days (range 7 to 23 days) in the ceftriaxone group compared to a mean of 9 days (range 6 to 13 days) in the ofloxacin group; 1 trial, 47 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: Based on very low- to low-certainty evidence, ceftriaxone is an effective treatment for adults and children with enteric fever, with few adverse effects. Trials suggest that there may be no difference in the performance of ceftriaxone compared with azithromycin, fluoroquinolones, or chloramphenicol. Cefixime can also be used for treatment of enteric fever but may not perform as well as fluoroquinolones.  We are unable to draw firm general conclusions on comparative contemporary effectiveness given that most trials were small and conducted over 20 years previously. Clinicians need to take into account current, local resistance patterns in addition to route of administration when choosing an antimicrobial.

Drug Resistance (Dapsone, Rifampicin, Ofloxacin) and Resistance-Related Gene Mutation Features in Leprosy Patients: A Systematic Review and Meta-Analysis.

Dapsone (DDS), Rifampicin (RIF) and Ofloxacin (OFL) are drugs recommended by the World Health Organization (WHO) for the treatment of leprosy. In the context of leprosy, resistance to these drugs occurs mainly due to mutations in the target genes (Folp1, RpoB and GyrA). It is important to monitor antimicrobial resistance in patients with leprosy. Therefore, we performed a meta-analysis of drug resistance in Mycobacterium leprae and the mutational profile of the target genes. In this paper, we limited the study period to May 2022 and searched PubMed, Web of Science (WOS), Scopus, and Embase databases for identified studies. Two independent reviewers extracted the study data. Mutation and drug-resistance rates were estimated in Stata 16.0. The results demonstrated that the drug-resistance rate was 10.18% (95% CI: 7.85-12.51). Subgroup analysis showed the highest resistance rate was in the Western Pacific region (17.05%, 95% CI:1.80 to 13.78), and it was higher after 2009 than before [(11.39%, 7.46-15.33) vs. 6.59% (3.66-9.53)]. We can conclude that the rate among new cases (7.25%, 95% CI: 4.65-9.84) was lower than the relapsed (14.26%, 95 CI%: 9.82-18.71). Mutation rates of Folp1, RpoB and GyrA were 4.40% (95% CI: 3.02-5.77), 3.66% (95% CI: 2.41-4.90) and 1.28% (95% CI: 0.87-1.71) respectively, while the rate for polygenes mutation was 1.73% (0.83-2.63). For further analysis, we used 368 drug-resistant strains as research subjects and found that codons (Ser, Pro, Ala) on RpoB, Folp1 and GyrA are the most common mutation sites in the determining region (DRDR). In addition, the most common substitution patterns of Folp1, RpoB, and GyrA are Pro→Leu, Ser→Leu, and Ala→Val. This study found that a higher proportion of patients has developed resistance to these drugs, and the rate has increased since 2009, which continue to pose a challenge to clinicians. In addition, the amino acid alterations in the sequence of the DRDR regions and the substitution patterns mentioned in the study also provide new ideas for clinical treatment options.

Aqueous Humour Ofloxacin Concentration after Topical Instillation in Patients with Dry Eye Disease.

Background and Objectives: A prospective, randomized clinical trial was conducted to evaluate the concentration of ofloxacin in the aqueous humour (AqH) of patients suffering from dry eye disease (DED) after topical instillation. Materials and Methods: Ninety-one (91) cataract patients scheduled for phacoemulsification were categorized into three groups according to DED severity. Group I (n = 17) was comprised of subjects without DED, patients in group II (n = 37) were evaluated as having non-severe DED, while group III (n = 37) consisted of patients suffering from severe DED. Preoperatively, patients received 4 drops of 0.3% of ofloxacin at 15 min intervals. One hour after the last instillation, aqueous samples were collected intraoperatively. Results: The median AqH concentration of ofloxacin in group I was 199.9 ng/mL (range 92.2−442.8 ng/mL), while in group II it was 530.5 ng/mL (range 283.7−1004.9 ng/mL), and 719.2 ng/mL (range 358.0−1512.4 ng/mL) in Group III, p < 0.001 (Kruskal-Wallis tests). Pairwise tests (two-tailed with Bonferroni corrections) between groups resulted in a p-value of 0.001 when group II was compared to group I and group III was compared to group I, and a p-value of 0.020 when group II was compared to group III. The severity of DED, across groups I, II, and III, and the levels of ofloxacin revealed a strong positive correlation (r = 0.639, p < 0.001). Conclusions: Ofloxacin concentration in the AqH after topical drop instillation may be affected by the degree of ocular surface inflammation in patients suffering from DED.

Ofloxacin resistance in multibacillary new leprosy cases from Purulia, West Bengal: a threat to effective secondary line treatment for rifampicin-resistant leprosy cases.

OBJECTIVES: Purulia is one of the high-endemic districts for leprosy in West Bengal (the eastern part of India). The annual new case detection rate (ANCDR) of leprosy in West Bengal is 6.04/100000 (DGHS 2019-20). Our earlier report provided evidence of secondary drug resistance in relapse cases of leprosy. The aim of the current study was to observe primary drug resistance patterns for dapsone, rifampicin, and ofloxacin amongst new leprosy patients from Purulia, West Bengal in order to better understand the emergence of primary resistance to these drugs. METHODS: In the present study, slit-skin smear samples were collected from 145 newly diagnosed leprosy cases from The Leprosy Mission (TLM) Purulia hospital between 2017 and 2018. DNA was extracted from these samples and the Mycobacterium leprae genome was analyzed for genes associated with drug resistance by polymerase chain reaction (PCR), followed by Sanger sequencing. Wild-type strain (Thai-53) and mouse footpad-derived drug-resistant strain (Z-4) were used as reference strains. RESULTS: Of 145 cases, 25 cases showed mutations in genes associated with resistance to rifampicin, dapsone, and ofloxacin (as described by the World Health Organization, rpoB, folP, and gyrA, respectively) through Sanger sequencing. Of these 25 cases, 16 cases showed mutations in ofloxacin, two cases showed mutations in combinations of ofloxacin and rifampicin, four cases showed a mutation only in rifampicin, one case showed mutations in combinations of rifampicin and dapsone, and two cases showed mutations only in dapsone. CONCLUSION: Results from this study indicated the emergence of resistance to antileprosy drugs in new cases of leprosy. As ofloxacin is the alternate drug for the treatment of rifampicin-resistant cases, the emergence of new cases with resistance to ofloxacin indicates that ofloxacin-resistant M. leprae strains are actively circulating in this endemic region (i.e., Purulia, West Bengal), posing challenges for the effective treatment of rifampicin-resistant cases.

Ofloxacin-loaded HMPB NPs for Klebsiella pneumoniae eradication in the surgical wound with the combination of PTT.

Klebsiella pneumoniae (K. pneumoniae) is a common bacterium whose drug-resistant can cause surgical failures and incurable infections in hospital patients. Thus, how to reverse or delay the resistance induction has become a great challenge for development antiresistant drug. Recently, the combination of nanomaterial-loaded antibiotics with photothermal therapy showed the efficient antibacteria ability under a low dosage of antibiotics. In this study, a nanocomposite of HMPB NPs with inherent photothermal therapy capability was used to eradicate K. pneumoniae after loading with Ofloxacin, an antibiotic against K. pneumoniae in vitro and in vivo. The nanocomplexes named as Ofloxacin@HMPB@HA NPs showed a higher effect against K. pneumoniae by destroying cell integrity and inducing ATP leakage with the assistance of laser irradiation, compared with sole Ofloxacin@HMPB@HA NPs or laser irradiation. Surgical wound infection assay further demonstrated the efficient killing K. pneumoniae and promoting the formation of new tissues, as well, which was reflected by the rapid healing of surgical wound. In summary, these results indicate the great potential of this combinational tactic based on Ofloxacin@HMPB@HA NPs for preventing the failure caused by K. pneumoniae infection.

Corynebacterium Keratitis: Pure Versus Mixed Infection and Antibiotic Susceptibility Patterns From Different Tertiary Eye Care Centers.

PURPOSE: The objective of this study was to compare the clinical and microbiological profiles of culture-proven pure Corynebacterium keratitis with mixed infection and their antibiotic susceptibility patterns over a 2-year period. METHODS: A retrospective analysis of culture-proven cases of Corynebacterium keratitis over a 2-year period was performed in 3 different tertiary eye care centers. All isolates were tested for antibiotic susceptibility in vitro using the disc-diffusion method for 7 antibiotics. RESULTS: Altogether 108 cases were identified as culture-positive Corynebacterium keratitis in 3 tertiary eye care centers. Of these, 60.2% (n = 65) and 39.8% (n = 43) of cases were due to pure Corynebacterium and mixed infection, respectively. The mean duration of symptoms was 23.2 ± 29.6 days. In the mixed-infection group, fungus was identified as the coexistent pathogen in 22 cases (51.1%). Ocular surface disorder was the most common risk factor (33.9%) in Corynebacterium keratitis. The most frequently isolated species was Corynebacterium amycolatum (22.2%) in both groups. Therapeutic keratoplasty was performed in 8.3% of cases. There was no significant difference in the outcome between the 2 groups. Cefazolin resistance was seen in 13.9% of patients, and all isolates were susceptible to vancomycin. The resistance pattern showed emerging resistance toward fluoroquinolone because the isolates were resistant to gatifloxacin (58.3%), moxifloxacin (47.2%), ciprofloxacin (54.6%), and ofloxacin (45.4%). CONCLUSIONS: Ocular surface disorder is the most common risk factor in Corynebacterium keratitis. Although fluoroquinolones are commonly used as first-line therapy in microbial keratitis, the in vitro resistance pattern indicates that these are less likely to be effective in infection with Corynebacterium species.

Design and evaluation of ocular hydrogel containing combination of ofloxacin and dexamethasone for the treatment of conjunctivitis

Abstract Conjunctivitis is an inflammation of the conjunctiva, which covers the white part of the eyeball. It can be caused by allergies, bacterial or viral infection. In situ hydrogels are three-dimensional hydrophilic cross-linked network of polymers. In situ hydrogel provided better therapeutic index when compared to conventional treatment. The present work describes the formulation and evaluation of ofloxacin and dexamethasone based on the concept of pH triggered in situ gelation. Carbopol 934p was used as the gelling agent in combination with HPMC, as a viscosity-enhancing agent, benzalkonium chloride as preservative, sodium chloride as tonicity adjusting agent. The prepared formulations were liquid at the low pH and underwent rapid transition into viscous gel at the pH of the tear fluid. Formulations were evaluated for various rheological, in vitro and in vivo release characteristics. Infrared spectroscopy studies showed that there were no interactions between the drug and polymers. Viscosity of the prepared hydrogels lies in the optimum range and drug was released up to 85 % as the end of 13 h. The prepared in situ hydrogel was sterile, non-irritant to the eye. The present study indicated that it is possible to develop safe and physiologically effective in situ hydrogel which is patient compliant.

Performance of GenoType MTBDRsl assay for detection of second-line drugs and ethambutol resistance directly from sputum specimens of MDR-TB patients in Bangladesh.

BACKGROUND: Rapid and early detection of drug susceptibility among multidrug-resistant tuberculosis (MDR-TB) patients could guide the timely initiation of effective treatment and reduce transmission of drug-resistant TB. In the current study, we evaluated the diagnostic performance of GenoType MTBDRsl (MTBDRsl) ver1.0 assay for detection of resistance to ofloxacin (OFL), kanamycin (KAN) and ethambutol (EMB), and additionally the XDR-TB among MDR-TB patients in Bangladesh. METHODS: The MTBDRsl assay was performed directly on 218 smear-positive sputum specimens collected from MDR-TB patients and the results were compared with the phenotypic drug susceptibility testing (DST) performed on solid Lowenstein-Jensen (L-J) media. We also analyzed the mutation patterns of gyrA, rrs, and embB genes for detection of resistance to OFL, KAN and EMB, respectively. RESULTS: The sensitivity and specificity of the MTBDRsl compared to phenotypic L-J DST were 81.8% (95% CI, 69.1-90.9) and 98.8% (95% CI, 95.6-99.8), respectively for OFL (PPV: 95.7% & NPV: 94.1%); 65.1% (95% CI, 57.5-72.2) and 86.7% (95% CI, 73.2-94.9), respectively for EMB (PPV: 94.9% & NPV: 39.4%); and 100% for KAN. The diagnostic accuracy of KAN, OFL and EMB were 100, 94.5 and 69.6%, respectively. Moreover, the sensitivity, specificity and diagnostic accuracy of MtBDRsl for detection of XDR-TB was 100%. The most frequently observed mutations were at codon D94G (46.8%) of gyrA gene, A1401G (83.3%) of rrs gene, and M306V (41.5%) of the embB gene. CONCLUSION: Considering the excellent performance in this study we suggest that MTBDRsl assay can be used as an initial rapid test for detection of KAN and OFL susceptibility, as well as XDR-TB directly from smear-positive sputum specimens of MDR-TB patients in Bangladesh.

Cost-effectiveness of Inpatient Tympanostomy Prophylaxis.

OBJECTIVE: Tympanostomy is the most common pediatric ambulatory surgery. Post-tympanostomy otorrhea is a prevalent complication leading to high costs to patients for treatment. The cost-effectiveness of intraoperative prophylaxis for both patient and institution has not been examined. STUDY DESIGN: An analytical observational study of data collected from the literature and purchasing records. METHODS: A break-even analysis was performed to determine the required absolute risk reduction (ARR) and final infection rate in post-tympanostomy otorrhea to make intraoperative prophylaxis using ofloxacin and ciprofloxacin dexamethasone otic version cost effective with the following outpatient treatments: ofloxacin, ciprofloxacin-dexamethasone ophthalmic version, and ciprofloxacin-dexamethasone otic version. Absolute risk reduction is a statistic used to express the difference in risk between a treatment and control. The conservative initial infection rate used was 10%. RESULTS: Ofloxacin intraoperative prophylaxis was not cost effective when prescribing ofloxacin outpatient treatment with an ARR of 0.20. Ofloxacin intraoperative prophylaxis was cost-effective with an ARR of 0.08 for ciprofloxacin-dexamethasone ophthalmic version outpatient treatment. Ofloxacin intraoperative prophylaxis was cost-effective for ciprofloxacin-dexamethasone otic version outpatient treatment with an ARR of 0.01.Ciprofloxacin-dexamethasone intraoperative prophylaxis was not cost-effective when prescribing ofloxacin outpatient treatment with an ARR of 1.52. Ciprofloxacin-dexamethasone intraoperative prophylaxis was not cost-effective when prescribing ciprofloxacin-dexamethasone ophthalmic version outpatient treatment with an ARR of 0.60. Ciprofloxacin-dexamethasone intraoperative prophylaxis was cost effective when prescribing ciprofloxacin-dexamethasone otic version outpatient treatment with an ARR of 0.09. CONCLUSION: Intraoperative prophylaxis can be cost effective for preventing post-tympanostomy otorrhea. Physicians can use this economic model to determine the cost-effectiveness of these interventions for their patients and institutions.

Drug resistance gene mutations and treatment outcomes in MDR-TB: A prospective study in Eastern China.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) poses a serious challenge to TB control. It is of great value to search for drug resistance mutation sites and explore the roles that they play in the diagnosis and prognosis of MDR-TB. METHODS: We consecutively enrolled MDR-TB patients from five cities in Jiangsu Province, China, between January 2013 and December 2014. Drug susceptibility tests of rifampin, isoniazid, ofloxacin, and kanamycin were routinely performed by proportion methods on Lowenstein-Jensen (LJ) medium. Drug resistance-related genes were sequenced, and the consistency of genetic mutations and phenotypic resistance was compared. The association between mutations and treatment outcomes was expressed as odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among 87 MDR-TB patients, 71 with treatment outcomes were involved in the analysis. The proportion of successful treatment was 50.7% (36/71). The rpoB gene exhibited the highest mutation rate (93.0%) followed by katG (70.4%), pncA (33.8%), gyrA (29.6%), eis (15.5%), rrs (12.7%), gyrB (9.9%) and rpsA (4.2%). Multivariable analysis demonstrated that patients with pncA gene mutations (adjusted OR: 19.69; 95% CI: 2.43-159.33), advanced age (adjusted OR: 13.53; 95% CI: 1.46-124.95), and nonstandard treatment (adjusted OR: 7.72; 95% CI: 1.35-44.35) had a significantly higher risk of poor treatment outcomes. CONCLUSIONS: These results suggest that Mycobacterium tuberculosis gene mutations may be related to phenotypic drug susceptibility. The pncA gene mutation along with treatment regimen and age are associated with the treatment outcomes of MDR-TB.

Ofloxacin-Containing Multidrug Therapy in Ambulatory Leprosy Patients: A Case Series.

BACKGROUND: Standard dapsone and clofazimine-containing multidrug therapy (MDT) for leprosy is limited by drug tolerability, which poses treatment adherence barriers. Although ofloxacin-based regimens are promising alternatives, current efficacy and safety data are limited, particularly outside of endemic areas. We evaluated treatment outcomes in patients with leprosy receiving ofloxacin-containing MDT (OMDT) at our center. METHODS: We performed a retrospective chart review of patients treated for leprosy at our center over an 8-year period (2011-2019). Primary outcomes evaluated were clinical cure rate, occurrence of leprosy reactions, antibiotic-related adverse events, and treatment adherence. Analyses were descriptive; however, data were stratified by age, sex, spectrum of disease, region of origin, and treatment regimen, and odds ratios were reported to assess associations with adverse outcomes. RESULTS: Over the enrolment period, 26 patients were treated with OMDT (n = 19 multibacillary, n = 7 paucibacillary), and none were treated with clofazimine-based standard MDT. At the time of analysis, 23 patients (88%) had completed their course of treatment, and all were clinically cured, while 3 (12%) were still on treatment. Eighteen patients (69%) experienced either ENL (n = 7, 27%), type 1 reactions (n = 7, 27%), or both (n = 4, 15%). No patients stopped ofloxacin due to adverse drug effects, and there were no cases of allergic hypersensitivity, tendinopathy or rupture, or C. difficile colitis. CONCLUSIONS: We demonstrate a high cure rate and tolerability of OMDT in this small case series over an 8-year period, suggesting its viability as an alternative to standard clofazimine-containing MDT.

A systematic review and meta-analysis of studies on the diagnostic accuracy and screening of tests to detect antimicrobial resistance in leprosy

Although multidrug therapy is considered an effective treatment for leprosy, antimicrobial resistance is a serious concern. We performed a systematic review of studies on the diagnostic accuracy and screening of tests for antimicrobial resistance in leprosy. This review was registered in PROSPERO (CRD42020177958). In April 2020, we searched for studies in the PubMed, EMBASE, Web of Science, Scopus, Scielo, and LILACS databases. A random effects regression model was used for the meta-analysis. We included 129 studies. Molecular tests for dapsone resistance had a sensitivity of 78.8% (95% confidence interval [CI] = 65.6−87.9) and a specificity of 97.0% (95% CI = 94.0−98.6). Molecular tests for rifampicin resistance had a sensitivity and specificity of 88.7% (95% CI = 80.0−93.9) and 97.3% (95% CI = 94.3−98.8), respectively. Molecular tests for ofloxacin resistance had a sensitivity and specificity of 80.9% (95% CI = 60.1−92.3) and 96.1% (95% CI = 90.2−98.5), respectively. In recent decades, no increase in the resistance proportion was detected. However, the growing number of resistant cases is still a clinical concern(AU).

Validação de modelo murino para avaliação da atividade antibacteriana de ofloxacina e clofazimina contra o Mycobacterium leprae / Validation of a murine model for the evaluation of the antibacterial activity of ofloxacin and clofazimine against Mycobacterium leprae

A hanseníase é uma doença infectocontagiosa crônica causada pelo Mycobacterium leprae (M. leprae). Manifesta-se, principalmente, por lesões de pele com alteração de sensibilidade térmica, dolorosa e tátil, decorrentes da predileção de seu agente etiológico por células cutâneas e nervosas periféricas. No mundo, em 2018, foram reportados à Organização Mundial da Saúde (OMS), 208.619 casos novos; desses, 28.660 foram notificados no Brasil, sendo o segundo país com maior número detectado. Acredita-se que a transmissão e infecção ocorram através de secreções provenientes das vias aéreas superiores, pelo contato íntimo e prolongado de indivíduo suscetível com paciente multibacilar sem tratamento, por meio da inalação dos bacilos. O tratamento preconizado pela OMS consiste na associação de três medicamentos ­ dapsona (DDS), rifampicina (RFP) e clofazimina (CLO) ­ com o objetivo de atuar na prevenção da seleção de cepas mutantes do M. leprae resistentes a uma ou mais drogas utilizadas. A ofloxacina (OFLO) é usada como esquema alternativo ao tratamento padrão, associando-se a RFP e CLO, sendo útil nos casos de resistência medicamentosa ou intolerância a uma das drogas. O bacilo não se reproduz em meios de cultura artificiais ou celulares ­ obstáculo para o avanço em estudos do patógeno. Em 1960, Charles Shepard, demonstrou pela primeira vez a multiplicação do M. leprae em coxim plantar de camundongo imunocompetente, técnica considerada marco na pesquisa do bacilo, propiciando a verificação de sua viabilidade e uma possível resistência às drogas utilizadas no tratamento da doença. O presente estudo teve como objetivo validar o método fenotípico, por meio da inoculação do bacilo em coxim plantar posterior de camundongos imunocompetentes da linhagem BALB/c (técnica de Shepard), para detecção de sensibilidade à CLO e OFLO. Os animais foram inoculados com suspensão de bacilos obtidos de camundongos nude mouse atímicos previamente infectados com a cepa Thai53, que possui perfil genético de sensibilidade às drogas, e divididos em grupo controle (não tratado), RFP (10mg/kg), CLO (50mg/kg) e OFLO (150mg/kg). Após cinco meses de inoculação e tratamento, os animais foram eutanasiados, e os coxins excisados para contagem do número de bacilos e análise histopatológica. No grupo controle, o número de bacilos recuperados foi maior que 1,0x105 /coxim, compatível com multiplicação bacilar; a análise histopatológica evidenciou infiltrado inflamatório intenso com bacilos agrupados ou em globias, íntegros e bem corados. Nos grupos tratados, não foi observada evidência de multiplicação bacilar, mostrando sensibilidade às drogas testadas; a análise histopatológica evidenciou infiltrado inflamatório discreto a moderado com ausência de bacilos. A técnica de Shepard é considerada padrão ouro para a multiplicação do bacilo, sendo fundamental para validar a identificação de novos alvos de mutação em genes determinantes da ação das drogas anti-hansênicas. Os resultados gerados no presente estudo terão grande impacto, principalmente para compreender a falha terapêutica em pacientes com recidiva que não apresentaram perfil de resistência pelos mecanismos moleculares até o momento descritos para a doença.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae). It is mainly manifested by skin lesions with changes in thermal, sensory and tactile sensitivity resulting from the predilection of its etiologic agent by skin and peripheral nerve cells. The World Health Organization (WHO) reported 208,619 new cases in 2018 worldwide; among these, 28,660 were reported in Brazil, the second country with the highest number detected. It is believed that transmission and infection occur by inhaling bacilli through the upper airways, while in close and prolonged contact of a susceptible individual with an untreated multibacillary patient. The treatment recommended by the WHO consists of the combination of three drugs -dapsone (DDS), rifampicin (RFP) and clofazimine (CLO) - in order to prevent the selection of mutant M. leprae strains resistant to one or more drugs. Ofloxacin (OFLO) is used as an alternative regimen to standard treatment, in association with RFP and CLO, being useful in cases of drug resistance or intolerance to one of the drugs. The bacillus does not reproduce in artificial or cellular culture media - an obstacle to progress in studies of the pathogen. In 1960, Charles Shepard, demonstrated for the first time the multiplication of M. leprae in an immunocompetent mouse footpad, a technique considered a landmark in the bacillus research, enabling the verification of its viability and a possible resistance to drugs used in the treatment of the disease. The present study aimed to validate the phenotypic method, by inoculating the bacillus in the hind footpads of immunocompetent BALB/c mice strain (Shepard's technique), to detect sensitivity to CLO and OFLO. The animals were inoculated with a suspension of bacilli obtained from athymic nude mouse previously infected with the Thai-53 strain, a sensitive strain. Mice were divided into a control (untreated), RFP (10mg / kg), CLO (50mg / kg) and OFLO (150mg / kg) groups. After five months of inoculation and treatment, the animals were euthanized and the foopads excised for enumeration of bacilli and histopathological analysis. In the control group, the number of bacilli recovered was greater than 1.0x105 /footpad, compatible with bacillary multiplication; histopathological analysis showed an intense inflammatory infiltrate with well stained grouped bacilli and globi. In the treated groups, there was no evidence of bacillary multiplication, showing sensitivity to the drugs tested; histopathological analysis showed mild to moderate inflammatory infiltrate with no bacilli. The Shepard technique is considered the gold standard for bacillus multiplication, being essential to validate the identification of new mutation targets in genes that determine anti-leprosy drugs activity. The results generated in the present study will have a great impact, mainly to understand the therapeutic failure in patients with recurrence who did not present a resistance profile using molecular mechanisms described so far for the disease.