Systematic Review: Clinical Features, Antimicrobial Treatment, and Outcomes of Human Tularemia, 1993-2023.

BACKGROUND: Francisella tularensis, the causative agent of tularemia, is endemic throughout the Northern Hemisphere and requires as few as 10 organisms to cause disease, making this potential bioterrorism agent one of the most infectious bacterial pathogens known. Aminoglycosides, tetracyclines, and, more recently, fluoroquinolones are used for treatment of tularemia; however, data on the relative effectiveness of these and other antimicrobial classes are limited. METHODS: Nine databases, including Medline, Global Health, and Embase, were systematically searched for articles containing terms related to tularemia. Articles with case-level data on tularemia diagnosis, antimicrobial treatment, and patient outcome were included. Patient demographics, clinical findings, antimicrobial administration, and outcome (eg, intubation, fatality) were abstracted using a standardized form. RESULTS: Of the 8878 publications identified and screened, 410 articles describing 870 cases from 1993 to 2023 met inclusion criteria. Cases were reported from 35 countries; more than half were from the United States, Turkey, or Spain. The most common clinical forms were ulceroglandular, oropharyngeal, glandular, and pneumonic disease. Among patients treated with aminoglycosides (n = 452 [52%]), fluoroquinolones (n = 339 [39%]), or tetracyclines (n = 419 [48%]), the fatality rate was 0.7%, 0.9%, and 1.2%, respectively. Patients with pneumonic disease who received ciprofloxacin had no fatalities and the lowest rates of thoracentesis/pleural effusion drainage and intubation compared to those who received aminoglycosides and tetracyclines. CONCLUSIONS: Aminoglycosides, fluoroquinolones, and tetracyclines are effective antimicrobials for treatment of tularemia, regardless of clinical manifestation. For pneumonic disease specifically, ciprofloxacin may have slight advantages compared to other antimicrobials.

Intramuscular therapeutic doses of enrofloxacin affect microbial community structure but not the relative abundance of fluoroquinolones resistance genes in swine manure.

Livestock manure is a major source of veterinary antibiotics and antibiotic resistance genes (ARGs). Elucidation of the residual characteristics of ARGs in livestock manure following the administration of veterinary antibiotics is critical to assess their ecotoxicological effects and environmental contamination risks. Here, we investigated the effects of enrofloxacin (ENR), a fluoroquinolone antibiotic commonly used as a therapeutic drug in animal husbandry, on the characteristics of ARGs, mobile genetic elements, and microbial community structure in swine manure following its intramuscular administration for 3 days and a withdrawal period of 10 days. The results revealed the highest concentrations of ENR and ciprofloxacin (CIP) in swine manure at the end of the administration period, ENR concentrations in swine manure in groups L and H were 88.67 ± 45.46 and 219.75 ± 88.05 mg/kg DM, respectively. Approximately 15 fluoroquinolone resistance genes (FRGs) and 48 fluoroquinolone-related multidrug resistance genes (F-MRGs) were detected in swine manure; the relative abundance of the F-MRGs was considerably higher than that of the FRGs. On day 3, the relative abundance of qacA was significantly higher in group H than in group CK, and no significant differences in the relative abundance of other FRGs, F-MRGs, or MGEs were observed between the three groups on day 3 and day 13. The microbial community structure in swine manure was significantly altered on day 3, and the altered community structure was restored on day 13. The FRGs and F-MRGs with the highest relative abundance were qacA and adeF, respectively, and Clostridium and Lactobacillus were the dominant bacterial genera carrying these genes in swine manure. In summary, a single treatment of intramuscular ENR transiently increased antibiotic concentrations and altered the microbial community structure in swine manure; however, this treatment did not significantly affect the abundance of FRGs and F-MRGs.

Green wastewater treatment of repurposed COVID-19 therapy (levofloxacin) using synthesized magnetite pectin nanoparticles, comparison with mesoporous silica nanoparticles.

RATIONALE: Antibiotics have been detected worldwide in the aquatic environment. Moreover, certain classes of antibiotics have been repurposed for the management of COVID-19, which increased their use and presence in wastewater. Their occurrence even in low concentrations leads to the development of antibiotic resistance. METHODOLOGY: Magnetite pectin nanoparticles (MPNP) were fabricated and compared to an established model of mesoporous silica nanoparticles (MSNP). Our studied adsorbate is levofloxacin, a fluoroquinolone antibiotic, commonly used in managing COVID-19 cases. RESULTS: The influence of various factors affecting the adsorption process was studied, such as pH, the type and concentration of the adsorbent, contact time, and drug concentration. The results illustrated that the optimum adsorption capacity for antibiotic clearance from wastewater using MPNP was at pH 4 with a contact time of 4 h; while using MSNP, it was found to be optimum at pH 7 with a contact time of 12 h at concentrations of 10 µg/mL and 16 g/L of the drug and nanoparticles, respectively, showing adsorption percentages of 96.55% and 98.89%. Drug adsorption equilibrium data obeyed the Sips isotherm model. DISCUSSION AND CONCLUSION: HPLC assay method was developed and validated. The experimental results revealed that the MPNP was as efficient as MSNP for removing the antibacterial agent. Moreover, MPNP is eco-friendly (a natural by-product of citrus fruit) and more economic as it could be recovered and reused. The procedure was evaluated according to the greenness assessment tools: AGREE calculator and Hexagon-CALIFICAMET, showing good green scores, ensuring the process's eco-friendliness.

Fluoroquinolone resistance mutations among Mycobacterium tuberculosis and their interconnection with treatment outcome.

Background: Fluoroquinolone (FQ) antibiotics are among the most potent second-line antitubercular drugs these days. The aim of the study was to analyze the frequency and pattern of genetic mutation in preextensive (pre-XDR) and extensively drug-resistant Mycobacterium tuberculosis using second-line line probe assay (LPA) and to compare drug-resistant mutations with different treatment outcomes. Methods: Sputum, lymph node aspirate, and cold accesses from patients with rifampicin-resistant Tuberculosis (TB) were subjected to first-line and second-line LPA (Genotype MTBDRsl by Hain Life Science, Germany) to assess additional drug resistance to fluoroquinolones (levofloxacin and moxifloxacin). Final treatment outcomes as per the National TB Elimination Program were assessed and compared with the mutation profile. Results: One hundred and fifty subjects were observed to have mutations associated with resistance to FQs and constituted the final study population. The most frequent mutation observed among GyrA drug resistance mutation was D94G (Gyr A MUT3C, 44/150, 66%) corresponding to high-level resistance to levofloxacin and moxifloxacin. The same mutation was associated with poor treatment outcome as died or treatment failure (odds ratio 2.50, relative risk 1.67, P = 0.043). The most common hetero-resistance mutation pattern observed in GyrA gene was wild type plus Asp94Gly mutation in 24.6% of isolates. Conclusions: GyrA MUT3C hybridization corresponding to single-point mutation of aspartic acid to glycine at codon 94 constitutes the most common mutation in GyrA gene locus in M. tuberculosis with significant association with treatment outcome as died compared to those with treatment outcome as cured.

Application of pharmacokinetic/pharmacodynamic concepts to the development of treatment regimens for sporadic canine urinary tract infections: Challenges and paths forward.

Antimicrobial efficacy can be predicted based on infection site exposure to the antimicrobial agent relative to the in vitro susceptibility of the pathogen to that agent. When infections occur in soft tissues (e.g., muscle, blood, and ligaments), exposure at the infection site is generally assumed to reflect an equilibrium between the unbound concentrations in plasma and that in the interstitial fluids. In contrast, for sporadic urinary tract infections (UTIs) in dogs and uncomplicated UTIs in humans, the primary site of infection is the bladder wall. Infection develops when bacteria invade the host bladder urothelium (specifically, the umbrella cells that form the urine-contacting layer of the stratified uroepithelium) within which these bacteria can avoid exposure to host defenses and antimicrobial agents. Traditionally, pathogen susceptibility has been estimated using standardized in vitro tests that measure the minimal concentration that will inhibit pathogen growth (MIC). When using exposure-response relationships during drug development to explore dose optimization, these relationships can either be based upon an assessment of a correlation between clinical outcome, drug exposure at the infection site, and pathogen MIC, or upon benchmark exposure-response relationships (i.e., pharmacokinetic/pharmacodynamic indices) typically used for the various drug classes. When using the latter approach, it is essential that the unbound concentrations at the infection site be considered relative to the MIC within the biological matrix to which the pathogen will be exposed. For soft tissue infections, this typically is the unbound plasma concentrations versus MICs determined in standardized media such as cation-adjusted Mueller Hinton broth, which is how many indices were originally established. However, for UTIs, it is the unbound drug concentrations within the urine versus the MICs in the actual urine biophase that needs to be considered. The importance of these relationships and how they are influenced by drug resistance, resilience, and inoculum are discussed in this review using fluoroquinolones and beta-lactams as examples.

The clinical treatment of bacterial keratitis: A review of drop instillation regimes.

Bacterial keratitis (BK) presentations are often treated using the commercially available second-generation fluoroquinolones ciprofloxacin 0.3% and ofloxacin 0.3% as monotherapy. The guidelines available for instillation regimes are often not supported by data from clinical studies. This review examines the peer-reviewed clinical studies and compared treatment failure rates for ciprofloxacin 0.3% and ofloxacin 0.3% for BK in relation to Day-1 drop-regimes. From the statistical analysis, this review derived evidence-based clinically applicable minimum drop-regimes for the treatment of BK on Day-1. Lower numbers of drops of ciprofloxacin on Day-1 were significantly associated with increased treatment failure rates (p < 0.002). The derived minimum number of drops on Day for ciprofloxacin on Day-1 was 47 drops, and for ofloxacin 24 drops. The mean number of drops used in the clinical studies was significantly lower than the manufacturers' recommended Day-1 regimes for both ciprofloxacin (p = 0.0006) and ofloxacin (p = 0.048). From Day-3 to -6 of treatment the drop rates for ciprofloxacin relative to recommended rates were higher, and for ofloxacin lower (p = 0.014). The findings of this review were then compared with a representative sample of published guidelines and case studies to determine the validity of applying those drop-regimes in clinical practice. Although the manufacturers' suggested minimum drop-regimes on Day-1 were significantly different (120 drops ciprofloxacin, 34 drops ofloxacin, p < 0.0001), many of the published guidelines suggested the same drop-regime for both fluoroquinolones. The suggested drop numbers on Day-1 for ciprofloxacin in these guidelines and case studies were significantly less than those used in the clinical studies (p = 0.043). Increased treatment failure rates for ciprofloxacin are associated with lower drop numbers on Day-1. The Day-1 dosing rates for ciprofloxacin and ofloxacin should be considered separately, and the regimes suggested in published guidelines and case studies may need be re-considered in light of the findings of this review.

Delafloxacin for the treatment of adult patients with community-acquired bacterial pneumonia.

INTRODUCTION: Delafloxacin is a novel fluoroquinolone with peculiar characteristics such as a weak acid character, frequent in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA), and a low potential for resistance selection compared with other fluoroquinolones. AREAS COVERED: The present narrative review summarizes the available data on the use of delafloxacin for the treatment of community-acquired bacterial pneumonia (CABP). EXPERT OPINION: Delafloxacin is a novel fluoroquinolone with a unique profile and some interesting characteristics for the treatment of CABP, such as its marked activity against gram-positive bacteria, including MRSA, the possible use as monotherapy (owing to anti-Gram-negative and anti-atypical bacteria activity), the retained activity against many Gram-positive organisms resistant to other fluoroquinolones, and the availability of both oral and intravenous formulations. The results of the DEFINE-CABP phase-3 randomized controlled trial have shown noninferiority of delafloxacin vs. moxifloxacin for the treatment of CABP, thereby providing a further option for this indication. Against this background, future post-marketing experiences remain of crucial importance for further refining the place in therapy of delafloxacin in the real-life management algorithms of CABP, either as first-line option or step-down/outpatient treatment.

Genome-Wide Association Study Reveals Genetic Markers for Antimicrobial Resistance in Mycoplasma bovis.

Mycoplasma bovis causes many health and welfare problems in cattle. Due to the absence of clear insights regarding transmission dynamics and the lack of a registered vaccine in Europe, control of an outbreak depends mainly on antimicrobial therapy. Unfortunately, antimicrobial susceptibility testing (AST) is usually not performed, because it is time-consuming and no standard protocol or clinical breakpoints are available. Fast identification of genetic markers associated with acquired resistance may at least partly resolve former issues. Therefore, the aims of this study were to implement a first genome-wide association study (GWAS) approach to identify genetic markers linked to antimicrobial resistance (AMR) in M. bovis using rapid long-read sequencing and to evaluate different epidemiological cutoff (ECOFF) thresholds. High-quality genomes of 100 M. bovis isolates were generated by Nanopore sequencing, and isolates were categorized as wild-type or non-wild-type isolates based on MIC testing results. Subsequently, a k-mer-based GWAS analysis was performed to link genotypes with phenotypes based on different ECOFF thresholds. This resulted in potential genetic markers for macrolides (gamithromycin and tylosin) (23S rRNA gene and 50S ribosomal unit) and enrofloxacin (GyrA and ParC). Also, for tilmicosin and the tetracyclines, previously described mutations in both 23S rRNA alleles and in one or both 16S rRNA alleles were observed. In addition, two new 16S rRNA mutations were possibly associated with gentamicin resistance. In conclusion, this study shows the potential of quick high-quality Nanopore sequencing and GWAS analysis in the evaluation of phenotypic ECOFF thresholds and the rapid identification of M. bovis strains with acquired resistance. IMPORTANCE Mycoplasma bovis is a leading cause of pneumonia but also causes other clinical signs in cattle. Since no effective vaccine is available, current M. bovis outbreak treatment relies primarily on the use of antimicrobials. However, M. bovis is naturally resistant to different antimicrobials, and acquired resistance against macrolides and fluoroquinolones is frequently described. Therefore, AST is important to provide appropriate and rapid antimicrobial treatment in the framework of AMR and to prevent the disease from spreading and/or becoming chronic. Unfortunately, phenotypic AST is time-consuming and, due to the lack of clinical breakpoints, the interpretation of AST in M. bovis is limited to the use of ECOFF values. Therefore, the objective of this study was to identify known and potentially new genetic markers linked to AMR phenotypes of M. bovis isolates, exploiting the power of a GWAS approach. For this, we used high-quality and complete Nanopore-sequenced M. bovis genomes of 100 isolates.

The Use of Experimental Evolution to Study the Response of Pseudomonas aeruginosa to Single or Double Antibiotic Treatment.

The widespread use of antibiotics promotes the evolution and dissemination of drug resistance and tolerance. Both mechanisms promote survival during antibiotic exposure and their role and development can be studied in vitro with different assays to document the gradual adaptation through the selective enrichment of resistant or tolerant mutant variants. Here, we describe the use of experimental evolution in combination with time-resolved genome analysis as a powerful tool to study the interaction of antibiotic tolerance and resistance in the human pathogen Pseudomonas aeruginosa . This method guides the identification of components involved in alleviating antibiotic stress and helps to unravel specific molecular pathways leading to drug tolerance or resistance. We discuss the influence of single or double drug treatment regimens and environmental aspects on the evolution of antibiotic resilience mechanisms.

Whole-genome analysis of drug-resistant Mycobacterium tuberculosis reveals novel mutations associated with fluoroquinolone resistance.

Multidrug-resistant and extensively drug-resistant tuberculosis (M/XDR-TB) remains a global public-health challenge. Known mutations in quinolone resistance-determination regions cannot fully explain phenotypic fluoroquinolone (FQ) resistance in Mycobacterium tuberculosis (Mtb). The aim of this study was to look for novel mutations in Mtb associated with resistance to FQ drugs using whole-genome sequencing analysis. Whole-genome sequences of 659 Mtb strains, including 214 with phenotypic FQ resistance and 445 pan-susceptible isolates, were explored for mutations associated with FQ resistance overall and with resistance to individual FQ drugs (ofloxacin, levofloxacin, moxifloxacin and gatifloxacin). Three novel genes (recC, Rv2005c and PPE59) associated with FQ resistance were identified (P < 0.00001 based on screening analysis and absence of relevant mutations in a pan-susceptible validation set of 360 strains). Nine novel single nucleotide polymorphisms (SNPs), including in gyrB (G5383A and G6773A), gyrA (G7892A), recC (G725900C and G726857T/C), Rv2005c (C2251373G, G2251420C and C2251725T) and PPE59 (C3847269T), were used for diagnostic performance analysis. Enhancing the known SNP set with five of these novel SNPs, including gyrA [G7892A (Leu247Leu)], recC [G725900C (Leu893Leu) and G726857T/C (Arg484Arg)], Rv2005c [G2251420C (Pro205Arg)] and PPE59 [C3847269T (Asn35Asn)] increased the sensitivity of detection of FQ-resistant Mtb from 83.2% (178/214) to 86.9% (186/214) while maintaining 100% specificity (360/360). No specific mutation associated with resistance to only a single drug (ofloxacin, levofloxacin, moxifloxacin or gatifloxacin) was found. In conclusion, this study reports possible additional mutations associated with FQ resistance in Mtb.

Effects of Magnesium, Calcium, and Aluminum Chelation on Fluoroquinolone Absorption Rate and Bioavailability: A Computational Study.

Fluoroquinolones (FQs) are a widespread class of broad-spectrum antibiotics prescribed as a first line of defense, and, in some cases, as the only treatment against bacterial infection. However, when administered orally, reduced absorption and bioavailability can occur due to chelation in the gastrointestinal tract (GIT) with multivalent metal cations acquired from diet, coadministered compounds (sucralfate, didanosine), or drug formulation. Predicting the extent to which this interaction reduces in vivo antibiotic absorption and systemic exposure remains desirable yet challenging. In this study, we focus on quinolone interactions with magnesium, calcium and aluminum as found in dietary supplements, antacids (Maalox) orally administered therapies (sucralfate, didanosine). The effect of FQ-metal complexation on absorption rate was investigated through a combined molecular and pharmacokinetic (PK) modeling study. Quantum mechanical calculations elucidated FQ-metal binding energies, which were leveraged to predict the magnitude of reduced bioavailability via a quantitative structure-property relationship (QSPR). This work will help inform clinical FQ formulation design, alert to possible dietary effects, and shed light on drug-drug interactions resulting from coadministration at an earlier stage in the drug development pipeline.

The first imported case of extensively drug-resistant Salmonella enterica serotype Typhi infection in Taiwan and the antimicrobial therapy.

The first imported case of XDR typhoid fever in Taiwan contracted with a bacterial strain, which was most closely related to the blaCTX-M-15-carrying strains linked to Pakistan. Meropenem, in combination with an antimicrobial with intracellular activity against Salmonella, should be used for the treatment of XDR typhoid fever.

Characterization and distribution of viridans group streptococci isolated from infectious endophthalmitis and keratitis / Caracterização e distribuição de estreptococos do grupo viridans isolados de endoftalmite infecciosa e ceratite

ABSTRACT Purpose: The aims of this study were to characterize alpha-hemolytic streptococci among isolates from cases of infectious endophthalmitis and keratitis and to determine their distributions. Methods: The sample included 27 and 35 nonduplicated isolates of alpha-hemolytic streptococci recovered from patients with infectious endophthalmitis (2002-2013) and keratitis (2008-2013), respectively. Isolates were identified by the optochin susceptibility and bile solubility tests, using a biochemical identification system. The minimum inhibitory concentration was determined by the broth microdilution method. Molecular identification was performed by analyses of three constitutive genes and the complementary multilocus sequence. The molecular epidemiology of Streptococcus pneumoniae was investigated using multilocus sequence typing, and the presence of the capsular polysaccharide-encoding gene was assessed using conventional polymerase chain reaction. Outcomes were evaluated using the patients' medical records. Results: Phenotypic tests differentiated S. pneumoniae from other alpha-hemolytic streptococci, consistent with later molecular identifications. Streptococcus oralis was significantly prevalent among the endophthalmitis isolates, as was S. pneumoniae in the keratitis isolates. High levels of susceptibility to antibiotics were observed, including vancomycin, cephalosporins, and fluoroquinolones. High genetic variability was detected among the 19 S. pneumoniae strains, with 15 predicted to be encapsulated. The medical records of patients with infectious endophthalmitis were reviewed (n=15/27; 56%), and final visual acuity was assessed in 12 cases (44%). Many patients progressed to a final visual acuity state of "no light perception" (6/12; 50%), "light perception" (3/12; 25%), or "hand motion" (1/12; 8%). The medical records of patients with infectious keratitis were also reviewed (n=24/35; 69%), and final visual acuity was assessed in 18 cases (51%). Similarly, most patients progressed to a final visual acuity state of "no light perception" (6/18; 33%), "light perception" (1/18; 6%), or "hand motion" (6/18; 33%). Overall, the majority of patients progressed to a final visual acuity state of "no light perception" (12/30), "light perception" (4/30), or "hand motion" (7/30). Conclusions: The distribution of alpha-hemolytic streptococci in ocular infections suggested the presence of a species-specific tissue tropism. The prognoses of patients with ocular streptococcal infections were highly unfavorable, and antibiotic resistance did not contribute to the unfavorable clinical progressions and poor outcomes.

RESUMO Objetivo: O objetivo deste estudo foi caracterizar os estreptococos alfa-hemolíticos isolados de endoftalmite infecciosa e ceratite e determinar sua distribuição. Métodos: A amostra incluiu 27 e 35 isolados não-duplicados de estreptococos alfa-hemolíticos recuperados de pacientes com endoftalmite infecciosa (2002-2013) e ceratite (2008-2013), respectivamente. Os isolados foram identificados pelos testes de suscetibilidade à optoquina e bile solubilidade, utilizando um sistema de identificação bioquímica. A concentração inibitória mínima foi determinada pelo método de microdiluição em caldo. A identificação molecular foi realizada pela análise de três genes constitutivos e análise complementar de sequências multilocus. A epidemiologia molecular do Streptococcus pneumoniae foi investigada por tipagem de sequência multilocus, e a presença do gene codificador do polissacarídeo capsular foi avaliada por reação em cadeia da polymerase convencional. Os resultados foram avaliados utilizando os prontuários médicos dos pacientes. Resultados: Os testes fenotípicos diferenciaram S. pneumoniae dos outros estreptococos alpha-hemolíticos, consistentes com identificações moleculares posteriores. S. oralis foi significativamente prevalente entre os isolados de endoftalmite, assim como S. pneumoniae nos isolados de ceratite. Foram observados altos níveis de suscetibilidade a antibióticos, incluindo vancomicina, cefalosporinas e fluoroquinolonas. Alta variabilidade genética foi detectada entre as 19 cepas de S. pneumoniae, com 15 previstas para serem encapsuladas. Os prontuários médicos dos pacientes com endoftalmite infecciosa foram revisados (n=15/27; 56%), e a acuidade visual final foi avaliada em 12 casos (44%). Muitos pacientes evoluiram para um estado final de acuidade visual de "sem percepção luminosa" (6/12; 50%), "percepção luminosa" (3/12; 25%) ou "movimentos de mãos" (1/12; 8%). Também foram revisados os prontuários médicos dos pacientes com ceratite infecciosa (n=24/35; 69%), e a acuidade visual final foi avaliada em 18 casos (51%). Da mesma foram, a maioria dos pacientes evoluiu para um estado final de acuidade visual de "sem percepção luminosa" (6/18; 33%), "percepção luminosa" (1/18; 6%) ou "movimentos de mãos" (6/18; 33%). No geral, a maioria dos pacientes evoluiu para um estado final de acuidade visual de "sem percepção luminosa" (12/30), "percepção luminosa" (4/30) ou "movimentos de mãos" (7/30). Conclusões: A distribuição de estreptococos alfa-hemolíticos nas infecções oculares sugeriu a presença de um tropismo de tecido específico da espécie. Os prognósticos dos pacientes com infeções oculares por estreptococos foram altamente desfavoráveis e a resistência a antibióticos contribuiu não para as progressões clínicas des­favoráveis e os maus resultados.

Initial resistance to companion drugs should not be considered an exclusion criterion for the shorter multidrug-resistant tuberculosis treatment regimen.

OBJECTIVES: We investigated whether companion drug resistance was associated with adverse outcomes of the shorter multidrug-resistant tuberculosis (MDR-TB) treatment regimen in Bangladesh after adjustment for fluoroquinolone resistance. METHODS: MDR-TB/rifampicin-resistant tuberculosis patients registered for treatment with a standardized gatifloxacin-based shorter MDR-TB treatment regimen were selected for the study. Drug resistance was determined by the proportion method, gatifloxacin and isoniazid minimum inhibitory concentration testing for selected isolates, and whole-genome sequencing. RESULTS: Low-level fluoroquinolone resistance and high-level fluoroquinolone resistance were the most important predictors of adverse outcomes, with pyrazinamide resistance having a significant yet lower impact. In patients with fluoroquinolone-/second-line-injectable-susceptible tuberculosis, non-eligibility for the shorter MDR-TB treatment regimen (initial resistance to pyrazinamide, ethionamide, or ethambutol) was not associated with adverse outcome (adjusted odds ratio 1.01; 95% confidence interval 0.4-2.8). Kanamycin resistance was uncommon (1.3%). Increasing levels of resistance to isoniazid predicted treatment failure, also in a subgroup of patients with high-level fluoroquinolone-resistant tuberculosis. CONCLUSIONS: Our results suggest that resistance to companion drugs in the shorter MDR-TB treatment regimen, except kanamycin resistance, is of no clinical importance as long as fluoroquinolone susceptibility is preserved. Hence, contrary to current WHO guidelines, exclusions to the standard regimen are justified only in the case of fluoroquinolone resistance. and possibly kanamycin resistance.

Longitudinal effects of enrofloxacin or tulathromycin use in preweaned calves at high risk of bovine respiratory disease on the shedding of antimicrobial-resistant fecal Escherichia coli.

The objective of this study was to longitudinally quantify Escherichia coli resistant to ciprofloxacin and ceftriaxone in calves treated with enrofloxacin or tulathromycin for the control of bovine respiratory disease (BRD). Dairy calves 2 to 3 wk of age not presenting clinical signs of pneumonia and at high risk of developing BRD were randomly enrolled in 1 of 3 groups receiving the following treatments: (1) single label dose of enrofloxacin (ENR); (2) single label dose of tulathromycin (TUL); or (3) no antimicrobial treatment (control, CTL). Fecal samples were collected immediately before administration of treatment and at d 2, 4, 7, 14, 21, 28, 56, and 112 d after beginning treatment. Samples were used for qualification of E. coli using a selective hydrophobic grid membrane filter (HGMF) master grid. The ENR group had a significantly higher proportion of E. coli resistant to ciprofloxacin compared with CTL and TUL at time points 2, 4, and 7. At time point 28, a significantly higher proportion of E. coli resistant to ciprofloxacin was observed only compared with CTL. The TUL group had a significantly higher proportion of E. coli resistant to ciprofloxacin compared with CTL at time points 2, 4, and 7. None of the treatment groups resulted in a significantly higher proportion of E. coli isolates resistant to ceftriaxone. Our study identified that treatment of calves at high risk of developing BRB with either enrofloxacin or tulathromycin resulted in a consistently higher proportion of ciprofloxacin-resistant E. coli in fecal samples.

4-month moxifloxacin containing regimens in the treatment of patients with sputum-positive pulmonary tuberculosis in South India - a randomised clinical trial.

BACKGROUND: Shortening tuberculosis (TB) treatment duration is a research priority. We tested the efficacy and safety of 3- and 4-month regimens containing moxifloxacin in a randomised clinical trial in pulmonary TB (PTB) patients in South India. METHODS: New, sputum-positive, adult, HIV-negative, non-diabetic PTB patients were randomised to 3- or 4-month moxifloxacin regimens [moxifloxacin (M), isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E)] or to a control regimen (2H3 R3 Z3 E3 /4R3 H3 ) [C]. The 4 test regimens were 3R7 H7 Z7 E7 M7 [M3], 2R7 H7 Z7 E7 M7 /2R7 H7 M7 [M4], 2R7 H7 Z7 E7 M7 /2R3 H3 M3 [M4-I] or 2R7 H7 Z7 E7 M7 /2R3 H3 E3 M3 [M4-IE]. Treatment was directly observed. Clinical and bacteriological assessments were done monthly during treatment and for 24 months post-treatment. The primary end point was TB recurrence post-treatment. RESULTS: Of 1371 patients, randomised, modified intention-to-treat (ITT) analysis was done in 1329 and per-protocol (PP) analysis in 1223 patients. Regimen M3 was terminated due to high TB recurrence rates. 'Favourable' response at end of treatment was 96-100% in the moxifloxacin regimens and 93% in the control  regimen. Among these, the TB recurrence occurred in 4.1% in the M4 regimen and in 4.5% in the control regimen and demonstrated equivalence within a 5% margin (95% CI -3.68, 4.55). Similar findings were observed in modified ITT analysis. The TB recurrence rates in the M4-I and M4-IE regimens did not show equivalence with the control regimen. Sixteen (1.4%) of 1087 patients in the moxifloxacin regimens required treatment modification. CONCLUSION: The 4-month daily moxifloxacin regimen [M4] was found to be equivalent and as safe as the 6-month thrice-weekly control regimen.

CONTEXTE: La réduction de la durée du traitement de la tuberculose (TB) est une priorité de recherche. Nous avons testé l'efficacité et la sécurité de schémas thérapeutiques contenant de la moxifloxacine pendant 3 et 4 mois dans un essai clinique randomisé chez des patients atteints de TB pulmonaire (PTB) dans le sud de l'Inde. MÉTHODES: De nouveaux patients PTB, adultes, non diabétiques, positifs pour les expectorations, VIH négatifs ont été randomisés pour des schémas thérapeutiques contenant de la moxifloxacine pendant 3 mois ou 4 mois [moxifloxacine (M), isoniazide (H), rifampicine (R), pyrazinamide (Z), l'éthambutol (E)] ou pour un régime témoin (2H3 R3 Z3 E3 /4R3 H3 ) [C]. Les 4 régimes de l'essai étaient 3R7 H7 Z7 E7 M7 [M3], 2R7 H7 Z7 E7 M7 /2R7 H7 M7 [M4], 2R7 H7 Z7 E7 M7 /2R3 H3 M3 [M4-I] ou 2R7 H7 Z7 E7 M7 /2R3 H3 E3 M3 [M4-IE]. Le traitement a été directement observé. Les évaluations cliniques et bactériologiques ont été effectuées mensuellement au cours du traitement et durant 24 mois après le traitement. Le critère d'évaluation principal était la récidive de la TB après le traitement. RÉSULTATS: Des 1.371 patients randomisés, une analyse en intention de traiter (ITT) modifiée a été effectuée sur 1.329 et une analyse par protocole (PP) sur 1.223 patients. Le régime M3 a été interrompu en raison de taux élevés de récidive de la TB. La réponse «favorable¼ à la fin du traitement était de 96 à 100% dans les bras moxifloxacine et 93% dans le bras témoin. Parmi ceux-ci, la récidive de la TB est survenue chez 4,1% dans le schéma M4 et chez 4,5% dans le schéma témoin et a démontré une équivalence dans une marge de 5% (IC95%: −3,68, 4,55). Des résultats similaires ont été observés dans l'analyse ITT modifiée. Les taux de récidive de la TB dans les schémas M4-I et M4-IE n'ont pas montré d'équivalence avec le schéma témoin. 16 (1,4%) des 1.087 patients dans les régimes à moxifloxacine ont nécessité une modification du traitement. CONCLUSION: Le régime quotidien de moxifloxacine pendant 4 mois [M4] s'est avéré équivalent et aussi sûr que le régime témoin de trois fois par semaine pendant 6 mois.

High Incidence of New-Onset Joint Pain in Patients on Fluoroquinolones as Antituberculous Treatment.

BACKGROUND: Joint pain is frequently observed in patients on antituberculous treatment, and pyrazinamide is known to be associated with joint pain in patients receiving antituberculous treatment. Fluoroquinolone-associated joint pain and tendon injury have been reported in long-term corticosteroid and transplant recipients, but data are lacking in patients with tuberculosis. OBJECTIVES: The objective of this study was to examine the incidence of joint pain manifested during administration of antituberculous therapy and their association with fluoroquinolones. METHODS: Patients diagnosed with tuberculosis attending the outpatient clinic over a period of 1 year were reviewed and divided into 3 groups: group A receiving pyrazinamide, group B receiving a fluoroquinolone, and group C receiving both pyrazinamide and a fluoroquinolone. Latency to onset of joint pain was noted in all 3 groups. Joint pain was initially managed with analgesics, and associated hyperuricemia was treated with allopurinol/febuxostat. Causative drugs were stopped in case of intolerable joint pain. RESULTS: 260 patients (47% females, aged 38 ± 18 years; mean ± SD) were included [group A (n = 140), group B (n = 81), and group C (n = 39)]. Overall, 76/260 (29%) patients developed joint pain: group A - 24/140 patients (17%), group B - 32/81 patients (40%), and group C - 20/39 patients (51%). The median latency to the onset of joint pain was 83 days (interquartile range, IQR 40-167): 55 days (IQR 32-66) in group A, 138 days (IQR 74-278) in group B, and 88 days (IQR 34-183) in group C. Hyperuricemia was present in 12/24 (50%) patients in group A and 11/20 (55%) patients in group C. Pyrazinamide was stopped in 7/140 (5%) patients in group A, fluoroquinolones in 6/81 (7%) patients in group B, and both pyrazinamide and fluoroquinolones were stopped in 5/39 (13%) patients in group C because of intolerable joint pain. Major joints affected were knees and ankles. CONCLUSION: There is a high incidence of joint pain in patients receiving antituberculous treatment, which is higher when fluoroquinolones or the pyrazinamide-fluoroquinolone combination are administered as compared to pyrazinamide alone.

Antimicrobial activity and inhibition of the NorA efflux pump of Staphylococcus aureus by extract and isolated compounds from Arrabidaea brachypoda.

Arrabidaea brachypoda is a native shrub of the Brazilian Cerrado widely used in the folk medicine for treatment of renal diseases and articular pains. This study aimed to, first, evaluate the antimicrobial activity of both extracts and isolated molecules Brachydins BR-A and BR-B obtained from the flowers of A. brachypoda against Staphylococcus aureus, Escherchia coli and Candida albicans species. A second objective was to investigate if these natural products were able to potentiate the Norfloxacin activity against the strain Staphylococcus aureus SA1199-B that overexpress the norA gene encoding the NorA efflux pump. Extracts and isolated compounds were analyzed by HPLC-PDA and LC-ESI-MS respectively. Minimal inhibitory concentrations of Norfloxacin or Ethidium Bromide (EtBr) were determined in the presence or absence of ethanolic extract, dichloromethane fraction, as well as BR-A or BR-B by microdilution method. Only BR-B showed activity against Candida albicans. Addition of ethanolic extract, dichloromethane fraction or BR-B to the growth media at sub-inhibitory concentrations enhanced the activity of both Norfloxacin and EtBr against S. aureus SA1199-B, indicating that these natural products and its isolated compound BR-B were able to modulate the fluoroquinolone-resistance possibly by inhibition of NorA. Moreover, BR-B inhibited the EtBr efflux in the SA1199-B strain confirming that it is a NorA inhibitor. Isolated BR-B was able to inhibit an important mechanism of multidrug-resistance very prevalent in S. aureus strains, thus its use in combination with Norfloxacin could be considered as an alternative for the treatment of infections caused by S. aureus strains overexpressing norA.

Fluoroquinolones for the treatment of latent Mycobacterium tuberculosis infection in liver transplantation.

Solid organ transplantation (SOT) is the best treatment option for end-stage organ disease. Newer immunosuppressive agents have reduced the incidence of graft rejection but have increased the risk of infection, particularly due to the reactivation of latent infections due to opportunistic agents such as Mycobacterium tuberculosis. Active tuberculosis (TB) after SOT is a significant cause of morbidity and mortality. Most cases of posttransplant TB are secondary to reactivation of latent tuberculosis infection (LTBI) due to the effects of long-term immunosuppressive therapy. Risk minimization strategies have been developed to diagnose LTBI and initiate treatment prior to transplantation. Isoniazid with vitamin B6 supplementation is the treatment of choice. However, liver transplantation (LT) candidates and recipients have an increased risk of isoniazid-induced liver toxicity, leading to lower treatment completion rates than in other SOT populations. Fluoroquinolones (FQs) exhibit good in vitro antimycobacterial activity and a lower risk of drug-induced liver injury than isoniazid. In the present review, we highlight the disease burden posed by posttransplant TB and summarize the emerging clinical evidence supporting the use of FQs for the treatment of LTBI in LT recipients and candidates.