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1.
BMC Res Notes ; 14(1): 413, 2021 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-34776013

RESUMO

OBJECTIVE: To determine at two distinct time points the prevalence of resistance to ofloxacin (OFX), the representative class drug of fluoroquinolones (FQs), in M. tuberculosis isolates susceptible to first-line drugs. RESULTS: There were 279 M. tuberculosis isolates from the two cohorts (2004-2005: 238 isolates; 2017: 41 isolates) that underwent OFX drug-susceptibility testing (critical concentration: 2 µg/ml). Of 238 isolates in Cohort 1, no resistance to OFX was detected (95% CI 0-0.016); likewise, in Cohort 2, no resistance to OFX was detected in 41 isolates (95% CI 0-0.086). Our findings suggest that FQ use remains a viable option for the treatment of first-line drug-susceptible TB in Peru.


Assuntos
Mycobacterium tuberculosis , Preparações Farmacêuticas , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Antituberculosos/farmacologia , Farmacorresistência Bacteriana , Fluoroquinolonas/farmacologia , Humanos , Levofloxacino , Testes de Sensibilidade Microbiana , Moxifloxacina , Peru/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia
3.
BMC Infect Dis ; 21(1): 1003, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34563128

RESUMO

BACKGROUND: Mycoplasma pneumoniae is a common pathogen that causes community-acquired pneumonia in school-age children. Macrolides are considered a first-line treatment for M. pneumoniae infection in children, but macrolide-refractory M. pneumoniae (MRMP) strains have become more common. In this study, we assessed the efficacy of tetracyclines and fluoroquinolones in MRMP treatment in children through a systematic review and meta-analysis. METHODS: Two reviewers individually searched 10 electronic databases (Medline/Pubmed, Embase, the Cochrane Library, and core Korean, Chinese, and Japanese journals) for papers published from January 1, 1990 to March 8, 2018. The following data for each treatment group were extracted from the selected studies: intervention (tetracyclines and fluoroquinolones/comparator), patient characteristics (age and sex), and outcomes (fever duration, hospital stay length, treatment success rate, and defervescence rates 24, 48, and 72 h after starting treatment). RESULTS: Eight studies involving 537 participants were included. Fever duration and hospital stay length were shorter in the tetracycline group than in the macrolide group (weighted mean difference [WMD] = - 1.45, 95% confidence interval [CI]: - 2.55 to - 0.36, P = 0.009; and WMD = - 3.33, 95% CI: - 4.32 to - 2.35, P < 0.00001, respectively). The therapeutic efficacy was significantly higher in the tetracycline group than in the macrolide group (odds ratio [OR]: 8.80, 95% CI: 3.12-24.82). With regard to defervescence rate, patients in the tetracycline group showed significant improvement compared to those in the macrolide group (defervescence rate after 24 h, OR: 5.34, 95% CI: 1.81-15.75; after 48 h, OR 18.37, 95% CI: 8.87-38.03; and after 72 h, OR: 40.77, 95% CI: 6.15-270.12). There were no differences in fever improvement within 24 h in patients in the fluoroquinolone group compared to those in the macrolide group (OR: 1.11, 95% CI: 0.25-5.00), although the defervescence rate was higher after 48 h in the fluoroquinolone group (OR: 2.78, 95% CI: 1.41-5.51). CONCLUSION: Tetracyclines may shorten fever duration and hospital stay length in patients with MRMP infection. Fluoroquinolones may achieve defervescence within 48 h in patients with MRMP infection. However, these results should be carefully interpreted as only a small number of studies were included, and they were heterogeneous.


Assuntos
Mycoplasma pneumoniae , Pneumonia por Mycoplasma , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Criança , Farmacorresistência Bacteriana , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Humanos , Macrolídeos/farmacologia , Macrolídeos/uso terapêutico , Pneumonia por Mycoplasma/tratamento farmacológico , Tetraciclinas/farmacologia , Tetraciclinas/uso terapêutico
4.
J Med Microbiol ; 70(9)2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34590993

RESUMO

Introduction. Failure of fluoroquinolones, the principal treatment option for macrolide-resistant Mycoplasma genitalium infections, has recently emerged. This is of particular concern for men who have sex with men (MSM), who have high proportions of macrolide-resistant M. genitalium infections. Treatment failure with moxifloxacin is likely the result of single nucleotide polymorphisms (SNPs) in parC, whilst concurrent gyrA mutations may play a role.Gap Statement. The levels of fluoroquinolone resistance and dual-class (i.e. macrolide and fluoroquinolone) resistance in M. genitalium among asymptomatic MSM is unknown.Aim. To (i) determine the proportion of fluoroquinolone resistance and dual-class resistance in M. genitalium infections among asymptomatic MSM, (ii) explore any clinical and behavioural associations with fluoroquinolone resistance, and (iii) determine the distribution of antibiotic resistance among M. genitalium mgpB sequence types (STs).Methodology. M. genitalium positive samples (N=94) were obtained from 1001 asymptomatic MSM enrolled in a study at Melbourne Sexual Health Centre (Carlton, Australia) between August 2016 and September 2017. Sanger sequencing was performed to determine the proportion of M. genitalium infections with SNPs in parC that have previously been associated with failure of moxifloxacin (corresponding to amino changes S83I, D83R, D87Y and D87N) and in gyrA (corresponding to amino acid changes M95I, D99N, D99Y and D99G). Associations between clinical/behavioural factors and parC SNPs were examined. Strain typing was performed by sequencing a portion of the mgpB gene.Results. The proportion of MSM with infections harbouring parC and gyrA SNPs was 13.0 % [95 % confidence interval (CI): 6.8-23.2 %] and 4.7 % (95 % CI: 1.1-13.4 %), respectively; dual-class resistance was 13.0 %. No significant clinical/behavioural associations were found. Antibiotic resistance was not restricted to specific mgpB STs.Conclusion. One in eight (13 %) of asymptomatic MSM with M. genitalium had an infection with dual-class-resistance mutations. Typing by mgpB sequence suggested fluoroquinolone resistance is arising from independent mutation events. This study illustrates that asymptomatic MSM may act as a reservoir for antibiotic-resistant M. genitalium.


Assuntos
Antibacterianos/farmacologia , Fluoroquinolonas/farmacologia , Infecções por Mycoplasma/tratamento farmacológico , Mycoplasma genitalium/efeitos dos fármacos , Minorias Sexuais e de Gênero , DNA Girase/química , DNA Girase/genética , DNA Topoisomerase IV/química , DNA Topoisomerase IV/genética , DNA Bacteriano/química , DNA Bacteriano/isolamento & purificação , Farmacorresistência Bacteriana , Humanos , Masculino , Mutação , Infecções por Mycoplasma/epidemiologia , Mycoplasma genitalium/genética , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Prevalência
5.
Sex Transm Dis ; 48(9): 680-684, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34397971

RESUMO

BACKGROUND: Mycoplasma genitalium is an emerging, sexually transmitted infection, which is more prevalent than Chlamydia trachomatis in some regions. An increase in antibiotic resistance, that is, azithromycin and moxifloxacin, recommended for treating M. genitalium infections has been noted. This is the first detailed report on the prevalence of M. genitalium and its antimicrobial resistance in Saskatchewan, Canada. METHODS: Aptima urine specimens (n = 1977), collected for the diagnosis of C. trachomatis/Neisseria gonorrhoeae, were tested for M. genitalium using the Aptima M. genitalium assay (MG-TMA). Antimicrobial resistance was ascertained using polymerase chain reaction and DNA sequencing of 23S rRNA (azithromycin) and parC (moxifloxacin) from Aptima M. genitalium assay-positive specimens; mutations predictive of resistance were noted. RESULTS: The prevalence of M. genitalium was 9.6% (189/1977). Predicted resistance to azithromycin (substitutions at positions 2058/2059 in 23S rRNA) was observed in 63.6% (70/110) of the specimens tested, whereas resistance to moxifloxacin (S83I in ParC) was observed in 10.6% (9/85) of the specimens. Mutations in both 23S rRNA and ParC were observed in 2.12% (4/189) of the specimens. Women aged 20 to 24 years had the highest prevalence (18.3%, P < 0.001), and in females, M. genitalium was significantly associated with C. trachomatis or N. gonorrhoeae/C. trachomatis (P < 0.001) coinfection. The prevalence of M. genitalium (9.6%) in the province of Saskatchewan was higher than that of the other 2 bacterial sexually transmitted infections (N. gonorrhoeae (3.09%) and C. trachomatis (6.85%). CONCLUSIONS: The prevalence of M. genitalium (9.6%) and associated resistance to azithromycin (63.6%) in Saskatchewan high, suggesting that empiric azithromycin therapy may not be adequate for treating M. genitalium infections.


Assuntos
Infecções por Mycoplasma , Mycoplasma genitalium , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana/genética , Feminino , Fluoroquinolonas/farmacologia , Humanos , Macrolídeos/farmacologia , Mutação , Infecções por Mycoplasma/tratamento farmacológico , Infecções por Mycoplasma/epidemiologia , Mycoplasma genitalium/genética , Prevalência , Saskatchewan/epidemiologia , Adulto Jovem
6.
Graefes Arch Clin Exp Ophthalmol ; 259(11): 3351-3357, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34379184

RESUMO

PURPOSE: To determine the relationship between fluoroquinolone susceptibility of gram-positive cocci (GPC) isolated from patients with bacterial keratitis and the age of the patients or the date of onset. METHODS: Bacterial isolates were obtained from corneal lesions of patients with infectious keratitis treated between January 2008 and December 2016. The fluoroquinolone susceptibility of GPC was assessed, and a retrospective review of microbiological records was performed. Fluoroquinolone susceptibility was measured through broth microdilution in accordance with protocols of the Clinical and Laboratory Standards Institute. Statistical analysis was performed using a generalized estimating equation and cubic spline to determine the association between fluoroquinolone susceptibility of GPC isolated from corneal lesions and patient age. RESULTS: Of the 1200 bacterial isolates, 471 GPC were identified. They included Staphylococcus epidermidis (45.6%), other coagulase-negative Staphylococcus sp. (17.8%), and Staphylococcus aureus (18.3%). Levofloxacin susceptibility of GPC exhibited a negative relationship with age and had an odds ratio of 0.893 (95% confidence interval, 0.825-0.967) for every 10 years of age. A non-adjusted cubic spline curve was well correlated with year-adjusted data in a generalized additive model, and the levofloxacin susceptibility of GPC was initially stable but gradually declined after 40 years of age, before re-stabilizing again after 70 years of age. CONCLUSION: The fluoroquinolone susceptibility of GPC isolated from corneal lesions of infectious keratitis is high in children under 15 years of age and declines with an increase in age of patients using a generalized estimating equation and cubic spline.


Assuntos
Infecções Oculares Bacterianas , Cocos Gram-Positivos , Ceratite , Fatores Etários , Idoso , Antibacterianos/farmacologia , Criança , Infecções Oculares Bacterianas/diagnóstico , Infecções Oculares Bacterianas/tratamento farmacológico , Infecções Oculares Bacterianas/epidemiologia , Fluoroquinolonas/farmacologia , Humanos , Ceratite/diagnóstico , Ceratite/tratamento farmacológico , Ceratite/epidemiologia , Testes de Sensibilidade Microbiana , Estudos Retrospectivos
7.
Antimicrob Agents Chemother ; 65(10): e0073621, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34339266

RESUMO

The in vitro activity and in vivo efficacy of delafloxacin were evaluated against the causative pathogen of melioidosis, Burkholderia pseudomallei. Delafloxacin MICs were determined by broth microdilution according to CLSI guidelines for 30 isolates of B. pseudomallei. The in vivo efficacy of delafloxacin was studied at a range of doses in a postexposure prophylaxis (PEP) murine model of melioidosis. Delafloxacin was active in vitro against B. pseudomallei (MIC90, 1 µg/ml). When the mice were dosed with 50 mg/kg body weight and 80 mg/kg body weight delafloxacin at both 16 and 24 h, greater survival was observed (90% to 100% survival) than with the 30-mg/kg-dosed mice (70% survival). All delafloxacin-treated cohorts contained no detectable B. pseudomallei in the spleens at the end of the study. This contrasts with ceftazidime 16- and 24-h administration, which had 40% and 20% survival, respectively. Complete clearance of infection was observed for most but not all surviving cohorts administered ceftazidime. In the mouse model of infection, survival curves for delafloxacin- and ceftazidime-treated animals at treatment start times of 16 and 24 h were statistically significant (P values of <0.0001). Estimated daily delafloxacin exposures in the B. pseudomallei murine aerosol study were similar to daily human exposures with the approved twice a day (BID) intravenous (i.v.) (300 mg) or oral (450 mg) dosing regimens. Based on its in vitro and in vivo activity, its safety, and its tolerability profile, delafloxacin may offer an attractive treatment option as PEP or eradication therapy for B. pseudomallei. Evaluation in other in vivo infection models for B. pseudomallei should be considered.


Assuntos
Burkholderia pseudomallei , Melioidose , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Fluoroquinolonas/farmacologia , Melioidose/tratamento farmacológico , Camundongos
8.
J Med Microbiol ; 70(8)2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34356003

RESUMO

Introduction. Fluoroquinolone (FQ) resistant Salmonella are classified as high priority pathogens by WHO. FQ resistance among Salmonella Typhi has emerged rapidly and is predominantly mediated by mutations in the topoisomerase genes gyrA, and parC. Mutations in GyrA result in classical FQ resistance (DCS-NAR) i.e. decreased susceptibility to ciprofloxacin (MIC of 0.12 to 0.5 µg ml-1) (DCS) and resistance to nalidixic acid (NAR). Previously a nalidixic acid disc test was proposed for detection of DCS. Recently isolates with non-classical FQ resistance caused by plasmid-mediated quinolone resistance (PMQR) and mutations in GyrB have emerged. These mechanisms also result in DCS but are nalidixic acid susceptible (NAS) and thus pose diagnostic challenges. CLSI and EUCAST have recommended use of 5 µg pefloxacin discs for detection of DCS in Salmonella.Hypothesis. The CLSI and EUCAST recommendations for use of 5 µg pefloxacin for detection of DCS has not been validated on typhoidal Salmonella and resistance mediated by GyrB mutation in Salmonella species.Aim. The aim of the present study was to validate the performance of the 5 µg pefloxacin discs to detect isolates of S. Typhi with DCS with special reference to GyrB mutations.Methodology. A total of 180 clinical isolates of Salmonella Typhi (2005-2014) were investigated for genetic mechanisms of resistance. Zone diameters for nalidixic acid (30µg), ciprofloxacin (5µg) and pefloxacin (5µg) and minimum inhibitory concentration (MIC) for ciprofloxacin were determined using CLSI guidelines. Performance of the three discs was evaluated to detect FQ resistance in S. Typhi.Results. Topoisomerase mutations in GyrB +/ ParC and GyrB were detected in 112 and 34 isolates respectively. Different mutations have a varied effect on the MIC for ciprofloxacin. The current breakpoints for susceptible (≤0.06 µg ml-1) and non-susceptible (≥0.125 µg ml-1), failed to detect all isolates with a resistance mechanism. Performance of both ciprofloxacin and pefloxacin discs were excellent compared to nalidixic acid in differentiating isolates with non-classical resistance mediated by GyrB from wild-type.Conclusion. The pefloxacin disc can be used to detect FQ resistance among S. Typhi. This is the first report of validation of pefloxacin for detection of FQ resistance in S. Typhi mediated by GyrB mutation.


Assuntos
DNA Girase/genética , Farmacorresistência Bacteriana/efeitos dos fármacos , Fluoroquinolonas/farmacologia , Pefloxacina/farmacologia , Salmonella typhi/efeitos dos fármacos , Antibacterianos/farmacologia , Ciprofloxacina/farmacologia , DNA Topoisomerase IV/genética , Farmacorresistência Bacteriana/genética , Humanos , Testes de Sensibilidade Microbiana , Mutação , Ácido Nalidíxico/farmacologia , Salmonella typhi/genética , Salmonella typhi/isolamento & purificação , Inibidores da Topoisomerase II/farmacologia , Febre Tifoide/microbiologia
9.
Sci Rep ; 11(1): 17387, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34462504

RESUMO

Multi-drug (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) continues to be a global public health problem especially in high TB burden countries like Nigeria. Many of these cases are undetected and go on to infect high risk individuals. Clinical samples from positive rifampicin resistant Xpert®MTB/Rif assay were subjected to direct whole genome sequencing and bioinformatics analysis to identify the full antibiotics resistance and lineage profile. We report two (2) XDR TB samples also belonging to the East-Asian/Beijing family of lineage 2 Mycobacterium tuberculosis complex from clinical samples in Nigeria. Our findings further reveal the presence of mutations that confer resistance to first-line drugs (rifampicin, isoniazid, ethambutol and pyrazanimide), second-line injectables (capreomycin, streptomycin, kanamycin and/or amikacin) and at least one of the fluoroquinolones (ofloxacin, moxifloxacin, levofloxacin and/or ciprofloxacin) in both samples. The genomic sequence data from this study not only provide the first evidence of XDR TB in Nigeria and West Africa, but also emphasize the importance of WGS in accurately detecting MDR and XDR TB, to ensure adequate and proper management treatment regimens for affected individuals. This will greatly aid in preventing the spread of drug resistance TB in high burden countries.


Assuntos
Tuberculose Extensivamente Resistente a Medicamentos/diagnóstico , Mycobacterium tuberculosis/genética , Adulto , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Capreomicina/farmacologia , Capreomicina/uso terapêutico , DNA Bacteriano/química , DNA Bacteriano/metabolismo , Tuberculose Extensivamente Resistente a Medicamentos/complicações , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Feminino , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mycobacterium tuberculosis/classificação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Nigéria , Filogenia , Rifampina/farmacologia , Rifampina/uso terapêutico , Sequenciamento Completo do Genoma , Adulto Jovem
10.
Front Public Health ; 9: 672473, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34262891

RESUMO

Campylobacter jejuni is the leading cause of bacterial gastroenteritis and antibiotic resistant C. jejuni are a serious threat to public health. Herein, we sought to evaluate trends in C. jejuni infections, quantify resistance frequencies, and identify epidemiological factors associated with infection. Campylobacter jejuni isolates (n = 214) were collected from patients via an active surveillance system at four metropolitan hospitals in Michigan between 2011 and 2014. The minimum inhibitory concentration for nine antibiotics was determined using microbroth dilution, while demographic and clinical data were used for the univariate and multivariate analyses. Over the 4-year period, a significant increase in the recovery of C. jejuni was observed (p ≤ 0.0001). Differences in infection rates were observed by hospital and several factors were linked to more severe disease. Patients residing in urban areas, for instance, were significantly more likely to be hospitalized than rural residents as were patients over 40 years of age and those self-identifying as non-White, highlighting potential disparities in disease outcomes. Among the 214 C. jejuni isolates, 135 (63.1%) were resistant to at least one antibiotic. Resistance was observed for all nine antibiotics tested yielding 11 distinct resistance phenotypes. Tetracycline resistance predominated (n = 120; 56.1%) followed by resistance to ciprofloxacin (n = 49; 22.9%), which increased from 15.6% in 2011 to 25.0% in 2014. Resistance to two antibiotic classes was observed in 38 (17.8%) isolates, while multidrug resistance, or resistance to three or more classes, was observed in four (1.9%). Notably, patients with ciprofloxacin resistant infections were more likely to report traveling in the past month (Odds Ratio (OR): 3.0; 95% confidence interval (CI): 1.37, 6.68) and international travel (OR: 9.8; 95% CI: 3.69, 26.09). Relative to patients with only tetracycline resistant infections, those with ciprofloxacin resistance were more likely to travel internationally, be hospitalized and have an infection during the fall or summer. Together, these findings show increasing rates of infection and resistance and highlight specific factors that impact both outcomes. Enhancing understanding of factors linked to C. jejuni resistance and more severe infections is critical for disease prevention, particularly since many clinical laboratories have switched to the use of culture-independent tests for the detection of Campylobacter.


Assuntos
Campylobacter jejuni , Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Fluoroquinolonas/farmacologia , Humanos , Michigan , Tetraciclina/farmacologia
11.
J Med Microbiol ; 70(7)2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34319224

RESUMO

Introduction. The emergence and spread of non-typhoidal Salmonella enterica (NTS) serovars resistant to fluoroquinolones and third- and higher-generation cephalosporins is a matter of great concern. Antimicrobial-resistant NTS is increasingly being discovered in humans, animals, food animals, food products, and agricultural environments. Pigs are considered a major reservoir of antimicrobial-resistant Salmonella spp.Hypothesis/Gap Statement. Fluoroquinolone-resistant Salmonella spp. warrant further surveillance and characterization for a better understanding of the bacteria isolated from animals.Aim. NTS isolated from pork from slaughterhouses across Thailand were characterized in terms of their serovars; resistance to fluoroquinolones, third-generation cephalosporins, and carbapenems; and antimicrobial resistance genes.Methodology. A total of 387 NTS isolates, collected from slaughtered pigs in ten provinces across Thailand between 2014 and 2015, were characterized based on their serovars, antimicrobial resistance genes, and susceptibility to fluoroquinolones, third-generation cephalosporins, and carbapenems.Results. Among all NTS isolates, S. enterica serovar Rissen was predominant. Antimicrobial resistance was exhibited in 93/387 isolates (24 %). Although 24 (6.2 %) isolates were susceptible to all the tested antimicrobials, they were found to possess ß-lactamase genes, such as bla TEM, bla SHV, or bla CTX-M. Mobilized colistin-resistant genes (mcr) and resistance to colistin were not observed in any tested isolate. Carbapenem resistance was detected in ten isolates (10.7 %); however, bla KPC, bla NDM, bla OXA-48-like, and bla IMP were not present. Among the 93 antimicrobial-resistant isolates, 87.1 % showed fluoroquinolone resistance with the quinolone resistance gene (qnrS) combined with topoisomerase genes parC (T57S) or gyrA (S83E/Y and D124E/G) substitutions, or topoisomerase gene substitutions alone.Conclusion. We found high fluoroquinolone resistance rates among the NTS isolates from pigs from slaughterhouses. The fluoroquinolone resistance mechanism in NTS was associated with the combination of qnrS and substitutions in gyrA, parC, or both. To prevent the transmission of antimicrobial-resistant NTS between animals and humans, continuous monitoring, surveillance, and regulation of Salmonella in the pork supply chain are pivotal.


Assuntos
Farmacorresistência Bacteriana/genética , Salmonelose Animal/microbiologia , Salmonella enterica , Suínos/microbiologia , Animais , Cefalosporinas/farmacologia , Fluoroquinolonas/farmacologia , Salmonella enterica/genética , Salmonella enterica/isolamento & purificação , Sorogrupo , Tailândia/epidemiologia
12.
Trop Med Int Health ; 26(9): 1057-1067, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34107112

RESUMO

OBJECTIVES: Differences among Mycobacterium tuberculosis complex (MTC) species may predict drug resistance or treatment success. Thus, we optimised and deployed the genotype MTBC assay (gMTBC) to identify MTC to the species level, and then performed comparative genotypic drug-susceptibility testing to anti-tuberculosis drugs from direct sputum of patients with presumed multidrug-resistant tuberculosis (MDR-TB) by the MTBDRplus/sl reference method. METHODS: Patients with positive Xpert® MTB/RIF (Xpert) results were consented to provide early-morning-sputum for testing by the gMTBC and the reference MTBDRplus/sl. Chi-square or Fisher's exact test compared proportions. Modified Poisson regression modelled detection of MTC by gMTBC. RESULTS: Among 73 patients, 53 (73%) were male and had a mean age of 43 (95% CI; 40-45) years. In total, 34 (47%), 36 (49%) and 38 (55%) had positive gMTBC, culture and MTBDR respectively. Forty patients (55%) had low quantity MTC by Xpert, including 31 (78%) with a negative culture. gMTBC was more likely to be positive in patients with chest cavity 4.18 (1.31-13.32, P = 0.016), high-quantity MTC by Xpert 3.03 (1.35-6.82, P = 0.007) and sputum smear positivity 1.93 (1.19-3.14, P = 0.008). The accuracy of gMTBC in detecting MTC was 95% (95% CI; 86-98; κ = 0.89) compared to MTBDRplus/sl. All M. tuberculosis/canettii identified by gMTB were susceptible to fluoroquinolone and aminoglycosides/capreomycin. CONCLUSIONS: The concordance between the gMTBC assay and MTBDRplus/sl in detecting MTC was high but lagged behind the yield of Xpert MTB/RIF. All M. tuberculosis/canettii were susceptible to fluoroquinolones, a core drug in MDR-TB treatment regimens.


Assuntos
Técnicas de Tipagem Bacteriana/métodos , Genótipo , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Escarro/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/genética , Adulto , Antituberculosos/farmacologia , Estudos Transversais , Feminino , Fluoroquinolonas/farmacologia , Humanos , Isoniazida/farmacologia , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mycobacterium tuberculosis/classificação , Mycobacterium tuberculosis/efeitos dos fármacos , Rifampina/farmacologia , Especificidade da Espécie , Tanzânia/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
13.
Braz J Biol ; 82: e239868, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34190800

RESUMO

Fluoroquinolones are important antimicrobial agents for the treatment of Pseudomonas infections. A total of 11 isolates of P. aeruginosa were collected from different clinical samples from different medical centers in the North West Bank-Palestine during 2017. In this study, resistance to fluoroquinolones and secretions of ß-lactamases were detected by phenotypic methods, while presence of ß-lactamase gene sequences and other virulence factors were detected by PCR technique. PCR product for gyrA, parC and parE genes were sequenced for further analyses. The phylogenetic analyses, population diversity indices and haplotypes determination were conducted using computer programs MEGA version 6, DnaSP 5.1001 and median-joining algorithm in the program Network 5, respectively. Results of this study showed that the MIC for ciprofloxacin and norfloxacin had a range of 32-256 µg/ml. In addition, all isolates carried either exoT or exoT and exoY genes, different ß-lactamase genes and 82% of these isolates harbored class 1 integrons. Analyses of the gyrA, parC and parE sequences were found to be polymorphic, had high haplotype diversity (0.945-0.982), low nucleotide diversity (0.01225-0.02001) and number of haplotypes were 9 for each gyrA and parE genes and 10 haplotypes for parC gene. The founder haplotypes being Hap-1 (18%), Hap-2 (27.3%) and Hap-6 (9.1%) for gyrA, parC and parE genes, respectively. Two of ParE haplotypes were detected as indel haplotypes. The Median-joining- (MJ) networks constructed from haplotypes of these genes showed a star-like expansion. The neutrality tests (Tajima's D test and Fu's Fs test) for these genes showed negative values. Palestinian fluoroquinolone resistant P. aeruginosa strains showed high MIC level for fluoroquinolones, ß-lactamase producers, carried type III secretion exotoxin-encoding genes, most of them had integrase I gene and had high level of mutations in QRDR regions in gyrA, parC and parE genes. All these factors may play an important role in the invasiveness of these strains and make them difficult to treat. Isolation of these strains from different medical centers, indicate the need for a strict application of infection control measures in Medical centers in the North West Bank-Palestine that aim to reduce expense and damage caused by P. aeruginosa infections. Molecular analyses showed that Palestinian fluoroquinolone resistant P. aeruginosa haplotypes are not genetically differentiated; however, more mutations may exist in these strains.


Assuntos
Fluoroquinolonas , Pseudomonas aeruginosa , DNA Topoisomerase IV/genética , Fluoroquinolonas/farmacologia , Testes de Sensibilidade Microbiana , Mutação , Filogenia , Pseudomonas aeruginosa/genética
14.
Proc Natl Acad Sci U S A ; 118(26)2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34185680

RESUMO

Translation of open reading frame 1b (ORF1b) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires a programmed -1 ribosomal frameshift (-1 PRF) promoted by an RNA pseudoknot. The extent to which SARS-CoV-2 replication may be sensitive to changes in -1 PRF efficiency is currently unknown. Through an unbiased, reporter-based high-throughput compound screen, we identified merafloxacin, a fluoroquinolone antibacterial, as a -1 PRF inhibitor for SARS-CoV-2. Frameshift inhibition by merafloxacin is robust to mutations within the pseudoknot region and is similarly effective on -1 PRF of other betacoronaviruses. Consistent with the essential role of -1 PRF in viral gene expression, merafloxacin impedes SARS-CoV-2 replication in Vero E6 cells, thereby providing proof-of-principle for targeting -1 PRF as a plausible and effective antiviral strategy for SARS-CoV-2 and other coronaviruses.


Assuntos
Antivirais/farmacologia , Mudança da Fase de Leitura do Gene Ribossômico/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Betacoronavirus , Chlorocebus aethiops , Fluoroquinolonas/farmacologia , Mudança da Fase de Leitura do Gene Ribossômico/genética , Mutação , Conformação de Ácido Nucleico , RNA Viral/química , RNA Viral/genética , SARS-CoV-2/fisiologia , Células Vero
15.
Molecules ; 26(9)2021 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-34063264

RESUMO

The present work aims to examine the worrying problem of antibiotic resistance and the emergence of multidrug-resistant bacterial strains, which have now become really common in hospitals and risk hindering the global control of infectious diseases. After a careful examination of these phenomena and multiple mechanisms that make certain bacteria resistant to specific antibiotics that were originally effective in the treatment of infections caused by the same pathogens, possible strategies to stem antibiotic resistance are analyzed. This paper, therefore, focuses on the most promising new chemical compounds in the current pipeline active against multidrug-resistant organisms that are innovative compared to traditional antibiotics: Firstly, the main antibacterial agents in clinical development (Phase III) from 2017 to 2020 are listed (with special attention on the treatment of infections caused by the pathogens Neisseria gonorrhoeae, including multidrug-resistant isolates, and Clostridium difficile), and then the paper moves on to the new agents of pharmacological interest that have been approved during the same period. They include tetracycline derivatives (eravacycline), fourth generation fluoroquinolones (delafloxacin), new combinations between one ß-lactam and one ß-lactamase inhibitor (meropenem and vaborbactam), siderophore cephalosporins (cefiderocol), new aminoglycosides (plazomicin), and agents in development for treating drug-resistant TB (pretomanid). It concludes with the advantages that can result from the use of these compounds, also mentioning other approaches, still poorly developed, for combating antibiotic resistance: Nanoparticles delivery systems for antibiotics.


Assuntos
Antibacterianos/farmacologia , Desenho de Fármacos , Farmacorresistência Bacteriana Múltipla , Animais , Ácidos Borônicos/farmacologia , Cefalosporinas/farmacologia , Química Farmacêutica/tendências , Clostridioides difficile , Infecções por Clostridium/tratamento farmacológico , Fluoroquinolonas/farmacologia , Gonorreia/tratamento farmacológico , Humanos , Meropeném/farmacologia , Neisseria gonorrhoeae , Nitroimidazóis/farmacologia , Sisomicina/análogos & derivados , Sisomicina/farmacologia , Tetraciclinas/farmacologia , Inibidores de beta-Lactamases/farmacologia
16.
Poult Sci ; 100(8): 101250, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34182220

RESUMO

Fluoroquinolones (FQs) have been used effectively antimicrobial agents of choice for treatment of various infections caused by E. coli and FQs-resistance of E. coli from broiler breeders has been implicated in its vertical transmission to their offspring. The objective of this study investigated the phenotypic and genotypic characteristics of FQ-resistant E. coli isolates from broiler breeder farms in Korea. A total of 106 FQ-resistant E. coli isolates were tested in this study and all isolates had mutations in quinolone resistance determining regions; all (100%) had mutations in gyrA, 89 (84.0%) had mutations in parE, 8 (7.5%) isolates showed the mutations with parC and parE, and none had mutations in gyrB. The predominant mutation type was double mutation in gyrA (S83L and D87N), and all FQ-resistant E. coli isolates that had mutations in parC or parE also had double mutations in gyrA. Especially, FQ-resistant E. coli isolates which possessed double mutations in gyrA in combination with double mutations in parC or single mutations in both parC and parE were shown high levels of minimum inhibitory concentrations rage. Of the 23 plasmid-mediated quinolone resistance (PMQR)-positive E. coli isolates, qnrS was detected in 10 (9.4%) isolates, and followed by qnrA (7 isolates, 6.6%), qnrB (4 isolates, 3.8%), and aac(6')-Ib-cr (2 isolates, 1.9%). Sixteen (69.6%) of the 23 PMQR-positive E. coli isolates harbored class 1 integrons with four different gene cassette arrangements and total of 9 plasmid replicon types were also identified in 23 PMQR-positive E. coli isolates. This is the first study to investigate the prevalence and characteristics of FQ-resistant and PMQR-positive E. coli isolated from the broiler breeder in Korea; it supports that constant monitoring and studies at the broiler breeder level are required to prevent the pyramidal transmission of FQ-resistant E. coli.


Assuntos
Infecções por Escherichia coli , Fluoroquinolonas , Animais , Antibacterianos/farmacologia , Galinhas , DNA Girase/genética , Farmacorresistência Bacteriana/genética , Escherichia coli/genética , Infecções por Escherichia coli/epidemiologia , Infecções por Escherichia coli/veterinária , Fazendas , Fluoroquinolonas/farmacologia , Testes de Sensibilidade Microbiana/veterinária , Mutação , República da Coreia/epidemiologia
17.
Sci Rep ; 11(1): 12472, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127720

RESUMO

Antimicrobial resistance is mostly studied by means of phenotypic growth inhibition determinations, in combination with PCR confirmations or further characterization by means of whole genome sequencing (WGS). However, the actual proteins that cause resistance such as enzymes and a lack of porins cannot be detected by these methods. Improvements in liquid chromatography (LC) and mass spectrometry (MS) enabled easier and more comprehensive proteome analysis. In the current study, susceptibility testing, WGS and MS are combined into a multi-omics approach to analyze resistance against frequently used antibiotics within the beta-lactam, aminoglycoside and fluoroquinolone group in E. coli and K. pneumoniae. Our aim was to study which currently known mechanisms of resistance can be detected at the protein level using liquid chromatography-mass spectrometry (LC-MS/MS) and to assess whether these could explain beta-lactam, aminoglycoside, and fluoroquinolone resistance in the studied isolates. Furthermore, we aimed to identify significant protein to resistance correlations which have not yet been described before and to correlate the abundance of different porins in relation to resistance to different classes of antibiotics. Whole genome sequencing, high-resolution LC-MS/MS and antimicrobial susceptibility testing by broth microdilution were performed for 187 clinical E. coli and K. pneumoniae isolates. Resistance genes and proteins were identified using the Comprehensive Antibiotic Resistance Database (CARD). All proteins were annotated using the NCBI RefSeq database and Prokka. Proteins of small spectrum beta-lactamases, extended spectrum beta-lactamases, AmpC beta-lactamases, carbapenemases, and proteins of 16S ribosomal RNA methyltransferases and aminoglycoside acetyltransferases can be detected in E. coli and K. pneumoniae by LC-MS/MS. The detected mechanisms matched with the phenotype in the majority of isolates. Differences in the abundance and the primary structure of other proteins such as porins also correlated with resistance. LC-MS/MS is a different and complementary method which can be used to characterize antimicrobial resistance in detail as not only the primary resistance causing mechanisms are detected, but also secondary enhancing resistance mechanisms.


Assuntos
Proteínas de Bactérias/análise , Farmacorresistência Bacteriana/genética , Regulação Bacteriana da Expressão Gênica , Proteogenômica/métodos , beta-Lactamases/análise , Acetiltransferases/análise , Acetiltransferases/genética , Acetiltransferases/metabolismo , Sequência de Aminoácidos , Aminoglicosídeos/farmacologia , Aminoglicosídeos/uso terapêutico , Antibacterianos/uso terapêutico , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , DNA Bacteriano/genética , DNA Bacteriano/isolamento & purificação , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Escherichia coli/genética , Escherichia coli/isolamento & purificação , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/enzimologia , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/isolamento & purificação , Metiltransferases/análise , Metiltransferases/genética , Metiltransferases/metabolismo , RNA Ribossômico 16S/metabolismo , Espectrometria de Massas em Tandem/métodos , Sequenciamento Completo do Genoma , beta-Lactamases/genética , beta-Lactamases/metabolismo , beta-Lactamas/farmacologia , beta-Lactamas/uso terapêutico
18.
J Hazard Mater ; 415: 125686, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34088184

RESUMO

The widespread use of antibiotics has led to their ubiquitous presence in water and wastewater and raised concerns about antimicrobial resistance. Clinical antibiotic susceptibility assays have been repurposed to measure removal of antimicrobial activity during water and wastewater treatment processes. The corresponding protocols have mainly employed growth inhibition of Escherichia coli. The present work focused on optimizing bacteria selection to improve the sensitivity of residual antimicrobial activity measurements by broth microdilution assays. Thirteen antibiotics from four classes (i.e., fluoroquinolones, macrolides, sulfonamides, tetracyclines) were investigated against three gram-negative organisms, namely E. coli, Mycoplasma microti, and Pseudomonas fluorescens. The minimum inhibitory concentration (MIC) and half-maximal inhibitory concentration (IC50) were calculated for each antibiotic-bacteria pair. P. fluorescens produces a fluorescent siderophore, pyoverdine, that was used to assess sublethal effects and further enhance the sensitivity of antimicrobial activity measurements. The optimal antibiotic-bacteria pairs were as follows: fluoroquinolone-E. coli (growth inhibition); macrolide- and sulfonamide-M. microti (growth inhibition); and, tetracycline-P. fluorescens (pyoverdine inhibition). Compared to E. coli growth inhibition, the sensitivity of antimicrobial activity analysis was improved by up to 728, 19, and 2.7 times for macrolides (tylosin), sulfonamides (sulfamethoxazole), and tetracyclines (chlortetracycline), facilitating application of these bioassays at environmentally-relevant conditions.


Assuntos
Anti-Infecciosos , Fluoroquinolonas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Escherichia coli , Fluoroquinolonas/farmacologia , Macrolídeos/farmacologia , Testes de Sensibilidade Microbiana , Mycoplasma , Tetraciclinas/farmacologia
19.
Antimicrob Agents Chemother ; 65(8): e0028121, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34097492

RESUMO

Bacteria have a repertoire of strategies to overcome antibiotics in clinical use, complicating our ability to treat and cure infectious diseases. In addition to evolving resistance, bacteria within genetically clonal cultures can undergo transient phenotypic changes and tolerate high doses of antibiotics. These cells, termed persisters, exhibit heterogeneous phenotypes; the strategies that a bacterial population deploys to overcome one class of antibiotics can be distinct from those needed to survive treatment with drugs with another mode of action. It was previously reported that fluoroquinolones, which target DNA topoisomerases, retain the capacity to kill nongrowing bacteria that tolerate other classes of antibiotics. Here, we show that in Escherichia coli stationary-phase cultures and colony biofilms, persisters that survive treatment with the anionic fluoroquinolone delafloxacin depend on the AcrAB-TolC efflux pump. In contrast, we did not detect this dependence on AcrAB-TolC in E. coli persisters that survive treatment with three other fluoroquinolone compounds. We found that the loss of AcrAB-TolC activity via genetic mutations or chemical inhibition not only reduces delafloxacin persistence in nongrowing E. coli MG1655 or EDL933 (an E. coli O157:H7 strain), but it limits resistance development in progenies derived from delafloxacin persisters that were given the opportunity to recover in nutritive medium following antibiotic treatment. Our findings highlight the heterogeneity in defense mechanisms that persisters use to overcome different compounds within the same class of antibiotics. They further indicate that efflux pump inhibitors can potentiate the activity of delafloxacin against stationary-phase E. coli and block resistance development in delafloxacin persister progenies.


Assuntos
Proteínas de Escherichia coli , Escherichia coli , Antibacterianos/farmacologia , Proteínas de Transporte , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Fluoroquinolonas/farmacologia
20.
J Clin Microbiol ; 59(8): e0025921, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34076476

RESUMO

Aerococcus urinae is a urinary pathogen with well-described resistance to fluoroquinolones. This study aimed to validate the gradient diffusion (GD) method (Etest) on cation-adjusted Mueller-Hinton agar with 5% sheep blood for testing the susceptibilities of Aerococcus urinae to the antimicrobial agents ciprofloxacin and levofloxacin and to compare the Etest to the broth microdilution (BMD) method from CLSI document M45-A3. Agar dilution (AD), as recommended by EUCAST, was used as an alternative reference method to arbitrate discrepancies or address technical issues. Aerococcus urinae isolates from urinary specimens were prospectively collected between June 2016 and December 2017 from six hospitals in Quebec, Canada, and identifications were confirmed using Vitek MS with the IVD 3.0 database. Of the 207 isolates tested using BMD, 37 (17.9%) showed trailing and 19 (9.2%) showed insufficient growth; these were tested using AD. Also, 38 isolates (18.4%) for ciprofloxacin and 13 isolates (6.3%) for levofloxacin showed a lack of essential or categorical agreement between the Etest and BMD and were also tested by AD. By use of a combined reference method (BMD or AD), the susceptibility rates of Aerococcus urinae were 82.6% and 81.6% for ciprofloxacin and levofloxacin, respectively. Categorical agreement between GD and the combined reference methods was 95.2% for ciprofloxacin and 97.1% for levofloxacin, with no very major error identified. Major and minor error rates were 0.6% and 4.3% for ciprofloxacin and 1.2% and 1.9% for levofloxacin. Overall, antimicrobial susceptibility testing (AST) using the Etest on sheep blood agar showed good agreement with the reference methods and can be considered by clinical laboratories wishing to perform AST on Aerococcus urinae isolates.


Assuntos
Antibacterianos , Fluoroquinolonas , Aerococcus , Animais , Antibacterianos/farmacologia , Canadá , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Fluoroquinolonas/farmacologia , Testes de Sensibilidade Microbiana , Quebeque , Ovinos
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