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Made available in DSpace on 2022-04-28T18:45:59Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-03-23 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Sao Paulo State University Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Aim: Antibiotic resistance is one of the biggest threats to global health, and this study aimed better understand how the efflux pumps are related to this process in tuberculosis clinical isolates. Results: The combination of antibiotics plus efflux pumps (EP) inhibitors was able to restore the susceptibility of clinical isolates in 100% of aminoglycosides resistance and 33.3% of the fluoroquinolones resistance. The relative expression of EP genes in pre-extensively drug-resistant isolates showed an increase of up to 1000-times. Conclusion: The rescue of susceptibility in the presence of EP inhibitors, the increased of activity and expression of the EP genes alert that the inhibition of EP can reduce the selection of resistant strains and improve treatment. Sao Paulo State Univ UNESP, Sch Pharmaceut Sci, TB Res Lab, Araraquara, SP, Brazil State Univ Maringa UEM, Dept Clin Anal & Biomed, Maringa, Parana, Brazil Sao Paulo State Univ UNESP, Sch Pharmaceut Sci, TB Res Lab, Araraquara, SP, Brazil FAPESP: FAPESP 2018/02344-2 FAPESP: 2018/12135-1 FAPESP: 2020/13497-4 CAPES: 001

The problem of drug therapy for bacterial eye infections in children has remained relevant for many years. The greatest interest of ophthalmologists in recent years is associated with the use of fluoroquinolones in the treatment of inflammatory eye diseases of the bacterial etiology. At the same time, new ophthalmic dosage forms of fluoroquinolones that have appeared in recent years naturally require additional research on their effectiveness.Objective: to study the clinical efficacy of the antibacterial drug Oftocypro (0.3 % cyprofloxacin in ophthalmic ointment) in the treatment of chronic blepharoconjunctivitis in children.Materials. The study involved 38 children aged 3 to 18 years (mean age 10.3 ± 2.7 years) with clinical manifestations of blepharoconjunctivitis. All patients were divided into 2 groups of equal size: 18 children (36 eyes) — with bacterial blepharoconjunctivitis and 20 (40) — with chlamydial blepharoconjunctivitis. The diagnosis was verified based on the clinical picture of blepharoconjunctivitis and laboratory data: detection of pathogenic microflora in the conjunctival cavity of patients of the first group and chlamydia antigen — in epithelial cells in scraping material from the conjunctiva by immunohistochemical analysis.Results. The analysis of the data obtained during the examination and treatment of children with blepharoconjunctivitis of bacterial etiology (group I), a reliable dynamics of controlled clinical and laboratory parameters was established. There was a significant positive dynamics of all controlled parameters of the clinical course of chronic bacterial blepharoconjunctivitis against the background of the drug Oftocipro ophthalmic ointment 0.3 % use. All children with chronic chlamydial blepharoconjunctivitis with the background of treatment with Oftocypro, ophthalmic ointment 0.3 %, showed a steady tendency towards relief of the estimated clinical signs of the disease. According to the results of laboratory studies, it was found that on the 28th day of treatment with Oftocypro chlamydia in the cells of the epithelium of the conjunctiva was re-detected in 4 out of 20 patients (20 %).Conclusion. The high efficacy of the drug Oftocypro ophthalmic ointment 0.3 %, in combination with the absence of pronounced side effects, makes it possible to recommend this drug for wider practical use.

Mycoplasma pneumoniae (MP) is the most common cause of childhood bacterial pneumonia. Although macrolide is known to be effective as a first-line therapy, the proportion of macrolide resistance in MP pneumonia has strikingly increased during recent 2 decades in East Asia. This is challenging to physicians since they have to decide more often whether to use secondary treatment. Diagnostic methods to detect macrolide-resistance of MP are currently not available in Korean hospitals. Even in the diagnosis of MP infection, both serologic and molecular test have limitation: inability to differentiate current illness from carriage or asymptomatic infection. Combining these 2 diagnostic methods and excluding infection caused by other respiratory pathogens allow a more reliable diagnosis. This effort is even more demanding in recent years to keep children from unnecessary exposure to secondary antibiotics. Although several observational studies have reported that tetracycline and fluoroquinolone, which are considered in the treatment of refractory MP pneumonia, have efficacy of shortening the duration of fever and respiratory symptoms, those findings need to be proven by well-designed prospective studies. The use of tetracycline and fluoroquinolone in children is generally tolerable, as supported by many observational data. However, since concerns about side effects still remain, careful consideration about benefits and risks is needed to decide their use.

People with cystic fibrosis (CF) are highly susceptible to bacterial infections of the airways. By adulthood, chronic Pseudomonas aeruginosa ( Pa) is the most prevalent infective organism and is difficult to eradicate owing to its adaptation to the CF lung microenvironment. Long-term suppressive treatment with inhaled antimicrobials is the standard care for reducing exacerbation frequency, improving quality of life and increasing measures of lung function. Levofloxacin (a fluoroquinolone antimicrobial) has been approved as an inhaled solution in Europe and Canada, for the treatment of adults with CF with chronic P. aeruginosa pulmonary infections. Here, we review the clinical principles relating to the use of inhaled antimicrobials and inhaled levofloxacin for the management of P. aeruginosa infections in patients with CF.

Growing resistance of microorganisms to antibiotics for the treatment of late-onset sepsis (LOS) in premature infants has led physicians to use antibiotics that are not well studied in neonatal populations. We aimed to determine the efficacy and safety of colistin and fluoroquinolone for the treatment of persistent LOS. We retrospectively reviewed infants with gram-negative LOS, who received either colistin or fluoroquinolone therapy, to determine if there was a significant difference in kidney and liver function tests and electrolyte levels before, during, and at the end of the treatment. Infants who received colistin and fluoroquinolone had 17 and 34 positive cultures with gram-negative organisms, respectively. Multi-drug resistant organisms were more common in infants who received colistin than in those who received fluoroquinolone. Microbiological clearance was found to be higher in infants treated with fluoroquinolone than in those treated with colistin. In both the groups, the median levels of kidney and liver function tests and electrolytes showed a significant increase during the treatment. The prescription of colistin and fluoroquinolones should be reserved for cases with no other safe and effective alternatives.

Antibiotics, especially fluoroquinolones, have been exhaustively used in animal husbandry. However, very limited information on the occurrence and exposure assessment of fluoroquinolone residues in chicken and pork in China is available to date. Thus, a total of 1754 chicken samples and 1712 pork samples were collected from 25 provinces in China and tested by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS) for residual determination of six common fluoroquinolones. The results revealed that the detection frequencies of fluoroquinolone residues were 3.99% and 1.69% in chicken and pork samples. The overall violation frequencies were 0.68% and 0.41% for chicken and pork. Enrofloxacin and its metabolite ciprofloxacin were found to be the most predominant fluoroquinolones. The occurrence of these antibiotics in different sampling regions and market types was analyzed. The %ADI values of enrofloxacin and ciprofloxacin were far less than 100, indicating the health risk associated with the exposure to these aforementioned fluoroquinolone residues via chicken and pork for Chinese children, adolescents, and adults was acceptable. The results provided useful references for Chinese consumers, and helped to appropriately use these antibiotics in poultry and livestock industry.

Antibiotics are detected worldwide in the aquatic environment, with continuously rising concentrations. Antibiotics in the environment have the potential to damage ecosystems and contribute to the development of resistance. Whilst a few antibiotics, such as some β-lactams, are eliminated by effluent treatment, others, such as fluoroquinolones, are not or just partially removed and enter the environment. Therefore, approaches are needed to tackle those problems at the compound level. Benign by design (BbD), an important part of green pharmacy, has the goal to integrate environmental fate and end-of-use considerations at the very beginning, i.e., into the design of active pharmaceutical ingredients. Hence, pharmaceuticals should be designed to be sufficiently active and stable during storage and usage but should degrade after excretion into the environment, so that they cannot cause any adverse effects. Fluoroquinolones (FQs) are important broad-spectrum antibiotics. They are known to be persistent in the environment and to be neither inactivated nor degraded or even mineralized during sewage treatment. The addition of new substituents via amidation, like glucosamine moieties, at the carboxylic group of FQs, led to better antimicrobial activity compared to its parent compounds against various microorganisms. To investigate if the addition of sugar moieties could improve the overall environmental biodegradability of FQs, eight novel quinolone and fluoroquinolone analogs conjugated with 1,3,4,6-Tetra-O-acetyl-β-d-glucosamine and 2-deoxy-d-glucopyranose have been investigated regarding their ready biodegradability (OECD 301D/F) and their degradation pathways have been analyzed. According to the OECD 301D test, none of the substances could be classified as readily biodegradable. However, the O-acetyl analogs did undergo a partial degradation of the O-acetyl glucosamine moiety, via stepwise deacetylation and the degradation of the whole glucosamine moiety. The degradation resulted in Fluoroquinolone-3-carboxamide derivatives. Those insights could be further used as input for fragment-based design of benign APIs that will degrade once they reached the environment.

Introduction The rapid emergence and variations of antibiotic resistance among common gram negative bacteria cause a significant concern specially in India and all over the world because of high mortality and morbidity rates. Methods In our study, we screened 189 bacterial isolates from Assam Medical College & Hospital, Dibrugarh for antibiotic resistance pattern and tried to identify the resistant genes causing responsible for β-lactam and fluoroquinolones resistance. Results More than 80% and 45% strains were resistant to all the 3rd generation cephalosporins, fluoroquinolones respectively. Among the 3rd generation cephalosporin resistant strains, 38% and 24% isolates were only ESBL and MBL producers respectively and 11% were reported to have both ESBL and MBL genes. The ESBL positive isolates have shown the dominance of CTX-M3 gene. VIM-1 gene was mostly reported in MBL producers. Our study probably for the first time reporting SIM-1 and SPM-1 MBL gene from India. Mutations in QRDR is found to be the primary cause of fluoroquinolone resistance along with efflux pump and PMQR presence. Conclusion The study represents the first detailed study on antibiotic resistance from NE India this could help to take control measures for the emerging antibiotic resistance in hospital and community based infections in North East India.

Sokleaph Cheng,1– 3 Mallorie Hide,3– 5 Sok Heng Pheng,6 Alexandra Kerléguer,2 Gauthier Delvallez,2 Sophan Sam,7 Tan Eang Mao,6 Thi Van Anh Nguyen,3,8 Anne-Laure Bañuls3– 5 1Institut Pasteur du Cambodge and Ministry of Health, Phnom Penh, Cambodia; 2Medical Biology Laboratory, Institut Pasteur du Cambodge, Phnom Penh, Cambodia; 3LMI Drug Resistance in South East Asia, Institut Pasteur du Cambodge, Phnom Penh, Cambodia; 4MIVEGEC, University of Montpellier, Institute of Research for Development, Centre National de la Recherche Scientifique, Montpellier, France; 5CREES (Centre de Recherche En Écologie Et Évolution de la Santé), Montpellier, France; 6National Center for Tuberculosis and Leprosy Control, Phnom Penh, Cambodia; 7Cambodian Health Committee, Phnom Penh, Cambodia; 8Department of Bacteriology, National Institute of Hygiene and Epidemiology, Hanoi, Martinique, VietnamCorrespondence: Sokleaph ChengInstitut Pasteur du Cambodge, No. 5, Monivong Boulevard, Phnom Penh 120210, CambodiaTel +855 12 222 684Email csokleaph@pasteur-kh.orgBackground: Due to the emergence of Mycobacterium tuberculosis (M.tb) clinical isolates resistant to most potent first-line drugs (FLD), second-line drugs (SLD) are being prescribed more frequently. We explore the genetic characteristics and molecular mechanisms of M.tb isolates phenotypically resistant to SLD, including pre-extensively drug-resistant (pre-XDR) and extensively drug-resistant (XDR) isolates.Methods: Drug-resistant (DR) M.tb isolates collected from 2012 to 2017 were tested using sequencing and phenotypic drug susceptibility testing. Genotypes were determined to explore their links with SLD resistance patterns.Results: Of the 272 DR M.tb isolates, 6 non-multidrug resistant (non-MDR) isolates were fluoroquinolones (FQ)-resistant, 3 were XDR and 16 were pre-XDR (14 resistant to FQ and 2 to second-line injectable drugs). The most frequent mutations in FQ-resistant and second-line injectable drugs resistant isolates were gyrA D94G (15/23) and rrs a1401g (3/5), respectively. Seventy-five percent of pre-XDR isolates and 100% of XDR isolates harbored mutations conferring resistance to pyrazinamide. All XDR isolates belonged to the Beijing genotype, of which one, named XDR+, was resistant to all drugs tested. One cluster including pre-XDR and XDR isolates was observed.Conclusion: This is the first description of SLD resistance in Cambodia. The data suggest that the proportion of XDR and pre-XDR isolates remains low but is on the rise compared to previous reports. The characterization of the XDR+ isolate in a patient who refused treatment underlines the risk of transmission in the population. In addition, genotypic results show, as expected, that the Beijing family is the main involved in pre-XDR and XDR isolates and that the spread of the Beijing pre-XDR strain is capable of evolving into XDR strain. This study strongly indicates the need for rapid interventions in terms of diagnostic and treatment to prevent the spread of the pre-XDR and XDR strains and the emergence of more resistant ones.Keywords: Mycobacterium tuberculosis, extensively drug-resistant tuberculosis, pre-extensively drug-resistant tuberculosis, fluoroquinolone, second-line injectable drugs

Background: Treatment of device-related infections by drug-resistant Staphylococcus aureus can be challenging, and combination therapy has been proposed as a potential solution. We compared the effectiveness of levofloxacin–rifampin and ciprofloxacin–rifampin combinations in killing methicillin-resistant S. aureus (MRSA) using a time–kill assay. Methods: We randomly selected 15 vancomycin-susceptible S. aureus (VSSA) strains, 3 vancomycin-intermediate S. aureus (VISA) strains, and 12 heterogeneous VISA (hVISA) strains from the Asian Bacterial Bank. Time–kill experiments were performed in duplicate for each isolate. Viable bacterial counts were determined at 0 h, 4 h, 8 h, and 24 h for the ciprofloxacin– and levofloxacin–rifampin combinations at 1× MIC and 0.5× MIC. We compared synergistic and antagonistic interactions between the two combinations. Results: The viable bacterial count significantly decreased after 24 h of exposure to ciprofloxacin–rifampin and levofloxacin–rifampin combinations, with synergy observed more frequently in isolates exposed to ciprofloxacin–rifampin (43.3%) than levofloxacin–rifampin (20.0%) (p = 0.0082). The synergistic interactions of both combinations were more frequently observed in resistant strains with high MICs of ciprofloxacin (≥16 mg/L) and levofloxacin (≥8 mg/L). Levofloxacin tended to exhibit more frequent antagonistic interactions with rifampin than ciprofloxacin, although there was no statistical difference in antagonism between the two combinations. Conclusions: Our study demonstrated that ciprofloxacin exhibits superior synergistic activity against MRSA strains, including VISA/hVISA, when combined with rifampin compared with levofloxacin. High MICs of fluoroquinolones were found to predict synergism. Our results suggest that ciprofloxacin may be a more effective choice than levofloxacin for combination therapy with rifampin in the treatment of MRSA infections.

Many micropollutants, such as pharmaceuticals and other chemicals, are present globally in the aquatic environment. During effluent treatment and in the environment, transformations result in new chemicals of often unknown structure, fate, and toxicity. The design of chemicals, that can be fully mineralized or broken down into non-hazardous fragments, is considered a green chemistry approach avoiding such problems from the very beginning (“benign by design”). N-heterocycles are central lead scaffolds for many important chemicals and pharmaceuticals such as quinolines, isoquinolines, quinolones, fluoroquinolones, naphthyridones, and quinazolinones. Understanding their environmental biodegradability is mandatory for the design of greener derivatives. While the biodegradability of simple quinolines has already been reported in the literature, information on more complex azaarenes and other N-heterocycles is rather scarce. The goal of this study was to investigate the ready biodegradability of several N-heterocycles to identify biodegradable lead scaffolds. LC-HRMS studies were performed to identify possible metabolites. Out of the 84 tested substances, only 14 were readily biodegradable in either the closed bottle test (OECD 301D) or the manometric respiratory test (OECD 301F). Hydroxylation at the C2 position increased the biodegradation level of the quinolines generally and tolerated even fluorine in the molecule. Moreover, 4-oxo-1,4-dihydroquinoline-3-carboxylic acid has been tested as readily biodegradable. It is an important bioactive lead scaffold with many different applications, i.e., in antibiotics. All other quinolones containing the β-keto-carboxylic acid moiety were persistent, including their bioisosteres. The identified biodegradable scaffolds can be used to design new environmentally biodegradable molecules following green fragment-based design.

Background: Despite high cure rates, treatment-related mortality in children with acute lymphoblastic leukemia (ALL) remains significant. About 4% of patients die during remission induction therapy and approximately two-thirds of treatment-related deaths are due to infectious complications. Methods: From May 2021 to June 2022, children aged one through 18 years, with a recent diagnosis of ALL, admitted to three pediatric oncology centers in Brazil, were enrolled in this multicenter, open-label, randomized, phase 3 clinical trial. Eligible patients were randomly divided into two groups, based on a 1:1 allocation ratio, to receive, or not, levofloxacin as a prophylactic agent during the induction phase. All patients were treated according to the IC-BFM 2009 chemotherapy protocol. Primary endpoints were carbapenemase-producing Enterobacteriaceae (CPE) colonization, Clostridioides difficile diarrhea, and other adverse events related to the use of levofloxacin. The secondary endpoint was febrile neutropenia during induction. The median follow-up was 289 days. Results: Twenty patients were included in this trial, 10 in each group (control and levofloxacin). Mild adverse reactions related to levofloxacin were observed in three patients (30%). Three patients had Clostridioides difficile diarrhea, two in the levofloxacin group and one in the control group (p > 0.99). Only one patient presented colonization by CPE. This patient belonged to the levofloxacin group (p > 0.99). Nine patients presented febrile neutropenia, five in the control group and four in the levofloxacin intervention group (p > 0.99), one patient died due to febrile neutropenia. Conclusion: The use of levofloxacin was shown to be safe in the induction phase in children with de novo ALL. The use of this medication did not increase the rate of colonization by CPE nor the rate of diarrhea by C. difficile. All adverse reactions were mild and remitted either spontaneously or after switching medicine administration from oral to intravenous route.

Purpose To investigate the effects of different antibiotic prophylaxis regimens in patients with diabetes mellitus (DM) candidates to trans-rectal ultrasound-guided prostate biopsy (TRUSPB). Methods 143 outpatients with DM who underwent TRUSPB during the period 2018–2020 were selected from a cohort of 1150 patients in 3 different institutions. Exclusion criteria were allergies, concomitant anti-platelet therapies and uncontrolled DM. Different antibiotic prophylaxis regimens were adopted. Bacterial resistance levels to fluoroquinolones into the different communities were also collected. Univariable and multivariable binomial logistic regression analyses were used to assess the odds ratio (OR) with 95% confidence intervals (CIs) testing the risk of infective complications' occurrence after adjusting for clinical covariates. Results Overall, DM patients were significantly associated with infective complications' occurrence (p 37 °C were found in 9.1% and 1.5% (p Conclusion Fluoroquinolones were active in antibiotic prophylaxis of diabetic patients who had undergone to TRUSPB independently from the level of bacterial resistance found in the community. These results conflict with the recent European warning and support the Japanese and American guidelines on the topic.

The generation of M. genitalium isogenic strains bearing selected point mutations in different locations of subunit A topoisomerase IV gene (parC) will help to determine the contribution of this gene to the origin of fluoroquinolone resistance phenotypes found in natural isolates of this microorganism.

Osteomyelitis is a limb- and life-threatening orthopedic infection predominantly caused by Staphylococcus aureus biofilms. Bone infections are extremely challenging to treat clinically. Therefore, we have been designing, synthesizing, and testing novel antibiotic conjugates to target bone infections. This class of conjugates comprises bone-binding bisphosphonates as biochemical vectors for the delivery of antibiotic agents to bone minerals (hydroxyapatite). In the present study, we utilized a real-time impedance-based assay to study the growth of Staphylococcus aureus biofilms over time and to test the antimicrobial efficacy of our novel conjugates on the inhibition of biofilm growth in the presence and absence of hydroxyapatite. We tested early and newer generation quinolone antibiotics (ciprofloxacin, moxifloxacin, sitafloxacin, and nemonoxacin) and several bisphosphonate-conjugated versions of these antibiotics (bisphosphonate-carbamate-sitafloxacin (BCS), bisphosphonate-carbamate-nemonoxacin (BCN), etidronate-carbamate-ciprofloxacin (ECC), and etidronate-carbamate-moxifloxacin (ECX)) and found that they were able to inhibit Staphylococcus aureus biofilms in a dose-dependent manner. Among the conjugates, the greatest antimicrobial efficacy was observed for BCN with an MIC of 1.48 µg/mL. The conjugates demonstrated varying antimicrobial activity depending on the specific antibiotic used for conjugation, the type of bisphosphonate moiety, the chemical conjugation scheme, and the presence or absence of hydroxyapatite. The conjugates designed and tested in this study retained the bone-binding properties of the parent bisphosphonate moiety as confirmed using high-performance liquid chromatography. They also retained the antimicrobial activity of the parent antibiotic in the presence or absence of hydroxyapatite, albeit at lower levels due to the nature of their chemical modification. These findings will aid in the optimization and testing of this novel class of drugs for future applications to pharmacotherapy in osteomyelitis.

The inhibitory effect of WQ-3810 on DNA gyrase was assayed to evaluate the potential of WQ-3810 as a candidate drug for the treatment of quinolone resistant Salmonella Typhymurium infection. The inhibitory effect of WQ-3810, ciprofloxacin and nalidixic acid was compared by accessing the drug concentration that halves the enzyme activity (IC50) of purified S. Typhimurium wildtype and mutant DNA gyrase with amino acid substitution at position 83 or/and 87 in subunit A (GyrA) causing quinolone resistance. As a result, WQ-3810 reduced the enzyme activity of both wildtype and mutant DNA gyrase at a lower concentration than ciprofloxacin and nalidixic acid. Remarkably, WQ-3810 showed a higher inhibitory effect on DNA gyrase with amino acid substitutions at position 87 than with that at position 83 in GyrA. This study revealed that WQ-3810 could be an effective therapeutic agent, especially against quinolone resistant Salmonella enterica having amino acid substitution at position 87.

In 2014, antimicrobial drug–resistant Campylobacter jejuni sequence type 6964 emerged contemporaneously in poultry from 3 supply companies in the North Island of New Zealand and as a major cause of campylobacteriosis in humans in New Zealand. This lineage, not previously identified in New Zealand, was resistant to tetracycline and fluoroquinolones. Genomic analysis revealed divergence into 2 major clades; both clades were associated with human infection, 1 with poultry companies A and B and the other with company C. Accessory genome evolution was associated with a plasmid, phage insertions, and natural transformation. We hypothesize that the tetO gene and a phage were inserted into the chromosome after conjugation, leaving a remnant plasmid that was lost from isolates from company C. The emergence and rapid spread of a resistant clone of C. jejuni in New Zealand, coupled with evolutionary change in the accessory genome, demonstrate the need for ongoing Campylobacter surveillance among poultry and humans.

Faecal E. coli can act as reservoirs for resistance genes. Here, we analyzed prevalence of drug resistance in faecal E. coli isolated from healthy children at a single kindergarten in Beijing, China, then used whole genome sequencing to characterize fluoroquinolone-non-susceptible strains. Our results revealed high resistance to ampicillin (54.0%), trimethoprim/sulphurmethoxazole (47.5%) and tetracycline (58.9%) among 576 faecal E. coli isolates, 49.2% of which exhibited multidrug resistance. A total of 113 E. coli isolates were not susceptible to ciprofloxacin, with four sequence types, namely ST1193 (25.7%), ST773 (13.3%), ST648 (8.8%) and ST131 (7.1%) found to be the most prevalent (54.9%). With regards to resistance to quinolones, we detected chromosomal mutations in gyrA, parC, and parE in 111 (98.2%), 105 (92.9%), and 67 (61.1%) isolates, respectively. blaCTX-M (37.2%) was the major ESBL gene, whereas blaCTX-M-14 (12.4%) and blaCTX-M-27 (11.5%) were the most frequent subtypes. A total of 90 (79.6%) ExPEC and 65 (57.5%) UPEC isolates were classified. Overall, these findings revealed clonal spread of certain prevalent STs, namely ST1193, ST773, ST648 and ST131 E. coli isolates in healthy children within a single kindergarten in Beijing, China, affirming the seriousness of the multidrug resistance problem and potential pathogenicity of E. coli isolates in healthy children. Therefore, there is an urgent need for increased surveillance to enhance control of this problem.

Introduction: Pseudomonas aeruginosa (PA) is a leading cause of healthcare-associated infections. A variety of antibiotic classes are used in the treatment of PA infections, including beta-lactams (BLs) and fluoroquinolones (FQs), given either together in combination therapy or alone in monotherapy. A systematic review and meta-analysis were performed to evaluate the therapeutic efficacy of BL agents versus FQ agents as active, definitive monotherapy in PA infections in adults. Methods: Comprehensive literature searches of the Medline and Scopus electronic databases, alongside hand searches of the Cochrane Database of Systematic Reviews, PubMed, and Google Scholar, were performed without a time restriction to identify studies published in English comparing BL and FQ agents given as monotherapy for PA infection in hospitalized adults for which mortality, bacteriological eradication, or clinical response was evaluated. One reviewer screened search results based on pre-defined selection criteria. Two reviewers independently assessed included studies for methodological quality using NIH assessment tools. Two fixed-effects meta-analyses were performed. Results: A total of 368 articles were screened, and six studies involving 338 total patients were included in the meta-analysis. Upon evaluation of methodological quality, two studies were rated good, three fair, and one poor. A meta-analysis of three studies demonstrates FQ monotherapy is associated with significantly improved survival compared to BL monotherapy for patients with PA bacteremia (OR, 3.65; 95% CI, 1.27–10.44; p = 0.02). A meta-analysis of three studies demonstrates FQ monotherapy is associated with equivalent bacteriological eradication compared to BL monotherapy for PA pneumonia or skin and soft tissue infection (RD, 0.07; 95% CI, −0.09 to 0.24; p = 0.39). Conclusion: The meta-analyses demonstrate FQ monotherapy significantly improves survival in PA bacteremia and is associated with similar rates of bacteriological eradication in pneumonia and skin and soft tissue infection caused by PA compared to BL monotherapy. However, more research is needed to make meaningful clinical recommendations.

Often dismissed as a commensal, Mycoplasma hominis is an increasingly prominent target of research due to its role in septic arthritis and organ transplant failure in immunosuppressed patients, particularly lung transplantation. As a mollicute, its highly reductive genome and structure render it refractile to most forms of treatment and growing levels of resistance to the few sources of treatment left, such as fluoroquinolones. We examined antimicrobial susceptibility (AST) to fluoroquinolones on 72 isolates and observed resistance in three (4.1%), with corresponding mutations in the quinolone resistance-determining region (QRDR) of S83L or E87G in gyrA and S81I or E85V in parC. However, there were high levels of polymorphism identified between all isolates outside of the QRDR, indicating caution for a genomics-led approach for resistance screening, particularly as we observed a further two quinolone-susceptible isolates solely containing gyrA mutation S83L. However, both isolates spontaneously developed a second spontaneous E85K parC mutation and resistance following prolonged incubation in 4 mg/L levofloxacin for an extra 24–48 h. Continued AST surveillance and investigation is required to understand how gyrA QRDR mutations predispose M. hominis to rapid spontaneous mutation and fluoroquinolone resistance, absent from other susceptible isolates. The unusually high prevalence of polymorphisms in M. hominis also warrants increased genomics’ surveillance.

BackgroundMycoplasma pneumoniaeis a common pathogen that causes community-acquired pneumonia in school-age children. Macrolides are considered a first-line treatment forM. pneumoniaeinfection in children, but macrolide-refractoryM. 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.MethodsTwo 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).ResultsEight 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 ConclusionTetracyclines 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.

[ES] El cáncer es una de las principales causas de muerte a nivel mundial. Los tratamientos anticancerígenos generalmente usados tienen diversos efectos secundarios producidos por su baja especificidad. Esta es una de las razones por las que se sigue en continua búsqueda de nuevos tratamientos. Dentro de estas nuevas investigaciones se encuentra el extenso campo de la nanomedicina, es decir, el estudio de nuevos materiales a escala nanométrica. Esta permite reducir dichos efectos secundarios aumentando la selectividad y especificidad de los tratamientos. Dentro de los nanomateriales se encuentran las nanopartículas de upconversion que son capaces de absorber luz en el infrarrojo cercano y emitirla en la región ultravioleta-visible. Por otro lado, desde el principio de la historia de la medicina la luz se ha empleado como forma de tratamiento teniendo un rol muy importante. Un inconveniente para dichos tratamientos suele ser la necesidad de emplear luz de la región ultravioleta-visible, pues las biomoléculas son capaces de absorber y produce daño celular. En este contexto, la presente Tesis Doctoral se centra en el estudio de nuevas formas de tratamiento anticancerígeno combinando nanomedicina y luz. Para ello se han desarrollado nuevos fármacos fototóxicos y nuevos materiales capaces de ser activados mediante luz infrarroja cercana. En primer lugar, se sintetizaron nuevas fluoroquinolonas para explorar sus propiedades fototóxicas para su uso en fotoquimioterapia (Capítulo 3 de la Tesis). Se estudiaron las características fotofísicas y fotoquímicas de los nuevos compuestos, además de su capacidad para producir mayor fototoxicidad en las células en comparación con las fluoroquinolonas como la lomefloxacina mediante la aplicación de luz ultravioleta. En base a los resultados obtenidos se realizó un estudio para determinar las diferencias entre las interacciones de algunas fluoroquinolonas dihalogenadas, incluidas las comentadas anteriormente, y biomoléculas como ADN y proteínas. La reactividad de sus intermedios fotogenerados también se estudió en el Capítulo 4. Tras conocer en profundidad la capacidad fototóxica de los nuevos fármacos, en el Capítulo 5 se llevó a cabo el diseño de un nanosistema compuesto por fluoroquinolonas y nanopartículas de conversión ascendente. Se demostró la alta capacidad fototóxica de este nuevo nanosistema. De esta manera, se generó actividad fototóxica a partir de una fluoroquinolona sin el uso de luz ultravioleta Por otro lado, la formación de profármacos abre la puerta a la administración selectiva de fármacos contra el cáncer. Los profármacos consisten en la unión fotolábil de una molécula capaz de ser activada por la luz y el fármaco de interés. Sin embargo, un conocimiento profundo de las propiedades fotofísicas y fotoquímicas del fotodisparador y de los potenciales redox de ambos miembros de la diada puede ser crucial para obtener la fotoliberación deseada. Así, en el Capítulo 6, se destacó la relevancia de estos datos utilizando un profármaco formado por un derivado de cumarina como molécula fotoactivable y colchicina como fármaco. Finalmente, en el Capítulo 7 se exploró la síntesis de un nuevo nanosistema que contiene un profármaco formado por un derivado de cumarina unido al fármaco contra el cáncer clorambucilo y nanopartículas biocomatibles de conversión ascendente. La adición de albúmina de suero humano como recubrimiento de las nanopartículas cumple la doble función de obtener nanopartículas biocompatibles y ser el lugar de carga del profármaco., [CA] El càncer és una de les principals causes de mort a nivell mundial. Els tractaments anticancerígens generalment usats tenen diversos efectes secundaris produïts per la seva baixa especificitat. Aquesta és una de les raons per les que se segueix en contínua recerca de nous tractaments. Dins d'aquestes noves investigacions es troba l'extens camp de la nanomedicina, és a dir, l'estudi de nous materials a escala nanomètrica. Aquesta permet reduir aquests efectes secundaris augmentant la selectivitat i especificitat dels tractaments. Dins dels nanomaterials es troben les nanopartícules de upconversion que són capaços d'absorbir llum en l'infraroig proper i emetre-la en la regió ultraviolada-visible. D'altra banda, des del principi de la història de la medicina la llum s'ha emprat com a forma de tractament tenint un paper molt important. Un inconvenient per aquests tractaments sol ser la necessitat d'emprar llum de la regió ultraviolada-visible, ja que les biomolècules són capaços d'absorbir-la i produïr dany cel·lular. En aquest context, la present Tesi Doctoral es centra en l'estudi de noves formes de tractament anticancerigen combinant nanomedicina i llum. Per això s'han desenvolupat nous fàrmacs fototòxics i nous materials capaços de ser activats mitjançant llum infraroja propera. En primer lloc, es van sintetitzar noves fluoroquinolones per explorar les seves propietats fototòxiques per al seu ús en fotoquimioteràpia (Capítol 3 de la Tesi). Es van estudiar les característiques fotofísiques i fotoquímiques dels nous compostos, a més de la seva capacitat per produir major fototoxicitat en les cèl·lules en comparació amb les fluoroquinolones com la lomefloxacina mitjançant l'aplicació de llum ultraviolada. En base als resultats obtinguts es va realitzar un estudi per determinar les diferències entre les interaccions d'algunes fluoroquinolones dihalogenades, incloses les comentades anteriorment, i biomolècules com ADN i proteïnes. La reactivitat de les seves intermedis fotogenerats també es va estudiar en el Capítol 4. Després de conèixer en profunditat la capacitat fototòxica dels nous fàrmacs, en el Capítol 5 es va dur a terme el disseny d'un nanosistema compost per fluoroquinolones i nanopartícules de upconversion. Es va demostrar l'alta capacitat fototòxica d'aquest nou nanosistema. D'aquesta manera, es va generar activitat fototòxica a partir d'una fluoroquinolona sense l'ús de llum ultraviolada D'altra banda, la formació de profàrmacs obre la porta a l'administració selectiva de fàrmacs contra el càncer. Els profàrmacs consisteixen en la unió fotolábil d'una molècula capaç de ser activada per la llum i el fàrmac d'interès. No obstant això, un coneixement profund de les propietats fotofísiques i fotoquímiques del fotodisparador i dels potencials redox de tots dos membres de la diada pot ser crucial per obtenir el fotoalliberament desitjada. Així, en el Capítol 6, es va destacar la rellevància d'aquestes dades utilitzant un profàrmac format per un derivat de cumarina com a molècula fotoactivable i colquicina com a fàrmac. Finalment, en el Capítol 7 es va explorar la síntesi d'un nou nanosistema que conté un profàrmac format per un derivat de cumarina unit a l'fàrmac contra el càncer clorambucilo i nanopartícules biocomatibles de upconversion. L'addició d'albúmina de sèrum humà com a recobriment de les nanopartícules compleix la doble funció d'obtenir nanopartícules biocompatibles i ser el lloc de càrrega del profàrmac., [EN] Cancer is one of the leading causes of death worldwide. Generally used anticancer treatments have various side effects produced by their low specificity. This is one of the reasons why the search for new treatments continues. Within these new investigations is the extensive field of nanomedicine, which can be explained as the study of new materials on a nanometric scale. It can be translated in the reduction of these side effects by increasing the selectivity and specificity of the treatments. Among the nanomaterials are upconversion nanoparticles that are capable of absorbing light in the near infrared and emit it in the ultraviolet-visible region. On the other hand, since the beginning of the history of medicine, light has been used as a form of treatment, having a very important role. A drawback for such treatments is sometimes the need to use light from the ultraviolet-visible region since biomolecules are capable of absorbing and causing cell damage. In this context, this Doctoral Thesis focuses on the study of new forms of anticancer treatment combining nanomedicine and light. For this, new phototoxic drugs and new materials capable of being activated by near infrared light have been developed. First, new fluoroquinolones were synthesized to explore their phototoxic properties for using in photochemotherapy (Chapter 3 of the Thesis). The photophysical and photochemical characteristics of the new compounds were studied, in addition to their ability to produce greater phototoxicity in cells than fluoroquinolones such as lomefloxacin by applying ultraviolet light. Based on the results obtained, a study was carried out to determine the differences between the interactions of some dihalogenated fluoroquinolones including the above commented, and biomolecules such as DNA and proteins. The reactivity of their photo-generated intermediates was also studied in Chapter 4. After a deep knowledge of the phototoxic capacity of the new drugs, design of a nanosystem composed of fluoroquinolones and upconversion nanoparticles was carried out in Chapter 5. The high phototoxic capacity of this new nanosystem was demonstrated. In this way phototoxic activity was generated from a fluoroquinolone without the use of ultraviolet light. On the other hand, the formation of prodrugs opens a door to the selective administration of anticancer drugs. Prodrugs consist of the photolabile binding of a molecule capable of being activated by light and the drug of interest. However, a knowledge of the photophysical and photochemical properties of the phototrigger as well as the redox potentials of both members of the dyad can be crucial to obtain the desired photorelease. Thus, in Chapter 6, the relevance of these data was highlighted using a prodrug formed by a coumarin derivative as a photoactivatable molecule and colchicine as a drug. Finally, in Chapter 7 the synthesis of a new nanosystem containing a prodrug formed by a derivative of coumarin linked to the anticancer drug chlorambucil, and upconversion biocompatible nanoparticles was explored. The addition of human serum albumin as a coating for the nanoparticles fulfills the dual function of obtaining biocompatible nanoparticles and being the loading site for the prodrug.

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

Background Treatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings. Methods endTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per protocol populations. Discussion The lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide. Trial registration ClinicalTrials.gov Identifier NCT02754765. Registered on 28 April 2016; the record was last updated for study protocol version 3.3, on 27 August 2019.

Background:Chlamydia pneumoniae (CPn) is a common community-acquired pneumonia. In the literature, CPn infection is demonstrated to exhibit an association with Alzheimer dementia (AD). We executed the present nationwide, population-based research with the goal of probing the association of CPn infection and antibiotic therapy with AD risk.Methods: We conducted a cohort study using a database extracted from Taiwan's National Health Insurance Research Database (NHIRD). All medical conditions for each enrolled individuals were categorized using the International Classification of Diseases, ninth Revision classifications. Hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between CPn pneumonia-associated hospitalizations and AD were estimated using Fine and Gray's survival analysis and adjusted for comorbidities. The effects of the antibiotics on the HRs for AD in the patients with CPn pneumonia-associated hospitalization were also analyzed.Results: Our analyses included 6,628 individuals, including 1,657 CPn-infected patients, as well as 4,971 controls matched by age, index date, and sex (1:3). In this study, patients hospitalized for CPn pneumonia exhibited a significantly higher AD risk (adjusted HR = 1.599, 95% CI = 1.284–1.971, p < 0.001). We also noted an association of macrolide use (≥15 days) and fluoroquinolone use (≥15 days) with decreased AD risk.Conclusions: We determined CPn pneumonia to be associated with a relatively high AD risk. The result in this study confirmed the findings from previous literatures, by using a large, nationwide, population-based database. Appropriate macrolide and fluoroquinolone treatment may attenuate this risk.

Faecal E. coli can act as reservoirs for resistance genes. Here, we analyzed prevalence of drug resistance in faecal E. coli isolated from healthy children at a single kindergarten in Beijing, China, then used whole genome sequencing to characterize fluoroquinolone-non-susceptible strains. Our results revealed high resistance to ampicillin (54.0%), trimethoprim/sulphurmethoxazole (47.5%) and tetracycline (58.9%) among 576 faecal E. coli isolates, 49.2% of which exhibited multidrug resistance. A total of 113 E. coli isolates were not susceptible to ciprofloxacin, with four sequence types, namely ST1193 (25.7%), ST773 (13.3%), ST648 (8.8%) and ST131 (7.1%) found to be the most prevalent (54.9%). With regards to resistance to quinolones, we detected chromosomal mutations in gyrA, parC, and parE in 111 (98.2%), 105 (92.9%), and 67 (61.1%) isolates, respectively. bla CTX-M (37.2%) was the major ESBL gene, whereas bla CTX-M-14 (12.4%) and bla CTX-M-27 (11.5%) were the most frequent subtypes. A total of 90 (79.6%) ExPEC and 65 (57.5%) UPEC isolates were classified. Overall, these findings revealed clonal spread of certain prevalent STs, namely ST1193, ST773, ST648 and ST131 E. coli isolates in healthy children within a single kindergarten in Beijing, China, affirming the seriousness of the multidrug resistance problem and potential pathogenicity of E. coli isolates in healthy children. Therefore, there is an urgent need for increased surveillance to enhance control of this problem.

The concerns regarding the occurrence of pharmaceuticals in wastewater treatment plants have increased in the last decades. Gatifloxacin (GAT), the fourth generation of fluoroquinolones, has been widely used to treat both Gram-positive and Gram-negative bacteria and has a limited metabolization. The present study aimed to evaluate ozonation as a technique to degrade GAT. An exchange A UHPLC-MS/MS by an UHPLC-MS/MS method was used to quantify the residual of GAT and to assess its degradation products. The removal efficiency was higher under alkaline conditions (pH = 10), reaching up to 99% of GAT after 4 min. It was also observed that the first ozone attack on the GAT molecule was through the carboxylic group. In contrast, under acid conditions (pH = 3), the ozone attack was first to the piperazinyl ring. The antimicrobial activity was evaluated using Escherichia coli and Bacillus subtilis as test organisms, and it was observed that the residual activity reduced most under alkaline conditions. In contrast, the best condition to remove the residual toxicity evaluated for the marine bacteria V. fischeri was the acidic one. Due to this, ozonation seemed to be an exciting process to remove GAT in aqueous media. Highlights Ozonation at pH 3 did not increase solution residual toxicity.; Antimicrobial activity decreased proportional to gatifloxacin conversion.; Ozonation at pH >7 increased solution residual toxicity.; Degradation products presented lower antimicrobial activity.; Proposed by-products presented lower toxicity.

Purpose: The morbidity and mortality due to typhoid fever can be significantly reduced with the use of effective antibiotics. At present, fluoroquinolones, third generation cephalosporins, and azithromycin are widely used to treat typhoid fever. However, changing antibiotic susceptibility among Salmonella Typhi and Salmonella Paratyphi poses a particular challenge to the therapeutic management of enteric fever. The objective of this study was to assess the antibiotic susceptibility pattern of Salmonella Typhi isolates. Patients and Methods: A total of 706 blood specimens were collected from febrile patients attending the outpatient department of Kathmandu Model Hospital during June to September, 2018. The antibiotic susceptibility testing for 11 different antibiotics (nalidixic acid, ciprofloxacin, ofloxacin, levofloxacin, cefixime, ceftriaxone, cefotaxime, azithromycin, cotrimoxazole, chloramphenicol, and amoxicillin) was performed by disk diffusion method. Furthermore, minimum inhibitory concentration (MIC) values of ciprofloxacin, ofloxacin, and azithromycin were determined by agar dilution method. Mutation at gyrA ser83 associated with reduced susceptibility to fluoroquinolones was determined by PCR-RFLP. Results: Out of 706 blood samples, 6.94% (n = 49) were culture positive for Salmonella enterica (S. Typhi, n = 46). It was revealed that 97.8% S. Typhi isolates were susceptible to conventional first-line antibiotics (ampicillin, chloramphenicol, and cotrimoxazole), 97.3% to cephalosporins and 95.7% to azithromycin. S. Typhi were either resistant or intermediately susceptible to fluoroquinolones: 97.8% to ciprofloxacin, 91.3% to ofloxacin, and 89.1% to levofloxacin. The MIC of ciprofloxacin, ofloxacin, and azithromycin for S. Typhi ranged from 0.008 to 32, 0.03 to 16, and 2 to 8 μg/mL, respectively. Out of 46 S. Typhi isolates, 44 (95.65%) had gyrA ser83 mutation. Conclusion: Fluoroquinolones have poor activity against Salmonella Typhi. The trends of increasing azithromycin MIC value among S. Typhi might limit its use for the treatment of typhoid fever. Effectiveness of conventional first-line antibiotics in vitro suggests considering their clinical use after large-scale studies.

A 53-year-old female patient presented with increased light sensitivity 3 weeks after oral intake of moxifloxacin tablets for an upper respiratory tract infection. The symptoms were anisocoria and the pupils did not react to light or accommodation. The examination of the anterior segment of the eye revealed extensive bilateral iris transillumination defects (ITD). We diagnosed a bilateral acute iris transillumination (BAIT) syndrome. The BAIT syndrome is a rare disorder associated with massive depigmentation of the iris and atrophy of the iris musculature. A risk factor for BAIT syndrome seems to be the oral intake of antibiotics, in particular moxifloxacin after an upper respiratory tract infection but cases of spontaneous occurrence have also been described. Middle-aged women are particularly affected. The exact cause of BAIT syndrome is so far unknown but a potential mechanism involves the concentration of the antibiotic in the vitreous body. Differential diagnoses include other causes for ITD, such as albinism, intraocular inflammation, pseudoexfoliation syndrome and pigment dispersion syndrome. To date there is no specific treatment for BAIT syndrome. Possible complications include increased light sensitivity and post-BAIT glaucoma. Knowledge of the rare BAIT syndrome can be useful in the clinical routine for the differential diagnostic classification of an anisocoria and can possibly contribute to avoidance of unnecessary diagnostic steps.Eine 53-jährige Patientin beklagte erhöhte Blendempfindlichkeit 3 Wochen nach Einnahme von Moxifloxacin-Tabletten bei Infekt der oberen Atemwege. Es bestand eine Anisokorie, die Pupillenreaktion, sowohl auf Licht als auch auf Naheinstellung, war aufgehoben. In der Untersuchung des vorderen Augenabschnittes fielen beidseits ausgeprägte Iristransilluminationsdefekte (ITD) auf. Wir diagnostizierten ein BAIT-Syndrom (bilaterales akutes Iristransilluminationssyndrom). Dies ist ein seltenes Syndrom, welches mit einer massiven Depigmentierung der Iris sowie einer Atrophie der Irismuskulatur einhergeht. Risikofaktor für die Entstehung eines BAIT-Syndroms scheint die orale Einnahme von Antibiotika, insbesondere Moxifloxacin, im Rahmen eines Infektes der oberen Atemwege zu sein, aber auch spontan auftretende Fälle sind beschrieben. Betroffen sind v. a. Frauen mittleren Alters. Die genaue Ursache des BAIT-Syndroms ist bisher unklar. Diskutiert wird ein möglicher Einfluss der Konzentration des Antibiotikums im Glaskörper. Differenzialdiagnostisch muss bei Iristransilluminationsdefekten insbesondere auch an Albinismus, intraokuläre Entzündungen, Pseudoexfoliationssyndrom und Pigmentdispersionssyndrom gedacht werden. Eine spezifische Therapie des BAIT-Syndroms besteht bisher nicht. Erhöhte Lichtempfindlichkeit und ein Post-BAIT-Glaukom können mögliche Komplikationen sein. Die Kenntnis des seltenen BAIT-Syndroms kann im klinischen Alltag hilfreich bei der differenzialdiagnostischen Einordnung einer Anisokorie sein und ggf. zur Vermeidung unnötiger diagnostischer Schritte beitragen.

New antimicrobial textiles were prepared through direct chemical linkage of bioactive molecules eugenol and fluoroquinolone derivatives, onto the surface of cotton fabrics. The attachment through a triazine moiety minimizes the leaching of the antimicrobial molecule into the surroundings of the material. Bacterial efficacy against Staphylococcus aureus and Pseudomonas aeruginosa was studied. The treated textile with fluoroquinolone demonstrated bacteriostatic antimicrobial effects having a tendency to decrease the population of S. aureus in the planktonic form. A significant effect was also observed in the prevention of S. aureus biofilm formation and in its ability to kill bacteria within a preformed biofilm. Eugenol-modified fabric was also active in the process of eradicating preformed P. aeruginosa biofilms. Further, in vitro assays using human dermal fibroblast cells indicate no effects on cell proliferation and viability, and in vivo tests in a murine skin wound model showed no increase of IL-6 for full-thickness wounds that were in contact with the fabrics.

Due to repeated reports of adverse effects with the use of fluoroquinolone antibiotics, these drugs become over and over again the object of the close attention of pharmacovigilance specialists and health care specialists. The aim : to study the frequency and the nature of adverse reactions associated with the use of ciprofloxacin, based on the analysis of the spontaneous reports received by the Russian pharmacovigilance service. Materials and Methods : A retrospective analysis of the spontaneous reports of ciprofloxacin was conducted on the data-base «Pharmacovigilance» of the automated information system of Roszdravnadzor from 2008 to 2018. Results : 3403 adverse reactions that occurred in 2083 patients using ciprofloxacin were recorded. The most frequently developed reactions were from skin and subcutaneous tissues (37.3 %), general disorders and disorders at the injection site (21.1 %), gastrointestinal tract reactions (14.9 %). More than a one third of the reports contained information about serious adverse reactions. Unexpected reactions were identified as not recorded in the instructions for the medical use of ciprofloxacin: bradycardia, atrial arrhythmia, cyanosis, increased blood pressure. Conclusions : fluoroquinolone antibiotics with proven efficacy and years of experience in clinical use, continue to be drugs whose safety requires constant monitoring. The results of the study confirmed the possibility of detecting a wide range of the adverse reactions using the method of spontaneous reports. Regulatory authorities of the Russian Federation should recommend to registration certificate holders to include the information of adverse reactions of ciprofloxacin that were registered in the post-marketing period in the instructions for medical use.

Investments to reduce the spread of antimicrobial resistance (AMR) in the European Union have been made, including efforts to strengthen prudent antimicrobial use. Using segmented regression, we report decreasing and stabilising trends in data reported to the European Surveillance of Antimicrobial Consumption Network and stabilising trends in data reported to the European Antimicrobial Resistance Surveillance Network. Our results could be an early indication of the effect of prioritising AMR on the public health agenda., Germán Peñalva was supported by El Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0001) - co-financed by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 2014–2020, and received a grant from the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) for a three-month study visit at ECDC during which the analysis was performed.

New antibiotics are seen as ‘drugs of last resort’ against virulent bacteria. However, development of resistance towards new antibiotics with time is a universal fact. Delafloxacin (DFX) is a new fluoroquinolone antibiotic that differs from existing fluoroquinolones by the lack of a protonatable substituent, which gives the molecule a weakly acidic nature, affording it higher antibacterial activity under an acidic environment. Furthermore, antibiotic-functionalized metallic nanoparticles have been recently emerged as a feasible platform for conquering bacterial resistance. In the present study, therefore, we aimed at preparing DFX-gold nano-formulations to increase the antibacterial potential of DFX. To synthesize DFX-capped gold nanoparticles (DFX-AuNPs), DFX was used as a reducing and stabilizing/encapsulating agent. Various analytical techniques such as UV-visible spectroscopy, TEM, DLS, FTIR and zeta potential analysis were applied to determine the properties of the synthesized DFX-AuNPs. The synthesized DFX-AuNPs revealed a distinct surface plasmon resonance (SPR) band at 530 nm and an average size of 16 nm as manifested by TEM analysis. In addition, Zeta potential results (−19 mV) confirmed the stability of the synthesized DFX-AuNPs. Furthermore, FTIR analysis demonstrated that DFX was adsorbed onto the surface of AuNPs via strong interaction between AuNPs and DFX. Most importantly, comparative antibacterial analysis of DFX alone and DFX-AuNPs against Gram-negative (Escherichia coli and Pseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus and Bacillus subtilis) verified the superior antibacterial activity of DFX-AuNPs against the tested microorganisms. To sum up, DFX gold nano-formulations can offer a promising possible solution, even at a lower antibiotic dose, to combat pathogenic bacteria.

Antimicrobial resistance (AMR) studies of Mycoplasma bovis have generally focused on specific loci versus using a genome-wide association study (GWAS) approach. A GWAS approach, using two different models, was applied to 194 Mycoplasma bovis genomes. Both a fixed effects linear model (FEM) and a linear mixed model (LMM) identified associations between nucleotide variants (NVs) and antimicrobial susceptibility testing (AST) phenotypes. The AMR phenotypes represented fluoroquinolones, tetracyclines, phenicols, and macrolides. Both models identified known and novel NVs associated (Bonferroni adjusted p < 0.05) with AMR. Fluoroquinolone resistance was associated with multiple NVs, including previously identified mutations in gyrA and parC. NVs in the 30S ribosomal protein 16S were associated with tetracycline resistance, whereas NVs in 5S rRNA, 23S rRNA, and 50S ribosomal proteins were associated with phenicol and macrolide resistance. For all antimicrobial classes, resistance was associated with NVs in genes coding for ABC transporters and other membrane proteins, tRNA-ligases, peptidases, and transposases, suggesting a NV-based multifactorial model of AMR in M. bovis. This study was the largest collection of North American M. bovis isolates used with a GWAS for the sole purpose of identifying novel and non-antimicrobial-target NVs associated with AMR.

Background:Chlamydia pneumoniae (CPn) is a common community-acquired pneumonia. In the literature, CPn infection is demonstrated to exhibit an association with Alzheimer dementia (AD). We executed the present nationwide, population-based research with the goal of probing the association of CPn infection and antibiotic therapy with AD risk. Methods: We conducted a cohort study using a database extracted from Taiwan's National Health Insurance Research Database (NHIRD). All medical conditions for each enrolled individuals were categorized using the International Classification of Diseases, ninth Revision classifications. Hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between CPn pneumonia-associated hospitalizations and AD were estimated using Fine and Gray's survival analysis and adjusted for comorbidities. The effects of the antibiotics on the HRs for AD in the patients with CPn pneumonia-associated hospitalization were also analyzed. Results: Our analyses included 6,628 individuals, including 1,657 CPn-infected patients, as well as 4,971 controls matched by age, index date, and sex (1:3). In this study, patients hospitalized for CPn pneumonia exhibited a significantly higher AD risk (adjusted HR = 1.599, 95% CI = 1.284–1.971, p < 0.001). We also noted an association of macrolide use (≥15 days) and fluoroquinolone use (≥15 days) with decreased AD risk. Conclusions: We determined CPn pneumonia to be associated with a relatively high AD risk. The result in this study confirmed the findings from previous literatures, by using a large, nationwide, population-based database. Appropriate macrolide and fluoroquinolone treatment may attenuate this risk.

Purpose: To evaluate the efficacy and safety of Escherichia coli Nissle 1917 (EcN) in association with levofloxacin in patients with chronic bacterial prostatitis (CBP). Methods: Patients with CBP referred to our clinic from September 2017 to July 2019 were enrolled. At baseline, the symptomatology was assessed with the NIH-Chronic Prostatitis Symptom Index (NIH-CPSI), while the Meares–Stamey test was used to diagnose the infection. Patients were randomized (1:1) in two groups (A and B). All subjects underwent oral administration of Levoxacin® 500mg once daily for 4weeks. Only the patients in Group B underwent oral administration of EcN® 320mg, twice daily for 4weeks and then once daily for 8weeks. After 3months, each patient repeated the NIH-CPSI questionnaire, while the Meares–Stamey test was repeated at 3 and 6months in patients who reported persistent symptoms. All adverse events (AEs) were recorded. Results: A total of 110 patients were enrolled. After 3months patients in Group B reported a significantly lower NIH-CPSI score (5.85 ± 3.07 vs. 7.64 ± 3.86; p = 0.009) and biological recurrences rate (9.8 vs. 26.9%; p = 0.043). At 6months the biological recurrences rate was significantly lower in Group B (8.7 vs. 28.9%; p = 0.038). Only three patients in Group A and six in Group B (p = 0.25) complained mild AEs. Conclusions: Combination therapy with EcN and levofloxacin allows a better control of symptoms and biological recurrences in patients with CBP, without worsening the safety of the treatment.

Background Antibiotics are no longer the primary approach for treating all travellers’ diarrhoea (TD): most cases resolve without antibiotics and using them predisposes to colonization by multidrug-resistant bacteria. Data are accumulating on increasing resistance among TD pathogens, yet research into the most common agents, diarrhoeagenic Escherichia coli (DEC), remains limited. Methods A total of 413 travellers to the (sub)tropics were analyzed for travel-acquired diarrhoeal pathogens and ESBL-PE. To identify ESBL-producing DEC, ESBL-producing E. coli (ESBL-EC) isolates were subjected to multiplex qPCR for various DEC pathotypes: enteroaggregative (EAEC), enteropathogenic (EPEC), enterotoxigenic (ETEC), enteroinvasive (EIEC) and enterohaemorrhagic (EHEC) E. coli. For a literature review, we screened studies among travellers and locals in low- and middle-income countries (LMICs) on the frequency of ESBL-producing DEC, and among travellers, also DEC with resistance to ciprofloxacin, azithromycin, and rifamycin derivatives. Results Our rate of ESBL-EC among all DEC findings was 2.7% (13/475); among EAEC 5.7% (10/175), EPEC 1.1% (2/180), ETEC 1.3% (1/80) and EHEC (0/35) or EIEC 0% (0/5). The literature search yielded three studies reporting ESBL-EC frequency and thirteen exploring resistance to TD antibiotics among travel-acquired DEC. For EAEC and ETEC, the ESBL-EC rates were 10–13% and 14–15%, resistance to fluoroquinolones 0–42% and 0–40%, azithromycin 0–29% and 0–61%, and rifaximin 0% and 0–20%. The highest rates were from the most recent collections. Proportions of ESBL-producing DEC also appear to be increasing among locals in LMICs and even carbapenemase-producing DEC were reported. Conclusion ESBL producers are no longer rare among DEC, and the overall resistance to various antibiotics is increasing. The data predict decreasing efficacy of antibiotic treatment, threatening its benefits, for disadvantages still prevail when efficacy is lost.

Introduction: Pseudomonas aeruginosa (PA) is a leading cause of healthcare-associated infections. A variety of antibiotic classes are used in the treatment of PA infections, including beta-lactams (BLs) and fluoroquinolones (FQs), given either together in combination therapy or alone in monotherapy. A systematic review and meta-analysis were performed to evaluate the therapeutic efficacy of BL agents versus FQ agents as active, definitive monotherapy in PA infections in adults.Methods: Comprehensive literature searches of Medline and Scopus electronic databases, alongside hand searches of the Cochrane Database of Systematic Reviews, PubMed, and Google Scholar, were performed without time restriction to identify studies published in English comparing BL and FQ agents given as monotherapy for PA infection in hospitalized adults for which mortality, bacteriological eradication, or clinical response was evaluated. One reviewer screened search results based on pre-defined selection criteria. Two reviewers independently assessed included studies for methodological quality using NIH assessment tools. Two fixed-effects meta-analyses were performed.Results: A total of 368 articles were screened, and 6 studies involving 338 total patients were included in the meta-analysis. Upon evaluation of methodological quality, 2 studies were rated good, 3 fair, and 1 poor. A meta-analysis of 3 studies demonstrates FQ monotherapy is associated with significantly improved survival compared to BL monotherapy for patients with PA bacteremia (OR, 3.65; 95% CI, 1.27-10.44; p=.02). A meta-analysis of 3 studies demonstrates FQ monotherapy is associated with equivalent bacteriological eradication compared to BL monotherapy for PA pneumonia or skin and soft tissue infection (RD, 0.07; 95% CI, -0.09 to 0.24; p=.39).Conclusion: The meta-analyses demonstrate FQ monotherapy significantly improves survival in PA bacteremia and is associated with similar rates of bacteriological eradication in pneumonia and skin and soft tissue infection caused by PA compared to BL monotherapy. However, more research is needed to make meaningful clinical recommendations.

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Introduction Increasing levels of antibiotic resistance are complicating treatment for the sexually transmitted pathogen Mycoplasma genitalium . Resistance to fluoroquinolones is associated with mutations in the parC gene. Although the precise mutations conferring resistance are not fully understood, the single nucleotide polymorphism (SNP) G248T/S83I is most implicated. Aim To evaluate the performance of the MG+parC(beta2) assay (SpeeDx, Australia), which detects single nucleotide polymorphisms (SNPs) in the parC gene at amino acid position S83 (A247C/S83R, G248T/S83I, G248A/S83N) and D87 (G259A/D87N, G259T/D87Y, G259C/D87H). Methods Clinical samples were analysed by MG+parC(beta2) assay and results compared to Sanger sequencing. Sensitivity, specificity, and predictive value for treatment failure were calculated. Results From analysis of 205 samples, the MG+parC(beta2) assay performed with a high sensitivity 98.2% (95% CI:90.3–100) and specificity 99.3% (95% CI:96.3–100) for parC SNP detection with a kappa of 0.97 (95% CI:0.94–1.00). The predictive value of G248T/S83I detection (the most common SNP, prevalence of 13% in the study population) was analysed with respect to treatment failure (patients received sequential doxycycline-moxifloxacin). The positive-predictive-value for moxifloxacin failure after detection of S83I was only 44% (95% CI:24.4–65.1), while negative-predictive-value was high at 96.9% (95% CI:92.7–99.0), suggesting that other SNPs are contributing to resistance. Conclusion MG+parC(beta2) performed with high concordance compared to Sanger sequencing. Such qPCR assays can assist in understanding causes of treatment failure, inform the development of diagnostic assays, and can be applied to surveillance of mutations in populations. Due to an incomplete understanding of the basis for fluoroquinolone resistance, such tests do not appear to be ready for clinical application.

Myasthenia gravis (MG) is an autoimmune neuromuscular disorder which is characterized by presence of antibodies against acetylcholine receptors (AChRs) or other proteins of the postsynaptic membrane resulting in damage to postsynaptic membrane, decreased number of AChRs or blocking of the receptors by autoantibodies. A number of drugs such as immune checkpoint inhibitors, penicillamine, tyrosine kinase inhibitors and interferons may induce de novo MG by altering the immune homeostasis mechanisms which prevent emergence of autoimmune diseases such as MG. Other drugs, especially certain antibiotics, antiarrhythmics, anesthetics and neuromuscular blockers, have deleterious effects on neuromuscular transmission, resulting in increased weakness in MG or MG-like symptoms in patients who do not have MG, with the latter usually being under medical circumstances such as kidney failure. This review summarizes the drugs which can cause de novo MG, MG exacerbation or MG-like symptoms in nonmyasthenic patients.

Fluoroquinolone (FQ)-resistant Group B Streptococcus (GBS) has been reported with considerable cross-resistance, worsening the crisis of multidrug-resistant (MDR) GBS in clinical settings. However, national epidemiological data on FQ-resistant GBS in mainland China have not been well-characterized. This study aimed to determine the prevalence of FQ resistance among GBS from neonatal invasive infections and maternal colonization in northern and southern China, to investigate the serotyping, multilocus sequence typing, and antibiotic cross-resistance, and to characterize the mutations in gyrA and parC genes in quinolone resistance-determining region (QRDR). In order to provide a comprehensive view of the location and structure of resistance genes, whole-genome sequencing on III/ST19 MDR isolates were performed. Among 426 GBS, 138 (32.4%) were FQ resistant, with higher prevalence in northern China than in southern China in both neonates (57.8%, 37/64 vs. 21.7%, 39/180) and pregnant women (50.9%, 29/57 vs. 26.4%, 33/125). Serotypes were distributed as III (48.5%), Ib (39.9%), V (6.5%), and Ia (5.1%). Sequence types were mainly ST19 (53.6%) and ST10 (39.1%), followed by ST12 (1.4%), ST17 (1.4%), ST23 (1.4%), and 0.7% each of ST27, ST188, ST197, and ST597. ST19 isolates were more prevalent in southern China than in northern China in both neonates (64.1%, 25/39 vs. 27.0%, 10/37) and pregnant women (81.8%, 27/33 vs. 41.4%, 12/29), whereas ST10 isolates were more common in northern China than in southern China in both neonates (64.9%, 24/37 vs. 20.5%, 8/39) and pregnant women (58.6%, 17/29 vs. 15.2%, 5/33). Serotype III isolates were mainly ST19 (89.6%, 60/67), while Ib isolates were largely ST10 (94.5%, 52/55). Sequencing data revealed several mutations in QRDR, including Ser81Leu in gyrA (99.2%, 130/131), Ser79Phe or Tyr in parC (76.2%, 48/63), and a previously unreported Ile218Thr and Ile219Phe double mutation pattern (49.2%, 31/63) in parC. ST10 isolates were associated with Ser79Phe (84%, 21/25), while ST19 isolates were limited to Ser79Tyr (95.7%, 22/23). A new integrative and conjugative element (ICE) harboring tetM and gyrA genes was identified in a III/ST19 isolate. This study investigates the molecular characteristics of FQ-resistant GBS in northern and southern China, emphasizing the need for continuous surveillance geographically and further research to characterize the mechanisms of ICE transfer.

The spread of antibiotic resistance genes (ARG) into agricultural soils, products, and foods severely limits the use of organic fertilizers in agriculture. In order to help designing agricultural practices that minimize the spread of ARG, we fertilized, sown, and harvested lettuces and radish plants in experimental land plots for two consecutive agricultural cycles using four types of fertilizers: mineral fertilization, sewage sludge, pig slurry, or composted organic fraction of municipal solid waste. The analysis of the relative abundances of more than 200,000 ASV (Amplicon Sequence Variants) identified a small, but significant overlap (, This work was supported by grants from the Spanish Ministry of Science, Innovation and University (MCIN/AEI/10.13039/501100011033, grants RTI2018-096175-B-I00 and AGL2017-89518-R), and the Generalitat de Catalunya (2017SGR902). CSL was supported by a FI predoctoral fellowship from the Generalitat de Catalunya and the European Social Fund (2018 FI B 00368, ESF Investing in your future). IDAEA-CSIC is a Centre of Excellence Severo Ochoa (Spanish Ministry of Science and Innovation, Project CEX2018-000794-S, ERDF A way of making Europe).

Corynebacterium species are commonly found in the conjunctiva of healthy adults and are recognized as non-pathogenic bacteria. In recent years, however, Corynebacterium species have been reported to be potentially pathogenic in various tissues. We investigated Corynebacterium species on the ocular surface and reviewed various species of Corynebacterium in terms of their antimicrobial susceptibility and the underlying molecular resistance mechanisms. We identified a risk for Corynebacterium-related ocular infections in patients with poor immunity, such as patients with diabetes or long-term users of topical steroids, and in those with corneal epithelial damage due to trauma, contact lens wear, lagophthalmos, and trichiasis. The predominant strain in the conjunctiva was C. macginleyi, and the species associated with keratitis and conjunctivitis were C. macginleyi, C. propinquum, C. mastitidis, C. pseudodiphtheriticum, C. accolens, C. striatum, C. xerosis, and C. bovis. Overall, Corynebacterium species present on the ocular surface were resistant to quinolones, whereas those in the nasal cavity were more susceptible. The prevalence of fluoroquinolone-resistant Corynebacterium has not changed in the past 10 years; however, Corynebacterium species remain susceptible to third-generation cephems. In conclusion, the use of third-generation cephems should be a reasonable and pragmatic approach for treatment of ocular infections caused by Corynebacterium species.

Previous studies on Escherichia coli demonstrated that sub-minimum inhibitory concentration (MIC) of fluoroquinolones induced the SOS response, increasing drug tolerance. We characterized the transcriptional response to moxifloxacin in Mycobacterium tuberculosis. Reference strain H37Rv was treated with moxifloxacin and gene expression studied by qRT-PCR. Five SOS regulon genes, recA, lexA, dnaE2, Rv3074 and Rv3776, were induced in a dose- and time-dependent manner. A range of moxifloxacin concentrations induced recA, with a peak observed at 2 × MIC (0.25 μg/mL) after 16 h. Another seven SOS responses and three DNA repair genes were significantly induced by moxifloxacin. Induction of recA by moxifloxacin was higher in log-phase than in early- and stationary-phase cells, and absent in dormant bacilli. Furthermore, in an H37Rv fluoroquinolone-resistant mutant carrying the D94G mutation in the gyrA gene, the SOS response was induced at drug concentrations higher than the mutant MIC value. The 2 × MIC of moxifloxacin determined no significant changes in gene expression in a panel of 32 genes, except for up-regulation of the relK toxin and of Rv3290c and Rv2517c, two persistence-related genes. Overall, our data show that activation of the SOS response by moxifloxacin, a likely link to increased mutation rate and persister formation, is time, dose, physiological state and, possibly, MIC dependent.

The binding of fluoroquinolones, the most commonly prescribed antibiotics, with melanin is well explored. However, their binding patterns and exact mechanism of interaction with tyrosinase, a key enzyme in melanogenesis, are not explored yet. Thus, in the present study, seven fluoroquinolone drugs were selected to characterize their interactions with the tyrosinase enzyme: ciprofloxacin, enoxacin sesquihydrate, ofloxacin, levofloxacin, sparfloxacin, moxifloxacin and gemifloxacin. The results confirmed that all the drugs execute excellent enzyme activity, with an inhibition range from IC50 = 28 ± 4 to 50 ± 1.9 μM, outperforming the standard hydroquinone (IC50 = 170 μM). Later, kinetic studies revealed that all the drugs showed irreversible, but mixed-type, tyrosinase inhibition, with a preferentially competitive mode of action. Further, 2D and 3D docked complexes and binding analyses confirmed their significant interactions in the active region of the target enzyme, sufficient for the downstream signaling responsible for the observed tyrosinase inhibition. Thus, this is the first report demonstrating their mechanism of tyrosinase inhibition, critical for melanin-dependent responses, including toxicity.

Fluoroquinolones (FQs) are a critical group of antimicrobials prescribed in urological infections as they have a broad antimicrobial spectrum of activity and a favorable tissue penetration at the site of infection. However, their clinical practice is not problem-free of treatment failure, risk of emergence of resistance, and rare but important adverse effects. Due to their critical role in clinical improvement, understanding the dose-response relation is necessary to optimize the effectiveness of FQs therapy, as it is essential to select the right antibiotic at the right dose for the right duration in urological infections. The aim of this study was to review the published literature about inter-individual variability in pharmacological processes that can be responsible for the clinical response after empiric dose for the most commonly prescribed urological FQs: ciprofloxacin, levofloxacin, and moxifloxacin. Interindividual pharmacokinetic (PK) variability, particularly in elimination, may contribute to treatment failure. Clearance related to creatinine clearance should be specifically considered for ciprofloxacin and levofloxacin. Likewise, today, undesired interregional variability in FQs antimicrobial activity against certain microorganisms exists. FQs pharmacology, patient-specific characteristics, and the identity of the local infecting organism are key factors in determining clinical outcomes in FQs use.

Background Mycolicibacterium fortuitum is a species of the rapidly growing mycobacteria that can cause pulmonary infection. It is susceptible to multiple antibiotics both in vitro and in clinical practice, so that any combination of susceptible drugs is effective. However, we encountered a case of infection due to fluoroquinolone-resistant M. fortuitum. In this study, we report the case and describe the mechanism of resistance. Case presentation A 65-year-old man with a history of total gastrectomy and immunosuppressant treatment for rheumatoid arthritis developed a recurrence of pulmonary infection caused by M. fortuitum. He was treated with clarithromycin and levofloxacin as a first-line treatment, based on the favorable susceptibility at that time. After recurrence, a high minimum inhibitory concentration to fluoroquinolones was detected. DNA sequencing of the pathogen showed the substitution of serine for tryptophan at residue 83 in the gyrA gene. He was successfully treated with a combination of other antibiotics. Conclusion This is the first report on the treatment of fluoroquinolone-resistant M. fortuitum and investigation of the mechanism of resistance. We suggest that the susceptibility test remains effective for determining the next line of treatment after a pathogen has acquired resistance, and resistance to fluoroquinolones in M. fortuitum can be attributed to a single change of amino acid.

Small mammals are known to carryCampylobacterspp.; however, little is known about the genotypes and their role in human infections. We studied intestinal content from small wild mammals collected in their natural habitats in Finland in 2010–2017, and in close proximity to 40 pig or cattle farms in 2017. The animals were trapped using traditional Finnish metal snap traps.Campylobacterspp. were isolated from the intestinal content using direct plating on mCCDA. A total of 19% of the captured wild animals (n= 577) and 41% of the pooled farm samples (n= 227) were positive forC. jejuni, which was the onlyCampylobacterspecies identified. The highest prevalence occurred in yellow-necked mice (Apodemus flavicollis) and bank voles (Myodes glareolus) which carriedCampylobacterspp. in 66.3 and 63.9% of the farm samples and 41.5 and 24.4% of individual animals trapped from natural habitats, respectively. Interestingly, all house mouse (Mus musculus) and shrew (Sorexspp.) samples were negative forCampylobacterspp.C. jejuniisolates (n= 145) were further characterized by whole-genome sequencing. Core genome multilocus sequence typing (cgMLST) clustering showed that mouse and vole strains were separated from the rest of theC. jejunipopulation (636 and 671 allelic differences, 94 and 99% of core loci, respectively). Very little or no alleles were shared withC. jejunigenomes described earlier from livestock or human isolates. FastANI results further indicated thatC. jejunistrains from voles are likely to represent a new previously undescribed species or subspecies ofCampylobacter. Core-genome phylogeny showed that there was no difference between isolates originating from the farm and wild captured animals. Instead, the phylogeny followed the host species-association. There was some evidence (one strain each) of livestock-associatedC. jejunioccurring in a farm-caughtA. flavicollisand a brown rat (Rattus norvegicus), indicating that although small mammals may not be the original reservoir ofCampylobactercolonizing livestock, they may sporadically carryC. jejunistrains occurring mainly in livestock and be associated with disease in humans.

Objectives To investigate the clinical and drug resistance characteristics of Providencia stuartii infections in the Huainan region of Anhui and provide a reference for the clinical selection of antimicrobial agents. Methods This single-center retrospective analysis included 76 patients with P. stuartii infection in Huainan during the period from October 2018 to March 2020. The hospital department in which the patients were treated and the drug susceptibility characteristics of the P. stuartii isolates were recorded. Results Among the 76 patients, the lung was the most common site of infection, and intensive care unit was the main hospital department. Extended spectrum beta-lactamase screening revealed expression by all 76 isolates of P. stuartii. Of the 76 isolates, 92.1% exhibited multiple drug resistance or extensive drug resistance. P. stuartii isolates were sensitive to cefepime and imipenem, but not to other beta-lactam antibiotics. Twenty isolates were resistant to all 21 types of antibiotics. Of the 20 patients infected with extensively drug-resistant isolates, nine (45%) died. Conclusions Drug resistance is increasing in P. stuartii. The antimicrobial agent imipenem may be effective for treatment of P. stuartii infections. Fluoroquinolones, aminoglycosides, and fourth-generation cephalosporins are suitable options for antibiotic therapy.