Antibiotic susceptibility patterns of bacterial isolates of patients with upper respiratory tract infections

Abstract To evaluate the antibiotic susceptibility patterns in URTIs reporting to tertiary hospitals of Lahore. A cross-sectional study employing 259 culture sensitivity reports obtained from tertiary care hospitals of Lahore. Using SPSS, descriptive statistics were used to estimate frequencies and percentages. In URTIs, S. aureus (5%) was the frequent gram-positive isolate followed by MRSA (1.5%) and MSSA (1.5%), while P. aeruginosa (15.8%) was the prevalent gram-negative isolate followed by Klebsiella (13.1%) and E. coli (6.9%). Against P. aeruginosa, ceftazidime (7.7%), cefuroxime/ceftriaxone (4.6%), amoxicillin (4.3%) and ciprofloxacin (4.2%), were tested resistant, while imipenem (11.2%), ciprofloxacin (9.2%), amikacin (9.2%), meropenem/ levofloxacin/gentamicin (8.1%) and piptaz (6.9%) were found sensitive. Against Klebsiella, carbepenems (7.3%), amikacin (6.5%), ciprofloxacin (5.4%) and gentamicin (5%) were tested sensitive, whereas, ceftazidime (8.5%), ceftriaxone (5.8%), cefaclor (5.5%), ampicillin (4.6%), co-amoxiclave (4.2%) and ciftazidime/ciprofloxacin (3.8%) were found resistant. Overall, imipenem (35%), meropenem (30.8%) and amikacin (31.9%) were the three most sensitive antibiotics, while ceftazidime (25.4%), ceftriaxone (19.2%) and ampicillin (18.5%) were the three most resistant antibiotics. Data suggested that P.aeruginosa and Klebsiella, were the most frequent bacterial isolates in URTIs of Lahore. These isolates were resistant to ampicillin, cefuroxime and ceftazidime, but were sensitive to carbapenem and aminoglycosides

Projecting the development of antimicrobial resistance in Neisseria gonorrhoeae from antimicrobial surveillance data: a mathematical modelling study.

BACKGROUND: The World Health Organization recommends changing the first-line antimicrobial treatment for gonorrhoea when ≥ 5% of Neisseria gonorrhoeae cases fail treatment or are resistant. Susceptibility to ceftriaxone, the last remaining treatment option has been decreasing in many countries. We used antimicrobial resistance surveillance data and developed mathematical models to project the time to reach the 5% threshold for resistance to first-line antimicrobials used for N. gonorrhoeae. METHODS: We used data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) in England and Wales from 2000-2018 about minimum inhibitory concentrations (MIC) for ciprofloxacin, azithromycin, cefixime and ceftriaxone and antimicrobial treatment in two groups, heterosexual men and women (HMW) and men who have sex with men (MSM). We developed two susceptible-infected-susceptible models to fit these data and produce projections of the proportion of resistance until 2030. The single-step model represents the situation in which a single mutation results in antimicrobial resistance. In the multi-step model, the sequential accumulation of resistance mutations is reflected by changes in the MIC distribution. RESULTS: The single-step model described resistance to ciprofloxacin well. Both single-step and multi-step models could describe azithromycin and cefixime resistance, with projected resistance levels higher with the multi-step than the single step model. For ceftriaxone, with very few observed cases of full resistance, the multi-step model was needed to describe long-term dynamics of resistance. Extrapolating from the observed upward drift in MIC values, the multi-step model projected ≥ 5% resistance to ceftriaxone could be reached by 2030, based on treatment pressure alone. Ceftriaxone resistance was projected to rise to 13.2% (95% credible interval [CrI]: 0.7-44.8%) among HMW and 19.6% (95%CrI: 2.6-54.4%) among MSM by 2030. CONCLUSIONS: New first-line antimicrobials for gonorrhoea treatment are needed. In the meantime, public health authorities should strengthen surveillance for AMR in N. gonorrhoeae and implement strategies for continued antimicrobial stewardship. Our models show the utility of long-term representative surveillance of gonococcal antimicrobial susceptibility data and can be adapted for use in, and for comparison with, other countries.

Antibiotic Resistance during COVID-19: A Systematic Review.

One of the public health issues faced worldwide is antibiotic resistance (AR). During the novel coronavirus (COVID-19) pandemic, AR has increased. Since some studies have stated AR has increased during the COVID-19 pandemic, and others have stated otherwise, this study aimed to explore this impact. Seven databases-PubMed, MEDLINE, EMBASE, Scopus, Cochrane, Web of Science, and CINAHL-were searched using related keywords to identify studies relevant to AR during COVID-19 published from December 2019 to May 2022, according to PRISMA guidelines. Twenty-three studies were included in this review, and the evidence showed that AR has increased during the COVID-19 pandemic. The most commonly reported resistant Gram-negative bacteria was Acinetobacterbaumannii, followed by Klebsiella pneumonia, Escherichia coli, and Pseudomonas aeruginosa. A. baumannii and K. pneumonia were highly resistant to tested antibiotics compared with E. coli and P. aeruginosa. Moreover, K. pneumonia showed high resistance to colistin. Commonly reported Gram-positive bacteria were Staphylococcus aureus and Enterococcus faecium. The resistance of E. faecium to ampicillin, erythromycin, and Ciprofloxacin was high. Self-antibiotic medication, empirical antibiotic administration, and antibiotics prescribed by general practitioners were the risk factors of high levels of AR during COVID-19. Antibiotics' prescription should be strictly implemented, relying on the Antimicrobial Stewardship Program (ASP) and guidelines from the World Health Organization (WHO) or Ministry of Health (MOH).

Updated knowledge, partitioning and ecological risk of pharmaceuticals and personal care products in global aquatic environments.

Over the last few decades, the occurrence of pharmaceuticals and personal care products (PPCPs) in aquatic environments has generated increasing public concern. In this review, data on the presence of PPCPs in environmental compartments from the past few years (2014-2022) are summarized by carrying out a critical survey of the partitioning among water, sediment, and aquatic organisms. From the available articles on PPCP occurrence in the environment, in Web of Science and Scopus databases, 185 articles were evaluated. Diclofenac, carbamazepine, caffeine, ibuprofen, ciprofloxacin, and sulfamethoxazole were reported to occur in 85% of the studies in at least one of the mentioned matrices. Risk assessment showed a moderate to high environmental risk for these compounds worldwide. Moreover, bioconcentration factors showed that sulfamethoxazole and trimethoprim can bioaccumulate in aquatic organisms, while ciprofloxacin and triclosan present bioaccumulation potential. Regarding spatial distribution, the Asian and European continents presented most studies on the occurrence and effects of PPCPs on the environment, while Africa and Asia are the most contaminated continents. In addition, the impact of COVID-19 on environmental contamination by PPCPs is discussed.

Right dose, right now: bedside, real-time, data-driven, and personalised antibiotic dosing in critically ill patients with sepsis or septic shock-a two-centre randomised clinical trial.

BACKGROUND: Adequate antibiotic dosing may improve outcomes in critically ill patients but is challenging due to altered and variable pharmacokinetics. To address this challenge, AutoKinetics was developed, a decision support system for bedside, real-time, data-driven and personalised antibiotic dosing. This study evaluates the feasibility, safety and efficacy of its clinical implementation. METHODS: In this two-centre randomised clinical trial, critically ill patients with sepsis or septic shock were randomised to AutoKinetics dosing or standard dosing for four antibiotics: vancomycin, ciprofloxacin, meropenem, and ceftriaxone. Adult patients with a confirmed or suspected infection and either lactate > 2 mmol/L or vasopressor requirement were eligible for inclusion. The primary outcome was pharmacokinetic target attainment in the first 24 h after randomisation. Clinical endpoints included mortality, ICU length of stay and incidence of acute kidney injury. RESULTS: After inclusion of 252 patients, the study was stopped early due to the COVID-19 pandemic. In the ciprofloxacin intervention group, the primary outcome was obtained in 69% compared to 3% in the control group (OR 62.5, CI 11.4-1173.78, p < 0.001). Furthermore, target attainment was faster (26 h, CI 18-42 h, p < 0.001) and better (65% increase, CI 49-84%, p < 0.001). For the other antibiotics, AutoKinetics dosing did not improve target attainment. Clinical endpoints were not significantly different. Importantly, higher dosing did not lead to increased mortality or renal failure. CONCLUSIONS: In critically ill patients, personalised dosing was feasible, safe and significantly improved target attainment for ciprofloxacin. TRIAL REGISTRATION: The trial was prospectively registered at Netherlands Trial Register (NTR), NL6501/NTR6689 on 25 August 2017 and at the European Clinical Trials Database (EudraCT), 2017-002478-37 on 6 November 2017.

Antibiotics in the Basque coast (N Spain): Occurrence in waste and receiving waters, and risk assessment (2017-2020).

The study of the presence of antibiotics in the aquatic environment is a preliminary step to analyse their possible harmful effects on aquatic ecosystems. In order to monitor their occurrence in the aquatic environment, the European Commission established in 2015, 2018, and 2020 three Watch Lists of substances for Union-wide monitoring (Decisions (EU) 2015/495, 2018/840, and 2020/1161), where some antibiotics within the classes of macrolides, fluoroquinolones and penicillins were included. In the Basque coast, northern Spain, three macrolide antibiotics (erythromycin, clarithromycin, azithromycin) and ciprofloxacin were monitored quarterly from 2017 to 2020 (covering a period before and after the COVID19 outbreak), in water samples collected from two Waste Water Treatment Plants (WWTPs), and three control points associated with receiving waters (transitional and coastal water bodies). This work was undertaken for the Basque Water Agency (URA). The three macrolide antibiotics in water showed a frequency of quantification >65 % in the Basque coast, with higher concentrations in the WWTP emission stations than in receiving waters. Their frequency of quantification decreased from 2017 to 2020, as did the consumption of antibiotics in Spanish primary care since 2015. Ciprofloxacin showed higher frequencies of quantification in receiving waters than in wastewaters, but the highest concentrations were observed in the WWTP emission stations. Although consumption of fluoroquinolones (among which is ciprofloxacin) in primary care in the Basque Country has decreased in recent years, this trend was not observed in the waters sampled in the present study. On the other hand, concentrations of clarithromycin, azithromycin, and ciprofloxacin in receiving waters exceeded their respective Predicted No-Effect Concentrations, so they could pose an environmental risk. These substances are widely used in human and animal medicine, so, although only ciprofloxacin is included in the third Watch List, it would be advisable to continue monitoring macrolides in the Basque coast as well.

Ozone-enhanced TiO2 nanotube arrays for the removal of COVID-19 aided antibiotic ciprofloxacin from water: Process implications and toxicological evaluation.

The purpose of this study was to evaluate the performance of synthesized TiO2 nanotube arrays (NTAs) for the removal of the COVID-19 aided antibiotic ciprofloxacin (CIP) and the textile dye methylene blue (MB) from model wastewater. Synthesis of TiO2 NTAs showed that anodization potential and calcination temperatures directly influence nanotube formation. The increased anodization potential from 10 to 40 V resulted in the development of larger porous nanotubes with a diameter of 36-170 nm, while the collapse of the tubular structure was registered at the highest applied potential. Furthermore, it was found that the 500 °C calcination temperature was the most prominent for the formation of the most photocatalytically active TiO2 NTAs, due to the optimal anatase/rutile ratio of 4.60. The degradation of both model compounds was achieved with all synthesized TiO2 NTAs; however, the most photocatalytically active NTA sample was produced at 30 V and 500 °C. Compared to photocatalysis, CIP degradation was greatly enhanced by 5-25 times when ozone was introduced to the photocatalytic cell (rates 0.4-4.2 × 10-1 min-1 versus 0.07-0.2 × 10-1 min-1). This resulted in the formation of CIP degradation by-products, with different mass-to-charge ratios from [M+H]+ 346 to 273 m/z. Even though the CIP degradation pathway is rather complex, three main mechanisms, decarboxylation, hydroxylation reaction, and piperazine ring cleavage, were proposed and explained. Furthermore, treated samples were placed in contact with the crustaceans Daphnia magna. It was found that 100% mortality was achieved when approximately 60% of the remaining TOC was present in the samples, indicating that toxic degradation by-products were formed.

Fosfomycin Vs Ciprofloxacin as Oral Step-Down Treatment for Escherichia coli Febrile Urinary Tract Infections in Women: A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial.

BACKGROUND: We aimed to determine the noninferiority of fosfomycin compared to ciprofloxacin as an oral step-down treatment for Escherichia coli febrile urinary tract infections (fUTIs) in women. METHODS: This was a double-blind, randomized, controlled trial in 15 Dutch hospitals. Adult women who were receiving 2-5 days of empirical intravenous antimicrobials for E. coli fUTI were assigned to step-down treatment with once-daily 3g fosfomycin or twice-daily 0.5g ciprofloxacin for 10 days of total antibiotic treatment. For the primary end point, clinical cure at days 6-10 post-end of treatment (PET), a noninferiority margin of 10% was chosen. The trial was registered on Trialregister.nl (NTR6449). RESULTS: After enrollment of 97 patients between 2017 and 2020, the trial ended prematurely because of the coronavirus disease 2019 pandemic. The primary end point was met in 36 of 48 patients (75.0%) assigned to fosfomycin and 30 of 46 patients (65.2%) assigned to ciprofloxacin (risk difference [RD], 9.6%; 95% confidence interval [CI]: -8.8% to 28.0%). In patients assigned to fosfomycin and ciprofloxacin, microbiological cure at days 6-10 PET occurred in 29 of 37 (78.4%) and 33 of 35 (94.3%; RD, -16.2%; 95% CI: -32.7 to -0.0%). Any gastrointestinal adverse event was reported in 25 of 48 (52.1%) and 14 of 46 (30.4%) patients (RD, 20.8%; 95% CI: 1.6% to 40.0%), respectively. CONCLUSIONS: Fosfomycin is noninferior to ciprofloxacin as oral step-down treatment for fUTI caused by E. coli in women. Fosfomycin use is associated with more gastrointestinal events. CLINICAL TRIAL REGISTRATION: Trial NL6275 (NTR6449).

Intermittent prophylactic antibiotics for bronchiectasis.

BACKGROUND: Bronchiectasis is a common but under-diagnosed chronic disorder characterised by permanent dilation of the airways arising from a cycle of recurrent infection and inflammation. Symptoms including chronic, persistent cough and productive phlegm are a significant burden for people with bronchiectasis, and the main aim of treatment is to reduce exacerbation frequency and improve quality of life. Prophylactic antibiotic therapy aims to break this infection cycle and is recommended by clinical guidelines for adults with three or more exacerbations a year, based on limited evidence. It is important to weigh the evidence for bacterial suppression against the prevention of antibiotic resistance and further evidence is required on the safety and efficacy of different regimens of intermittently administered antibiotic treatments for people with bronchiectasis. OBJECTIVES: To evaluate the safety and efficacy of intermittent prophylactic antibiotics in the treatment of adults and children with bronchiectasis. SEARCH METHODS: We identified trials from the Cochrane Airways Trials Register, which contains studies identified through multiple electronic searches and handsearches of other sources. We also searched trial registries and reference lists of primary studies. We conducted searches on 6 September 2021, with no restriction on language of publication. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of at least three months' duration comparing an intermittent regime of prophylactic antibiotics with placebo, usual care or an alternate intermittent regimen. Intermittent prophylactic administration was defined as repeated courses of antibiotics with on-treatment and off-treatment intervals of at least 14 days' duration. We included adults and children with a clinical diagnosis of bronchiectasis confirmed by high resolution computed tomography (HRCT), plain film chest radiograph, or bronchography and a documented history of recurrent chest infections. We excluded studies where participants received high dose antibiotics immediately prior to enrolment or those with a diagnosis of cystic fibrosis, allergic bronchopulmonary aspergillosis (ABPA), primary ciliary dyskinesia, hypogammaglobulinaemia, sarcoidosis, or a primary diagnosis of COPD. Our primary outcomes were exacerbation frequency and serious adverse events. We did not exclude studies on the basis of review outcomes. DATA COLLECTION AND ANALYSIS: We analysed dichotomous data as odds ratios (ORs) or relative risk (RRs) and continuous data as mean differences (MDs) or standardised mean differences (SMDs). We used standard methodological procedures expected by Cochrane. We conducted GRADE assessments for the following primary outcomes: exacerbation frequency; serious adverse events and secondary outcomes: antibiotic resistance; hospital admissions; health-related quality of life. MAIN RESULTS: We included eight RCTs, with interventions ranging from 16 to 48 weeks, involving 2180 adults. All evaluated one of three types of antibiotics over two to six cycles of 28 days on/off treatment: aminoglycosides, ß-lactams or fluoroquinolones. Two studies also included 12 cycles of 14 days on/off treatment with fluoroquinolones. Participants had a mean age of 63.6 years, 65% were women and approximately 85% Caucasian. Baseline FEV1 ranged from 55.5% to 62.6% predicted. None of the studies included children. Generally, there was a low risk of bias in the included studies. Antibiotic versus placebo: cycle of 14 days on/off. Ciprofloxacin reduced the frequency of exacerbations compared to placebo (RR 0.75, 95% CI 0.61 to 0.93; I2 = 65%; 2 studies, 469 participants; moderate-certainty evidence), with eight people (95% CI 6 to 28) needed to treat for an additional beneficial outcome. The intervention increased the risk of antibiotic resistance more than twofold (OR 2.14, 95% CI 1.36 to 3.35; I2 = 0%; 2 studies, 624 participants; high-certainty evidence). Serious adverse events, lung function (FEV1), health-related quality of life, and adverse effects did not differ between groups. Antibiotic versus placebo: cycle of 28 days on/off. Antibiotics did not reduce overall exacerbation frequency (RR 0.92, 95% CI 0.82 to 1.02; I2 = 0%; 8 studies, 1695 participants; high-certainty evidence) but there were fewer severe exacerbations (OR 0.59, 95% CI 0.37 to 0.93; I2 = 54%; 3 studies, 624 participants), though this should be interpreted with caution due to low event rates. The risk of antibiotic resistance was more than twofold higher based on a pooled analysis (OR 2.20, 95% CI 1.42 to 3.42; I2 = 0%; 3 studies, 685 participants; high-certainty evidence) and consistent with unpooled data from four further studies. Serious adverse events, time to first exacerbation, duration of exacerbation, respiratory-related hospital admissions, lung function, health-related quality of life and adverse effects did not differ between study groups. Antibiotic versus usual care. We did not find any studies that compared intermittent antibiotic regimens with usual care. Cycle of 14 days on/off versus cycle of 28 days on/off. Exacerbation frequency did not differ between the two treatment regimens (RR 1.02, 95% CI 0.84 to 1.24; I2 = 71%; 2 studies, 625 participants; moderate-certainty evidence) However, inconsistencies in the results from the two trials in this comparison indicate that the apparent aggregated similarities may not be reliable. There was no evidence of a difference in antibiotic resistance between groups (OR 1.00, 95% CI 0.68 to 1.48; I2 = 60%; 2 studies, 624 participants; moderate-certainty evidence). Serious adverse events, adverse effects, lung function and health-related quality of life did not differ between the two antibiotic regimens. AUTHORS' CONCLUSIONS: Overall, in adults who have frequent chest infections, long-term antibiotics given at 14-day on/off intervals slightly reduces the frequency of those infections and increases antibiotic resistance. Intermittent antibiotic regimens result in little to no difference in serious adverse events. The impact of intermittent antibiotic therapy on children with bronchiectasis is unknown due to an absence of evidence, and further research is needed to establish the potential risks and benefits.

Sulopenem: An Intravenous and Oral Penem for the Treatment of Urinary Tract Infections Due to Multidrug-Resistant Bacteria.

Sulopenem (formerly known as CP-70,429, and CP-65,207 when a component of a racemic mixture with its R isomer) is an intravenous and oral penem that possesses in vitro activity against fluoroquinolone-resistant, extended spectrum ß-lactamases (ESBL)-producing, multidrug-resistant (MDR) Enterobacterales. Sulopenem is being developed to treat patients with uncomplicated and complicated urinary tract infections (UTIs) as well as intra-abdominal infections. This review will focus mainly on its use in UTIs. The chemical structure of sulopenem shares properties of penicillins, cephalosporins, and carbapenems. Sulopenem is available as an oral prodrug formulation, sulopenem etzadroxil, which is hydrolyzed by intestinal esterases, resulting in active sulopenem. In early studies, the S isomer of CP-65,207, later developed as sulopenem, demonstrated greater absorption, higher drug concentrations in the urine, and increased stability against the renal enzyme dehydropeptidase-1 compared with the R isomer, which set the stage for its further development as a UTI antimicrobial. Sulopenem is active against both Gram-negative and Gram-positive microorganisms. Sulopenem's ß-lactam ring alkylates the serine residues of penicillin-binding protein (PBP), which inhibits peptidoglycan cross-linking. Due to its ionization and low molecular weight, sulopenem passes through outer membrane proteins to reach PBPs of Gram-negative bacteria. While sulopenem activity is unaffected by many ß-lactamases, resistance arises from alterations in PBPs (e.g., methicillin-resistant Staphylococcus aureus [MRSA]), expression of carbapenemases (e.g., carbapenemase-producing Enterobacterales and in Stenotrophomonas maltophilia), reduction in the expression of outer membrane proteins (e.g., some Klebsiella spp.), and the presence of efflux pumps (e.g., MexAB-OprM in Pseudomonas aeruginosa), or a combination of these mechanisms. In vitro studies have reported that sulopenem demonstrates greater activity than meropenem and ertapenem against Enterococcus faecalis, Listeria monocytogenes, methicillin-susceptible S. aureus (MSSA), and Staphylococcus epidermidis, as well as similar activity to carbapenems against Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes. With some exceptions, sulopenem activity against Gram-negative aerobes was less than ertapenem and meropenem but greater than imipenem. Sulopenem activity against Escherichia coli carrying ESBL, CTX-M, or Amp-C enzymes, or demonstrating MDR phenotypes, as well as against ESBL-producing Klebsiella pneumoniae, was nearly identical to ertapenem and meropenem and greater than imipenem. Sulopenem exhibited identical or slightly greater activity than imipenem against many Gram-positive and Gram-negative anaerobes, including Bacteroides fragilis. The pharmacokinetics of intravenous sulopenem appear similar to carbapenems such as imipenem-cilastatin, meropenem, and doripenem. In healthy subjects, reported volumes of distribution (Vd) ranged from 15.8 to 27.6 L, total drug clearances (CLT) of 18.9-24.9 L/h, protein binding of approximately 10%, and elimination half-lives (t½) of 0.88-1.03 h. The estimated renal clearance (CLR) of sulopenem is 8.0-10.6 L/h, with 35.5% ± 6.7% of a 1000 mg dose recovered unchanged in the urine. An ester prodrug, sulopenem etzadroxil, has been developed for oral administration. Initial investigations reported a variable oral bioavailability of 20-34% under fasted conditions, however subsequent work showed that bioavailability is significantly improved by administering sulopenem with food to increase its oral absorption or with probenecid to reduce its renal tubular secretion. Food consumption increases the area under the curve (AUC) of oral sulopenem (500 mg twice daily) by 23.6% when administered alone and 62% when administered with 500 mg of probenecid. Like carbapenems, sulopenem demonstrates bactericidal activity that is associated with the percentage of time that free concentrations exceed the MIC (%f T > MIC). In animal models, bacteriostasis was associated with %f T > MICs ranging from 8.6 to 17%, whereas 2-log10 kill was seen at values ranging from 12 to 28%. No pharmacodynamic targets have been documented for suppression of resistance. Sulopenem concentrations in urine are variable, ranging from 21.8 to 420.0 mg/L (median 84.4 mg/L) in fasted subjects and 28.8 to 609.0 mg/L (median 87.3 mg/L) in those who were fed. Sulopenem has been compared with carbapenems and cephalosporins in guinea pig and murine systemic and lung infection animal models. Studied pathogens included Acinetobacter calcoaceticus, B. fragilis, Citrobacter freundii, Enterobacter cloacae, E. coli, K. pneumoniae, Proteus vulgaris, and Serratia marcescens. These studies reported that overall, sulopenem was non-inferior to carbapenems but appeared to be superior to cephalosporins. A phase III clinical trial (SURE-1) reported that sulopenem was not non-inferior to ciprofloxacin in women infected with fluoroquinolone-susceptible pathogens, due to a higher rate of asymptomatic bacteriuria in sulopenem-treated patients at the test-of-cure visit. However, the researchers reported superiority of sulopenem etzadroxil/probenecid over ciprofloxacin for the treatment of uncomplicated UTIs in women infected with fluoroquinolone/non-susceptible pathogens, and non-inferiority in all patients with a positive urine culture. A phase III clinical trial (SURE-2) compared intravenous sulopenem followed by oral sulopenem etzadroxil/probenecid with ertapenem in the treatment of complicated UTIs. No difference in overall success was noted at the end of therapy. However, intravenous sulopenem followed by oral sulopenem etzadroxil was not non-inferior to ertapenem followed by oral stepdown therapy in overall success at test-of-cure due to a higher rate of asymptomatic bacteriuria in the sulopenem arm. After a meeting with the US FDA, Iterum stated that they are currently evaluating the optimal design for an additional phase III uncomplicated UTI study to be conducted prior to the potential resubmission of the New Drug Application (NDA). It is unclear at this time whether Iterum intends to apply for EMA or Japanese regulatory approval. The safety and tolerability of sulopenem has been reported in various phase I pharmacokinetic studies and phase III clinical trials. Sulopenem (intravenous and oral) appears to be well tolerated in healthy subjects, with and without the coadministration of probenecid, with few serious drug-related treatment-emergent adverse events (TEAEs) reported to date. Reported TEAEs affecting ≥1% of patients were (from most to least common) diarrhea, nausea, headache, vomiting and dizziness. Discontinuation rates were low and were not different than comparator agents. Sulopenem administered orally and/or intravenously represents a potentially well tolerated and effective option for treating uncomplicated and complicated UTIs, especially in patients with documented or highly suspected antimicrobial pathogens to commonly used agents (e.g. fluoroquinolone-resistant E. coli), and in patients with documented microbiological or clinical failure or patients who demonstrate intolerance/adverse effects to first-line agents. This agent will likely be used orally in the outpatient setting, and intravenously followed by oral stepdown in the hospital setting. Sulopenem also allows for oral stepdown therapy in the hospital setting from intravenous non-sulopenem therapy. More clinical data are required to fully assess the clinical efficacy and safety of sulopenem, especially in patients with complicated UTIs caused by resistant pathogens such as ESBL-producing, Amp-C, MDR E. coli. Antimicrobial stewardship programs will need to create guidelines for when this oral and intravenous penem should be used.

Suspect screening of wastewaters to trace anti-COVID-19 drugs: Potential adverse effects on aquatic environment.

During the first period of the SARS-CoV-2 pandemic, the lack of specific therapeutic treatments led to the provisional use of a number of drugs, with a continuous review of health protocols when new scientific evidence emerged. The management of this emergency sanitary situation could not take care of the possible indirect adverse effects on the environment, such as the release of a large amount of pharmaceuticals from wastewater treatment plants. The massive use of drugs, which were never used so widely until then, implied new risks for the aquatic environment. In this study, a suspect screening approach using Liquid Chromatography-High Resolution Mass Spectrometry techniques, allowed us to survey the presence of pharmaceuticals used for COVID-19 treatment in three WWTPs of Lombardy region, where the first European cluster of SARS-CoV-2 cases was detected. Starting from a list of sixty-three suspect compounds used against COVID-19 (including some metabolites and transformation products), six compounds were fully identified and monitored together with other target analytes, mainly pharmaceuticals of common use. A monthly monitoring campaign was conducted in a WWTP from April to December 2020 and the temporal trends of some anti-COVID-19 drugs were positively correlated with those of COVID-19 cases and deaths. The comparison of the average emission loads among the three WWTPs evidenced that the highest loads of hydroxychloroquine, azithromycin and ciprofloxacin were measured in the WWTP which received the sewages from a hospital specializing in the treatment of COVID-19 patients. The monitoring of the receiving water bodies evidenced the presence of eight compounds of high ecological concern, whose risk was assessed in terms of toxicity and the possibility of inducing antibiotic and viral resistance. The results clearly showed that the enhanced, but not completely justified, use of ciprofloxacin and azithromycin represented a risk for antibiotic resistance in the aquatic ecosystems.

Investigation of the effects of three different generations of fluoroquinolone derivatives on antioxidant and immunotoxic enzyme levels in different rat tissues.

Fluoroquinolones (FQs) are synthetic and broad-spectrum antimicrobial drugs derived from nalidixic acid. FQs are used against SARS-CoV-2 in our country, and for the treatment of some urinary tract diseases, gastrointestinal diseases, respiratory tract diseases, sexually transmitted diseases, and dermatological diseases. The present study investigated the effect of 1-,7-,14-day treatments of three different FQ derivatives; ciprofloxacin (CIP) 80 mg/kg/day, levofloxacin (LVX) 40 mg/kg/day, and moxifloxacin (MXF) 40 mg/kg/day, on biochemical parameters, lipid peroxidation, antioxidant enzymes, and immunotoxicity. 72 Wistar albino male rats were distributed to four groups including 18 rats in each group and were sacrificed on three different time points. The 14-day treatment of MXF significantly reduced the levels of aspartate aminotransferase (AST), glucose, reduced glutathione (GSH), malondialdehyde (MDA), catalase (CAT), myeloperoxidase (MPO), adenosine deaminase (ADA), and glutathione peroxidase (GPx). Furthermore, 14-day treatment of LVX increased liver [GSH, MPO, ADA, superoxide dismutase (SOD)], and GSH (erythrocyte) levels; whereas it significantly reduced the levels of AST, TG (triglycerides) and associated parameters levels in all the tissues (MDA), erythrocytes, and liver (MPO, CAT, SOD, GPx). After 14-day treatment of CIP; the erythrocyte levels of GSH, MPO, GPx, and CAT significantly decreased; whereas the levels of glucose, creatinine, MPO (liver), and GST (kidney and erythrocyte) significantly increased. It has been concluded that FQ derivatives used in this experiment did not display any correlation in terms of the efficacies in the different time points and tissues. Thus, it is recommended to use such FQ derivatives considering the duration of use and target tissue.

In vitro inhibition and molecular docking of a new ciprofloxacin-chalcone against SARS-CoV-2 main protease.

BACKGROUND/AIM: SARS-CoV-2 is one of the coronavirus families that emerged at the end of 2019. It infected the respiratory system and caused a pandemic worldwide. Fluoroquinolones (FQs) have been safely used as antibacterial agents for decades. The antiviral activity of FQs was observed. Moreover, substitution on the C-7 position of ciprofloxacin enhanced its antiviral activity. Therefore, this study aims to investigate the antiviral activity of 7-(4-(N-substituted-carbamoyl-methyl)piperazin-1yl)-chalcone in comparison with ciprofloxacin against SARS-CoV-2 main protease (Mpro ). MATERIALS AND METHODS: Vero cells were infected with SARS-CoV-2. After treatment with ciprofloxacin and the chalcone at the concentrations of 1.6, 16, 160 nmol/L for 48 h, SARS-CoV-2 viral load was detected using real-time qPCR, SARS-CoV-2 infectivity was determined using plaque assay, and the main protease enzyme activity was detected using in vitro 3CL-protease inhibition assay. The activity of the chalcone was justified through molecular docking within SARS-CoV-2 Mpro , in comparison with ciprofloxacin. RESULTS: The new chalcone significantly inhibited viral load replication where the EC50 was 3.93 nmol/L, the plaque formation ability of the virus was inhibited to 86.8% ± 2.47. The chalcone exhibited a significant inhibitory effect against SARS-CoV-2 Mpro in vitro in a dose-dependent manner. The docking study into SARS-CoV-2 Mpro active site justified the importance of adding a substitution to the parent drug. Additionally, the assessment of the drug-likeness properties indicated that the chalcone might have acceptable ADMET properties. CONCLUSION: The new chalcone might be useful and has new insights for the inhibition of SARS-CoV-2 Mpro .

The application of in silico experimental model in the assessment of ciprofloxacin and levofloxacin interaction with main SARS-CoV-2 targets: S-, E- and TMPRSS2 proteins, RNA-dependent RNA polymerase and papain-like protease (PLpro)-preliminary molecular docking analysis.

BACKGROUND: The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified at the end of 2019. Despite growing understanding of SARS-CoV-2 in virology as well as many molecular studies, except remdesivir, no specific anti-SARS-CoV-2 drug has been officially approved. METHODS: In the present study molecular docking technique was applied to test binding affinity of ciprofloxacin and levofloxacin-two commercially available fluoroquinolones, to SARS-CoV-2 S-, E- and TMPRSS2 proteins, RNA-dependent RNA polymerase and papain-like protease (PLPRO). Chloroquine and dexamethasone were used as reference positive controls. RESULTS: When analyzing the molecular docking data it was noticed that ciprofloxacin and levofloxacin possess lower binding energy with S protein as compared to the references. In the case of TMPRSS2 protein and PLPRO protease the best docked ligand was levofloxacin and in the case of E proteins and RNA-dependent RNA polymerase the best docked ligands were levofloxacin and dexamethasone. Moreover, a molecular dynamics study also reveals that ciprofloxacin and levofloxacin form a stable complex with E- and TMPRSS2 proteins, RNA polymerase and papain-like protease (PLPRO). CONCLUSIONS: The revealed data indicate that ciprofloxacin and levofloxacin could interact and potentially inhibit crucial SARS-CoV-2 proteins.

Neuroprotective role of camphor against ciprofloxacin induced depression in rats: modulation of Nrf-2 and TLR4.

BACKGROUND: Depression affects people feeling to be anxious, worried, and restless. They also lose interest in activities, concentrating and appetite, they finally may attempt suicide. Depression is the second chronic disease, as a source of the global burden of disease, after heart disease. Its prevalence elevated seven times during the COVID-19. AIM: The current study was designed to evaluate camphor neuroprotective role against rats' ciprofloxacin-induced depression. MATERIALS AND METHODS: Depression was induced by administration of ciprofloxacin (50 mg/kg; orally) for 21 days. Wister albino male rats were divided into five groups. Group I (normal control): rats were given normal saline. Group II: rats received camphor (10 mg/kg; i.p.) for 21 days. Group III (depression control): rats received ciprofloxacin only. Groups IV and V: rats received camphor (5 and 10 mg/kg; i.p.) for 21 days concurrent with ciprofloxacin. Behavior tests as forced swimming test, activity cage, and rotarod were estimated. Oxidative stress and antioxidant biomarkers as malondialdehyde (MDA), nitric oxide (NO), catalase, and nuclear factor erythroid 2-related factor 2 (Nrf-2) besides inflammatory biomarkers as Toll-like receptor 4 (TLR4) and tumor necrosis factor alpha (TNF-α) as well as neurotransmitters were determined. Finally, histopathological examination was done. RESULTS: Camphor increased catalase and Nrf-2 activities, decreased NO, MDA, TNF-α, TLR4 serum levels, and elevating brain contents of serotonin, dopamine, gamma-amino butyric acid (GABA) and P190-RHO GTP protein with normal neuronal cells of the frontal cortex. CONCLUSION: Camphor has neuroprotective effect via modulation of Nrf-2 and TLR4 against ciprofloxacin-induced depression in rats.

Fluoroquinolone Antibiotics Exhibit Low Antiviral Activity against SARS-CoV-2 and MERS-CoV.

Repurposing FDA-approved drugs that treat respiratory infections caused by coronaviruses, such as SARS-CoV-2 and MERS-CoV, could quickly provide much needed antiviral therapies. In the current study, the potency and cellular toxicity of four fluoroquinolones (enoxacin, ciprofloxacin, levofloxacin, and moxifloxacin) were assessed in Vero cells and A549 cells engineered to overexpress ACE2, the SARS-CoV-2 entry receptor. All four fluoroquinolones suppressed SARS-CoV-2 replication at high micromolar concentrations in both cell types, with enoxacin demonstrating the lowest effective concentration 50 value (EC50) of 126.4 µM in Vero cells. Enoxacin also suppressed the replication of MERS-CoV-2 in Vero cells at high micromolar concentrations. Cellular toxicity of levofloxacin was not found in either cell type. In Vero cells, minimal toxicity was observed following treatment with ≥37.5 µM enoxacin and 600 µM ciprofloxacin. Toxicity in both cell types was detected after moxifloxacin treatment of ≥300 µM. In summary, these results suggest that the ability of fluoroquinolones to suppress SARS-CoV-2 and MERS-CoV replication in cultured cells is limited.

Antimicrobial properties of diethylamine NONOate, a nitric oxide donor, against Escherichia coli: a pilot study.

The emergence of SARS-CoV-2, the causative agent of COVID-19, highlights the increasing need for new and effective antiviral and antimicrobial agents. The FDA has recently banned several active ingredients used in hand sanitizers, including triclosan and benzethonium chloride. Nitric oxide (NO) is involved in the innate immune response and is a major component of macrophage-mediated attack on foreign viruses and bacteria. The specific aim of this study was to assess the antibacterial effects of 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA-NONOate) against Escherichia coli (E. coli). A bacterial growth assay was compared to an adenosine triphosphate (ATP) activity assay at various time points to assess effects of DEA-NONOate on E. coli growth. A UV/Vis spectrophotometer was used to determine concentration of E. coli by measuring optical density (OD) at 630 nm. A luminescent assay was used to measure ATP activity correlating to viable cells. DEA-NONOate at a concentration of 65 mM was able to inhibit the growth of E. coli with the same efficacy as 1 µg ml-1 concentration of ciprofloxacin. Both the OD and ATP assays demonstrated a 99.9% reduction in E. coli. Both a 1 µg ml-1 concentration of ciprofloxacin and a 65 mM concentration of DEA-NONOate achieved 99.9% inhibition of E. coli, verified using both optical density measurement of bacterial cultures in 96 well plates and a luminescent ATP activity assay. The bactericidal effects of DEA-NONOate against E. coli is proof-of-concept to pursue evaluation of nitric oxide-based formulations as antimicrobial and antiviral agents as hand sanitizers.

Ciprofloxacin and moxifloxacin could interact with SARS-CoV-2 protease: preliminary in silico analysis.

BACKGROUND: A large body of research has focused on fluoroquinolones. It was shown that this class of synthetic antibiotics could possess antiviral activity as a broad range of anti-infective activities. Based on these findings, we have undertaken in silico molecular docking study to demonstrate, for the first time, the principle for the potential evidence pointing ciprofloxacin and moxifloxacin ability to interact with COVID-19 Main Protease. METHODS: In silico molecular docking and molecular dynamics techniques were applied to assess the potential for ciprofloxacin and moxifloxacin interaction with COVID-19 Main Protease (Mpro). Chloroquine and nelfinavir were used as positive controls. RESULTS: We revealed that the tested antibiotics exert strong capacity for binding to COVID-19 Main Protease (Mpro). According to the results obtained from the GOLD docking program, ciprofloxacin and moxifloxacin bind to the protein active site more strongly than the native ligand. When comparing with positive controls, a detailed analysis of the ligand-protein interactions shows that the tested fluoroquinolones exert a greater number of protein interactions than chloroquine and nelfinavir. Moreover, lower binding energy values obtained from KDEEP program were stated when compared to nelfinavir. CONCLUSIONS: Here, we have demonstrated for the first time that ciprofloxacin and moxifloxacin may interact with COVID-19 Main Protease (Mpro).