Safety and efficacy of nightly nitrofurantoin as prophylaxis in dogs with recurrent urinary tract infections: 13 cases (2015-2021).

OBJECTIVES: To report the protocol, efficacy and adverse events in dogs receiving nightly nitrofurantoin therapy as antimicrobial prophylaxis for recurrent urinary tract infections. MATERIALS AND METHODS: Retrospective case series of dogs prescribed nitrofurantoin as prophylaxis for recurrent urinary tract infections. Data on urological history, diagnostic investigation, protocol, adverse events and efficacy (through serial urine cultures) were extracted from medical records. RESULTS: Thirteen dogs were included. Before therapy, dogs had a median of 3 (range 3 to 7) positive urine cultures in the past year. In all but one dog, standard antimicrobial therapy was given before starting the nightly nitrofurantoin. The nightly nitrofurantoin was then prescribed at a median dose of 4.1 mg/kg orally every 24 hours for a median of 166 days (range 44 to 1740). The median infection-free interval on therapy was 268 days (95% confidence interval: 165 to undefined). Eight dogs had no positive urine cultures while on therapy. Of these, five (three which discontinued and two which remained on nitrofurantoin) had no return of clinical signs or bacteriuria at time of last follow-up evaluation or death, and three had suspected or confirmed bacteriuria 10 to 70 days after discontinuation. Five dogs developed bacteriuria on therapy, four of which were nitrofurantoin-resistant Proteus spp. Most other adverse events were minor; none were considered likely caused by the drug on causality assessment. CLINICAL SIGNIFICANCE: Based on this small study group, nightly nitrofurantoin appears well tolerated and might be efficacious prophylaxis for recurrent urinary tract infections in dogs. Infection with nitrofurantoin-resistant Proteus spp. was a common reason for treatment failure.

Prevalence of Bacterial Urinary Tract Infection Among Patients With Type 2 Diabetes Mellitus on Sodium-Glucose Cotransporter-2 Inhibitors: A Prospective Real-World Setting Study.

Background: Genitourinary tract infections, mycotic as well as bacterial, as defined by clinical symptoms, are one of the common adverse effects associated with the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in type 2 diabetes mellitus (T2DM) patients in clinical trials. However, Indian data in terms of the prevalence of culture-proven bacterial type of urinary tract infection (UTI), and the causative organism is limited. Objective: This study aimed to determine the prevalence and causative agents of bacterial UTI among patients with T2DM on SGLT2i. Methodology: This was a prospective longitudinal study involving all patients with T2DM who were prescribed with SGLT2i, uncontrolled on other oral anti-diabetic medications, from June 2019 to February 2020. Prevalence of bacterial UTI was evaluated at baseline and 12 weeks after initiation of SGLT2i. Results: A total of 80 patients were started on SGLT2i. One female patient on canagliflozin had significant asymptomatic bacteriuria and the causative agent was Acinetobacter baumannii. One male patient on dapagliflozin had symptomatic UTI with negative urine culture study. Four patients developed genital mycotic infection. Conclusion: In this real-world study, SGLT2i as a class, was well tolerated with favorable safety profile, and risk of developing significant bacteriuria and/or symptomatic UTI was minimal.

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.

Investigation of subclinical bacteriuria in cats with dermatological disease receiving long-term glucocorticoids and/or ciclosporin.

BACKGROUND: Dogs receiving long-term glucocorticoids or ciclosporin have an increased frequency of bacteriuria. No studies have investigated the frequency of bacteriuria in cats receiving long-term glucocorticoids and/or ciclosporin. HYPOTHESES/OBJECTIVES: To document whether subclinical bacteriuria occurs in cats receiving long-term glucocorticoid and/or ciclosporin for management of chronic disease. ANIMALS: Thirty two cats treated with parenteral glucocorticoids and/or oral glucocorticoids and/or ciclosporin were included. METHODS: Thirty two cats receiving oral glucocorticoids and/or ciclosporin for at least three months or at least two injections of long-acting glucocorticoids within the preceding six months were evaluated. Thirty four healthy cats were used as a control group. Urinalysis and urine culture was performed on urine samples collected by cystocentesis from each cat. RESULTS: In the glucocorticoid/ciclosporin group, none of 32 cats had a positive urine culture. In the control group, one of 34 cats had a positive urine culture. There were no statistically significant differences between the urinalyses from either group. CONCLUSIONS AND CLINICAL IMPORTANCE: There was no evidence to suggest that administration of long-term glucocorticoids and/or ciclosporin is associated with bacteriuria in cats.

The frequency of urinary tract infection and subclinical bacteriuria in dogs with allergic dermatitis treated with oclacitinib: a prospective study.

BACKGROUND: Oclacitinib is a selective Janus kinase inhibitor for the treatment of canine allergic pruritus and atopic dermatitis in dogs. Glucocorticoids and ciclosporin increase urinary tract infection (UTI) frequency in dogs with inflammatory skin disease. OBJECTIVE: Prospective study to evaluate the frequency of UTI and subclinical bacteriuria in dogs with allergic dermatitis receiving oclacitinib. METHODS: Client-owned dogs ≥2 years of age with a history of allergic dermatitis without apparent history of urinary tract disease or predisposition to UTI were included. Prior to enrolment, urinalysis and quantitative urine culture were performed after a washout period of at least 14 days from systemic antimicrobial drugs and 28 days for ciclosporin and systemic glucocorticoids. Dogs received oclacitinib at labelled dosing for an intended period of 180-230 days with a follow-up urinalysis and urine culture performed regardless of urinary tract signs. Systemic antimicrobial and immune-modulating drugs were not administered during the study. RESULTS: None of the 55 dogs in this study developed UTI while receiving oclacitinib based on follow-up urinalysis and urine culture performed during a range of 58-280 days (mean 195 days). Two dogs developed self-limiting abnormal urinary tract signs without urine culture or urinalysis findings consistent with UTI. CONCLUSIONS AND CLINICAL IMPORTANCE: These findings indicate that bacteriuria is not an expected adverse effect in dogs treated with oclacitinib without a prior history of UTI or predisposing condition during this treatment period. Therefore, routine urine culture is not indicated for such dogs in the absence of abnormal urinalysis or clinical signs of urinary tract disease.

Effect of acetohydroxamic acid on prevention of canine struvite uroliths.

Long-term administration of acetohydroxamic acid (AHA) to dogs with experimentally induced urease-positive staphylococcal urinary tract infections, and bladder zinc disk foreign bodies inhibited urolith growth in 2 dogs and prevented urolith growth in 4 dogs. Inhibition and prevention of urolith growth were associated with reduction in urine urease activity, crystalluria, pyuria, hematuria, and proteinuria. Lesions in the urinary tract of AHA-treated dogs were less severe than those of infected control dogs. Administration of AHA for 6 months induced mild morphologic abnormalities in RBC, but did not cause hemolytic anemia.

[Oral contraceptives: a new suspicion]. / Contraceptifs oraux: une nouvelle méfiance.

PIP: It is possible that oral contraception (OC) may cause hepatic side effects, such as liver tumors, jaundice, and biliar lithiasis. Carcinogenic side effects of OC depend widely on age, education, marital status, and, apparently, even religion of users. Cervical cancer, endometrial cancer, and breast cancer are problems continuously investigated with different results. Contradictory studies have been conducted on the possibility of infections of the urinary tract in OC users, and on the possibility of congenital abnormalities in children of OC users. Statistics concerning OC must be carefully studied, and the balance between advantages and risks carefully weighted. Patients on OC must be regularly surveilled throughout the period of treatment.^ieng

Relation between regular intake of phenacetin-containing analgesics and laboratory evidence for urorenal disorders in a working female population of Switzerland.

A study group of 623 employed Swiss women aged 30-49 years showing objective evidence of intake of phenacetin-containing analgesics, and a control group of 621 comparable women showing no such intake, were observed for 4 years (1969-72) for laboratory evidence of urorenal disorders. In both study and control groups morbidity was low. There was no difference between the study and control groups with respect to subsequent proteinuria, bacteriuria, and haematuria. The 4-year incidence of low urine specific gravity after overhight thirsting was significantly higher in the study group than in the control group (3-8% v. 0-8%) and the incidence of raised serum-creatinine was also significantly higher in the study group (2-9% v. 0-4%). However, when the study group was further subdivided into a sub-group showing evidence of high intake of phenacetincontaining analgesics and one showing low intake, only the high-intake subgroup had an incidence of raised serum-creatinine (5-4%) significantly higher than the control group (0-4%), whereas the low-intake subgroup had an incidence (0-4%) similar to the control group.