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Despite therapeutic advances, vulvovaginal candidosis remains a common problem worldwide, affecting all strata of society. Understanding of anti-candida host defence mechanisms in the vagina has developed slowly and, despite a growing list of recognised risk factors, a fundamental grasp of pathogenic mechanisms continues to elude us. The absence of rapid, simple, and inexpensive diagnostic tests continues to result in both overdiagnosis and underdiagnosis of vulvovaginal candidosis. I review the epidemiology and pathogenesis of this infection, and also discuss management strategies.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.

Background. The global emergence of carbapenem-resistant Enterobacteriaceae highlights the urgent need to reduce carbapenem dependence. The phase 3 RECAPTURE program compared the efficacy and safety of ceftazidime-avibactam and doripenem in patients with complicated urinary tract infection (cUTI), including acute pyelonephritis. Methods. Hospitalized adults with suspected or microbiologically confirmed cUTI/acute pyelonephritis were randomized 1:1 to ceftazidime-avibactam 2000 mg/500 mg every 8 hours or doripenem 500 mg every 8 hours (doses adjusted for renal function), with possible oral antibiotic switch after ≥5 days (total treatment duration up to 10 days or 14 days for patients with bacteremia). Results. Of 1033 randomized patients, 393 and 417 treated with ceftazidime-avibactam and doripenem, respectively, were eligible for the primary efficacy analyses; 19.6% had ceftazidime-nonsusceptible baseline pathogens. Noninferiority of ceftazidimeavibactam vs doripenem was demonstrated for the US Food and Drug Administration co-primary endpoints of (1) patient-reported symptomatic resolution at day 5: 276 of 393 (70.2%) vs 276 of 417 (66.2%) patients (difference, 4.0% [95% confidence interval {CI}, −2.39% to 10.42%]); and (2) combined symptomatic resolution/microbiological eradication at test of cure (TOC): 280 of 393 (71.2%) vs 269 of 417 (64.5%) patients (difference, 6.7% [95% CI, .30% to 13.12%]). Microbiological eradication at TOC (European Medicines Agency primary endpoint) occurred in 304 of 393 (77.4%) ceftazidime-avibactam vs 296 of 417 (71.0%) doripenem patients (difference, 6.4% [95% CI, .33% to 12.36%]), demonstrating superiority at the 5% significance level. Both treatments showed similar efficacy against ceftazidime-nonsusceptible pathogens. Ceftazidime-avibactam had a safety profile consistent with that of ceftazidime alone. Conclusions. Ceftazidime-avibactam was highly effective for the empiric treatment of cUTI (including acute pyelonephritis), and may offer an alternative to carbapenems in this setting. Clinical Trials Registration. NCT01595438; NCT01599806.

Background Vulvovaginal candidiasis (VVC) is a common infection affecting women worldwide. Reports of patterns/risk factors/trends for episodic/recurrent VVC (RVVC) are largely outdated. The purpose of this study was to obtain current patient perspectives of several aspects of VVC/RVVC. Methods Business cards containing on-line survey information were distributed to healthy volunteers and patients seeking standard, elective, or referral gynecologic care in university-affiliated Obstetrics/Gynecology clinics. The internet-based questionnaire was completed by 284 non-pregnant women (78% Caucasian, 14% African American, 8% Asian). Results The majority of the participants (78%) indicated a history of VVC with 34% defined as having RVVC. The most common signs/symptoms experienced were itching, burning and redness with similar ranking of symptoms among VVC and RVVC patients. Among risk factors, antibiotic use ranked highest followed by intercourse, humid weather and use of feminine hygiene products. A high number of respondents noted ‘no known cause’ (idiopathic episodes) that was surprisingly similar among women with a history of either VVC or RVVC. VVC/RVVC episodes reported were primarily physician-diagnosed (73%) with the remainder mostly reporting self-diagnosis and treating with over-the-counter (OTC) medications. Most physician-diagnosed attacks utilized a combination of pelvic examination and laboratory tests followed by prescribed antifungals. Physician-treated cases achieved a higher level of symptom relief (84%) compared to those who self-medicated (57%). The majority of women with RVVC (71%) required continual or long-term antifungal medication as maintenance therapy to control symptoms. Conclusions Current patient perspectives closely reflect historically documented estimates of VVC/RVVC prevalence and trends regarding symptomatology, disease management and post-treatment outcomes.

Refractory responses to standard-of-care oral metronidazole among recurrent bacterial vaginosis (BV) patients is not rare, and recurrence within a year is common. A better understanding of the bacterial determinants of these outcomes is essential. In this study we ask whether changes in specific species of Gardnerella are associated with poor short or long term clinical outcomes, and if and how resurgence of Lactobacillus species affects these outcomes. We quantify Lactobacillus isolates as a proportion of total vaginal bacteria using the LbRC5 qPCR assay, and 5 prevalent species of Gardnerella using primers that target species-specific polymorphisms within the cpn60 gene. The study includes 43 BV patients: 18 refractory, 16 recurrent, and 11 remission patients, sampled daily for up to two weeks post-treatment; clinical outcomes were tracked for up to 9 months. Persistently high titers of Gardnerella Gsp07 were associated with refractory responses, and persistently low abundance of Gardnerella Gsp07 and G . swidsinskii / G . leopoldii were associated with remission. Lactobacillus species abundance rose in 4–14 days after initiation of treatment in most but not all recurrent and remission patients, although increases were more sustained among remission patients. The findings suggest that Gardnerella Gsp07 and G . swidsinskii / G . leopoldii are markers of poor clinical outcome or may directly or indirectly suppress recovery of Lactobacillus species, thereby interfering with clinical recovery. Therapies that target these strains may improve patient outcome.

Bacterial vaginosis (BV) is associated with a state of vaginal dysbiosis typically involving depletion of otherwise dominant populations of Lactobacillus . The causes of this microbial succession are not known; there may be multiple causes. Standard treatment includes oral metronidazole, which typically restores Lactobacillus species to dominance. However, recurrence rates are high; recurrent BV patients recur 3–4 times annually and are often refractory to treatment. Our previous qPCR-based study of recurrent BV patients pointed to putatively more virulent species of Gardnerella that were associated with refractory responses to oral metronidazole, and less robust recovery of Lactobacillus species associated with recurrence after an initial period of remission. However, these associations did not account for outcomes in all patients, suggesting that other bacterial species were involved. In this follow-up study, we sequenced the V4 domain of 16S rRNA sequences of 41of these same patients pre- and posttreatment. Overall compositions among pretreatment clinical outcome groups were not different, although alpha diversity significantly decreased: refractory > recurrent > remission. Combinations of key species were associated with and prognostic for outcome. Higher pretreatment abundance of Megasphaera lornae together with lower abundance of Gardnerella Gsp07 and Finegoldia magna predicted long term remission after oral metronidazole. Furthermore, a subset of refractory patients that did not have high levels of Gardnerella Gsp07 , instead had elevated levels of alternative species including Atopobium vaginae , Mageeibacillus indolicus (BVAB3) , and Prevotella timonensis . Patients who recurred after transient remission had elevated abundance of species including Atopobium vaginae , Gardnerella , and Aerococcus christensenii , compared to long-term remission patients. Core bacterial species among refractory patients did not change in abundance after metronidazole, suggesting resistance or tolerance, in contrast to the loss in abundance of the same species among recurrent or remission patients. These findings have potential prognostic and therapeutic implications.

Among the infectious causes of vulvovaginal symptoms, bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC) dominate. Apart from infrequent mixed infections, both are considered independent and caused by unrelated pathogenic mechanisms. Clinical experience, however, is strongly suggestive that in some populations these infections are linked with recurrent BV (RBV) serving as the dominant etiopathogenic trigger for development of recurrent VVC (RVVC) with profound clinical and therapeutic consequences. The biologic basis for this critical interrelationship is discussed and suggests that as a consequence of BV dysbiosis, and not necessarily because of antibiotics prescribed, immune defenses are compromised, neutralizing vaginal yeast tolerance. The consequent BV-induced vaginal proinflammatory environment predisposes to mixed infection or consecutive episodes of post-treatment VVC. Recurrent BV and repeated antimicrobial drug exposure also predispose to acquired fluconazole resistance in C. albicans isolates, contributing to refractory vulvovaginal candidiasis.

Bacterial vaginosis (BV) is the most common vaginal dysbiosis to affect women globally, yet an unacceptably high proportion of women experience BV recurrence within 6 months of recommended antibiotic therapy. The low rate of sustained cure highlights our limited understanding of the pathogenesis of BV recurrence, which has been attributed to possible persistence and re-emergence of BV-associated bacteria (BVAB) or a BV-associated biofilm following antimicrobials and/or reinfection occurring from sexual partners. There is a robust body of evidence to support the exchange of bacteria between partners during sexual activity, and while the hypothesis that women treated for BV are subsequently reinfected with BVAB following sex with an untreated sexual partner is not new, failure of past partner treatment trials has eroded confidence in this concept. If reinfection is a key driver of recurrence, current antimicrobial regimens directed to women alone are unlikely to achieve a high level of sustained cure, and the approach of partner treatment to reduce reinfection is justified. In this manuscript, we present the molecular and epidemiological evidence that underlies the hypothesis that BV is sexually transmitted, and summarise why research that continues to consider sexual partnerships is necessary. We also outline the significant barriers and challenges that we have identified while undertaking partner treatment studies, and we discuss the factors that impact on our ability to determine their effectiveness. Ultimately, the pathogenesis of BV recurrence is likely to be multifaceted and not attributable to a single mechanism in all women. If we are to achieve sustained cure for women, it is likely that combined and individualised approaches to eradicate BVAB, support an optimal vaginal microbiome, and prevent reinfection from partners will be required.

The fungal pathogen Candida glabrata has emerged as a major health threat since it readily acquires resistance to multiple drug classes, including triazoles and/or echinocandins. Thus far, cellular mechanisms promoting the emergence of resistance to multiple drug classes have not been described in this organism. Here we demonstrate that a mutator phenotype caused by a mismatch repair defect is prevalent in C. glabrata clinical isolates. Strains carrying alterations in mismatch repair gene MSH2 exhibit a higher propensity to breakthrough antifungal treatment in vitro and in mouse models of colonization, and are recovered at a high rate (55% of all C. glabrata recovered) from patients. This genetic mechanism promotes the acquisition of resistance to multiple antifungals, at least partially explaining the elevated rates of triazole and multi-drug resistance associated with C. glabrata . We anticipate that identifying MSH2 defects in infecting strains may influence the management of patients on antifungal drug therapy. The fungal pathogen Candida glabrata readily acquires resistance to multiple types of antifungal drugs. Here, Healey et al . show that C. glabrata clinical isolates often carry mutations in a gene involved in DNA mismatch repair, and this is associated with increased propensity to develop antifungal resistance.

Bacterial vaginosis (BV), the most common cause of vaginal discharge, is characterized by a shift in the vaginal microbiota from Lactobacillus species dominance to a diverse array of facultative and strict anaerobic bacteria which form a multi-species biofilm on vaginal epithelial cells. The rate of BV recurrence after therapy is high, often >60%. The BV biofilm itself likely contributes to recurrent and refractory disease after treatment by reducing antimicrobial penetration. However, antimicrobial resistance in BV-associated bacteria, including those both within the biofilm and the vaginal canal, may be the result of independent, unrelated bacterial properties. In the absence of new, more potent antimicrobial agents to eradicate drug-resistant pathogenic vaginal microbiota, treatment advances in refractory and recurrent BV have employed new strategies incorporating combination therapy. Such strategies include the use of combination antimicrobial regimens as well as alternative approaches such as probiotics and vaginal fluid transfer. Our current recommendations for the treatment of refractory and recurrent BV are provided.