Resistance to Fluconazole of Candida albicans in Vaginal Isolates: a 10-Year Study in a Clinical Referral Center.

Review of vaginal isolates of Candida albicans that caused clinical failure in a 10-year collection of vaginal C. albicans specimens obtained in a university vaginitis referral clinic indicated an increase in fluconazole resistance. Factors contributing to azole resistance are discussed, including treatment choice associated with fluconazole-resistant C. albicans vaginal infection.

Efficacy and safety of oral ibrexafungerp for the treatment of acute vulvovaginal candidiasis: a global phase 3, randomised, placebo-controlled superiority study (VANISH 306).

OBJECTIVE: To evaluate the efficacy and safety of ibrexafungerp versus placebo for acute vulvovaginal candidiasis (VVC) treatment. DESIGN: Global phase 3, randomised, placebo-controlled superiority study. SETTING: Study sites in the USA (n = 19) and Bulgaria (n = 18). POPULATION: Female patients aged ≥12 years with acute VVC and a vulvovaginal signs and symptoms (VSS) score ≥4 at baseline. METHODS: Patients were randomly assigned 2:1 to ibrexafungerp (300 mg twice for 1 day) or placebo. MAIN OUTCOME MEASURES: The primary endpoint was the percentage of patients with a clinical cure (VSS = 0) at the test-of-cure visit (day 11 ± 3). Secondary endpoints included percentages of patients with mycological eradication, clinical cure and mycological eradication (overall success), clinical improvement (VSS ≤1) at test-of-cure visit, and complete resolution of symptoms at follow-up visit (day 25 ± 4). RESULTS: At the test-of-cure visit, patients receiving ibrexafungerp had significantly higher rates of clinical cure (63.3% [119/188] versus 44.0% [37/84]; P = 0.007), mycological eradication (58.5% [110/188] versus 29.8% [25/84]; P < 0.001), overall success (46.1% [82/188] versus 28.4% [23/84]; P = 0.022) and clinical improvement (72.3% [136/188] versus 54.8% [46/84]; P = 0.01) versus those receiving placebo. Symptom resolution was sustained and further increased with ibrexafungerp (73.9%) versus placebo (52.4%) at follow-up (P = 0.001). Ibrexafungerp was generally well tolerated. Adverse events were primarily gastrointestinal and were mild to moderate in severity. CONCLUSIONS: Ibrexafungerp demonstrated statistical superiority over placebo for the primary and secondary endpoints. Ibrexafungerp is a promising novel, well-tolerated and effective oral 1-day treatment for acute VVC. TWEETABLE ABSTRACT: Ibrexafungerp is statistically superior to placebo for the treatment of vulvovaginal candidiasis.

Vulvovaginitis Caused by Candida Species Following Antibiotic Exposure.

PURPOSE OF REVIEW: Goal was to review epidemiology, pathophysiology, and prevention of post-antibiotic Candida vulvovaginitis (VVC). RECENT FINDINGS: Antibacterial therapy, whether systemic or locally applied to the vagina, represents the single most frequent and predictable cause or triggering mechanism of symptomatic vulvovaginal candidiasis (VVC). Such initiating mechanisms may precipitate sporadic or recurrent episodes of VVC. In spite of this widely recognized association, the exact mechanism whereby antibiotics of all classes cause acute exacerbation of symptomatic vaginal disease remains largely unstudied and therefore largely unknown. Pathophysiology is hypothesized to be reduction or alteration of vaginal microbiome restraints of yeast colonization, proliferation, and expression of virulence characteristics. The predictable link between antibiotic use and post-antibiotic VVC affords practitioners an opportunity for timely intervention using selective, convenient antimycotics usually drugs but possibly probiotic measures. Indications and limitation of these steps are discussed.

Candida parapsilosis Vaginal Infection-a New Site of Azole Drug Resistance.

PURPOSE OF REVIEW: Evaluation of pathogenicity of an uncommon vaginal Candida species, Candida parapsilosis with particular references to susceptibility to conventional antifungal agents. RECENT FINDINGS: C. parapsilosis vaginal isolates usually present in asymptomatic women as commensals but may induce vulvovaginal symptoms indistinguishable from C. albicans requiring antifungal therapy; however, recent experience reveals clinically relevant resistance to the azole class of antimycotics. CONCLUSION: Clinicians are required to determine a causal relationship between vaginal isolates of C. parapsilosis before prescribing antifungal agents, recognizing the possibility of fluconazole resistance to explain refractory symptomatology.

Current treatment options for vulvovaginal candidiasis caused by azole-resistant Candida species.

INTRODUCTION: Clinicians are increasingly challenged by patients with refractory vulvovaginal candidiasis (VVC) caused by azole-resistant Candida species. Fluconazole resistant C.albicans is a growing and perplexing problem following years of indiscriminate drug prescription and unnecessary drug exposure and for which there are few therapeutic alternatives. Regrettably, although the azole class of drugs has expanded, new classes of antifungal drugs have not been forthcoming, limiting effective treatment options in patients with azole resistant Candida vaginitis. AREAS COVERED: This review covers published data on epidemiology, pathophysiology and treatment options for women with azole-resistant refractory VVC. EXPERT OPINION: Fluconazole resistant C.albicans adds to the challenge of azole resistant non-albicans Candida spp. Both issues follow years of indiscriminate drug prescription and unnecessary fluconazole exposure. Although an understanding of azole resistance in yeast has been established, this knowledge has not translated into useful therapeutic advantage. Treatment options for such women with refractory symptoms are extremely limited. New therapeutic options and strategies are urgently needed to meet this challenge of azole drug resistance.

Gardnerella vaginalis population dynamics in bacterial vaginosis.

Bacterial vaginosis (BV) is the leading cause of vaginal discharge and is associated with the facultative Gram-variable bacterium Gardnerella vaginalis, whose population structure consists of four clades. Our goal was to determine if these clades differ with regard to abundance during BV. We performed a short-term longitudinal study of BV. Patients were evaluated according to the Amsel criteria and Nugent scoring at initial diagnosis, immediately after treatment and at a 40- to 45-day follow-up visit. G. vaginalis clade abundance was determined by quantitative real-time polymerase chain reactions (qPCRs). Among all specimens, the abundance of clades 1 and 4 were higher than that of clades 2 and 3 (P < 0.001). In general, the abundance of each clade increased with the degree of vaginal dysbiosis, as determined by the Nugent score and was greater in women with Amsel 4 compared with those with Amsel 0. Only clade 1 abundance was greater when Amsel 0 or 1 specimens were compared with Amsel 2 or 3 specimens (P < 0.01). Following antimicrobial treatment, abundance of clades 1 (P < 0.001) and 4 (P < 0.05) decreased regardless of the clinical and microbiological outcome, whereas clade 2 only decreased in women who had a sustained treatment response for 40-45 days (P < 0.01). Recurrent BV was characterized by post-treatment increases of clade 1 and 2 (P < 0.01). Clades 1 and 4 predominate in vaginal specimens. Clade abundance differs with regard to the Nugent score, the Amsel criteria, and response to therapy and BV recurrence.

Association of a variable number tandem repeat in the NLRP3 gene in women with susceptibility to RVVC.

Vaginal infections with Candida spp. frequently occur in women of childbearing age. A small proportion of these women experience recurrent vulvovaginal candidosis (RVVC), which is characterized by at least three episodes of infection in one year. In addition to known risk factors such as antibiotics, diabetes, or pregnancy, host genetic variation and inflammatory pathways such as the IL-1/Th17 axis have been reported to play a substantial role in the pathogenesis of RVVC. In this study, we assessed a variable number tandem repeat (VNTR) polymorphism in the NLRP3 gene that encodes a component of the inflammasome, processing the proinflammatory cytokines IL-1ß and IL-18. A total of 270 RVVC patients and 583 healthy controls were analyzed, and increased diseases susceptibility was associated with the presence of the 12/9 genotype. Furthermore, functional studies demonstrate that IL-1ß production at the vaginal surface is higher in RVVC patients bearing the 12/9 genotype compared to controls, whereas IL-1Ra levels were decreased and IL-18 levels remained unchanged. These findings suggest that IL-1ß-mediated hyperinflammation conveyed by the NLRP3 gene plays a causal role in the pathogenesis of RVVC and may identify this pathway as a potential therapeutic target in the disease.

Efficacy of the clinical agent VT-1161 against fluconazole-sensitive and -resistant Candida albicans in a murine model of vaginal candidiasis.

Vulvovaginal candidiasis (VVC) and recurrent VVC (RVVC) remain major health problems for women. VT-1161, a novel fungal CYP51 inhibitor which has potent antifungal activity against fluconazole-sensitive Candida albicans, retained its in vitro potency (MIC50 of ≤0.015 and MIC90 of 0.12 µg/ml) against 10 clinical isolates from VVC or RVVC patients resistant to fluconazole (MIC50 of 8 and MIC90 of 64 µg/ml). VT-1161 pharmacokinetics in mice displayed a high volume of distribution (1.4 liters/kg), high oral absorption (73%), and a long half-life (>48 h) and showed rapid penetration into vaginal tissue. In a murine model of vaginal candidiasis using fluconazole-sensitive yeast, oral doses as low as 4 mg/kg VT-1161 significantly reduced the fungal burden 1 and 4 days posttreatment (P < 0.0001). Similar VT-1161 efficacy was measured when an isolate highly resistant to fluconazole (MIC of 64 µg/ml) but fully sensitive in vitro to VT-1161 was used. When an isolate partially sensitive to VT-1161 (MIC of 0.12 µg/ml) and moderately resistant to fluconazole (MIC of 8 µg/ml) was used, VT-1161 remained efficacious, whereas fluconazole was efficacious on day 1 but did not sustain efficacy 4 days posttreatment. Both agents were inactive in treating an infection with an isolate that demonstrated weaker potency (MICs of 2 and 64 µg/ml for VT-1161 and fluconazole, respectively). Finally, the plasma concentrations of free VT-1161 were predictive of efficacy when in excess of the in vitro MIC values. These data support the clinical development of VT-1161 as a potentially more efficacious treatment for VVC and RVVC.

The Role of PCR in the Diagnosis of Candida Vulvovaginitis-a New Gold Standard?

PCR is recognized as a reliable technique for detection of all types of microorganisms. Being highly objective and reproducible also sensitive and specific, PCR is now widely used for sexually transmitted infection (STI) diagnosis. Potential, however, exists for detecting non-pathogens, and not identifying a pathogenic state decreases specificity or clinical significance. PCR Candida tests of vaginal specimens are now widely available and frequently used offering a modest to moderate increase in sensitivity and are likely to replace traditional culture and DNA homology testing. Nevertheless, there remain considerable gaps in our knowledge regarding the usefulness and applications of these expensive tests.

Vulvovaginal candidiasis in pregnancy.

Prevalence studies indicate that Candida species colonize the vagina in at least 20 % of all women, rising to 30 % in pregnancy. Although, some studies concluded that pregnant women were more likely to have symptomatic vaginal infections caused by Candida, yet other studies found a high prevalence of asymptomatic infection only during pregnancy. Most episodes of symptomatic vulvovaginal candidiasis (VVC) occur during the second and third trimesters. The increased risk of VVC in pregnancy is likely sustained by pregnancy-related factors, such as immunologic alterations, increased estrogen levels, and increased vaginal glycogen production. Although evidence is incomplete, there is some emerging data which suggests that candidiasis in pregnancy may be associated with increased risk of pregnancy complications, such as premature rupture of membranes, preterm labor, chorioamnionitis, and congenital cutaneous candidiasis. In contrast to nonpregnant women, there are no formal studies, evaluating the use of long-term suppressive maintenance oral azoles in the treatment of recurrent VVC (RVVC) in pregnancy. Most clinicians do not offer suppressive therapy in pregnancy and prefer to treat individual symptomatic episodes only utilizing a topical imidazole vaginally for 7 days to minimize systemic exposure to medications.

The relationship between the new taxonomy of Streptococcus bovis and its clonality to colon cancer, endocarditis, and biliary disease.

BACKGROUND: The nomenclature of Streptococcus bovis has changed. The study aims were to examine and compare the clinical characteristics and outcomes of infections based on the new taxonomy and the genetic relatedness of strains. METHODS: Bacteremic cases from 2004 to 2010 at Assaf Harofeh Medical Center were reviewed. VITEK 2 later confirmed with polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was used for subspecies identification. VITEK 2 later confirmed with Etests was used for minimal inhibitory concentration (MIC) testing. Repetitive extragenic palindromic polymerase chain reaction (rep-PCR) was used to determine the genetic relatedness of strains. RESULTS: Twenty-four bacteremia cases were included. The median age of patients was 81 years (range 1 day to 91 years), two were neonates, three were pregnant, and 18 were elderly (≥ 65 years of age). The Charlson's combined conditional age-related score was 8.2 ± 2.9, and 11 (58 %) patients were immunosuppressed. There were 13 patients who had S. gallolyticus subsp. pasteurianus, six had S. gallolyticus subsp. gallolyticus, four had S. infantarius subsp. coli, and one had S. infantarius subsp. infantarius. Ten of 19 non-pregnant adult patients had colon adenoma or carcinoma, three had acute biliary disease, and five had endocarditis. Two patients died in the hospital. rep-PCR revealed polyclonality. There were no significant associations between subspecies or genotypes and the various clinical characteristics or outcomes. CONCLUSION: S. bovis bacteremia is a serious disease that affects elderly immunosuppressed individuals. Infection is strongly associated with colon pathology and endocarditis, regardless of the new taxonomy or clone complex. The identification of S. bovis is of paramount importance, and microbiology laboratories should differentiate its processing from that of other S. viridans.

Safety and tolerability of voriconazole in patients with baseline renal insufficiency and candidemia.

Acutely ill patients with candidemia frequently suffer from renal insufficiency. Voriconazole's intravenous formulation with sulfobutylether beta-cyclodextrin (SBECD) is restricted in patients with renal insufficiency. We evaluated the use of intravenous voriconazole formulated with SBECD in candidemic patients with renal insufficiency and compared treatment outcome and safety to those who received a short course of amphotericin B deoxycholate followed by fluconazole. We reviewed data on treatment outcome, survival, safety, and tolerability from the subset of patients with moderate (creatinine clearance [CrCl], 30 to 50 ml/min) or severe (CrCl, <30 ml/min) renal insufficiency enrolled in a trial of voriconazole compared to amphotericin B deoxycholate followed by fluconazole for treatment of candidemia in 370 patients. Fifty-eight patients with renal impairment were identified: 41 patients on voriconazole and 17 on amphotericin B/fluconazole. The median duration of treatment was 14 days for voriconazole (median, 7 days intravenous) and 11 days for amphotericin B/fluconazole, 3 days of which were for amphotericin B. Despite the short duration of exposure, worsening of renal function or newly emerged renal adverse events were reported in 53% of amphotericin B-treated patients compared to 39% of voriconazole-treated patients. During treatment, median serum creatinine decreased in the voriconazole arm, whereas creatinine increased in the amphotericin B/fluconazole arm, before return to baseline at week 3. All-cause mortality at 14 weeks was 49% in the voriconazole arm compared to 65% in the amphotericin B/fluconazole arm. Intravenous voriconazole formulated with SBECD was effective in patients with moderate or severe renal insufficiency and candidemia and was associated with less acute renal toxicity than amphotericin B/fluconazole.

The vaginal microbiome: new information about genital tract flora using molecular based techniques.

Vaginal microbiome studies provide information that may change the way we define vaginal flora. Normal flora appears dominated by one or two species of Lactobacillus. Significant numbers of healthy women lack appreciable numbers of vaginal lactobacilli. Bacterial vaginosis (BV) is not a single entity, but instead consists of different bacterial communities or profiles of greater microbial diversity than is evident from cultivation-dependent studies. BV should be considered a syndrome of variable composition that results in different symptoms, phenotypical outcomes, and responses to different antibiotic regimens. This information may help to elucidate the link between BV and infection-related adverse outcomes of pregnancy.

Current debate on the use of antibiotic prophylaxis for caesarean section.

Caesarean delivery is frequently complicated by surgical site infections, endometritis and urinary tract infection. Most surgical site infections occur after discharge from the hospital, and are increasingly being used as performance indicators. Worldwide, the rate of caesarean delivery is increasing. Evidence-based guidelines recommended the use of prophylactic antibiotics before surgical incision. An exception is made for caesarean delivery, where narrow-range antibiotics are administered after umbilical cord clamping because of putative neonatal benefit. However, recent evidence supports the use of pre-incision, broad-spectrum antibiotics, which result in a lower rate of maternal morbidity with no disadvantage to the neonate.

Long-term follow-up of patients with candiduria.

Candiduria is commonly encountered in hospitalized patients, particularly those with indwelling urinary catheters. While risk factors and therapy are well described in previous studies, little is known about long-term outcomes and recurrence rates of candiduria. We studied 188 patients with candiduria in a retrospective chart review at a single institution from January 1999 to December 2000. Data were collected regarding risk factors and underlying disease, therapy, follow-up cultures until December 2003, and mortality. Ninety-one patients with at least one follow-up culture >1 month after the initial culture (range 2-48) were available for further study. In this group, patients receiving antifungal therapy for asymptomatic candiduria were paradoxically more likely to have subsequent positive urine cultures than patients who never received antifungal therapy. Six patients developed candidemia during follow-up, although in none was this considered to represent a consequence of candiduria. Mortality rate at the end of the follow-up period (mean of 18 months) was 43%, including one death attributed to candidemia. Therapy for candiduria does not appear to reduce candiduria recurrence rates through 48 months of follow-up and little evidence of treatment benefit was identified.

Susceptibility profile of vaginal isolates of Candida albicans prior to and following fluconazole introduction - impact of two decades.

Current treatment options for vulvovaginal candidiasis due to Candida albicans include over-the-counter and prescription antifungal agents. Fluconazole has been used extensively with an unknown impact on susceptibility. To investigate antifungal susceptibility trends in clinical vaginal isolates of C. albicans from 1986 to 2008, microdilution susceptibility was performed on randomly selected single isolates. Minimum inhibitory concentrations (MICs) were determined for: fluconazole, clotrimazole, miconazole, ketoconazole, itraconazole, voriconazole, flucytosine and amphotericin B. The MIC(90) for each drug was then calculated for the time periods: 1986-1989, 1992-1996 and 2005-2007. A total of 250 C. albicans vaginal isolates were included. The MIC(90) (mcg ml(-1) ) for fluconazole was 0.25, 0.5 and 0.5 mcg ml(-1) for each grouping, respectively. The corresponding MIC(90) for flucytosine was 1, 2 and 8 mcg ml(-1) , respectively. The MIC(90) for the remaining agents remained unchanged across time periods mentioned. Of note, the percentage of isolates with MIC ≥1 and ≥2 mcg ml(-1) for fluconazole increased from 3% to 9% over the study period. Although the C. albicans MIC(90) to fluconazole in vaginal isolates has not shown a clinically significant increase since 1986, there is an increasing number of isolates with elevated MICs. The implications of this increase are unknown, but given the achievable vaginal concentrations of fluconazole, reduced susceptibility may have clinical relevance.

Parvovirus B19 infection in human pregnancy.

Human parvovirus B19 infection is widespread. Approximately 30-50% of pregnant women are nonimmune, and vertical transmission is common following maternal infection in pregnancy. Fetal infection may be associated with a normal outcome, but fetal death may also occur without ultrasound evidence of infectious sequelae. B19 infection should be considered in any case of nonimmune hydrops. Diagnosis is mainly through serology and polymerase chain reaction. Surveillance requires sequential ultrasound and Doppler screening for signs of fetal anaemia, heart failure and hydrops. Immunoglobulins, antiviral and vaccination are not yet available, but intrauterine transfusion in selected cases can be life saving.