In the search for appropriateness in the cure of vaginitis: a model of anti-fungal stewardship?

Antimicrobial resistance remains a worldwide issue with a major clinical and economic impact, leading to exceeding mortality, increased frequency of hospitalization and a great burden on the healthcare systems. Vulvovaginitis, especially when due to mixed infections, has emerged as a condition for which appropriate selection of antimicrobial therapy and proper antimicrobial stewardship programs (ASPs) may contribute to minimizing the resistance development. This review discusses the appropriateness of selecting treatment for vulvovaginitis in order to reduce the development of resistance in gynecological practice. Narrative review based on a selection of literature performed according to the Authors' experience and a MEDLINE search using the following keywords: "vaginitis" OR "Candida" OR "fungal infection" AND "antifungal therapy". No limits were applied, but papers were selected for inclusion in this narrative review according to their relevance to the topic, as judged by the Authors. Worldwide, antimicrobial treatment in gynecology and ASPs focuses on prescribing systemic and expensive antifungal drugs, while treatment selection should consider several factors. Recently, topical azoles have been recommended as suitable alternatives to oral systemic azoles, given their similar efficacy in limiting clinical recurrence. In particular, fenticonazole has already been proposed as an alternative to systemic antifungal drugs to limit the onset of resistance. Optimizing the selection of antimicrobial treatment can help reduce the development of resistance in gynecological practice. Given its wide action spectrum and ability to exert antimicrobial activity against fungi, bacteria and mixed infections, fenticonazole may be considered a suitable first-line, empiric therapy for vaginal and mixed infections, avoiding alteration of intestinal microflora and minimizing the risk of selection of drug-resistant microbial strains.

The impact of carbapenemase-producing Enterobacteriaceae colonization on infection risk after liver transplantation: a prospective observational cohort study.

OBJECTIVE: To investigate the impact of colonization with carbapenemase-producing Enterobacteriaceae (CPE) on the CPE infection risk after liver transplantation (LT). METHODS: Prospective cohort study of all adult patients undergoing LT at our centre over an 8-year period (2010-2017). Individuals were screened for CPE colonization by rectal swabs at inclusion onto the waiting list, immediately before LT and weekly after LT until hospital discharge. Asymptomatic carriers did not receive decolonization, anti-CPE prophylaxis or pre-emptive antibiotic therapy. Participants were followed up for 1 year after LT. RESULTS: We analysed 553 individuals who underwent a first LT, 38 were colonized with CPE at LT and 104 acquired colonization after LT. CPE colonization rates at LT and acquired after LT increased significantly over the study period: incidence rate ratios (IRR) 1.21 (95% CI 1.05-1.39) and 1.17 (95% CI 1.07-1.27), respectively. Overall, 57 patients developed CPE infection within a median of 31 (interquartile range 11-115) days after LT, with an incidence of 3.05 cases per 10 000 LT-recipient-days and a non-significant increase over the study period (IRR 1.11, 95% CI 0.98-1.26). In multivariable analysis, CPE colonization at LT (hazard ratio (HR) 18.50, 95% CI 6.76-50.54) and CPE colonization acquired after LT (HR 16.89, 95% CI 6.95-41.00) were the strongest risk factors for CPE infection, along with combined transplant (HR 2.60, 95% CI 1.20-5.59), higher Model for End-Stage Liver Disease at the time of LT (HR 1.03, 95% CI 1.00-1.07), prolonged mechanical ventilation (HR 2.63, 95% CI 1.48-4.67), re-intervention (HR 2.16, 95% CI 1.21-3.84) and rejection (HR 2.81, 95% CI 1.52-5.21). CONCLUSIONS: CPE colonization at LT or acquired after LT were the strongest predictors of CPE infection. Prevention strategies focused on LT candidates and recipients colonized with CPE should be investigated.

Role of biclotymol-based products in the treatment of infectious sore throat.

OBJECTIVE: In clinical practice, physicians often prescribe antibiotics for the treatment of sore throat. However, current guidelines clarify that antibiotics should not be used in patients with less severe presentation of this condition in order to relieve symptoms. With the aim to limit the onset of resistance and reduce the occurrence of adverse events, other remedies can be used instead. For the past forty years, the use of biclotymol-based products has been a common practice for the treatment of sore throat. This paper reviews and critically discusses the role of biclotymol-based products as a local treatment of infectious oropharyngeal diseases. MATERIALS AND METHODS: Papers for consideration for the present article were retrieved in Authors' personal collection of literature. In order to extend the number of considered papers, a PubMed search was also conducted. Papers were selected for inclusion according to their relevance for the topic, as judged by the Authors. RESULTS: Biclotymol is a molecule characterized by a marked antibacterial efficacy, also associated with evident anti-inflammatory and analgesic action demonstrated in a number of preclinical studies. Noteworthy, all these actions have a fast onset of effect and are long-lasting. Two well-conducted investigations have assessed biclotymol in spray formulation. Notably, both studies proved its efficacy, with the wide majority of patients reporting "very good" or "good" efficacy. The analgesic and anti-inflammatory properties of biclotymol were also demonstrated. Tolerability was excellent. CONCLUSIONS: Enough evidence exists to recommend the use of biclotymol as a prompt, effective and safe first-line option for the treatment of sore throat.

Fenticonazole: an effective topical treatment for superficial mycoses as the first-step of antifungal stewardship program.

The resistance of microorganisms to antimicrobial drugs is a major issue for public health, with important consequences in terms of morbidity, mortality and resource use. The phenomenon is so serious that in some areas of the world resistant strains to all available drugs have been selected. Many conditions may result in the development of resistance: they include the indiscriminate or inappropriate (e.g., for viral infection or colonization) use of antibiotics, the excessive duration of the prescribed treatment regimens, as well as inadequate dosing or administration routes. Resistance is well-known, but less studied, also for infections caused by fungi. In the last decade, an impressive outbreak of candidiasis due to non-albicans strains (with variable patterns of resistance to azoles) was observed. This outbreak was likely associated with inappropriate use of oral azoles for the treatment of non-complicated candidiasis, such as vulvovaginal candidiasis or Candida dermatitis. In this setting, fenticonazole may represent an effective topical drug for the treatment of mycotic infections of skin and mucosa. Topical treatment of superficial mycoses still holds a major importance as it helps reduce the exposure to oral systemic azoles - mainly fluconazole and itraconazole - of intestinal microbiota, which represents the main human reservoir of yeasts. This strategy can contribute to reduce the selection of resistant strains of Candida, within the context of a really-effective antifungal stewardship program.

Superficial swab versus deep-tissue biopsy for the microbiological diagnosis of local infection in advanced-stage pressure ulcers of spinal-cord-injured patients: a prospective study.

OBJECTIVE: To assess the predictive value of superficial ulcer swab culture to make a microbiological diagnosis of deep wound infections in spinal cord injury (SCI) patients with advanced-stage pressure ulcers. METHODS: From July 2011 to February 2014, we performed a prospective, single-centre study on adult SCI patients undergoing scheduled surgical debridement and reconstruction for advanced-stage pressure ulcers, at Montecatone Rehabilitation Institute, a 150-bed hospital dedicated to SCI care. Three superficial ulcer swabs were preoperatively collected using the Levine technique, then sent for culture. In surgery, multiple bone and soft-tissue specimens were taken and sent for culture and histological examination. No antibiotics were administered before surgery. The results of swabs and intraoperative specimens were compared. RESULTS: In all, 116 patients were included, median age 49 years; a majority were males with post-traumatic paraplegia. According to intraoperative specimen cultures, the most common micro-organisms were Staphylococcus aureus, Proteus mirabilis, and Pseudomonas aeruginosa, found in 31, 27, and 16 cases, respectively. Concordance between superficial swabs and intraoperative specimen culture was found in only in 25 out of 116 cases (22%). The main reason for non-concordance was the yielding of different micro-organisms (41 out of 116); false negatives (swab negative/intraoperative positive) accounted for 31 out of 116 and false positives (swab positive/intraoperative negative) for 19 out of 116. When compared with intraoperative specimens, sensitivity and specificity of the swab culture were 80% and 54%, respectively. CONCLUSIONS: Our results confirm that in patients with advanced-stage pressure ulcers, the cultures of a superficial ulcer swab are not useful in either the diagnosis of a superinfection or the prediction of the role of involved micro-organisms.

Antifungal prophylaxis in liver transplant recipients: one size does not fit all.

BACKGROUND: Targeted antifungal prophylaxis against Candida species or against Candida species and Aspergillus species, according to individual patient risk factors (RFs), is recommended by experts. However, recent studies have reported fluconazole is as effective as broader spectrum antifungals for preventing invasive fungal infection (IFI) after liver transplantation (LT). METHODS: We performed a retrospective cohort study of all adult patients who underwent LT at our 1420-bed tertiary teaching hospital, from June 2010 to December 2014, to assess the rate and etiology of IFI within 100 days after LT, to investigate the compliance with targeted prophylaxis, and to analyze risk factors for developing IFI. RESULTS: In total, 303 patients underwent LT. Patients were classified as having low (no RFs), intermediate (1 RF for invasive candidiasis [IC]), and high risk (1 RF for invasive aspergillosis [IA] or ≥2 RFs for IC) for IFI in 20%, 30%, and 50% of cases, respectively. A total of 139 patients received antifungal prophylaxis: 98 with a mold-active drug and 41 with fluconazole. Overall adherence to targeted prophylaxis was 53%. Nineteen patients (6.3%) developed IFI: 7 IC and 12 IA. Multivariate Cox regression analysis, adjusted for median model for end-stage liver disease score at LT, stratification risk group, and adherence to targeted prophylaxis, showed that graft dysfunction, renal replacement therapy, and prophylaxis with fluconazole were independent risk factors for IFI. Seven of the 9 patients who received fluconazole prophylaxis and developed IFI were classified as having high risk for IFI, and 6 developed IA. CONCLUSION: Recommended stratification is accurate for predicting patients at very high risk for IFI, who should receive prophylaxis with a mold-active drug.

Risk factors for infection with carbapenem-resistant Klebsiella pneumoniae after liver transplantation: the importance of pre- and posttransplant colonization.

Improved understanding of risk factors associated with carbapenem-resistant-Klebsiella pneumoniae (CR-KP) infection after liver transplantation (LT) can aid development of effective preventive strategies. We performed a prospective cohort study of all adult patients undergoing LT at our hospital during 30-month period to define risk factors associated with CR-KP infection. All patients were screened for CR-KP carriage by rectal swabs before and after LT. No therapy was administered to decolonize or treat asymptomatic CR-KP carriers. All patients were monitored up to 180 days after LT. Of 237 transplant patients screened, 41 were identified as CR-KP carriers (11 at LT, 30 after LT), and 20 developed CR-KP infection (18 bloodstream-infection, 2 pneumonia) a median of 41.5 days after LT. CR-KP infection rates among patients non-colonized, colonized at LT, and colonized after LT were 2%, 18.2% and 46.7% (p < 0.001). Independent risk factors for CR-KP infection identified by multivariate analysis, included: renal-replacement-therapy; mechanical ventilation > 48 h; HCV recurrence, and colonization at any time with CR-KP. Based on these four variables, we developed a risk score that effectively discriminated patients at low versus higher risk for CR-KP infection (AUC 0.93, 95% CI 0.86-1.00, p < 0.001). Our results may help to design preventive strategies for LT recipients in CR-KP endemic areas.

Impact of a hospital-wide multifaceted programme for reducing carbapenem-resistant Enterobacteriaceae infections in a large teaching hospital in northern Italy.

We performed a quasi-experimental study of a multifaceted infection control programme for reducing carbapenem-resistant Enterobacteriaceae (CRE) transmission and bloodstream infections (BSIs) in a 1420-bed university-affiliated teaching hospital during 2010-2014, with 30 months of follow-up. The programme consisted of the following: (a) rectal swab cultures were performed in all patients admitted to high-risk units (intensive-care units, transplantation, and haematology) to screen for CRE carriage, or for any room-mates of CRE-positive patients in other units; (b) cohorting of carriers, managed with strict contact precautions; (c) intensification of education, cleaning and hand-washing programmes; and (d) promotion of an antibiotic stewardship programme carbapenem-sparing regimen. The 30-month incidence rates of CRE-positive rectal cultures and BSIs were analysed with Poisson regression. Following the intervention, the incidence rate of CRE BSI (risk reduction 0.96, 95% CI 0.92-0.99, p 0.03) and CRE colonization (risk reduction 0.96, 95% CI 0.95-0.97, p <0.0001) significantly decreased over a period of 30 months. After accounting for changes in monthly census and percentage of externally acquired cases (positive at ≤72 h), the average institutional monthly rate of compliance with CRE screening procedures was the only independent variable associated with a declining monthly incidence of CRE colonization (p 0.002). The monthly incidence of CRE carriage was predictive of BSI (p 0.01). Targeted screening and cohorting of CRE carriers and infections, combined with cleaning, education, and antimicrobial stewardship measures, significantly decreased the institutional incidence of CRE BSI and colonization, despite endemically high CRE carriage rates in the region.

Hospital statistics for antibiotics: defined versus prescribed daily dose.

PURPOSE: Defined daily doses (DDD) are widely used as a unit to measure drug use in hospital and community settings. However, discrepancies exist between DDD and actual prescribed daily dose (PDD). The present study aims at estimating an alternative PDD (PDD-proxy) to calculate rates of systemic antibiotic consumption and to compare these results with those obtained using DDD. METHODS: The study considered a 9-year period (2004-2012) and included the 17 Health Trusts (HTs) in the Emilia-Romagna Region, Italy. Drugs under study were antibacterials for systemic use (group J01). Data were obtained from the database for hospital drug prescription of Emilia-Romagna Region. The PDD-proxy was estimated by averaging the doses of antibiotic prescriptions from a point prevalence survey for healthcare-associated infections and antimicrobial use, conducted in Emilia-Romagna hospitals in 2012. RESULTS: Significant discrepancies between DDD and PDD were observed, especially for some antibiotics, resulting in DDD rates that were systematically higher than PDD-proxy rates. In 2012, HT median rates of antibiotic consumption were 90 DDD/100 bed days and 70 PDD-proxy/100 bed-days. However, PDD-proxy and DDD rates showed comparable trends within HTs, although some HTs ranked differently when one or the other measure was used. Interquartile ranges of DDD rates were systematically wider than those of PDD-proxy rates in most years in the period of interest. CONCLUSIONS: Comparison of HT antibiotic consumption using DDDs may artificially increase observed differences and affect the true HT ranking. Therefore, an additional unit of measurement is useful for in-depth analysis at the local level.

Spinal infection multidisciplinary management project (SIMP): from diagnosis to treatment guideline.

Spine infections require a multidisciplinary approach to be treated and solved. A guide line to drive physicians in the deep complexity of such a disease is extremely helpful. SIMP suggests a flow-chart built up on clear concepts such as right and well managed antibiotic therapy, sound stability of the spine, correct and smart use of the standard and functional imaging techniques, such as f18 FDG PET/CT. In 16 months a total of 41 patients have been treated for spondylodiscitis, discitis and vertebral osteomyelitis by our team of physicians and 25 patients have been enrolled in a prospective study whose target is the assessment of the SIMP flow-chart and of every single aspect that characterize it.

Successful treatment of rhinomaxillary form of mucormycosis infection after liver transplantation: a case report.

Mucormycosis is a rare opportunistic infection, usually associated with immunocompromised states. Several conditions such as hematologic malignancy (leukemia, lymphoma, myeloma), solid organ transplantation, diabetes mellitus, corticosteroid therapy, or chemotherapy predispose patients to infection. The aim of this study was to present a single case of mucor infection after 900 consecutive liver transplantations. Rhinomaxillary mucormycosis must be suspected in a transplant recipient showing fever, maxillary swelling, and edema. This condition can be successfully treated with early diagnosis and a combination of aggressive surgery and antifungal therapy.

Effects of dialysis membrane nature on intradialytic phagocytizing activity.

Blood-membrane contact in the extracorporeal circuit affects the activation of many biological systems. Among these, phagocytizing activity has been reported to be influenced by the nature of the hemodialysis membrane used, whether cellulosic or synthetic. This work reports on an ex-vivo, comparative test between cellulosics and synthetics concerning the effects of blood-membrane contact on the polymorphonucleate and monocyte phagocytizing function, both during and after the hemodialysis session. By means of flow cytometry, we evaluated the capacity for phagosoma formation and oxidative burst both in polymorphonucleates and monocytes. Ten hemodialysis patients were included in the study. Six separate dialysis procedures for each patient were considered, one per dialyzer (3 cellulosic and 3 synthetic membranes). Tests were performed at 15', 60', 210' and 4 hours after the session end. Comparative evaluation was made according to Student's t test. Polymorphonucleate phagocytosis and oxidative burst activation were globally more marked for synthetic than cellulosic membranes, tending to level out in the post-dialysis. This result could be affected by their functional exhaustion following pulmonary sequestration. Monocyte intradialytic phagocytosis and oxidative burst proved more activated by cellulosic membrane. All differences tended to vanish in the post-dialysis.

A randomized, double-blind trial on the use of a triple combination including nevirapine, a nonnucleoside reverse transcriptase HIV inhibitor, in antiretroviral-naive patients with advanced disease.

The immunologic and virologic activity of nevirapine in combination with two nucleosides (zidovudine [ZDV] and didanosine [ddI]) was evaluated in antiretroviral-naive patients with a CD4 count <200/mm3 or clinical AIDS. In all, 68 patients were enrolled in a 48-week double-blind, placebo-controlled trial. A group of 32 patients received ZDV + ddI + nevirapine, and 36 patients received ZDV + ddI. Primary efficacy parameters were the activity on HIV-1 RNA and on peripheral blood CD4+ cells, with differences between groups analyzed by the Wilcoxon's nonparametric two-sample test. Baseline RNA was high in both treatment groups (median values, 5.8 and 5.7 log10). RNA and CD4 responses were significantly higher with the triple combination (median RNA reductions, 2.69 versus 1.05 log10 at 24 weeks and 1.97 versus 1.20 log10 at 48 weeks; median CD4 increases, 81 versus 64 cells/mm3 at 24 weeks and 101 versus 27 cells/mm3 at 48 weeks). This study demonstrates that a triple combination of ZDV + ddI + nevirapine used as first-line regimen in antiretroviral-naive patients can induce sustained virologic and immunologic response in patients with low CD4 count or a previous diagnosis of AIDS.

An erythroid and megakaryocytic common precursor cell line (B1647) expressing both c-mpl and erythropoietin receptor (Epo-R) proliferates and modifies globin chain synthesis in response to megakaryocyte growth and development factor (MGDF) but not to erythropoietin (Epo).

A human megakaryocyte cell line (B1647) has been established from bone marrow cells obtained from a patient with acute myelogenous leukaemia (FAB M2). The cells were CD34-, CD33+, HLA-DR+, CD38+, and expressed the immunophenotypic markers of the megakaryocyte lineage (CD41 and von Willebrand factor). Moreover the cells expressed the c-mpl (thrombopoietin receptor) mRNA and protein. On the other hand, the B1647 cells also possessed erythroid lineage characteristics: the vast majority of cells were glycophorin positive, and about 10% of unstimulated cells stained with an anti-globin gamma chain MoAb. In addition, S1 protection analysis demonstrated expression of beta-globin mRNA, and Epo receptor (Epo-R) protein was detected by cytofluorimetric assay. Several growth factors, when tested alone or in combination, failed to influence the B1647 cell growth. A significant increase of cell proliferation was observed only after the addition, in serum-free culture, of recombinant human megakaryocyte growth development factor (MGDF), a recombinant c-mpl ligand encompassing the receptor-binding domain and identical to thrombopoietin (TPO), at concentrations ranging from 0.01 to 1 ng/ml. Interestingly, MGDF failed to induce megakaryocytic differentiation of the B1647 cells, but significantly increased the synthesis of the globin gamma-chain. B1647 cells could be a useful model for studying the biological effect of TPO on common megakaryocyte and erythroid progenitors.

Growth hormone (GH) and the immune system: impaired phagocytic function in children with idiopathic GH deficiency is corrected by treatment with biosynthetic GH.

Thirty-seven prepubertal children evaluated for severe growth retardation were studied by assessment of total granulocyte, monocyte and lymphocyte count, lymphocyte subsets CD3+, CD3+Dr+, CD3+Dr-, CD4+, CD8+, CD8+CD57+, CD8+CD57-, CD16+, CD20+ and CD23+, serum immunoglobulin concentrations, and phagocytic activity of circulating neutrophils and monocytes (by a flow cytometric assay). Idiopathic GH deficiency was diagnosed in 21 of 37 patients; the remaining 16 healthy subjects served as controls. Fourteen patients received biosynthetic GH (rhGH), and their immune parameters were assessed at baseline and after 6 months of therapy. Phagocytic function mediated by both polymorphonuclears and monocytes was significantly impaired in GH-deficient subjects compared to controls (p < 0.003 for neutrophils, p < 0.007 for monocytes), while a significant increase of phagocytic activity was obtained during long-term rhGH replacement therapy (p < 0.02 for neutrophils, p < 0.001 for monocytes), thus suggesting that GH may affect the functional activity of circulating phagocyte cells. No significant differences were found in total granulocyte, monocyte and lymphocyte counts, T- and B-lymphocyte subsets and immunoglobulin levels, between GH-deficient patients and controls, and between values observed before and during rhGH substitution treatment.

Detection of circulating p24 antigen-positive CD4+ cells during HIV infection by flow cytometry.

OBJECTIVES: To determine the amount of circulating CD4+ cells positive for intracellular p24 antigen during HIV infection, and to correlate the results with clinical, virological and therapeutic parameters. METHODS: Data were obtained from 24 anti-HIV-negative subjects (controls) and 47 anti-HIV-positive patients classified according to clinical diagnosis, serum p24-antigen assay results, and antiretroviral treatment with zidovudine, using a modified flow cytometric assay for the detection of intracellular HIV p24 antigen (p24-FCA) in circulating CD4+ lymphocytes. RESULTS: The proportion of CD4+ lymphocytes positive for p24-FCA correlated well with HIV infection (1.685 +/- 1.902 versus 0.160 +/- 0.152 in controls; P < 0.001) and clinical progression [Centers for Disease Control (CDC) stage II: 1.310 +/- 1.187; CDC stage III 1.145 +/- 1.442; CDC stage IVA/C2: 2.335 +/- 2.112; CDC stage IVC1: 2.066 +/- 2.420]. The percentage of CD4+ cells positive for HIV p24-FCA was inversely correlated with an absolute peripheral blood CD4+ lymphocyte count (Spearman's rank correlation = -0.324; P < 0.05). However, there was no statistically significant difference between patients in presence (n = 27; 1.938 +/- 2.095) or absence (n = 20; 1.343 +/- 1.594) of serum p24 Ag. The variable linked most strongly to the detection of intracellular p24 in anti-HIV-positive patients was zidovudine treatment: the proportion of p24-FCA-positive CD4+ lymphocytes was significantly lower (0.825 +/- 0.910) in the treated patients (n = 25) than in the untreated patients (n = 22; 2.662 +/- 2.248; P < 0.001). CONCLUSIONS: Our results suggest that CD4+ p24 Ag-FCA is a rapid and easy test for the identification of the proportion of CD4+ lymphocytes with intracellular p24 Ag, and that it could be more appropriate than serum p24 Ag assay in evaluating disease progression and efficacy of antiretroviral treatment.

Recombinant interleukin-2 (rIL-2) in acquired immune deficiency syndrome (AIDS): preliminary report in patients with lymphoma associated with HIV infection.

In an ongoing phase II study, 12 patients with lymphoma and HIV infection were treated with zidovudine (ZDV) and recombinant interleukin-2 (rIL-2) to evaluate if this association may produce beneficial effect on the immunologic status and the outcome of lymphoma. The protocol included daily doses of rIL-2 at 6 MIU/m2 over 5 days in c.i. per week for a total 4 courses; ZDV was associated at 600 mg/d in the period under study. An improved CD4 count, exceeding 2- to 4-fold the basal count, was obtained in patients with a basal CD4 number greater than 100/microliters accompanied by a significant increase of NK and LAK activity (p less than 0.001). From the clinical point of view the reduction of tumor manifestation was proportional to CD4 basal number; 2 patients from those with CD4 greater than 100/microliters obtained a complete remission after rIL-2 and ZVD. The p24 antigen, taken as parameter of viral replication, remained invariably negative after rIL-2 and ZDV in patients already negative and became negative in 1 patient previously positive. Our conclusion is that the association of rIL-2 and AZT is safe and useful in patients with lymphoma and HIV infection.