Impact of the Inclusion of an Aminoglycoside to the Initial Empirical Antibiotic Therapy for Gram-Negative Bloodstream Infections in Hematological Neutropenic Patients: a Propensity-Matched Cohort Study (AMINOLACTAM Study).

To test the hypothesis that the addition of an aminoglycoside to a ß-lactam antibiotic could provide better outcomes than ß-lactam monotherapy for the initial empirical treatment of hematological neutropenic patients with subsequently documented Gram-negative bacillus (GNB) bloodstream infection (BSI), a multinational, retrospective, cohort study of GNB BSI episodes in hematological neutropenic patients in six centers (2010 to 2017) was conducted. Combination therapy (ß-lactam plus aminoglycoside) was compared to ß-lactam monotherapy. The primary endpoint was the case fatality rate, assessed at 7 and 30 days from BSI onset. Secondary endpoints were nephrotoxicity and persistent BSI. Propensity score (PS) matching was performed. Among 542 GNB BSI episodes, 304 (56%) were initially treated with combination therapy, with cefepime plus amikacin being most common (158/304 [52%]). Overall, Escherichia coli (273/304 [50.4%]) was the main etiological agent, followed by Pseudomonas aeruginosa, which predominated in the combination group (76/304 [25%] versus 28/238 [11.8%]; P < 0.001). Multidrug resistance rates were similar between groups (83/294 [28.2%] versus 63/233 [27%]; P = 0.95). In the multivariate analysis, combination therapy was associated with a lower 7-day case fatality rate (odds ratio [OR], 0.37; 95% CI, 0.14 to 0.91; P = 0.035) with a tendency toward lower mortality at 30 days (OR, 0.56; 95% CI, 0.29 to 1.08; P = 0.084). After PS matching, these differences remained for the 7-day case fatality rate (OR, 0.33; 95% CI, 0.13 to 0.82; P = 0.017). In addition, aminoglycoside use was not significantly associated with renal function impairment (OR, 1.12; 95% CI, 0.26 to 4.87; P = 0.9). The addition of an aminoglycoside to the initial empirical therapy regimen for febrile neutropenic hematological patients should be considered.

Clinical Predictive Model of Multidrug Resistance in Neutropenic Cancer Patients with Bloodstream Infection Due to Pseudomonas aeruginosa.

We aimed to assess the rate and predictive factors of bloodstream infection (BSI) due to multidrug-resistant (MDR) Pseudomonas aeruginosa in neutropenic cancer patients. We performed a multicenter, retrospective cohort study including oncohematological neutropenic patients with BSI due to P. aeruginosa conducted across 34 centers in 12 countries from January 2006 to May 2018. A mixed logistic regression model was used to estimate a model to predict the multidrug resistance of the causative pathogens. Of a total of 1,217 episodes of BSI due to P. aeruginosa, 309 episodes (25.4%) were caused by MDR strains. The rate of multidrug resistance increased significantly over the study period (P = 0.033). Predictors of MDR P. aeruginosa BSI were prior therapy with piperacillin-tazobactam (odds ratio [OR], 3.48; 95% confidence interval [CI], 2.29 to 5.30), prior antipseudomonal carbapenem use (OR, 2.53; 95% CI, 1.65 to 3.87), fluoroquinolone prophylaxis (OR, 2.99; 95% CI, 1.92 to 4.64), underlying hematological disease (OR, 2.09; 95% CI, 1.26 to 3.44), and the presence of a urinary catheter (OR, 2.54; 95% CI, 1.65 to 3.91), whereas older age (OR, 0.98; 95% CI, 0.97 to 0.99) was found to be protective. Our prediction model achieves good discrimination and calibration, thereby identifying neutropenic patients at higher risk of BSI due to MDR P. aeruginosa The application of this model using a web-based calculator may be a simple strategy to identify high-risk patients who may benefit from the early administration of broad-spectrum antibiotic coverage against MDR strains according to the local susceptibility patterns, thus avoiding the use of broad-spectrum antibiotics in patients at a low risk of resistance development.

Evaluation of a new chromogenic medium, chromID OXA-48, for recovery of carbapenemase-producing Enterobacteriaceae from patients at a university hospital in Turkey.

The purpose of this study was to evaluate a new chromogenic medium, chromID OXA-48, for the isolation of carbapenemase-producing Enterobacteriaceae (CPE) directly from rectal swabs. chromID CARBA and chromID OXA-48 are two chromogenic media that have been commercialized for the isolation of CPE directly from clinical samples. Both media were evaluated alongside a broth enrichment method recommended by the CDC for isolation of CPE, with rectal swabs from 302 unique hospitalized patients at the Hacettepe University Hospital, Ankara, Turkey. A total of 33 patients (11 %) were found to be colonized with CPE using a combination of all methods, and all CPE produced OXA-48 carbapenemase. Klebsiella pneumoniae was by far the most dominant species of CPE and was isolated from 31 patients. Culture on chromID OXA-48 offered the highest sensitivity (75.8 %) for detection of CPE compared with the other two methods (sensitivity for both other methods was 57.6 %) and also offered the highest specificity (99.3 %). However, a combination of methods (either chromID OXA-48 plus CDC method or chromID OXA-48 plus chromID CARBA) was necessary to achieve an acceptable sensitivity (90.9 %). For isolation of CPE, in a setting where OXA-48 carbapenemase is the dominant type of carbapenemase, chromID OXA-48 is a highly useful medium but using a combination of methods is optimal for adequate detection. The combined use of two chromogenic media offered acceptable sensitivity (90.9 %) and the highest specificity (98.5 %) and also allowed for isolation of CPE within 18-20 h.

The features of infectious diseases departments and anti-infective practices in France and Turkey: a cross-sectional study.

The aim of this study was to assess the infectious diseases (ID) wards of tertiary hospitals in France and Turkey for technical capacity, infection control, characteristics of patients, infections, infecting organisms, and therapeutic approaches. This cross-sectional study was carried out on a single day on one of the weekdays of June 17-21, 2013. Overall, 36 ID departments from Turkey (n = 21) and France (n = 15) were involved. On the study day, 273 patients were hospitalized in Turkish and 324 patients were followed in French ID departments. The numbers of patients and beds in the hospitals, and presence of an intensive care unit (ICU) room in the ID ward was not different in both France and Turkey. Bed occupancy in the ID ward, single rooms, and negative pressure rooms were significantly higher in France. The presence of a laboratory inside the ID ward was more common in Turkish ID wards. The configuration of infection control committees, and their qualifications and surveillance types were quite similar in both countries. Although differences existed based on epidemiology, the distribution of infections were uniform on both sides. In Turkey, anti-Gram-positive agents, carbapenems, and tigecycline, and in France, cephalosporins, penicillins, aminoglycosides, and metronidazole were more frequently preferred. Enteric Gram-negatives and hepatitis B and C were more frequent in Turkey, while human immunodeficiency virus (HIV) and streptococci were more common in France (p < 0.05 for all significances). Various differences and similarities existed in France and Turkey in the ID wards. However, the current scene is that ID are managed with high standards in both countries.

Emergence of ceftazidime/avibactam resistance in carbapenem-resistant Klebsiella pneumoniae in China.

OBJECTIVES: The aim was to investigate the activity of ceftazidime/avibactam (CAZ/AVI) against carbapenem-resistant Klebsiella pneumoniae (CRKP) and identify the resistance mechanisms before CAZ/AVI coming to Chinese market. METHODS: Clinical CRKP isolates were continuously collected from 36 tertiary hospitals in China from 1 March 2017 to 31 July 2017. CAZ/AVI MICs were determined by agar dilution method. CAZ/AVI resistant isolates were submitted to whole genome sequencing. The copy number and relative expression of blaKPC were determined by quantitative PCR. RESULTS: A total of 872 CRKP isolates were collected, and MIC50 and MIC90 of CAZ/AVI were 4 and 8 mg/L. The resistant rate of CAZ/AVI was 3.7% (32/872). Among the resistant isolates, 53.1% (17/32) were metallo-ß-lactamase-producing K. pneumoniae (MBL-KP), 40.6% (13/32) were Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-KP) and 6.3% (2/32) produced both MBL and KPC. One of the KPC-KP with high level CAZ/AVI resistance (>128 mg/L) harboured mutated blaKPC-2 (D179Y). In 12 wild-type blaKPC-2 isolates, the relative copy number and expression of blaKPC-2 gene were 2.5-fold and 2.7-fold higher than that in the CAZ/AVI MIC ≤0.5 mg/L group (p < 0.05), and when added avibactam at a fixed concentration of 8 mg/L, 91.7% (11/12) isolates could restore susceptibility. CONCLUSIONS: Resistance against CAZ/AVI in CRKP emerged before clinical use of CAZ/AVI in China, although most of the CRKP isolates maintained the susceptibility. MBL production, blaKPC-2 point mutation and high KPC expression played an important role in CAZ/AVI resistance.

Mixed fungaemia: an 18-year report from a tertiary-care university hospital and a systematic review.

BACKGROUND: While fungaemia caused by two or more different species of yeasts (mixed fungaemia, MF) is infrequent, it might be underestimated. AIMS: This study aimed to determine the incidence of MF, clinical characteristics of the patients, and antifungal susceptibility profiles of the isolates with a systematic review of the literature. SOURCES: Data sources were PubMed and Scopus. STUDY ELIGIBILITY CRITERIA: Studies reporting ten or more mixed fungaemia episodes. CONTENT: Study included MF episodes in adults between January 2000 and August 2018 in Hacettepe University Hospitals, Turkey. The isolation, identification and antifungal susceptibility testing (AFST) of the isolates were by standard mycological methods. Patient data were obtained retrospectively. Literature search was performed using relevant keywords according to PRISMA systematic review guidelines. A total of 32 patients with 33 MF episodes were identified. Among all fungaemia episodes, MF incidence was 3.7% (33/883). All patients had one or more underlying disorders among which solid-organ cancer (50.0%, 16/32) was the most common. Overall mortality was 51.5% (17/33). The most preferred antifungal agents for initial treatment were fluconazole (48.5%, 16/33) and echinocandins (39.4%, 13/33). Fluconazole susceptible-dose-dependent (S-DD) or -resistant Candida species were detected in 15 episodes, and an isolate of C. parapsilosis was classified as S-DD by AFST. All Candida isolates were susceptible to echinocandins. Non-candida yeasts with intrinsic resistance/reduced susceptibility to both echinocandins and fluconazole were detected in two episodes. Systematic review of the literature revealed 24 studies that reported more than ten MF episodes. Methodology was variable. Improvement of detection rates was reported when chromogenic agars were used. Most studies underlined detection of isolates with reduced susceptibility. IMPLICATIONS: Although rare, the MF rate is affected by the detection methods, which have improved in recent years. Fluconazole and echinocandins were used for initial treatment in accordance with the current guideline recommendations; however, isolates non-susceptible to both were detected. Detection of a mixed infection offers an opportunity for optimum treatment.

ESCMID white paper: a guide on ESCMID guidance documents.

BACKGROUND AND AIM: The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) aims to further develop its role in international medical and scientific guidance in the field of Clinical Microbiology and Infectious Diseases, where many types of guidance documents exist. The ESCMID Executive Committee and the Clinical Microbiology and Infection (CMI) editorial board wish to clarify the terminology and format to be used in ESCMID guidance documents submitted for publication in CMI, and to highlight the principles behind ESCMID guidance documents. TYPES OF GUIDANCE DOCUMENTS: There are five types of ESCMID guidance documents: White Papers, Clinical Practice Guidelines, Consensus Statements, State-of-the-Science Statements, and Position Papers. They differ in scope, methods of development, drafting group composition and preferred publication format. Guidance documents can be proposed, developed and published by ESCMID Study Groups, Committees and individual members; often, other scientific societies are involved. The full disclosure of potential conflicts of interest of all drafting group members is a requirement. FINAL REMARKS: Guidance documents constitute a common cultural and scientific background to people in the same and related professions. Also, they are an important educational and training tool. Developing a guidance document is a scientific endeavour, where a sound and transparent development process is needed, requiring multidisciplinary and personal skills.

Ultrastructural evaluation of urine alkalinization versus hydration on colistin-induced nephrotoxicity.

OBJECTIVES: Colistin is a vital antibiotic used in multidrug-resistant infections. Its most important side effect is nephrotoxicity. Colistin is a weak acid. This study aims to evaluate whether urine alkalinization is protective in the nephrotoxicity of colistin. METHODS: Twenty-eight male Sprague-Dawley rats were divided into groups. Group I (n = 4) was injected with intramuscular distilled water twice a day for 7 days. Group II (n = 8) was injected with 750,000 IU/kg/day colistin for 7 days. Group III (n = 8) was injected with the same dose of colistin after their urinary pH was ≥7 through the addition of bicarbonate in their drinking water. Group IV (n = 8) was injected with the same dose of colistin after their urine density fell below 1010 through the addition of NaCl molds in their food and 12.6 mg/L NaCl in their drinking water. RESULTS: According to tubular degenerations (scored 0-5), group I scored 0, group II scored 4.25, group III scored 2, and group IV scored 1.5. In groups III and IV, protection was achieved (p = 0.001). The bicarbonate group was not superior to the NaCl group (p = 0.789). In transmission electron microscopy, group III had more microvilli integrity and autophagic vacuoles compared to group IV. Group IV had mitochondrial swelling and cristae lysis. A lower urine density was related to lower tubular scores (p = 0.001). CONCLUSIONS: Colistin was highly nephrotoxic without protection. Light microscopy findings revealed that urinary alkalinization and NaCl hydration were similarly protective. Urine alkalinization further prevents ultrastructural changes as revealed by electron microscopy.

Sulbactam-containing beta-lactamase inhibitor combinations.

Sulbactam irreversibly inhibits the hydrolytic activity of beta-lactamases. This compound is commercially available in combination with either ampicillin or cefoperazone. In each instance, the activity of the partner antibiotic against beta-lactamase-producing bacteria is restored. One of the particular advantages of using sulbactam-containing combinations is that sulbactam itself has inherent activity against some Acinetobacter baumannii. Sulbactam combinations have not demonstrated strong selective pressures for extended-spectrum beta-lactamase-producing Enterobacteriaceae and vancomycin-resistant enterococci. In contrast to clavulanate, sulbactam does not induce class I (Ampc) chromosomal beta-lactamases in Enterobacteriaceae.

[Detection of HPV DNA in lymph nodes in early stages cervical cancers]. / Stanovení DNA HPV v lymfatických uzlinách u casných stadií karcinomu delozního hrdla.

OBJECTIVE: Review recent knowledge concerning significance of detection of DNA HPV in regional lymph nodes in cervical cancer patients. TYPE OF THE STUDY: Literature review. SETTING: Department of Obstetrics and Gyneacology, 1st Faculty of Medicine, Charles University and General Teaching Hospital, Prague. RESULTS: Metastatic involvement of pelvic lymph nodes is the most important prognostic parameter in early stages cervical cancer. Still, almost 20% of patients with negative pelvic nodes experience recurrence. Detection of HPV DNA in lymph nodes might be a marker of occult metastatic involvement. However, published data are limited, mostly due to inconsistent methodology. Only 3 prospective studies evaluating HPV from fresh or frozen tissue were published till now, all other retrospective studies extracted HPV DNA from paraffin embedded samples. A few papers showed correlation between HPV DNA and metastatic involvement of pelvic lymph nodes. DNA HPV identification in histopatology-negative nodes was considered as a risk factor for recurrence. Presence of DNA HPV 18 in histopathology-negative pelvic nodes was described as a poor prognostic factor; however prognostic significance of individual genotype is still unclear. CONCLUSION: Detection of high risk HPV DNA in regional lymph nodes is a good candidate for prognostic parameter in early stages cervical cancers. The group of women with both absence of metastatic involvement and negative HPV DNA evaluation of regional lymph node should represent a cohort of patients with particularly good prognosis.

Predictors of outcome in patients with severe sepsis or septic shock due to extended-spectrum ß-lactamase-producing Enterobacteriaceae.

PURPOSE: There are few data in the literature regarding sepsis or septic shock due to extended-spectrum ß-lactamases (ESBL)-producing Enterobacteriaceae (E). The aim of this study was to assess predictors of outcome in septic patients with bloodstream infection (BSI) caused by ESBL-E. METHODS: Patients with severe sepsis or septic shock and BSI due to ESBL-E were selected from the INCREMENT database. The primary endpoint of the study was the evaluation of predictors of outcome after 30 days from development of severe sepsis or septic shock due to ESBL-E infection. Three cohorts were created for analysis: global, empirical-therapy and targeted-therapy cohorts. RESULTS: 367 septic patients were analysed. Overall mortality was 43.9% at 30 days. Escherichia coli (62.4%) and Klebsiella pneumoniae (27.2%) were the most frequent isolates. ß-lactam/ß-lactamase inhibitor (BLBLI) combinations were the most empirically used drug (43.6%), followed by carbapenems (29.4%). Empirical therapy was active in vitro in 249 (67.8%) patients, and escalation of antibiotic therapy was reported in 287 (78.2%) patients. Cox regression analysis showed that age, Charlson Comorbidity Index, McCabe classification, Pitt bacteremia score, abdominal source of infection and escalation of antibiotic therapy were independently associated with 30-day mortality. No differences in survival were reported in patients treated with BLBLI combinations or carbapenems in empirical or definitive therapy. CONCLUSIONS: BSI due to ESBL-E in patients who developed severe sepsis or septic shock was associated with high 30-day mortality. Comorbidities, severity scores, source of infection and antibiotic therapy escalation were important determinants of unfavorable outcome.

Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline.

The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint Clinical Guidelines focus on diagnosis and management of aspergillosis. Of the numerous recommendations, a few are summarized here. Chest computed tomography as well as bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis (IA) are strongly recommended. For diagnosis, direct microscopy, preferably using optical brighteners, histopathology and culture are strongly recommended. Serum and BAL galactomannan measures are recommended as markers for the diagnosis of IA. PCR should be considered in conjunction with other diagnostic tests. Pathogen identification to species complex level is strongly recommended for all clinically relevant Aspergillus isolates; antifungal susceptibility testing should be performed in patients with invasive disease in regions with resistance found in contemporary surveillance programmes. Isavuconazole and voriconazole are the preferred agents for first-line treatment of pulmonary IA, whereas liposomal amphotericin B is moderately supported. Combinations of antifungals as primary treatment options are not recommended. Therapeutic drug monitoring is strongly recommended for patients receiving posaconazole suspension or any form of voriconazole for IA treatment, and in refractory disease, where a personalized approach considering reversal of predisposing factors, switching drug class and surgical intervention is also strongly recommended. Primary prophylaxis with posaconazole is strongly recommended in patients with acute myelogenous leukaemia or myelodysplastic syndrome receiving induction chemotherapy. Secondary prophylaxis is strongly recommended in high-risk patients. We strongly recommend treatment duration based on clinical improvement, degree of immunosuppression and response on imaging.

[Genotyping of CYP2D6 and CYP2C19]. / Genotypizace cytochromu P450 2D6 a 2C19.

BACKGROUND: Polymorphisms in drug metabolizing enzymes are considered as a major factor influencing the incidence of adverse drug reactions or failure of pharmacotherapy. Our aim was to compare the distribution of functional polymorphisms in the genes CYP2D6 and CYP2C19 between healthy control group and of patients reffered to our department due to adverse drug reactions or insufficient efficacy of a treatment. METHODS AND RESULTS: The group of patients comprised of 60 subjects, 218 healthy unrelated subjects were included in the cotrol group. In both groups genotypes of CYP2D6 and CYP2C19 were analyzed. There were significantly fewer extensive metabolizers of CYP2D6 in the patient group comparison with healthy control subjects (25.0% vs. 49.8%) while the proportion of intermediate metabolizers was significantly higher than in helthy population (58.3% vs. 38.5%). We also observed more poor metabolizers than in control group (13.3% vs. 6.8%), but the difference did not reach level of statistical significance probably due to low number of subjects. The distribution of either ultrarapid metabolizers of CYP2D6 or deficient alleles of CYP2C19 was similar in both groups. CONCLUSIONS: Clinically apparent alteration of drug effects are often caused by partial or complete deficit of CYP2D6 activity. Our results confirm the importance of CYP2D6 polymorphisms on the efficycy and safety of pharmacotherapy.

Clinical efficacy of ß-lactam/ß-lactamase inhibitor combinations for the treatment of bloodstream infection due to extended-spectrum ß-lactamase-producing Enterobacteriaceae in haematological patients with neutropaenia: a study protocol for a retrospective observational study (BICAR).

INTRODUCTION: Bloodstream infection (BSI) due to extended-spectrum ß-lactamase-producing Gram-negative bacilli (ESBL-GNB) is increasing at an alarming pace worldwide. Although ß-lactam/ß-lactamase inhibitor (BLBLI) combinations have been suggested as an alternative to carbapenems for the treatment of BSI due to these resistant organisms in the general population, their usefulness for the treatment of BSI due to ESBL-GNB in haematological patients with neutropaenia is yet to be elucidated. The aim of the BICAR study is to compare the efficacy of BLBLI combinations with that of carbapenems for the treatment of BSI due to an ESBL-GNB in this population. METHODS AND ANALYSIS: A multinational, multicentre, observational retrospective study. Episodes of BSI due to ESBL-GNB occurring in haematological patients and haematopoietic stem cell transplant recipients with neutropaenia from 1 January 2006 to 31 March 2015 will be analysed. The primary end point will be case-fatality rate within 30 days of onset of BSI. The secondary end points will be 7-day and 14-day case-fatality rates, microbiological failure, colonisation/infection by resistant bacteria, superinfection, intensive care unit admission and development of adverse events. SAMPLE SIZE: The number of expected episodes of BSI due to ESBL-GNB in the participant centres will be 260 with a ratio of control to experimental participants of 2. ETHICS AND DISSEMINATION: The protocol of the study was approved at the first site by the Research Ethics Committee (REC) of Hospital Universitari de Bellvitge. Approval will be also sought from all relevant RECs. Any formal presentation or publication of data from this study will be considered as a joint publication by the participating investigators and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE). The study has been endorsed by the European Study Group for Bloodstream Infection and Sepsis (ESGBIS) and the European Study Group for Infections in Compromised Hosts (ESGICH).

[Cervical cancer precursors: cytohistologic correlation with the results of HPV testing]. / Prekurzorové léze karcinomu delozního cípku: korelace cytologických a histologických nálezu s výsledkem HPV testu.

Persistence of high-risk types of human papillomavirus (HPV) is responsible for the development, maintenance and progression of squamous intraepithelial lesions (SILs). Cytohistologic correlation with the results of the HPV testing in 52 patients over a 3year period is presented. Two patients out of the 52 patients presented in this histologic follow up bore the diagnosis high-grade squamous intraepithelial lesion (HSIL) with the former cytology ASC-H. Low grade squamous intraepithelial lesions (LSIL) were found in eight patients, half of them diagnosed identically on cytology. Another four cases were formerly diagnosed cytologically as ASC-US. All women with the histologically confirmed dysplastic changes were HR HPV DNA positive. Our results indicate that significant histologic lesions may be discovered in patients exhibiting the high-risk HPV DNA positivity in the category of ASC-US (Atypical Squamous Cells of Undetermined Significance) and especially ASC-H (ASC cannot exclude high-grade squamous intraepithelial lesion). A combined screening test thus offers the possibility of greater protection and /or longer screening intervals.

The global threat of antimicrobial resistance: science for intervention.

In the last decade we have witnessed a dramatic increase in the proportion and absolute number of bacterial pathogens resistant to multiple antibacterial agents. Multidrug-resistant bacteria are currently considered as an emergent global disease and a major public health problem. The B-Debate meeting brought together renowned experts representing the main stakeholders (i.e. policy makers, public health authorities, regulatory agencies, pharmaceutical companies and the scientific community at large) to review the global threat of antibiotic resistance and come up with a coordinated set of strategies to fight antimicrobial resistance in a multifaceted approach. We summarize the views of the B-Debate participants regarding the current situation of antimicrobial resistance in animals and the food chain, within the community and the healthcare setting as well as the role of the environment and the development of novel diagnostic and therapeutic strategies, providing expert recommendations to tackle the global threat of antimicrobial resistance.

Corrigendum to "The global threat of antimicrobial resistance: science for intervention" [New Microbes New Infect 6 (2015): 22-29].

[This corrects the article DOI: 10.1016/j.nmni.2015.02.007.].

An open multicentre comparative study of the efficacy, safety and tolerance of fluconazole and itraconazole in the treatment of cancer patients with oropharyngeal candidiasis.

Oropharyngeal candidiasis is a frequent infection in cancer patients who receive cytotoxic drugs. In this study, the efficacy, safety and tolerance of fluconazole and itraconazole were compared in non-neutropenic cancer patients with oropharyngeal candidiasis. Of 279 patients who were randomised between the two treatment groups, 252 patients were considered to be eligible (126 in each group). The clinical cure rate was 74% for fluconazole and 62% for itraconazole (P=0.04, 95% Confidence Interval (CI): 0.5-23.3%). The mycological cure rate was 80% for fluconazole and 68% for itraconazole (P=0.03, 95% CI: 1.2-22.6%). The safety and tolerance profile of both drugs were comparable. This study has shown that in patients with cancer and oropharyngeal candidiasis, fluconazole has a significantly better clinical and mycological cure rate compared with itraconazole.

Susceptibility to beta-lactam antibiotics of mutant strains of Xanthomonas maltophilia with high- and low-level constitutive expression of L1 and L2 beta-lactamases.

Xanthomonas maltophilia produces two inducible beta-lactamases, L1 and L2, and resists the antimicrobial activity of beta-lactam antibiotics, including carbapenems. L1 is a zinc-metaloenzyme with carbapenemase activity; L2 is an unusual cephalosporinase. Mutant strains with high- and low-level constitutive expression of these enzymes were derived from three reference strains of X. maltophilia. With a single exception, the mutant strains had altered expression of both enzymes, indicating that these beta-lactamases share regulatory components. The exception was a mutant strain that had low-level constitutive (basal) expression of L1 enzyme but remained inducible for L2. A parent strain with low-level beta-lactamase inducibility was more susceptible to penicillins, cephalosporins and carbapenems than were those in which higher levels of enzyme activity were inducible. Mutations that caused high-level constitutive beta-lactamase expression increased resistance to penicillins and newer cephalosporins. beta-Lactamase basal mutant strains, including the one that remained inducible for L2 enzyme, were more susceptible than inducible strains to these drugs. Organisms with inducible or high-level constitutive beta-lactamase expression were equally resistant to meropenem and imipenem but basal mutant strains, including the one that remained inducible for L2 enzyme, were more susceptible to meropenem than imipenem. Minimal inhibitory concentrations of meropenem, penicillins and cephalosporins, but not imipenem, were greater on Mueller Hinton agar than on IsoSensitest or Diagnostic Sensitivity Test agars. This behaviour was independent of beta-lactamase inducibility, and may reflect permeability differences between cells grown on different media.