Population pharmacokinetics of colistin and the relation to survival in critically ill patients infected with colistin susceptible and carbapenem-resistant bacteria.

OBJECTIVES: The aim was to analyse the population pharmacokinetics of colistin and to explore the relationship between colistin exposure and time to death. METHODS: Patients included in the AIDA randomized controlled trial were treated with colistin for severe infections caused by carbapenem-resistant Gram-negative bacteria. All subjects received a 9 million units (MU) loading dose, followed by a 4.5 MU twice daily maintenance dose, with dose reduction if creatinine clearance (CrCL) < 50 mL/min. Individual colistin exposures were estimated from the developed population pharmacokinetic model and an optimized two-sample per patient sampling design. Time to death was evaluated in a parametric survival analysis. RESULTS: Out of 406 randomized patients, 349 contributed pharmacokinetic data. The median (90% range) colistin plasma concentration was 0.44 (0.14-1.59) mg/L at 15 minutes after the end of first infusion. In samples drawn 10 hr after a maintenance dose, concentrations were >2 mg/L in 94% (195/208) and 44% (38/87) of patients with CrCL ≤120 mL/min, and >120 mL/min, respectively. Colistin methanesulfonate sodium (CMS) and colistin clearances were strongly dependent on CrCL. High colistin exposure to MIC ratio was associated with increased hazard of death in the multivariate analysis (adjusted hazard ratio (95% CI): 1.07 (1.03-1.12)). Other significant predictors included SOFA score at baseline (HR 1.24 (1.19-1.30) per score increase), age and Acinetobacter or Pseudomonas as index pathogen. DISCUSSION: The population pharmacokinetic model predicted that >90% of the patients had colistin concentrations >2 mg/L at steady state, but only 66% at 4 hr after start of treatment. High colistin exposure was associated with poor kidney function, and was not related to a prolonged survival.

Combining VITEK® 2 with colistin agar dilution screening assist timely reporting of colistin susceptibility.

OBJECTIVES: The rise in carbapenem resistance among Gram-negative bacteria has renewed interest in colistin. Recently, the EUCAST-CLSI Polymyxin Breakpoints Working Group declared that broth microdilution (BMD) is the only valid method for colistin susceptibility testing. BMD is not easily incorporated into the routine work of clinical laboratories, and usually this test is incorporated serially, resulting in delayed susceptibility reporting. We tested a strategy of combining VITEK® 2 with a 2 µg/mL colistin agar dilution (VITEK® 2/AD) screening plate to improve performance and time to reporting of colistin susceptibility. METHODS: Colistin susceptibility for 364 clinical isolates was determined by VITEK® 2/AD and compared with the reference standard BMD according to the ISO 20776-1:2007 and CLSI guidelines. The EUCAST colistin susceptibility breakpoint of ≤2 µg/mL was used. Escherichia coli NCTC 13846 served as quality control strain. Agreement, very major error (VME) and major error rates were determined using ISO 20776-2:2007. RESULTS: The VME rate for VITEK® 2 alone was 30.6% (15/49, 95% CI 18.3-45.4%), and was reduced to 10.2% (5/49, 95% CI 3.4-22.2%) using the VITEK® 2/AD combined testing. The combined testing had categorical agreement with BMD of 97% (354/364, 95% CI 95.0-98.7%), and a major error (ME) rate of 1.6% (5/315, 95% CI 0.5-3.7%). Using the combined testing, even against challenging strains, 349 (95.8%, 95% CI 93.3-97.7%) colistin susceptibility results could be reported, and only 15 isolates required further analysis by BMD. DISCUSSION: Our method is simple to apply and allows rapid reporting of colistin susceptibility.

Challenges in the diagnosis and treatment of mucormycosis.

The diagnosis and treatment of mucormycosis are challenging. The incidence of the disease seems to be increasing. Hematological malignancies are the most common underlying disease in countries with high income and uncontrolled diabetes in developing countries. Clinical approach to diagnosis lacks sensitivity and specificity. Radiologically, multiple (≥10) nodules and pleural effusion are reportedly associated with pulmonary mucormycosis. Another finding on computerized tomography (CT) scan, which seems to indicate the presence of mucormycosis, is the reverse halo sign. Microscopy (direct and on histopathology) and culture are the cornerstones of diagnosis. Molecular assays can be used either for detection or identification of mucormycetes, and they can be recommended as valuable add-on tools that complement conventional diagnostic procedures. Successful management of mucormycosis is based on a multimodal approach, including reversal or discontinuation of underlying predisposing factors, early administration of active antifungal agents at optimal doses, complete removal of all infected tissues, and use of various adjunctive therapies. Our armamentarium of antifungals is slightly enriched by the addition of two newer azoles (posaconazole and isavuconazole) to liposomal amphotericin B, which remains the drug of choice for the initial antifungal treatment, according to the recently published guidelines by ECIL-6, as well as those published by ECMM/ESCMID. Despite the efforts for better understanding of the pathogenesis, early diagnosis and aggressive treatment of mucormycosis, the mortality rate of the disease remains high.

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.

Mucormycosis in Iran: A six-year retrospective experience.

Mucormycosis is a devastating infection caused by Mucoralean fungi (Mucormycotina, Mucorales). Data concerning the global epidemiology of mucormycosis are scarce and little is known about the characteristics of mucormycosis in Iran. In this study, we aimed to understand the distribution of this infection in Iran retrospectively and to ascertain whether the patterns of infection are associated with specific host factors or not. A total of 208 cases were included in this study occurring during 2008-2014 and were validated according to (EORTC/MSG) criteria. A rising trend as significant increase from 9.7% in 2008 to 23.7% in 2014 was observed. The majority of patients were female (51.4%) with median age of 50 and the infections were seen mostly in autumn season (39.4%). Diabetes mellitus (75.4%) was the most common underlying condition and sinus involvement (86%) was the mostly affected site of infection. Amphotericin B (AmB) was the drug of choice for the majority of cases. Sixty four isolates did not show any growth in the lab and only 21 cases were evaluated by ITS sequencing, among them; Rhizopus arrhizus var. arrhizus was the dominant species. Considering the high mortality rate of mucormycosis, early and accurate diagnosis, with the aid of molecular methods may provide accurate treatments and improve the survival rate. Therefore, increased monitoring and awareness of this life-threatening disease is critical.

ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis 2013.

These European Society for Clinical Microbiology and Infectious Diseases and European Confederation of Medical Mycology Joint Clinical Guidelines focus on the diagnosis and management of mucormycosis. Only a few of the numerous recommendations can be summarized here. To diagnose mucormycosis, direct microscopy preferably using optical brighteners, histopathology and culture are strongly recommended. Pathogen identification to species level by molecular methods and susceptibility testing are strongly recommended to establish epidemiological knowledge. The recommendation for guiding treatment based on MICs is supported only marginally. Imaging is strongly recommended to determine the extent of disease. To differentiate mucormycosis from aspergillosis in haematological malignancy and stem cell transplantation recipients, identification of the reverse halo sign on computed tomography is advised with moderate strength. For adults and children we strongly recommend surgical debridement in addition to immediate first-line antifungal treatment with liposomal or lipid-complex amphotericin B with a minimum dose of 5 mg/kg/day. Amphotericin B deoxycholate is better avoided because of severe adverse effects. For salvage treatment we strongly recommend posaconazole 4×200 mg/day. Reversal of predisposing conditions is strongly recommended, i.e. using granulocyte colony-stimulating factor in haematological patients with ongoing neutropenia, controlling hyperglycaemia and ketoacidosis in diabetic patients, and limiting glucocorticosteroids to the minimum dose required. We recommend against using deferasirox in haematological patients outside clinical trials, and marginally support a recommendation for deferasirox in diabetic patients. Hyperbaric oxygen is supported with marginal strength only. Finally, we strongly recommend continuing treatment until complete response demonstrated on imaging and permanent reversal of predisposing factors.

ESCMID and ECMM joint clinical guidelines for the diagnosis and management of systemic phaeohyphomycosis: diseases caused by black fungi.

The aetiological agents of many invasive fungal infections are saprobes and opportunistic pathogens. Some of these fungi are darkly pigmented due to melanin production and traditionally have been named 'dematiaceous'. The melanized fungi cause a wide array of clinical syndromes ranging from superficial to deep-seated infections. Diagnosis relies on histopathological examination of clinical specimens and on examination of cultures. Sequencing is recommended for accurate species identification, especially for unusual or newly described pathogens. In cases of mycetoma and chromoblastomycosis, pathognomonic histological findings are useful and the Fontana-Masson stain, specific for melanin, usually confirms the diagnosis. There are no standardized therapies but voriconazole, posaconazole and itraconazole demonstrate the most consistent in vitro activity against this group of fungi. Oral itraconazole has been considered the drug of choice, given the extensive clinical experience with this drug. However, voriconazole may presumably be superior for central nervous system infections because of its ability to achieve good levels in the cerebrospinal fluid. Posaconazole is a well-tolerated alternative drug, backed by less clinical experience but with excellent salvage treatment results after failure of other antifungals. Amphotericin B has been useful as alternative therapy in some cases. Combination antifungal therapy is recommended for cerebral abscesses when surgery is not possible and for disseminated infections in immunocompromised patients.

ESCMID and ECMM joint guidelines on diagnosis and management of hyalohyphomycosis: Fusarium spp., Scedosporium spp. and others.

Mycoses summarized in the hyalohyphomycosis group are heterogeneous, defined by the presence of hyaline (non-dematiaceous) hyphae. The number of organisms implicated in hyalohyphomycosis is increasing and the most clinically important species belong to the genera Fusarium, Scedosporium, Acremonium, Scopulariopsis, Purpureocillium and Paecilomyces. Severely immunocompromised patients are particularly vulnerable to infection, and clinical manifestations range from colonization to chronic localized lesions to acute invasive and/or disseminated diseases. Diagnosis usually requires isolation and identification of the infecting pathogen. A poor prognosis is associated with fusariosis and early therapy of localized disease is important to prevent progression to a more aggressive or disseminated infection. Therapy should include voriconazole and surgical debridement where possible or posaconazole as salvage treatment. Voriconazole represents the first-line treatment of infections due to members of the genus Scedosporium. For Acremonium spp., Scopulariopsis spp., Purpureocillium spp. and Paecilomyces spp. the optimal antifungal treatment has not been established. Management usually consists of surgery and antifungal treatment, depending on the clinical presentation.

Epidemiology of mucormycosis in Europe.

Zygomycosis (mucormycosis) is being increasingly recognized as causing infection in recent years. National and multinational European surveys attempting to analyse the epidemiological parameters of this potentially devastating infection are very few. Although the exact incidence could not be defined due to the different methodologies used in these studies and the absence of a denominator, there were some useful observations made regarding the clinical presentation, sites of infection and diagnostic practices. Moreover, the importance for a prompt and accurate diagnosis has been stressed. As early diagnosis can significantly affect the initiation of treatment and decrease mortality, future research should focus on the development of an epidemiological risk assessment tool and novel diagnostic methods.

Zygomycosis in Europe: analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) Working Group on Zygomycosis between 2005 and 2007.

Zygomycosis is an important emerging fungal infection, associated with high morbidity and mortality. The Working Group on Zygomycosis of the European Confederation of Medical Mycology (ECMM) prospectively collected cases of proven and probable zygomycosis in 13 European countries occurring between 2005 and 2007. Cases were recorded by a standardized case report form, entered into an electronic database and analysed descriptively and by logistic regression analysis. During the study period, 230 cases fulfilled pre-set criteria for eligibility. The median age of the patients was 50 years (range, 1 month to 87 years); 60% were men. Underlying conditions included haematological malignancies (44%), trauma (15%), haematopoietic stem cell transplantation (9%) and diabetes mellitus (9%). The most common manifestations of zygomycosis were pulmonary (30%), rhinocerebral (27%), soft tissue (26%) and disseminated disease (15%). Diagnosis was made by both histology and culture in 108 cases (44%). Among 172 cases with cultures, Rhizopus spp. (34%), Mucor spp. (19%) and Lichtheimia (formerly Absidia) spp. (19%) were most commonly identified. Thirty-nine per cent of patients received amphotericin B formulations, 7% posaconazole and 21% received both agents; 15% of patients received no antifungal therapy. Total mortality in the entire cohort was 47%. On multivariate analysis, factors associated with survival were trauma as an underlying condition (p 0.019), treatment with amphotericin B (p 0.006) and surgery (p <0.001); factors associated with death were higher age (p 0.005) and the administration of caspofungin prior to diagnosis (p 0.011). In conclusion, zygomycosis remains a highly lethal disease. Administration of amphotericin B and surgery, where feasible, significantly improve survival.

Serum bactericidal activity of three different dosing regimens of colistin with implications for optimum clinical use.

Although colistin methanesulfonate (CMS) has been used extensively in critically ill patients infected with multidrug-resistant organisms, the optimum dosing regimen remains to be determined. Herein, we examined the pharmacokinetics of three different dosing regimens of CMS, 3 million units every 8 h (regimen A), 4.5 million units every 12 h (regimen B), 9 million units every 24 h (regimen C) and evaluated the bactericidal activity of serum containing various concentrations of colistin against Pseudomonas aeruginosa with a minimum inhibitory concentration (MIC) of 1 microg/ml. the means +/- SE serum C(max )of colistin for regimens A, B, and C were 3.34+/-0.35, 2.98+/-0.27, and 5.63+/-0.87 microg/ml, respectively. All serum samples containing colistin >4 microg/ml (serum concentration/MIC >4) eliminated P. aeruginosa whereas only 40% of samples containing colistin <4 microg/ml resulted in complete bacterial killing. these findings indicate that the currently used dosing regimens might not provide the most effective therapy with CMS and justify administering larger dosages in longer intervals.

Cutaneous zygomycosis.

The prevalence of cutaneous and soft tissue zygomycosis appears to have increased in recent years. We reviewed 78 case reports of cutaneous zygomycosis published from 2004 through 2008. Most patients with cutaneous zygomycosis have underlying conditions such as haematological malignancies, diabetes mellitus or solid organ transplantation, but a large proportion of them are immunocompetent. Trauma is the most common predisposing factor leading to zygomycosis in immunocompetent patients. If the patient is immunocompromised, the infection may disseminate. Cutaneous zygomycosis may be localized, may extend to deep underlying tissues, or may be disseminated. The most common clinical presentation is induration of the skin with surrounding erythema, rapidly progressing to necrosis. Histological examination and culture of soft tissue are important for the diagnosis of cutaneous zygomycosis. Treatment consists of surgical debridement, administration of antifungal agents (amphotericin B formulations and/or posaconazole) and, occasionally, hyperbaric oxygen. Mortality rates are approximately 30%.

Disseminated zygomycosis with involvement of the central nervous system.

Zygomycosis of the central nervous system (CNS) can manifest in three distinct clinical forms, as rhinocerebral zygomycosis, as disseminated zygomycosis with CNS involvement, and as isolated cerebral zygomycosis. We present a case of a 2-year-old boy with leukaemia and disseminated zygomycosis, caused by Absidia corymbifera, involving the brain, spinal cord, lung and liver. The child received treatment with liposomal amphotericin B and posaconazole for 6 months. Although the lesions of the lungs and liver resolved, those of the CNS persisted and the child is in a vegetative state. A review of the literature after 2004 identified ten additional cases of disseminated zygomycosis with cerebral involvement, all but one of which had concurrent lung infection. The most common underlying disease in these cases was haematological malignancy and the mortality rate was 70%. Disseminated zygomycosis with cerebral involvement is a fatal disease. Early recognition and prompt intervention with combined medical and surgical treatment may improve the outcome.

Efficacy of teicoplanin, administered in two different regimens, in the treatment of experimental endocarditis due to Enterococcus faecalis.

Using a rabbit model of endocarditis, we studied the efficacy of teicoplanin against a strain of Enterococcus faecalis resistant to ampicillin. Rabbits were randomly assigned to receive no antibiotics, teicoplanin 12 or 18 mg/kg of body weight every 12h, for 9 days. The effect of treatment on bacterial counts of vegetations and survival of the animals was evaluated at the end of treatment and 10 days thereafter. The two treatment regimens of teicoplanin produced peak serum levels 18.51+/-1.84 and 34.66+/-4.19 microg/ml, and trough levels above 10 x MIC of teicoplanin for the infecting organism. Both regimens resulted in significant bacterial reduction in the vegetations as compared to the control group (p<0.001). The drug prevented relapse of the infection 10 days after discontinuation of treatment. By increasing the teicoplanin dosage no additional therapeutic benefit was observed in terms of bacterial killing, sterilization of the vegetations, and survival of the animals, although the higher doses gave numerically superior results. These findings may have meaning for the optimum use of teicoplanin in the treatment of enterococcal endocarditis.

Native valve Aspergillus endocarditis in two patients with aplastic anaemia.

Native valve fungal endocarditis is an uncommon disease with a high mortality rate. We present the clinical features, histological findings and outcome of 2 patients with native valve Aspergillus endocarditis. Both patients had aplastic anaemia as a predisposing disease. The diagnosis was made by Duke's criteria in 1 case and by histology in the other. Surgery was precluded owing to profound thrombocytopenia. Both patients had fatal outcome despite administration of liposomal amphotericin beta.

Mucormycosis: ten-year experience at a tertiary-care center in Greece.

Presented here are the results of a retrospective analysis of all mucormycoses infections recorded at a tertiary hospital in Greece during the last 10 years. A total of 24 patients were identified, 15 male and 9 female, with ages ranging from 37 to 80 years. Twelve of the patients had soft tissue infections (2 with concomitant pulmonary infections), and 12 had rhinocerebral infections. Transmission could be traced in two cases; to nitroglycerin patches in one patient and to a lemon-tree-thorn scratch in the other. Among the 17 patients who underwent surgery, 11 survived. All seven patients on whom surgery was not performed died. Rapid diagnosis and treatment of mucormycosis are essential for patient survival. The severity of the patient's underlying condition, the degree of immunosuppression, and prompt surgical treatment are the most important factors contributing to the outcome.

Pulmonary Balantidium coli infection in a leukemic patient.

A 59-year-old woman suffering from chronic lymphocytic leukemia developed pulmonary lesions; bronchoalveolar lavage was performed for possible systemic fungal infection. However, direct microscopic analysis revealed ciliated protozoa identified as Balantidium coli. B. coli is the only known pathogenic ciliate, and is usually associated with intestinal infection in areas associated with pig rearing. On very rare occasions the organisms may invade extra-intestinal organs, in this case the lungs of an immunocompromised patient. This case is unusual as balantidiasis is rare in Europe, the patient had no obvious contact with pigs, and there was no history of diarrhea prior to pulmonary colonization. Metronidazole was rapidly administered, and the condition improved after 24-48 hr.

Case report. Successful treatment of two cases of post-surgical sternal osteomyelitis, due to Candida krusei and Candida albicans, respectively, with high doses of triazoles (fluconazole, itraconazole).

Two female patients, aged 75 and 59 years, respectively, with candidal sternal osteomyelitis were successfully treated by the administration of triazoles. Both had developed post-operative wound infection after sternotomy for coronary artery by-pass grafting. Sternal osteomyelitis was confirmed by bone scans with technetium 99Tc and gallium 67Ga. The cultures, from the pus draining at the site of the sternotomy scar, grew Candida krusei in the first case. The fistula closed after a 9-week course of itraconazole therapy (800 mg daily, followed by 600 mg daily) and the patient completed a 6-month period of therapy. The second patient had underlying diabetes mellitus. Post-operatively she developed two fistulae draining pus on the sternum. The pus cultures grew C. albicans. Initial treatment with oral fluconazole (400 mg daily) failed. Subsequent treatment with liposomal amphotericin B also failed. A dramatic improvement was noted when the patient received high doses of fluconazole (800 mg daily). The fistulae gradually closed after 1 month. Oral fluconazole was continued for 6 months. The cure was confirmed by bone scans. Three years later, both patients remained well.