Serum bactericidal titres for monitoring antimicrobial therapy: current status and potential role in the management of multidrug-resistant Gram-negative infections.

BACKGROUND: Serum bactericidal titres (SBTs) were widely used in the 1970s and 1980s to monitor antimicrobial therapy but are now seldom recommended. It is the only laboratory test that integrates drug pharmacodynamics, host pharmacokinetics and synergistic or antagonistic interactions of antimicrobial combinations into a single index of antimicrobial activity. We hypothesized that SBTs could play a renewed role in monitoring antibiotic treatment of multidrug-resistant Gram-negative infections. However, the last critical appraisal of the test was published over 30 years ago. OBJECTIVES: This narrative review provides an updated assessment of the SBT test and its methodological limitations. We performed a diagnostic meta-analysis to estimate the value of SBTs for predicting clinical failure or death during antibiotic treatment. SOURCES: A comprehensive literature search of PubMed including all English publications was performed in December 2019 using the Medical Subject Headings (MeSH search terms "serum", "bactericidal", "inhibitory", "titre", "monitoring", "anti-infective agents" "antimicrobial therapy" and "therapeutic drug monitoring"). CONTENT: Although standardized methods for performing SBTs were approved in 1999, the test remains labour intensive, and results may not be available until 72 hr. However, the use of non-culture-based endpoints (i.e. spectrophotometric or fluorescent) may shorten test time to 24 hr. Despite considerable heterogeneity in published studies, a meta-analysis of 11 evaluable studies published from 1974 to 2007 indicated a critical SBT result (peak SBT ≤1:8 or trough ≤1:2) is associated with a diagnostic odds ratio for clinical failure during antibiotic treatment of 12.27 (95% confidence interval 5.28-28.54) and a 5.32 (95% 1.32-21.42) odds of death. IMPLICATIONS: SBTs have prognostic value for identifying patients at high risk for antibiotic treatment failure, but the slow turnaround time of the current test limits its clinical utility. Standardization of a more rapid SBT testing method is needed.

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.

The changing face of nosocomial candidemia: epidemiology, resistance, and drug therapy.

The changing epidemiology and therapy of nosocomial candidemia are discussed. The frequency of nosocomial bloodstream infections by Candida species has risen dramatically in the past two decades. The arrival of antifungal drugs with better tolerability than conventional amphotericin B has resulted in widespread use of systemic antifungal therapy. With the introduction of new systemic antifungals, however, there have been major shifts in the epidemiology of candidal bloodstream infections toward species with less susceptibility to the available antifungal agents. Reports of in situ antifungal resistance are also becoming more common. Strategies for preventing the emergence of resistance have been suggested but have not undergone clinical trials. Antifungal susceptibility testing is becoming an increasingly important tool in the management of nosocomial candidemia. Treatments that have been undergoing investigation for use in these infections include combination therapies, lipid-based amphotericin B formulations, cytokines as adjuvant therapy, and novel antifungal agents such as voriconazole, SCH56592, and echinocandins. New antifungals in development may offer enhanced activity against pathogenic Candida species with less toxicity than amphotericin B. Antifungal susceptibility testing will play a major role in determining the treatment of resistant infections.

Therapy of Candida infections: susceptibility testing, resistance, and therapeutic options.

OBJECTIVE: Review the epidemiology of fungal infections, approved susceptibility testing methods, the scope of antifungal resistance, and advances in the treatment of fungal infections. DATA SOURCES: MEDLINE databases (from 1966 to March 1998) were searched for literature pertaining to the epidemiology and management of fungal infections. STUDY SELECTION AND DATA EXTRACTION: Articles were selected to assist in providing the reader an understanding of the epidemiology and management of fungal infections. DATA SYNTHESIS: Fungi have emerged as an important class of pathogens. Even though fungi rank as the fourth most commonly encountered nosocomial bloodstream pathogen, and are associated with the highest mortality of commonly encountered pathogens, only within the past year have methods for conducting and guidelines for interpreting in vitro susceptibility tests been approved. Under the guidance of these standards, we have begun to understand important issues regarding fungi such as the scope and mechanisms of antifungal resistance. Although there has not been a significant addition to our antifungal armamentarium since 1992, advances in antifungal therapy have been realized with the reformulation of available agents and the delineation of the pharmacodynamic characteristics of several antifungals. Additionally, several new agents, including a new class of antifungals, probably will enter into clinical use within the next 5 years. CONCLUSIONS: We have entered an era in which our understanding of fungi is increasing tremendously. Clinicians need to familiarize themselves with the current concepts surrounding the management of fungal infections in order to provide optimal care for their patients.