David R. Andes

Clinical Practice Guidelines for the Management of Candidiasis: 2009 Update by the Infectious Diseases Society of America

Guidelines for the management of patients with invasive candidiasis and mucosal candidiasis were prepared by an Expert Panel of the Infectious Diseases Society of America. These updated guidelines replace the previous guidelines published in the 15 January 2004 issue of Clinical Infectious Diseases and are intended for use by health care providers who care for patients who either have or are at risk of these infections. Since 2004, several new antifungal agents have become available, and several new studies have been published relating to the treatment of candidemia, other forms of invasive candidiasis, and mucosal disease, including oropharyngeal and esophageal candidiasis. There are also recent prospective data on the prevention of invasive candidiasis in high-risk neonates and adults and on the empiric treatment of suspected invasive candidiasis in adults. This new information is incorporated into this revised document.

Clinical practice guideline: Adult sinusitis

OBJECTIVE This guideline provides evidence-based recommendations on managing sinusitis, defined as symptomatic inflammation of the paranasal sinuses. Sinusitis affects 1 in 7 adults in the United States, resulting in about 31 million individuals diagnosed each year. Since sinusitis almost always involves the nasal cavity, the term rhinosinusitis is preferred. The guideline target patient is aged 18 years or older with uncomplicated rhinosinusitis, evaluated in any setting in which an adult with rhinosinusitis would be identified, monitored, or managed. This guideline is intended for all clinicians who are likely to diagnose and manage adults with sinusitis. PURPOSE The primary purpose of this guideline is to improve diagnostic accuracy for adult rhinosinusitis, reduce inappropriate antibiotic use, reduce inappropriate use of radiographic imaging, and promote appropriate use of ancillary tests that include nasal endoscopy, computed tomography, and testing for allergy and immune function. In creating this guideline the American Academy of Otolaryngology-Head and Neck Surgery Foundation selected a panel representing the fields of allergy, emergency medicine, family medicine, health insurance, immunology, infectious disease, internal medicine, medical informatics, nursing, otolaryngology-head and neck surgery, pulmonology, and radiology. RESULTS The panel made strong recommendations that 1) clinicians should distinguish presumed acute bacterial rhinosinusitis (ABRS) from acute rhinosinusitis caused by viral upper respiratory infections and noninfectious conditions, and a clinician should diagnose ABRS when (a) symptoms or signs of acute rhinosinusitis are present 10 days or more beyond the onset of upper respiratory symptoms, or (b) symptoms or signs of acute rhinosinusitis worsen within 10 days after an initial improvement (double worsening), and 2) the management of ABRS should include an assessment of pain, with analgesic treatment based on the severity of pain. The panel made a recommendation against radiographic imaging for patients who meet diagnostic criteria for acute rhinosinusitis, unless a complication or alternative diagnosis is suspected. The panel made recommendations that 1) if a decision is made to treat ABRS with an antibiotic agent, the clinician should prescribe amoxicillin as first-line therapy for most adults, 2) if the patient worsens or fails to improve with the initial management option by 7 days, the clinician should reassess the patient to confirm ABRS, exclude other causes of illness, and detect complications, 3) clinicians should distinguish chronic rhinosinusitis (CRS) and recurrent acute rhinosinusitis from isolated episodes of ABRS and other causes of sinonasal symptoms, 4) clinicians should assess the patient with CRS or recurrent acute rhinosinusitis for factors that modify management, such as allergic rhinitis, cystic fibrosis, immunocompromised state, ciliary dyskinesia, and anatomic variation, 5) the clinician should corroborate a diagnosis and/or investigate for underlying causes of CRS and recurrent acute rhinosinusitis, 6) the clinician should obtain computed tomography of the paranasal sinuses in diagnosing or evaluating a patient with CRS or recurrent acute rhinosinusitis, and 7) clinicians should educate/counsel patients with CRS or recurrent acute rhinosinusitis regarding control measures. The panel offered as options that 1) clinicians may prescribe symptomatic relief in managing viral rhinosinusitis, 2) clinicians may prescribe symptomatic relief in managing ABRS, 3) observation without use of antibiotics is an option for selected adults with uncomplicated ABRS who have mild illness (mild pain and temperature <38.3 degrees C or 101 degrees F) and assurance of follow-up, 4) the clinician may obtain nasal endoscopy in diagnosing or evaluating a patient with CRS or recurrent acute rhinosinusitis, and 5) the clinician may obtain testing for allergy and immune function in evaluating a patient with CRS or recurrent acute rhinosinusitis. DISCLAIMER This clinical practice guideline is not intended as a sole source of guidance for managing adults with rhinosinusitis. Rather, it is designed to assist clinicians by providing an evidence-based framework for decision-making strategies. It is not intended to replace clinical judgment or establish a protocol for all individuals with this condition, and may not provide the only appropriate approach to diagnosing and managing this problem.

Executive Summary: Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patients individual circumstances.

Pharmacokinetics and pharmacodynamics of antibiotics in otitis media

The pharmacology of antimicrobial chemotherapy can be divided into two components. Pharmacokinetics deals with the absorption, distribution and elimination of antimicrobials. These factors, combined with the dosing regimen, determine the time course of drug concentrations in serum and in body tissue

Inhibition of Mutation and Combating the Evolution of Antibiotic Resistance

The emergence of drug-resistant bacteria poses a serious threat to human health. In the case of several antibiotics, including those of the quinolone and rifamycin classes, bacteria rapidly acquire resistance through mutation of chromosomal genes during therapy. In this work, we show that preventing induction of the SOS response by interfering with the activity of the protease LexA renders pathogenic Escherichia coli unable to evolve resistance in vivo to ciprofloxacin or rifampicin, important quinolone and rifamycin antibiotics. We show in vitro that LexA cleavage is induced during RecBC-mediated repair of ciprofloxacin-mediated DNA damage and that this results in the derepression of the SOS-regulated polymerases Pol II, Pol IV and Pol V, which collaborate to induce resistance-conferring mutations. Our findings indicate that the inhibition of mutation could serve as a novel therapeutic strategy to combat the evolution of antibiotic resistance.

Impact of Treatment Strategy on Outcomes in Patients with Candidemia and Other Forms of Invasive Candidiasis: A Patient-Level Quantitative Review of Randomized Trials

BACKGROUND Invasive candidiasis (IC) is an important healthcare-related infection, with increasing incidence and a crude mortality exceeding 50%. Numerous treatment options are available yet comparative studies have not identified optimal therapy. METHODS We conducted an individual patient-level quantitative review of randomized trials for treatment of IC and to assess the impact of host-, organism-, and treatment-related factors on mortality and clinical cure. Studies were identified by searching computerized databases and queries of experts in the field for randomized trials comparing the effect of ≥2 antifungals for treatment of IC. Univariate and multivariable analyses were performed to determine factors associated with patient outcomes. RESULTS Data from 1915 patients were obtained from 7 trials. Overall mortality among patients in the entire data set was 31.4%, and the rate of treatment success was 67.4%. Logistic regression analysis for the aggregate data set identified increasing age (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.00-1.02; P = .02), the Acute Physiology and Chronic Health Evaluation II score (OR, 1.11; 95% CI, 1.08-1.14; P = .0001), use of immunosuppressive therapy (OR, 1.69; 95% CI, 1.18-2.44; P = .001), and infection with Candida tropicalis (OR, 1.64; 95% CI, 1.11-2.39; P = .01) as predictors of mortality. Conversely, removal of a central venous catheter (CVC) (OR, 0.50; 95% CI, .35-.72; P = .0001) and treatment with an echinocandin antifungal (OR, 0.65; 95% CI, .45-.94; P = .02) were associated with decreased mortality. Similar findings were observed for the clinical success end point. CONCLUSIONS Two treatment-related factors were associated with improved survival and greater clinical success: use of an echinocandin and removal of the CVC.

Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patients individual circumstances.

Voriconazole Therapeutic Drug Monitoring

ABSTRACT We report on 28 patients who underwent voriconazole monitoring because of disease progression or toxicity. A relationship (P < 0.025) between disease progression and drug concentration was detected. Favorable responses were observed in 10/10 patients with concentrations above 2.05 μg/ml, while disease progressed in 44% (n = 18) of patients with concentrations below 2.05 μg/ml.

Critical role of Bcr1-dependent adhesins in C. albicans biofilm formation in vitro and in vivo.

The fungal pathogen Candida albicans is frequently associated with catheter-based infections because of its ability to form resilient biofilms. Prior studies have shown that the transcription factor Bcr1 governs biofilm formation in an in vitro catheter model. However, the mechanistic role of the Bcr1 pathway and its relationship to biofilm formation in vivo are unknown. Our studies of biofilm formation in vitro indicate that the surface protein Als3, a known adhesin, is a key target under Bcr1 control. We show that an als3/als3 mutant is biofilm-defective in vitro, and that ALS3 overexpression rescues the biofilm defect of the bcr1/bcr1 mutant. We extend these findings with an in vivo venous catheter model. The bcr1/bcr1 mutant is unable to populate the catheter surface, though its virulence suggests that it has no growth defect in vivo. ALS3 overexpression rescues the bcr1/bcr1 biofilm defect in vivo, thus arguing that Als3 is a pivotal Bcr1 target in this setting. Surprisingly, the als3/als3 mutant forms a biofilm in vivo, and we suggest that additional Bcr1 targets compensate for the Als3 defect in vivo. Indeed, overexpression of Bcr1 targets ALS1, ECE1, and HWP1 partially restores biofilm formation in a bcr1/bcr1 mutant background in vitro, though these genes are not required for biofilm formation in vitro. Our findings demonstrate that the Bcr1 pathway functions in vivo to promote biofilm formation, and that Als3-mediated adherence is a fundamental property under Bcr1 control. Known adhesins Als1 and Hwp1 also contribute to biofilm formation, as does the novel protein Ece1.

Antifungal Therapeutic Drug Monitoring: Established and Emerging Indications

The successful management of invasive fungal infections continues to pose a difficult challenge to clinicians. As the population of at-risk immunocompromised patients increases, the incidence of invasive mycosis has risen in parallel (57). Despite recent advances in antifungal pharmacology, the morbidity and mortality due to invasive fungal infections remain unacceptably high. Numerous factors determine the outcome of these infections, including the host immune state, pathogen variables including drug susceptibility, location of the infection, timing of diagnosis relative to initiation of antifungal therapy, management of the infection source (e.g., surgery or vascular catheter removal), and effective administration of the appropriate dose of the most potent and safe antifungal drug (Fig. ​(Fig.1).1). Few of these variables are under the control of the clinician. The choices of antifungal drug and dosing regimen are among the factors which the clinician can dictate. However, even if the appropriate drug and regimen are initiated, drug exposure at the site of infection may be inadequate due to pharmacokinetic variability and may contribute to treatment failure. Conversely, antifungal exposures may exceed those anticipated and may result in toxicity. Many antifungal drugs exhibit marked variability in drug blood concentrations due to inconsistent absorption, metabolism, elimination, or interaction with concomitant medications. An understanding of the pharmacokinetics and pharmacodynamics of these drugs has been demonstrated to be important to optimize drug choice and dosing regimen design. One tool to detect drug exposures outside of the therapeutic window is monitoring of drug concentration in blood. The utility of this tool to inform drug choice and dosing decisions is being increasingly explored. FIG. 1. Determinants for outcome of invasive mycoses. Several factors must be considered in determining the role of therapeutic drug monitoring in patient management (32, 86, 88). An accurate, rapid, and cost-effective drug assay must be readily available to the clinician. Two pharmacological features then determine the relevance of monitoring of concentrations of drug in blood. The foremost variable is an unpredictable drug dose-exposure relationship. Next, there must be a clear relationship between concentrations of drug in blood and either toxicity or treatment efficacy. Consideration of these pharmacological variables for available antifungal compounds is the focus of this review.