Mary L. Townsend

Tigecycline: a new glycylcycline antimicrobial.

Tigecycline is a new glycyclcycline antimicrobial recently approved for use in the USA, Europe and elsewhere. While related to the tetracyclines, tigecycline overcomes many of the mechanisms responsible for resistance to this class. It demonstrates favourable in vitro potency against a variety of aerobic and anaerobic Gram‐positive and Gram‐negative pathogens, including those frequently demonstrating resistance to multiple classes of antimicrobials. This includes methicillin‐resistant Staphylococcus aureus, penicillin‐resistant S. pneumoniae, vancomycin‐resistant enterococci, Acinetobacter baumannii, beta‐lactamase producing strains of Haemophilis influenzae and Moraxella catarrhalis, and extended‐spectrum beta‐lactamase producing strains of Escherichia coli and Klebsiella pneumoniae. In contrast, minimum inhibitory concentrations for Pseudomonas and Proteus spp. are markedly elevated. Tigecycline is administered parenterally twice daily. Randomised, controlled trials have demonstrated that tigecycline is non‐inferior to the comparators for the treatment of complicated skin and skin structure infections, as well as complicated intra‐abdominal infections. The most frequent and problematic side effect associated with its administration to date has been nausea and/or vomiting.

Overview of treatment options for invasive fungal infections

The introduction of several new antifungals has significantly expanded both prophylaxis and treatment options for invasive fungal infections (IFIs). Relative to amphotericin B deoxycholate, lipid-based formulations of amphotericin B have significantly reduced the incidence of nephrotoxicity, but at a significant increase in drug acquisition cost. Newer, broad-spectrum triazoles (notably voriconazole and posaconazole) have added significantly to both the prevention and treatment of IFIs, most notably Aspergillus spp. (with voriconazole) and the treatment of some emerging fungal pathogens. Finally, a new class of parenteral antifungals, the echinocandins, is employed most frequently against invasive candidal infections. While the role of these newer agents continues to evolve, this review summarizes the activity, safety and clinical applications of agents most commonly employed in the treatment of IFIs.

A comparison of the effectiveness of lipid-lowering therapy between HIV-and non-HIV-infected subjects with hyperlipidaemia

This retrospective cohort study conducted at the Durham Veterans Affairs Medical Center evaluated the effectiveness and safety of lipid-lowering therapy (LLT) in a HIV-infected population as compared with a general population with hyperlipidaemia. Fifty-three HIV-infected subjects who developed dyslipidaemia and 53 age-matched non-HIV-infected subjects receiving LLT were selected. Efficacy of LLT was assessed after three and six months. Non-HIV-infected subjects were more likely to achieve total cholesterol (TC) goals at three and six months (P = 0.045, P = 0.005) and triglyceride (TG) goals at six months (P = 0.017). Less than 45% of HIV-infected subjects met National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) goals at three or six months. While non-HIV-infected subjects were more likely to achieve TC and TG goals than HIV-infected subjects, overall achievement of NCEP III goals was poor. This result was likely due to treatment with inappropriately low doses of statins.

Recent advances in the treatment of life-threatening, invasive fungal infections

Introduction: Invasive fungal infections (IFIs) pose significant morbidity and are often life-threatening to many high-risk patients. Timely diagnosis and treatment of these infections with optimal therapy is imperative. Areas covered: Advances have been made in diagnostic biomarkers such as peptide nucleic acid fluorescent in situ hybridization, β-D-glucan and galactomannan, although more research is needed in this area to assist with both diagnosis and monitoring for improvement of IFI management. Novel antifungal agents (azole antifungals and echinocandins) are being investigated that have activity against Candida spp. and Aspergillus spp. Optimizing the pharmacodynamics (PD) of our current antifungal therapies through such strategies as continuous infusion of amphotericin B and dose escalation of echinocandins and liposomal formulations of amphotericin B have also been investigated with mixed results. Therapeutic drug monitoring (TDM) shows promise as evident from data with such agents as flucytosine, itraconazole, voriconazole and posaconazole. Expert opinion: The goal for the future of biomarkers in IFIs will be to have excellent sensitivity and specificity to ideally identify a particular fungus causing the infection or eliminate its existence to prevent unnecessary costs, resistance and antifungal usage. In addition, further developments of new antifungals are needed and judicious use of the current regimens needs to be optimized through antifungal PD properties and TDM.

Potential role of tigecycline in the treatment of community-acquired bacterial pneumonia.

Tigecycline is a member of the glycylcycline class of antimicrobials, which is structurally similar to the tetracycline class. It demonstrates potent in vitro activity against causative pathogens that are most frequently isolated in patients with community-acquired bacterial pneumonia (CABP), including (but not limited to) Streptococcus pneumoniae (both penicillin-sensitive and -resistant strains), Haemophilus influenzae and Moraxella catarrhalis (including β-lactamase-producing strains), Klebsiella pneumoniae, and ‘atypical organisms’ (namely Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila). Comparative randomized clinical trials to date performed in hospitalized patients receiving tigecycline 100 mg intravenous (IV) × 1 and then 50 mg IV twice daily thereafter have demonstrated efficacy and safety comparable to the comparator agent. Major adverse effects were primarily gastrointestinal in nature. Tigecycline represents a parenteral monotherapy option in hospitalized patients with CABP (especially in patients unable to receive respiratory fluoroquinolones). However, alternate and/or additional therapies should be considered in patients with more severe forms of CABP in light of recent data of increased mortality in patients receiving tigecycline for other types of severe infection.

Medication adherence in combat veterans with traumatic brain injury

PURPOSE Medication adherence in combat veterans with traumatic brain injury (TBI) was evaluated. METHODS Patients with a diagnosis of TBI were identified by a computer search of veterans enrolled in the Operation Enduring Freedom/Operation Iraqi Freedom or TBI/polytrauma clinics at Durham Veterans Affairs Medical Center (VAMC) between September 15, 2007, and September 15, 2008. Patients were included if they were at least 18 years old, received medical care and medications at the VAMC for at least 12 continuous months, and were taking at least one maintenance medication. A randomly selected age-matched comparator group without TBI was obtained through a computer-generated convenience sample. A composite adherence score for each patient was calculated using the medication possession ratio (MPR). The most commonly prescribed medications and indicators of increased adherence among the TBI group were also identified. RESULTS The composite MPR did not significantly differ between groups. The most commonly prescribed medications were selective serotonin-reuptake inhibitors and serotonin-norepinephrine-reuptake inhibitors and other antidepressants; however, these classes were associated with the lowest adherence rates. Factors associated with increased adherence included taking more than five maintenance medications (78%), living with a spouse or significant other (77%), owning a memory-assistance device (74%), and comorbid diagnosis of posttraumatic stress disorder (PTSD) (74%). CONCLUSION Medication adherence rates were similar among combat veterans with a diagnosis of TBI and an age-matched comparator group. Factors associated with increased adherence included taking more than five maintenance medications, living with a spouse or significant other, owning a memory-assistance device, and a comorbid diagnosis of PTSD.

Trimethoprim-Sulfamethoxazole-Induced Hepatotoxicity in a Pediatric Patient

Due to the escalating rates of community‐acquired methicillin‐resistant Staphylococcus aureus (CA‐MRSA) infection, trimethoprim‐sulfamethoxazole (TMP‐SMX) is being used increasingly in the pediatric population for skin and soft tissue infections. Although this combination agent has been associated with a hypersensitivity syndrome involving cutaneous skin eruptions, pediatric cases of TMP‐SMX‐induced hepatotoxicity are rare. We describe a relatively healthy, 9–year‐old boy who developed a CA‐MRSA skin and soft tissue infection and was treated with TMP‐SMX. After 14 days of therapy, he was taken to the emergency department with a 3–day history of fever, headache, and neck pain. He was diagnosed with a viral syndrome, acetaminophen was prescribed, and he was sent home. Three days later, the patient returned to the emergency department with fever, vomiting, decreased energy and appetitie, and suprapubic abdominal pain, and he was hospitalized. Laboratory test results revealed elevated liver function test values. After other potential causes of liver toxicity were excluded, TMP‐SMX was determined to be the cause of his acute liver toxicity. The drug was discontinued, his symptoms resolved, and his liver function tests returned to normal. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 5) between the patients development of hepatotoxicity and the TMP‐SMX therapy. This rare adverse reaction to TMP‐SMX has been reported in adults; however, to our knowledge, it has been reported in only five other children. Due to the increasing use of TMP‐SMX in children, clinicians should be aware of this potentially life‐threatening, immune‐mediated hypersensitivity reaction. Fortunately, however, the hepatotoxicity appears to resolve after discontinuation of the TMP‐SMX therapy in most reported cases. This case report illustrates the importance of early detection of drug‐induced hepatotoxicity and timely drug discontinuation to prevent the need for liver transplantation.

Antifungal catheter lock therapy for the management of a persistent Candida albicans bloodstream infection in an adult receiving hemodialysis.

Antifungal catheter lock therapy (AfLT) with liposomal amphotericin B has been used in the treatment of pediatric central line infections caused by Candida species; however, reports describing the use of liposomal amphotericin B lock therapy in the adult hemodialysis patient population are lacking. Management of central line–associated candidemia with systemic therapy alone is often challenging due to the propensity of Candida species to form biofilms on foreign bodies. We describe a 64‐year‐old woman who was receiving hemodialysis 3 times/week and was hospitalized with persistent fungemia. Despite receiving intravenous micafungin, she had multiple positive blood cultures for Candida albicans, which finally cleared after 7 days. Her double‐lumen catheter was considered the most likely nidus of infection. Although catheter removal would have been preferred, this was not possible given her vasculopathy, history of multiple bloodstream infections, and lack of other available sites for vascular access. Catheter exchange was performed, and liposomal amphotericin B AfLT was administered in combination with intravenous micafungin for a total of 6 days. During this time, the patient experienced no discernible adverse effects secondary to AfLT. At discharge, AfLT was discontinued, and intravenous micafungin was changed to oral fluconazole. After 6 months of treatment, the patient remained culture negative and maintained her dialysis access. To our knowledge, this is the first case report of liposomal amphotericin B catheter lock therapy used to manage a persistent C. albicans bloodstream infection in an adult receiving hemodialysis. AfLT is a novel concept for treating catheter‐associated fungal infections. Liposomal amphotericin B was chosen based on its favorable in vitro activity against Candida species biofilms in catheter lock environments. We identified several barriers to implementing AfLT, and these issues may prohibit the use of AfLT. This case report illustrates the benefits and challenges of managing catheter‐associated fungal infections with AfLT. Further study is required to examine the efficacy, safety, and feasibility of this approach.

Incidence of Severe Hepatotoxicity Related to Antiretroviral Therapy in HIV/HCV Coinfected Patients

Introduction. Hepatotoxicity is a concern in HIV/hepatitis C virus (HCV) coinfected patients due to their underlying liver disease. This study assessed the incidence of hepatotoxicity in HIV/HCV co-infected patients in two outpatient infectious diseases clinics. Methods. HIV/HCV co-infected adults were included in this retrospective study if they were PI or NNRTI naïve at their first clinic visit and were initiated on an NNRTI- and/or PI-based antiretroviral regimen. Patients were excluded if they had active or chronic hepatitis B virus (HBV). The primary objective was to determine the overall incidence of severe hepatotoxicity. Results. Fifty-six of the 544 patients identified met inclusion criteria. The incidence of severe hepatotoxicity was 10.7% (6/56 patients). Severe hepatotoxicity occurred with efavirenz (N = 2), nevirapine (N = 1), indinavir (N = 1), nelfinavir (N = 1), and saquinavir/ritonavir (N = 1). Conclusion. The incidence of severe hepatotoxicity appears to be low in this retrospective analysis of HIV/HCV co-infected patients receiving a PI-and/or NNRTI-based regimen.

Predictors of glycaemic control among HIV-positive veterans with diabetes.

Antiretroviral therapy has decreased HIV-related mortality. However, the incidence of diabetes as a co-morbidity is increasing as HIV-positive patients age. The purpose of this study was to assess the correlation between markers of HIV-infection and diabetes and to determine the proportion of patients achieving an haemoglobin A1c (HbA1c) goal <7% according to specific antiretroviral therapy regimens and adherence. In this retrospective study, HIV-positive veterans with diabetes from 2007 to 2012 were identified. Patients were required to be on the same antiretroviral therapy and diabetes regimen for ≥3 months. In 56 patients, it was identified that for each unit increase in log10 viral load, HbA1c increased 0.67 units (p = 0.0085). Only 38% of patients prescribed a protease inhibitor–based regimen vs. 56% of patients not on a protease inhibitor–based regimen achieved an HbA1c goal (p = 0.1864). Additionally, patients on an insulin-based regimen and patients that were less adherent were less likely to be at HbA1c goal (p = 0.018 and p = 0.0378, respectively). Patients with higher viral loads and patients that were less adherent to antiretroviral therapy were more likely to have a higher HbA1c demonstrating that poor adherence to antiretroviral therapy leads to poor control of both disease states.