John F. Mohr

Point: Vancomycin Is Not Obsolete for the Treatment of Infection Caused by Methicillin-Resistant Staphylococcus aureus

Since the discovery, development, and US Food and Drug Administration approval of vancomycin in the 1950s, this agent has remained a mainstay for the treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). However, because of the development of new antistaphylococcal antibiotics and reports of vancomycin failures, the utility of vancomycin has recently been questioned. Although vancomycin did not undergo the strict US Food and Drug Administration approval process that is in place today to demonstrate efficacy, there is considerable information available that sheds light on the role vancomycin has in infectious diseases pharmacotherapy today. In addition, although we look to in vitro susceptibility testing to assess vancomycin activity against S. aureus, we have come to appreciate that resistance of S. aureus to vancomycin can be a continuous--rather than a categorical--phenomenon. This has resulted in clinical microbiology laboratories having difficulty identifying S. aureus that may not respond to conventional doses of vancomycin. A better understanding is needed of the pharmacodynamic relationship between vancomycin and MRSA as relates to optimal dosing strategies, including consideration for loading doses, and development of rational categorical breakpoints for susceptibility based on clinical outcomes. By better understanding these critical issues, it may be possible to optimize the use of vancomycin, resulting in a cost-effective treatment option for many patients infected with MRSA.

Prospective Survey of (1→3)-β-d-Glucan and Its Relationship to Invasive Candidiasis in the Surgical Intensive Care Unit Setting

ABSTRACT Non-culture-based diagnostic strategies are needed for diagnosing invasive candidiasis (IC). We evaluated serial serum (1→3)-β-d-glucan (BG) levels in patients in the surgical trauma intensive care unit (SICU) patients with clinical evidence of IC. Serum samples from patients admitted to the SICU for a minimum of 3 days were collected twice weekly and analyzed for BG by using a Fungitell kit with a positive cutoff of ≥80 pg/ml. Diagnosis of IC was done using a set of predefined and validated clinical practice-based criteria. A total of 57 patients consented to participate and were enrolled. The median ICU stay was 16 days (range, 3 to 51). A total of 14 of 57 (25%) false positives were observed in the first sample (ICU day 3) and, overall, 73% of the day 3 samples had higher BG levels than subsequent samples. On the date of clinical diagnosis of IC, the sensitivity of a positive BG for identifying invasive candidiasis was 87%, with a 73% specificity. In patients with evidence of IC, the median BG value was significantly higher than those without evidence of IC (171 versus 48 pg/ml, P = 0.02), respectively. In the three patients with proven IC, BG was detected 4 to 8 days prior to diagnosis. BG serum detection may be a useful tool to aid in the early diagnosis of IC in SICU patients, particularly after day 3 and in patients with at least two positive samples drawn several days apart. Elevated BG levels within the first 3 days need to be further characterized.

A Retrospective, Comparative Evaluation of Dysglycemias in Hospitalized Patients Receiving Gatifloxacin, Levofloxacin, Ciprofloxacin, or Ceftriaxone

Study Objectives. To compare rates of blood glucose abnormalities in hospitalized patients receiving fluoroquinolones or ceftriaxone, and to describe the characteristics of patients who develop blood glucose abnormalities while receiving these agents.

Current Options in Antifungal Pharmacotherapy

Infections caused by yeasts and molds continue to be associated with high rates of morbidity and mortality in both immunocompromised and immunocompetent patients. Many antifungal drugs have been developed over the past 15 years to aid in the management of these infections. However, treatment is still not optimal, as the epidemiology of the fungal infections continues to change and the available antifungal agents have varying toxicities and drug‐interaction potential. Several investigational antifungal drugs, as well as nonantifungal drugs, show promise for the management of these infections.

Update on the Efficacy and Tolerability of Meropenem in the Treatment of Serious Bacterial Infections

Meropenem is a carbapenem antibiotic approved by the US Food and Drug Administration for the treatment of complicated skin and skin-structure infections, complicated intra-abdominal infections, and pediatric bacterial meningitis (in patients >or=3 months of age). In clinical trials, it also has shown efficacy as initial empirical therapy for the treatment of nosocomial pneumonia. Unlike other beta-lactam antibiotics, including third-generation cephalosporins, carbapenems have shown activity against extended-spectrum beta-lactamase-producing and AmpC chromosomal beta-lactamase-producing bacteria. Compared with imipenem, meropenem is more active against gram-negative pathogens and somewhat less active against gram-positive pathogens, and it does not require coadministration of a renal dehydropeptidase inhibitor. In most comparative trials, clinical and bacteriological response rates with imipenem and meropenem were similar. Compared with clindamycin/tobramycin, meropenem is associated with a reduced length of hospital stay and a shorter duration of therapy among patients with complicated intra-abdominal infections. Meropenem is well tolerated by children and adults and has an acceptable safety profile. Alternative meropenem dosing strategies for the optimization of outcomes are under investigation.

Pharmacokinetic Evaluation of Single-Dose Intravenous Daptomycin in Patients with Thermal Burn Injury

ABSTRACT Daptomycin pharmacokinetics were evaluated for burn patients. Burn patients had decreases in the maximum concentration of the drug in serum (44%) and the area under the concentration-time curve (47%) and increases in the volume of distribution (64%) and total clearance (77%) compared to healthy volunteers. In burn patients, daptomycin at 10 to 12 mg/kg of body weight/day would be required to achieve drug exposures similar to those for healthy volunteers receiving 6 mg/kg.

Correlation of Clinical Outcomes with β-Glucan Levels in Patients with Invasive Candidiasis

ABSTRACT The correlation of β-glucan (BG) levels with clinical outcomes in invasive candidiasis (IC) remains unknown. Patients with proven IC were followed prospectively from diagnosis to outcome with twice-weekly serum BG sampling. Correlation of BG with clinical outcome was assessed in each patient. BG levels tend to decrease in successfully treated patients and increase in treatment failures. BG levels may be useful as surrogates for outcome evaluation of IC.

Past, Present, and Future of Antibacterial Economics: Increasing Bacterial Resistance, Limited Antibiotic Pipeline, and Societal Implications.

Growing antimicrobial resistance and a dwindling antibiotic pipeline have resulted in an emerging postantibiotic era, as patients are now dying from bacterial infections that were once treatable. The fast‐paced “Golden Age” of antibiotic development that started in the 1940s has lost momentum; from the 1980s to the early 2000s, there was a 90% decline in the approval of new antibiotics as well as the discovery of few new novel classes. Many companies have shifted away from development due to scientific, regulatory, and economic hurdles that proved antibiotic development to be less attractive compared with more lucrative therapeutic areas. National and global efforts are focusing attention toward potential solutions for reinvigorating the antibiotic pipeline and include “push” incentives such as public–private partnerships and “pull” incentives such as reimbursement reform and market exclusivity. Hybrid models of incentives, global coordination among stakeholders, and the appropriate balance of antibiotic pricing, volume of drug used, and proper antimicrobial stewardship are key to maximizing efforts toward drug development to ensure access to patients in need of these therapies.

Pharmacokinetics of Intravenous Itraconazole in Stable Hemodialysis Patients

ABSTRACT The pharmacokinetics of intravenous itraconazole (ITC) was studied in dialysis patients. Dialysis had no effect on the half-life and clearance of ITC or OH-ITC. However, dialysis allowed the clearance of hydroxypropyl-β-cyclodextrin (HP-β-CD). The area under the concentration-time curve from time zero to infinity (AUC0-∞) for HP-β-CD administered before dialysis was lower than the AUC0-∞ when it was administered after dialysis (P < 0.01). Administration of ITC intravenously just prior to hemodialysis appears to produce adequate systemic exposures of ITC and OH-ITC while allowing dialysis clearance of HP-β-CD. Studies of multiple administrations are warranted.

Dysglycaemias and fluoroquinolones.

The fluoroquinolones are an extremely popular class of antibacterials, owing to their broad spectrum of activity and the convenience of their intravenous and oral dosage formulations. Overall, the currently available fluoroquinolones have a good safety profile; however, certain fluoroquinolones within the class have been associated with severe and life-threatening adverse drug reactions. Dysglycaemic episodes (hyperglycaemia and hypoglycaemia) have been observed in patients taking multiple antibacterials, including the fluoroquinolones. Although gatifloxacin has been associated with dysglycaemias more frequently than other fluoroquinolones, dysglycaemic events have been reported with some of the other currently available fluoroquinolones as well. Hypoglycaemia appears to be related to insulin release and is an early-onset event. However, hyperglycaemia tends to present several days into therapy and the exact mechanism by which it is caused is still unclear. Recent studies point towards the important role of the adenosine triphosphate (ATP)-sensitive K+ channels in the pancreatic β cell and the importance of anti-insulin hormones. Several retrospective studies have elucidated risk factors associated with fluoroquinolone exposure and subsequent dysglycaemic events. These studies suggest that dysglycaemia is a dose-related adverse effect involving the fluoroquinolone class; however, some drugs within the class appear to have a greater association. This may be related to the affinity of fluoroquinolones to the ATP-sensitive K+ channel or higher concentrations of drugs achieved in certain patients who are already at risk for hyperglycaemia and hypoglycaemia. Understanding these risk factors will allow the fluoroquinolones to be utilized in a way that minimizes the probability of associated dysglycaemic events.