Treatment options for neonatal infections in the post-cefotaxime era.

INTRODUCTION: Cefotaxime has been used for the management of neonatal infections since the 1990s for suspected meningitis and to mitigate gentamicin-associated renal injury. Its shortage in 2015 and subsequent removal from the U.S. pharmaceutical market forced providers to consider alternatives. Ceftriaxone, a cephalosporin with an identical antibacterial spectrum of activity to cefotaxime, is contraindicated in neonates due to its risk of biliary pseudolithiasis. Ceftazidime was recommended as an alternative by the American Academy of Pediatrics but is inequivalent. AREAS COVERED: This article addresses indications for cephalosporin use and considerations when selecting an alternative to cefotaxime. Differences among cefotaxime, ceftriaxone, ceftazidime, and cefepime are discussed and compared to the standard-of-care presumptive regimen, ampicillin, and gentamicin. The authors consider the data behind the neonatal contraindication to ceftriaxone and provide recommendations for their application to practice. EXPERT OPINION: The data against ceftriaxone use in neonates remain poor, particularly in the context of the cefotaxime shortage and lack of an equivalent alternative. Ceftriaxone could be considered in low-risk neonates without hyperbilirubinemia or exposure to calcium-containing fluids on a case-by-case basis. Ceftazidime monotherapy for presumptive management of neonatal infections is inappropriate; cefepime should be more frequently utilized in neonates who are poor candidates for ceftriaxone.

Evaluation of clinical outcome in children and adolescents receiving vancomycin for invasive infections due to methicillin-resistant Staphylococcus aureus: impact of increasing vancomycin MICs.

BACKGROUND: Vancomycin is the preferred drug for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in children. In adults, treatment failure with vancomycin has been associated with an area under the curve/24 hrs /MIC (AUC24/MIC) ratio of ≤400 and high minimum inhibitory concentrations (MIC ≥1.0 mg/L). Vancomycin dosing information to ensure optimal AUC24/MIC in the pediatric population remains limited. METHODS: A retrospective chart review from August 2008 to 2011 and a prospective study from September 2011 to October 2013 was conducted on all pediatric patients at two hospitals in Brooklyn, NY with positive cultures for MRSA who received vancomycin. Treatment failure was defined as persistent positive cultures (≥5 days) or persistence of clinical symptoms. Vancomycin AUC24/MICs were calculated. RESULTS: Twenty-three children with MRSA infection, 0-18 years of age, were identified; 18 of 23 (78.3%) were community acquired. MICs of 91% of the isolates were ≥1.5 µg/mL and 9 had MICs of 2 µg/mL. Treatment failure was seen in 12 (52%) patients with MICs of 1.5 µg/mL and above. Vancomycin trough levels >15 µg/mL and AUC24/MIC >400 were achieved in only 18% and 0% of patients, respectively. CONCLUSIONS: High treatment failure rates with vancomycin was associated with MIC ≥1.5 µg/mL. Current recommended vancomycin dosing in children did not achieve a trough concentration of >15 µg/mL in majority of the patients and none achieved an AUC24/MIC>400.

Use of cethromycin, a new ketolide, for treatment of community-acquired respiratory infections.

BACKGROUND: The ketolides are a subclass of macrolides, which were designed specifically to overcome macrolide-resistant respiratory pathogens. Ketolides lack the cladinose sugar, which is replaced with a 3-ketone group. Ketolides bind to a secondary region on domain II of the 23S rRNA subunit. Telithromycin was the first ketolide to be approved by the FDA in 2004 for treatment of community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB) and sinusitis. However, in 2006, after reports of serious hepatotoxicity, the FDA issued a public health advisory followed by a warning. In 2007 the indications for treatment of AECB and sinusitis were removed from the labeling. Cethromycin (ABT-773) is the only other ketolide currently under clinical development. OBJECTIVE: To review currently available data on cethromycin, including chemistry, in vitro activity, pharmacokinetics, pharmacodynamics, in vivo activity and results of treatment studies in humans. METHODS: A search was made in PubMed, pharmaceutical databases and meeting abstracts using the terms ketolides, ABT-773 and cethromycin. RESULTS/CONCLUSIONS: Cethromycin has comparable tissue penetration, pharmacokinetics and in vitro activity compared with telithromycin to Streptococcus pneumoniae, including multidrug-resistant isolates, Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, Mycoplasma pneumoniae and Legionella pneumophila. There is only one published CAP treatment study that compared cethromycin 150 mg q.d. with 150 mg b.i.d. One Phase II and a Phase II/III study have been presented in abstract form, both were non-comparative, dose-ranging studies, which suggested that 150 mg q.d. or 300 mg q.d. were comparable in terms of clinical response and bacterial eradication, although data on the latter are limited. Data on side effects are limited and appear to be mainly gastrointestinal. There have been no reports of serious hepatotoxicity at the time of this writing. Cethromycin may have other uses in addition to treatment of CAP respiratory infections, including treatment of infections due to Neisseria gonorrhoeae and Chlamydia trachomatis and bioterrorism agents including Bacillus anthracis, Yersinia pestis and Francisella tularensis.

Microbiological efficacy of ABT-773 (cethromycin) for the treatment of community-acquired pneumonia due to Chlamydia pneumoniae.

Nasopharyngeal specimens for culture of Chlamydia pneumoniae were obtained from patients with community-acquired pneumonia enrolled in a randomized study comparing the novel ketolide antibiotic ABT-773 at a dose of 150 mg once a day to 150 mg twice a day, by mouth for 10 days. C. pneumoniae was eradicated from the nasopharynx of 10 of 10 (100%) microbiologically evaluable patients. MICs and MBCs for 13 isolates of C. pneumoniae from 12 patients obtained before and after therapy were performed against ABT-773. The MIC90 and MBC90 of ABT-773 were 0.015 mg/L.

Effect of prolonged treatment with azithromycin, clarithromycin, or levofloxacin on Chlamydia pneumoniae in a continuous-infection Model.

Persistent infections with Chlamydia pneumoniae have been implicated in the development of chronic diseases, such as atherosclerosis and asthma. Although azithromycin, clarithromycin, and levofloxacin are frequently used for the treatment of respiratory C. pneumoniae infections, little is known about the dose and duration of therapy needed to treat a putative chronic C. pneumoniae infection. In this study, we investigated the effect of prolonged treatment with azithromycin, clarithromycin, or levofloxacin on the viability of C. pneumoniae and cytokine production in an in vitro model of continuous infection. We found that a 30-day treatment with azithromycin, clarithromycin, and levofloxacin at concentrations comparable to those achieved in the pulmonary epithelial lining fluid reduced but did not eliminate C. pneumoniae in continuously infected HEp-2 cells. All three antibiotics decreased levels of interleukin-6 (IL-6) and IL-8 in HEp-2 cells, but this effect appeared to be secondary to the antichlamydial activity, as the cytokine levels correlated with the concentrations of microorganisms. The levels of IL-1beta, IL-4, IL-10, tumor necrosis factor alpha, and gamma interferon were too low to assess the effect of antibiotics. These data suggest that the dosage and duration of antibiotic therapy currently being used may not be sufficient to eradicate a putative chronic C. pneumoniae infection.