Limitations of ceftriaxone compared with cefazolin against MSSA: an integrated pharmacodynamic analysis.

Objectives: Despite the convenience of once-daily dosing, the use of ceftriaxone for Staphylococcus aureus infections has significant limitations, including scarce clinical evidence and increasingly questionable pharmacodynamic activity. Our goal was to conduct an integrated pharmacokinetic-pharmacodynamic analysis of the appropriateness of ceftriaxone compared with cefazolin for treating serious MSSA infections. Methods: Ceftriaxone and cefazolin activity against five clinical MSSA isolates was characterized in an in vitro pharmacodynamic model. Monte Carlo simulations were then used to evaluate various dosing regimens of ceftriaxone and cefazolin based on relevant patient pharmacokinetic data, significant pharmacodynamic targets derived from the in vitro studies (55%ƒT>MIC for bacteriostasis, 75%ƒT>MIC for 1 log10 bacterial kill, 100%ƒT>MIC for ≥3 log10 bacterial kill) and MIC distributions for MSSA from national surveillance data. Results: Ceftriaxone at 1 g once daily had poor activity against MSSA with net bacterial growth predicted in 76% of simulated subjects. The standard 2 g of ceftriaxone once daily had predicted bacterial growth or bacteriostasis in 54% of cases with bactericidal effects in only 17%. Cefazolin at 2 g once daily was notably similar to ceftriaxone in expected target attainments. Cefazolin at 2 g twice daily demonstrated maximal pharmacodynamic activity with bactericidal effects in 97% of simulated subjects. Conclusions: Given the limited activity of ceftriaxone against S. aureus, particularly for serious infections when bacterial kill is desired, the convenience of once-daily dosing should be weighed against the risks of using an overly broad, suboptimal therapy. Cefazolin warrants further consideration, particularly as optimal pharmacodynamics against MSSA may be achieved with twice-daily dosing in most patients.

Fatal Bacterial Meningitis Possibly Associated with Substandard Ceftriaxone--Uganda, 2013.

The burden of disease from bacterial meningitis is highest in low-income countries (1). Early initiation of antibiotic therapy is important in reducing the risk for mortality. Current treatment guidelines recommend the use of an expanded-spectrum cephalosporin (cefotaxime or ceftriaxone) (2), but these therapies increasingly are limited by drug resistance, and are threatened by the proliferation of substandard and falsified medicines (3,4). In February 2013, a case of bacterial meningitis following a middle ear infection was diagnosed in an adolescent at the Mulago National Referral Hospital in Kampala, Uganda. Once-daily treatment with 2 g of intravenous ceftriaxone administered according to guidelines failed, and the patient died. To determine whether the patient's treatment failure and subsequent death might be related to the ceftriaxone product administered, a sealed vial similar to the one administered to the patient was analyzed at the University of Ottawa, Canada, and was found to contain only 0.455 g of the drug, not 1 g as stated by the manufacturer. This would have resulted in subtherapeutic dosing. Substandard medicines are a global problem that disproportionately affects low-income countries, leading to fatal consequences and promoting the emergence of drug resistance (4).

Quality of ceftriaxone in Pakistan: reality and resonance.

The quality of pharmaceuticals is a global concern, counterfeit/ poor quality/ substandard medicines can cause harms in various ways: In a number of developing countries including Pakistan there is reportedly a high incidence of the availability of substandard drugs. The majority of these reports do not contain quantitative data to support these claims, nor do they describe the methodology employed for the quality assessment. Quality of drugs available in Pakistan are being questioned and topic of discussion in local news paper, TV channels in general public including journalist and physicians due to disparity of price among same generics, lack of knowledge for such science and unknown reasons. Since, quality of drugs can neither be assessed by naked eye or by every one therefore, randomly selected, 96 samples of different strength of injection ceftriaxone sodium and its generic, a widely used third generation cephalosporin in Pakistan since 1982 and 1994 till date respectively included in the said study to know the reality. 15.62% of ceftriaxone injection was found to be out of specification, however, not a single sample was found fake (spurious) out of 96 tested samples. Nevertheless, quality is a wide ranging concept covering all matters that individually or collectively influence the excellence of a product hence price and other related issues are also analyzed in the study.

A pilot study evaluating the prescribing of ceftriaxone in hospitals in Ghana: findings and implications.

BACKGROUND AND OBJECTIVES: Widespread empiric use of antibiotics exists especially in developing countries. This is a concern since inappropriate use of antibiotics, including their extended inappropriate use, will increase resistance rates. Consequently, there is a need to evaluate antibiotic utilisation across healthcare sectors to improve future use. This includes ceftriaxone, widely used among hospitals including those in Ghana. METHODS: A cross-sectional study to evaluate the appropriateness of ceftriaxone prescribing in a leading hospital in Ghana. Ceftriaxone prescribing in patient-record cards was assessed using a modified WHO drug-utilization evaluation criteria as well as referencing the national standard treatment guidelines in Ghana and the ceftriaxone package insert. RESULTS: A total of 251 patients were assessed. Ceftriaxone was most commonly prescribed for comorbid malaria with bacterial infections, urinary tract infections, sepsis and gastroenteritis. The appropriateness of the indication was 86% (n = 218). The doses most prescribed were 1g (41%) and 2g (39%). Stat dose and once-daily dosage regimen constituted 51.4% and 84.5%, respectively. The most common duration of treatment was 1 (51.4%) and 2 days (35.1%). The overall appropriateness of prescribing was 93% against a pre-set threshold of 97%. CONCLUSION: The appropriateness of ceftriaxone prescribing was high in this leading hospital in Ghana; however, there is room for improvement with targeted education initiatives, with further research planned.

Pharmaceutical quality of eight generics of ceftriaxone preparation for injection in Eastern Asia.

OBJECTIVES: To compare the pharmaceutical quality of original and generic ceftriaxone sodium preparations for injection produced in Eastern Asia. METHODS: Standard physical and chemical laboratory tests were performed. Participants/material: Ceftriaxone (Rocephin®, Roche, Switzerland) was the reference material. Generics produced in China, India, and Indonesia were sampled in China and Myanmar within their expiration dates. RESULTS: Eight generics obtained from Eastern Asia markets in January 2013 were analysed. All eight generics failed the specifications in three or more tests. Residues of solvents and metals were detected in all generics, four were not particle free, and two were not sterile. CONCLUSIONS: All tested generic ceftriaxone products failed to meet the pharmaceutical quality standards of the branded original. The high levels of impurities and the identified contamination of particles and residues are of clinical concern, as they could impact tolerability and safety in patients in need of an effective parenteral antibiotic.

Association of clinical practice guidelines with emergency department management of febrile infants ≤56 days of age.

BACKGROUND: Differences among febrile infant institutional clinical practice guidelines (CPGs) may contribute to practice variation and increased healthcare costs. OBJECTIVE: Determine the association between pediatric emergency department (ED) CPGs and laboratory testing, hospitalization, ceftriaxone use, and costs in febrile infants. DESIGN: Retrospective cross-sectional study in 2013. SETTING: Thirty-three hospitals in the Pediatric Health Information System. PATIENTS: Infants aged ≤56 days with a diagnosis of fever. EXPOSURES: The presence and content of ED-based febrile infant CPGs assessed by electronic survey. MEASUREMENTS: Using generalized estimating equations, we evaluated the association between CPG recommendations and rates of urine, blood, cerebrospinal fluid (CSF) testing, hospitalization, and ceftriaxone use at ED discharge in 2 age groups: ≤28 days and 29 to 56 days. We also assessed CPG impact on healthcare costs. RESULTS: We included 9377 ED visits; 21 of 33 EDs (63.6%) had a CPG. For neonates ≤28 days, CPG recommendations did not vary and were not associated with differences in testing, hospitalization, or costs. Among infants 29 to 56 days, CPG recommendations for CSF testing and ceftriaxone use varied. CSF testing occurred less often at EDs with CPGs recommending limited testing compared to hospitals without CPGs (adjusted odds ratio: 0.5, 95% confidence interval: 0.3-0.8). Ceftriaxone use at ED discharge varied significantly based on CPG recommendations. Costs were higher for admitted and discharged infants 29 to 56 days old at hospitals with CPGs. CONCLUSIONS: CPG recommendations for febrile infants 29 to 56 days old vary across institutions for CSF testing and ceftriaxone use, correlating with observed practice variation. CPGs were not associated with lower healthcare costs.

Pharmaceutical quality of ceftriaxone generic drug products compared with Rocephin.

The pharmaceutical qualities of 34 ceftriaxone generic products were compared with Rocephin as the reference standard. Quality standards specified in the European and US Pharmacopoeias were violated on 18 occasions, including those for sterility (4 products) and impurities (5 products). All 34 generics tested failed to meet Roche specifications for Rocephin, with 100 contraventions of the Roche Pharmaceutical standards. The most common failures amongst generic drug products were clarity of solution (30 products) and presence of thiotriazinone (33 products).

Single low-dose ceftriaxone for the treatment of gonococcal ophthalmia--implications for the national programme for the syndromic management of sexually transmitted diseases.

We prospectively analysed a total of 21 baby-mother pairs with culture-proven Neisseria gonorrhoeae treated with a single low dose of ceftriaxone, namely 62.5 mg for babies and 125 mg for mothers respectively. N. gonorrhoeae was eradicated from all babies' eyes with no residual damage, as well as from the mothers' cervixes. A single low dose of 62.5 mg ceftriaxone has emerged as the treatment of choice for gonococcal ophthalmia neonatorum because of its excellent activity against N. gonorrhocae, including penicillinase-producing strains.