Fatal Bacterial Meningitis Possibly Associated with Substandard Ceftriaxone — Uganda, 2013

Jason W. Nickerson, PhD1; Amir Attaran, DPhil2; Brian D. Westerberg, MD3; Sharon Curtis, PhD2; Sean Overton2; Paul Mayer, PhD2

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).

On February 7, 2013, a boy aged 13 years from central Kampala was evaluated at the Mulago National Referral Hospital in Kampala, Uganda. He had experienced 10 days of confusion, followed by fevers, chills, rigors, and intermittent vomiting. On otoscopic examination, pus was visible in the right ear canal, and there was tenderness over the right mastoid. Neither computed tomography nor lumbar puncture testing was available at the time of the patient's evaluation, and a presumptive diagnosis of otogenic bacterial meningitis was made. The patient was admitted to the hospital, and treatment with 2 g intravenous ceftriaxone once daily was initiated. Ceftriaxone is recommended as the primary drug for treatment of meningitis and is available in the public health system in Uganda (2).

On the fourth treatment day, the patient remained febrile and lethargic, and 500 mg of intravenous metronidazole given twice daily was added to the regimen. The following day, the patient had a worsening headache, and he became irritable and agitated. Antibiotic therapy was continued, and because of the failure of medical therapy, a mastoidectomy was planned for treatment day 7; however, the patient had seizures that day. Computed tomography, which became available only that day, demonstrated multiple small abscesses in the posterior cranial fossa. Neurosurgeons advised that these abscesses were likely to respond to antibiotics (5), and considering the risks associated with neurosurgery in a resource-constrained setting, recommended a conservative approach. Therefore, only the planned mastoidectomy was performed; no specimens were sent for culture. Postoperatively, the patient was admitted to the intensive care unit and started on second-line treatment with meropenem (1 g three times daily), phenytoin (500 mg daily), and tramadol (50 mg three times daily). On day 8, when the patient failed to respond to treatment, levofloxacin and clindamycin were added. On day 10, the patient experienced acute respiratory failure, requiring endotracheal intubation and mechanical ventilation. On day 11, peripheral and corneal reflexes were absent, and the patient was declared brain dead, presumably from elevated intracranial pressure. On day 12, treatment was withdrawn.

Suspecting that the patient's initial treatment failure might be related to the potency of the ceftriaxone product administered, physicians obtained a sealed vial of injectable ceftriaxone sodium (labeled 1 g), similar to that administered to the patient, from the hospital dispensary for testing. The sample was unexpired and stored according to manufacturer's guidelines. Upon examination of the vial, no obvious signs of falsification (such as spelling or typographical errors on the packaging or on the vial) were observed. It was unknown whether this vial was from the same lot as the one used to treat the patient.

Analysis of the sample was performed at the John L. Holmes Mass Spectrometry Facility at the University of Ottawa, Canada, using established laboratory methods (6). The presence and quantity of active ingredient was verified by mass spectrometry with an analytical standard of 92% ceftriaxone disodium salt and a vial of ceftriaxone sodium BP. The sample contained only 0.455 g of the drug, not 1 g as stated by the manufacturer and indicated on the label. If the vials administered to the patient were similarly compromised, the patient would have received a subtherapeutic dose of ceftriaxone, which might have contributed to treatment failure (7).

Discussion

Although antibiotic resistance has been documented globally, and treatment failure can result from multiple factors related to limitations common in resource-poor environments, including complex or atypical disease progression, ceftriaxone is the recommended first-line treatment for bacterial meningitis in Africa (2). Substandard or intentionally adulterated medicinal products are a global problem that disproportionately affects low-income countries, where regulation of the pharmaceutical market is often limited. In addition to leading to treatment failures, these medicines also contribute to emerging antibiotic resistance in the community, and can erode confidence in health systems (4). Drugs containing little or no active ingredient, including first-line therapies for the treatment of tuberculosis, malaria, and human immunodeficiency virus, have been found in many low-income countries (4). A recent meta-analysis of 21 surveys of antimalarial drug quality in 21 sub-Saharan African countries revealed that, of 2,297 samples included, 796 (35%) failed chemical analysis, and 79 of 389 (20%) samples appeared falsified, and thus criminal in origin (8). A study from Pakistan highlighted similar quality concerns in injectable ceftriaxone, finding that 15.6% of 96 samples tested were outside acceptable quality ranges (9). In May 2015, the World Health Organization released a Medical Product Alert warning of falsified meningitis vaccines circulating in West Africa.* Substandard medicines can result from multiple supply chain factors, including manufacturing or handling problems, deliberate criminal fraud by drug manufacturers, or other criminal practices that exploit regulatory vulnerabilities in drug markets.

The findings in this report are subject to at least three limitations. First, because of a lack of reliable diagnostic tools (e.g., computed tomography, lumbar puncture, or bacterial culture), the specific pathogen present in this case was not identified, potentially resulting in the selection of an incorrect antimicrobial therapy. Second, it is not known whether the antibiotic that was tested came from the same lot that was used to treat this patient. Finally, because of delayed (10 days into the clinical course) or inadequate interventions, such as reliance on antibiotics as the sole therapy (e.g., no surgical treatment of the abscesses), and the possibility that the patient's disease could have progressed beyond a point where single antibiotic therapy might have been effective, it is not known whether higher quality medicines would have altered the progression of disease in this case. However, the lack of clinical response to first-line therapy prompted clinicians to question whether the antibiotic might have been substandard, and analysis found the sample to contain less than half of the stated amount of antibiotic.

This case highlights the problem of poor quality medicines and can alert practitioners in Africa to consider the possibility that substandard or falsified ceftriaxone might be a cause of treatment failure in bacterial meningitis. Averting a global public health crisis attributed to low-quality medicines requires coordinated international and national efforts to identify and remove these products at all levels of distribution. Establishment of product standards and robust pharmacovigilance systems, in tandem with stronger criminal legislation, are important for ensuring that patients have access to quality medications (10) and for enforcing penalties for those who intentionally produce or sell substandard or falsified medicines.

Acknowledgment

Eleanor Reimer, MD, British Columbia Children's Hospital, Vancouver, Canada.

1Bruyère Research Institute, Ottawa, Ontario, Canada; 2University of Ottawa, Ottawa, Ontario, Canada; 3University of British Columbia, Vancouver, British Columbia, Canada; St. Paul's Rotary Hearing Clinic, Vancouver, British Columbia, Canada.

Corresponding author: Jason W. Nickerson, Jason.Nickerson@uottawa.ca, 613-562-6262 ext. 2906.

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