Skip directly to search Skip directly to A to Z list Skip directly to site content
CDC Home

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).


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.


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,, 613-562-6262 ext. 2906.


  1. Edmond K, Clark A, Korczak VS, Sanderson C, Griffiths UK, Rudan I. Global and regional risk of disabling sequelae from bacterial meningitis: a systematic review and meta-analysis. Lancet Infect Dis 2010;10:317–28.
  2. World Health Organization. Managing meningitis epidemics in Africa: a quick reference guide for health authorities and health-care workers. Geneva, Switzerland: World Health Organization; 2015. Available at
  3. Brouwer MC, Tunkel AR, van de Beek D. Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis. Clin Microbiol Rev 2010;23:467–92.
  4. Hajjou M, Krech L, Lane-Barlow C, et al. Monitoring the quality of medicines: results from Africa, Asia, and South America. Am J Trop Med Hyg 2015;92(Suppl):68–74.
  5. Rosenblum ML, Hoff JT, Norman D, Edwards MS, Berg BO. Nonoperative treatment of brain abscesses in selected high-risk patients. J Neurosurg 1980;52:217–25.
  6. Willard H, Merritt L, Dean J, Settle F. Instrumental methods of analysis. 7th ed. Marceline, MO: Wadsworth Publishing Company; 1988.
  7. Prasad K, Kumar A, Gupta PK, Singhal T. Third generation cephalosporins versus conventional antibiotics for treating acute bacterial meningitis. Cochrane Database Syst Rev 2007;(4):CD001832.
  8. Nayyar GM, Breman JG, Newton PN, Herrington J. Poor-quality antimalarial drugs in southeast Asia and sub-Saharan Africa. Lancet Infect Dis 2012;12:488–96.
  9. Obaid A. Quality of ceftriaxone in Pakistan: reality and resonance. Pak J Pharm Sci 2009;22:220–9.
  10. Binagwaho A, Bate R, Gasana M, et al. Combatting substandard and falsified medicines: a view from Rwanda. PLoS Med 2013;10:e1001476.


What is already known on this topic?

Falsified and substandard medicines, particularly antimalarial and antiretroviral drugs, are a major threat to global public health, and have been detected in markets around the world. The scope of this problem across different drug classes, including antibiotics, has not been adequately characterized.

What is added by this report?

A case of fatal bacterial meningitis was possibly associated with administration of substandard ceftriaxone containing less than half of the stated active pharmaceutical ingredient. Substandard or falsified ceftriaxone might be a cause of treatment failure in bacterial meningitis in Africa.

What are the implications for public health practice?

The presence and use of substandard medicines, particularly antibiotics, is likely to contribute to treatment failures and emergence of drug resistance. It is important for public health practitioners to be aware of both the potential harms and the large scale of these medicines. National and international pharmacovigilance is important to prospectively identify poor quality medicines.

Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services.

References to non-CDC sites on the Internet are provided as a service to MMWR readers and do not constitute or imply endorsement of these organizations or their programs by CDC or the U.S. Department of Health and Human Services. CDC is not responsible for the content of pages found at these sites. URL addresses listed in MMWR were current as of the date of publication.

All MMWR HTML versions of articles are electronic conversions from typeset documents. This conversion might result in character translation or format errors in the HTML version. Users are referred to the electronic PDF version ( and/or the original MMWR paper copy for printable versions of official text, figures, and tables. An original paper copy of this issue can be obtained from the Superintendent of Documents, U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800. Contact GPO for current prices.

**Questions or messages regarding errors in formatting should be addressed to The U.S. Government's Official Web PortalDepartment of Health and Human Services
Centers for Disease Control and Prevention   1600 Clifton Road Atlanta, GA 30329-4027, USA
800-CDC-INFO (800-232-4636) TTY: (888) 232-6348 - Contact CDC–INFO
A-Z Index
  1. A
  2. B
  3. C
  4. D
  5. E
  6. F
  7. G
  8. H
  9. I
  10. J
  11. K
  12. L
  13. M
  14. N
  15. O
  16. P
  17. Q
  18. R
  19. S
  20. T
  21. U
  22. V
  23. W
  24. X
  25. Y
  26. Z
  27. #