Canada Communicable Disease Report

November 2008 Volume 34 Number 11

Monthly Report

A new twist on an old problem: A case of pediatric meningitis caused by multidrug-resistant Streptococcus pneumoniae serotype 19A

W Ciccotelli, MD (1,2), S Poutanen, MD, MPH (3,4,5), S Morris, MD, MPH (6), M Alqahtani, MD (7,8), P Cox, MBChB, DCH (8,9), D Low, MD (4,8,10), D Pillai, MD, PhD (4,8,10), M Opavsky, MD, PhD (6)

1. Department of Infectious Diseases and Medical Microbiology, McMaster University, Hamilton, Ontario, Canada
2. M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada
3. University Health Network, Department of Microbiology, Toronto, Ontario, Canada
4. Mount Sinai Hospital Department of Microbiology, Toronto, Ontario, Canada
5. University of Toronto Departments of Laboratory Medicine and Pathobiology and Medicine, Toronto, Ontario, Canada
6. Division of Infectious Diseases, Hospital for Sick Children, Toronto, Ontario, Canada
7. Division of Infectious Diseases, Toronto General Hospital, Toronto, Ontario, Canada
8. University of Toronto, Toronto, Ontario, Canada
9. Department of Critical Care Medicine, Hospital for Sick Children, Toronto, Ontario, Canada
10. Ontario Ministry of Health and Long Term Care, Toronto, Ontario, Canada

Abstract

Recent studies show that multidrug-resistant Streptococcus pneumoniae serotype 19A continues to emerge as a cause of invasive pneumococcal disease after the introduction of Prevnar®. We report a case of multidrug-resistant S. pneumoniae serotype 19A meningitis successfully treated with vancomycin and levofloxacin. This case reinforces the need for the empiric use of vancomycin in meningitis and the need for alternative treatments.

Case Report

A 14 month-old healthy child presented to a community hospital with a short focal seizure involving the left hand and foot. This followed a 2-day history of fever and vomiting. On examination, a fever was present, there was no otitis media, no evidence of pneumonia, and the neurological examination was unremarkable. At initial presentation, all hematologic, biochemical and coagulation parameters were normal. A head CT scan revealed left ethmoid sinus opacification and small bilateral cerebral and white matter hypodensities. The child was admitted to hospital and treated with intravenous cefuroxime.

Twenty-four hours later, the child's neurological status deteriorated, with the development of signs of raised intracranial pressure. A lumbar puncture done at this time was consistent with bacterial meningitis [WBC 63x10⁹/L (25% neutrophils), glucose 0.1 mM/L, protein 3.6 g/L]. Grampositive cocci in pairs and chains were identified. Intravenous vancomycin and cefotaxime were commenced and the child was urgently transferred to the intensive care unit of a local tertiary care pediatric hospital. The patient presented in septic shock with fever, a GCS of 6, a bulging anterior fontanelle, and multi-organ dysfunction. The child required vasopressors and mechanical ventilation. A brain MRI was consistent with meningoencephalitis. There was extensive cortical diffusion restriction in the right cerebral hemisphere, with two right and one left punctate foci of restriction in the white matter. Leukopenia (WBC 1.1x10⁹/L) thrombocytopenia (platelets 10x10⁹/L), a coagulopathy (INR 2.2, PTT 106s), renal failure requiring dialysis, and hepatocellular injury (AST 3399 U/L, ALT 983 U/L) developed. Blood and cerebral spinal fluid (CSF) cultures grew S. pneumoniae. The organism was resistant to penicillin, amoxicillin, cefprozil, cefuroxime, ceftriaxone, meropenem, clindamycin, erythromycin, trimethoprim-sulfamethoxazole, and tetracycline. It was susceptible to vancomycin, levofloxacin, rifampin and telithromycin (Table 1). The isolate was serotyped as 19A by latex pool antisera and pneumococcal antisera (Statens Serum Institut, Denmark). Multi-locus sequence typing (MLST) revealed this to be sequence type 320. With the identification of the isolate as a multidrug-resistant S. pneumoniae strain, levofloxacin was started 3 days after initial presentation (10 mg/kg q12hr for day 1; then 10 mg/kg daily). Vancomycin was continued and dosed to maintain a daily serum trough of 15 to 20 mg/L. Ceftriaxone was discontinued. Rifampin was avoided due to significant hepatic dysfunction. Further history revealed that the child did not attend daycare and there were no ill contacts or travel outside the province. The child's vaccination status was up-to-date including three doses of the seven-valent conjugate pneumococcal vaccine (PCV7), Prevnar (Wyeth, United States (US); covers serotypes 4, 6B, 9V, 14, 18C, 19F and 23F).

Within 48 hours of starting levofloxacin, the raised intracranial pressure and sepsis resolved, and repeat blood cultures showed no bacteremia. Although repeat CSF culture was delayed due to the significant coagulopathy, it had sterilized after 2 weeks of antibiotics.

Serial follow-up head CTs demonstrated the development of a communicating hydrocephalus. Subsequent immunological workup did not identify any relevant immunodeficiency, with normal immunoglobulin levels (and IgG subsets) and a normal total haemolytic complement (CH50). Neurologic recovery had initially been incomplete, but 6 months after hospital discharge the child was verbal, interactive and regaining age-appropriate milestones.

 

Table 1. Summary of antibiotic susceptibility testing for the clinical isolate from the patient's CSF

Antibiotic	Minimum Inhibitory concentration+	Clinical Laboratory Standards Institute Breakpoints*	Interpretation
Amoxicillin Cefprozil Ceftriaxone Cefuroxime Clindamycin Erythromycin Levofloxacin   Meropenem Penicillin Rifampin Telithromycin Tetracycline Trimethoprim/ sulfamethoxazole Vancomycin	8 mg/L 16 mg/L 2 mg/L 16 mg/L > 16 mg/L > 32 mg/L ≤ 0.25 mg/L 1 mg/L (Etest®, AB Biodisk (Sweden)) 4 mg/L 36 mm, MDψ 0.5 mg/L 8 mg/L 8/152 mg/L ≤ 0.5 mg/L	≤ 2 mg/L, ≥ 8 mg/L# ≤ 2 mg/L, ≥ 8 mg/L ≤ 0.5 mg/L, ≥ 2 mg/L# ≤ 0.5 mg/L, ≥ 2 mg/L ≤ 0.25 mg/L, ≥ 1 mg/L ≤ 0.25 mg/L, ≥ 1 mg/L ≤ 2 mg/L, ≥ 8 mg/L ≤ 0.25 mg/L, ≥ 1 mg/L ≤ 0.06 mg/L, ≥ 0.12 mg/L ≤ 19 mm, ≥ 16 mm ≤ 1 mg/L, ≥ 4 mg/L ≤ 2 mg/L, ≥ 8 mg/L ≤ 0.5/9.5 mg/L, ≥ 4/76 mg/L ≤ 1 mg/Lф	Resistant Resistant Resistant Resistant Resistant Resistant Susceptible   Resistant Resistant Susceptible Susceptible Resistant Resistant Susceptible
+ Minimum inhibitory concentration (MIC) by broth microdilution unless otherwise stated. * Listed as susceptible and resistant breakpoints, respectively; Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; Eighteenth Informational Supplement. CLSI document M100-S18. Wayne, PA: Clinical and Laboratory Standards Institute; 2008. # Amoxicillin breakpoints reflect non-CSF isolates (CSF breakpoints do not exist); CSF breakpoints are listed for ceftriaxone and penicillin. ψ DD = disc diff usion ф No resistance breakpoint defined.

Discussion

This is the first published case of meningitis caused by a multidrug-resistant serotype 19A S. pneumoniae (SP19A), to the best of our knowledge. The implications for both empiric therapy of bacterial meningitis and options for prevention of disease with pneumococcal vaccines are significant. The North American introduction of PCV7 has resulted in a sustained decrease in the incidence of invasive pneumococcal disease (IPD) and IPD caused by vaccine serotypes resistant to penicillin^(1,2) . However, serotype replacement by vaccinerelated and non-vaccine serotypes has begun to emerge⁽³⁾ . Reports from the US have demonstrated a significant increase in SP19A as a cause of IPD^(1,4,5) . A more recent and alarming trend is that SP19A is also becoming increasingly penicillin-, ceftriaxone- and multidrug- (= 3 drugs) resistant^(1,4-6) .

The shifting resistance pattern of IPD re-enforces the need for vancomycin as part of empiric therapy for meningitis. While rates of resistance in S. pneumoniae are lower in Canada compared to the US, they are still significant. Data from the Canadian Bacterial Surveillance Network revealed that 17% of all invasive and non-invasive S. pneumoniae submitted in 2007 were penicillin-non-susceptible, 3% were ceftriaxonenon- susceptible and 10% were multidrug-resistant (defined as non-susceptible to penicillin and any 2 of: erythromycin, TMP/SMX, tetracycline, ciprofloxacin (MIC > 4mg/L)). A significant increase in multidrug-resistant SP19A was also noted⁽⁷⁾ . For S. pneumoniae meningitis caused by a fully cephalosporin-resistant strain, the Red Book (2006) recommends: vancomycin and ceftriaxone (or cefotaxime), and the addition of rifampin should be considered⁽⁸⁾ . Infectious Diseases Society of America (IDSA) guidelines recommend that vancomycin and ceftriaxone (or cefotaxime) be combined with rifampin for fully cephalosporinresistant (MIC > 2 mg/L) S. pneumoniae meningitis. Fluoroquinolones are also considered as alternative agents in the IDSA guidelines⁽⁹⁾ . Levofloxacin's lipophilic nature should permit a rapid attainment of a CSF drug concentration that is bactericidal for both penicillin susceptible and nonsusceptible S. pneumoniae^(9-12) . Although there is limited clinical data to support the use of levofloxacin to treat meningitis, and the safety of fluoroquinolones in children is debatable, the potential benefits in this case were outweighed by theoretical risks.

As serotype 19A increases in prevalence as a cause of childhood IPD, the development of an effective vaccine that provides protection against this serotype becomes increasingly important. Candidate conjugated pneumococcal vaccines undergoing clinical trials include a 9-, 11- or 13- valent formulations (with the latter the only one to contain 19A)^(13,14) . Despite the promise of these vaccines their long term success is uncertain. Evidence has emerged that the most rapidly expanding SP19A MLST clonal complex in the United States since the introduction of PCV7 is CC320 (the clonal complex in which our isolate lies)⁽⁵⁾ .. It has been postulated that multidrug-resistant SP19A; CC320 in the US emerged due to serotype switching through genetic recombination between non-CC320 SP19A and the internationally disseminated multidrug-resistant CC320 Taiwan^19F-14 which is covered by PCV7⁽⁵⁾ . Other serotype switching events have also been proposed that are thought to be due to antimicrobial selective pressure and the immunologic pressure due to the introduction of PCV7^(5,15,16) . Laboratory-based surveillance including serotype determination and MLST of IPD isolates is critical to be able to determine which new vaccine would offer the best protection now and in the future.

 

Acknowledgements

Thanks to Remy A. Pollock (Ontario Ministry of Health and Long Term Care, Toronto, ON) for the MLST work. As well we acknowledge the valuable contributions of Drs. Alison McGeer and Neil Rau for their contribution to the laboratory work-up of this strain.

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