|Year : 2017 | Volume
| Issue : 2 | Page : 228-236
Increasing incidence of penicillin- and cefotaxime-resistant Streptococcus pneumoniae causing meningitis in India: Time for revision of treatment guidelines?
Valsan Philip Verghese1, Balaji Veeraraghavan2, Ranjith Jayaraman2, Rosemol Varghese2, Ayyanraj Neeravi2, Yuvaraj Jayaraman3, Kurien Thomas4, Sanjay M Mehendale3
1 Department of Paediatrics, Christian Medical College and Hospital, Vellore, Tamil Nadu, India
2 Department of Clinical Microbiology, Christian Medical College and Hospital, Vellore, Tamil Nadu, India
3 National Institute of Epidemiology, ICMR, Chennai, Tamil Nadu, India
4 Department of General Medicine, Christian Medical College and Hospital, Vellore, Tamil Nadu, India
|Date of Web Publication||5-Jul-2017|
Valsan Philip Verghese
Department of Paediatrics, Christian Medical College and Hospital, Vellore, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Purpose: Pneumococcal meningitis is a life-threatening infection, requiring prompt diagnosis and effective treatment. Penicillin resistance in pneumococcal infections is a concern. Here, we present the antibiotic susceptibility profile of pneumococcal meningeal isolates from January 2008 to August 2016 to elucidate treatment guidelines for pneumococcal meningitis. Materials and Methods: Invasive pneumococcal isolates from all age groups, were included in this study. Minimum inhibitory concentrations for the isolates were identified by agar dilution technique and VITEK System 2. Serotyping of isolates was done by co-agglutination technique. Results: Out of 830 invasive pneumococcal isolates, 167 (20.1%) isolates were from meningeal infections. Cumulative penicillin resistance in pneumococcal meningitis was 43.7% and cefotaxime non-susceptibility was 14.9%. Penicillin resistance amongst meningeal isolates in those younger than 5 years, 5–16 years of age and those aged 16 years and older was 59.7%, 50% and 27.3%, respectively, with non-susceptibility to cefotaxime in the same age groups being 18%, 22.2% and 10.4%. Penicillin resistance amongst pneumococcal meningeal isolates increased from 9.5% in 2008 to 42.8% in 2016, whereas cefotaxime non-susceptibility increased from 4.7% in 2008 to 28.5% in 2016. Serotypes 14, 19F, 6B, 6A, 23F, 9V and 5 were the most common serotypes causing meningitis, with the first five accounting for over 75% of resistant isolates. Conclusions: The present study reports increasing penicillin resistance and cefotaxime non-susceptibility to pneumococcal meningitis in our setting. This highlights the need for empiric therapy with third-generation cephalosporins and vancomycin for all patients with meningitis while awaiting results of culture and susceptibility testing.
Keywords: Cefotaxime non-susceptible, combination therapy, India, penicillin resistance, pneumococcal meningitis
|How to cite this article:|
Verghese VP, Veeraraghavan B, Jayaraman R, Varghese R, Neeravi A, Jayaraman Y, Thomas K, Mehendale SM. Increasing incidence of penicillin- and cefotaxime-resistant Streptococcus pneumoniae causing meningitis in India: Time for revision of treatment guidelines?. Indian J Med Microbiol 2017;35:228-36
|How to cite this URL:|
Verghese VP, Veeraraghavan B, Jayaraman R, Varghese R, Neeravi A, Jayaraman Y, Thomas K, Mehendale SM. Increasing incidence of penicillin- and cefotaxime-resistant Streptococcus pneumoniae causing meningitis in India: Time for revision of treatment guidelines?. Indian J Med Microbiol [serial online] 2017 [cited 2017 Nov 19];35:228-36. Available from: http://www.ijmm.org/text.asp?2017/35/2/228/209590
| ~ Introduction|| |
Pneumococcal meningitis is lethal even in optimal therapeutic settings, with a case fatality rate close to 30%, and long-term neurological sequelae in a significant proportion of survivors., The burden of disease is also high in resource-poor developing countries like India, indicating the need for strategies to prevent disease and to formulate effective treatment guidelines.
Penicillin was the standard drug of choice for treating pneumococcal infections for many years until increasing global resistance to penicillin , necessitated the use of alternative antibiotics. Penicillin susceptibility break points for Streptococcus pneumoniae of <0.06 μg/mL, 0.12–1 μg/mL and >2 μg/mL for susceptibility, intermediate susceptibility and resistance, respectively, were derived by the Clinical and Laboratory Standards Institute (CLSI) in the 1970s and followed till 2007. These guidelines, meant to ensure success in treating pneumococcal meningeal infections, were adapted for all pneumococcal infections. However, large observational studies documenting the clinical success of parenteral penicillin therapy in patients with penicillin non-susceptible pneumococcal pneumonia and bacteraemia showed that break points formulated for successful treatment of pneumococcal meningeal infections may not be applicable to non-meningeal infections.,, This resulted in the introduction by the CLSI in January 2008 of two separate susceptibility break points for pneumococcal meningeal and non-meningeal infections. The new susceptibility break point changes were derived based on reviews on microbiological, pharmacokinetics and/or pharmacodynamics and clinical outcome data. The revised 2008 CLSI break point changes for penicillin are represented in [Table 1]. Cefotaxime minimum inhibitory concentration (MIC) break points defining susceptibility, intermediate susceptibility and resistance published by CLSI are ≤0.5, 1.0 and ≥2 μg/mL, respectively, for meningeal infections from 1994 and ≤1.0, 2.0 and ≥4 μg/mL for non-meningeal infections from 2002.
|Table 1: Comparison of earlier and revised Clinical and Laboratory Standards Institute susceptibility break points for penicillin for treating pneumococcal infections|
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The revised CLSI susceptibility break points for penicillin in 2008 resulted in decreased penicillin non-susceptibility amongst non-meningeal pneumococcal isolates reported before 2008 due to the increase in non-susceptibility cut-offs to 4 μg/mL. Although the number of penicillin non-susceptible meningeal isolates remained unchanged, the number of isolates classified as resistant increased as those previously classified as having intermediate susceptibility with MIC 0.12–1 μg/mL were now re-categorised as resistant (MIC ≥0.12 μg/mL) under the 2008 break points., Despite these changes, non-susceptibility to penicillin and cefotaxime continues to increase over time amongst both meningeal and non-meningeal pneumococcal infections , indicating the need for ever-evolving strategies for effective treatment guidelines.
In this study, we identify the pattern of antibiotic susceptibility in invasive pneumococcal infections over a period of 8 years and 8 months, with special emphasis on resistance to penicillin and non-susceptibility to third-generation cephalosporins in pneumococcal isolates causing meningitis, and review existing treatment guidelines for pneumococcal meningitis.
| ~ Materials And Methods|| |
This laboratory-based prospective study was conducted at Christian Medical College Hospital, a tertiary care hospital in South India, from January 2008 to August 2016. Invasive pneumococcal isolates from blood, cerebrospinal fluid (CSF) and sterile body fluids in all age groups from our hospital as part of invasive bacterial disease surveillance and those from other sentinel sites as a part of reference laboratory activity for hospital-based sentinel surveillance of bacterial meningitis were included in this study. Pneumococcal isolation and confirmation were based on standard laboratory protocols. MIC testing of isolates was done by agar dilution  from 2008 to 2010 and with VITEK System 2 (BioMerieux, France) from 2011 to 2016. Antimicrobial susceptibility testing interpretations were based on CLSI guidelines 2016. Serotyping of isolates was done by co-agglutination technique  with Neufeld antisera obtained from Statens Serum Institut, Denmark.
Pneumococcal meningeal infection was defined as isolation of S. pneumoniae from CSF or blood in a patient with a clinical syndrome consistent with meningitis: CSF leucocytosis >100 cells/mm 3 or 10–100 cells/mm 3 with either an elevated CSF protein (>100 mg/dL) or decreased CSF glucose (<40 mg/dl). Pneumococcal non-meningeal infection was defined as isolation of S. pneumoniae from blood or sterile body fluids from a patient without a meningitis clinical syndrome.
| ~ Results|| |
A total of 830 invasive pneumococcal isolates were investigated in this study, of which 37.5% (311) of the isolates were in children aged <5 years, 12.8% (106) in children aged 5–16 years and 49.7% (413) of the isolates were from those 16 years of age and older. 20.1% (167) of the isolates were from meningeal infection, whereas 79.9% (663) of the isolates were from non-meningeal infections.
Of the 167 isolates causing meningitis in our study group, 43.7% (73) and 14.9% (25) were non-susceptible to penicillin and cefotaxime, respectively [Table 2], with all isolates non-susceptible to cefotaxime being non-susceptible to penicillin as well. Amongst the 25 meningeal isolates non-susceptible to cefotaxime, 17 isolates had intermediate susceptibility, whereas 8 isolates were fully resistant to cefotaxime. Non-susceptibility to erythromycin and co-trimoxazole was found in 37.1% (62) and 97% (162) respectively. Non-susceptibility to erythromycin along with penicillin was noted in 29.9% (50) of isolates causing meningitis. Multidrug resistance (non-susceptibility to penicillin, cefotaxime and erythromycin) was found in 12.3% (20) of study isolates causing pneumococcal meningitis.
|Table 2: Penicillin resistance and cefotaxime non-susceptibility in invasive pneumococcal isolates, January 2008 - August 2016|
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Amongst pneumococcal isolates causing meningitis in <5 year, 5–16 year and ≥16 year age groups, 59.7% (43), 50% (9) and 27.3% (21), respectively, were non-susceptible to penicillin. Cefotaxime non-susceptibility amongst meningeal isolates was 18% (13), 22.2% (4) and 10.4% (8) in 0–5 years, 5–16 year and ≥16 year age groups, with nine, three and five isolates, respectively, having intermediate susceptibility to cefotaxime while four, one and three isolates were fully resistant amongst each of the age groups. Amongst non-meningeal isolates, non-susceptibility to penicillin was seen in four isolates (0.60%). Three of these isolates were from children younger than 5 years, with one isolate being fully resistant and the other two having intermediate susceptibility to penicillin. Only one isolate from a subject older than 16 years had intermediate susceptibility to penicillin. Overall, penicillin non-susceptibility was 9.3% from all invasive pneumococcal disease (IPD) isolates [Table 2].
Over the study period, penicillin resistance amongst pneumococcal meningeal isolates increased from 9.5% in 2008 to 42.8% in 2016, whereas cefotaxime non-susceptibility increased from 4.7% in 2008 to 28.5% in 2016 [Figure 1].
|Figure 1: Trend analysis of penicillin and cefotaxime non-susceptibility in pneumococcal meningeal isolates, January 2008 – August 2016.|
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Serotypes 14 (22 isolates), 19F (17 isolates), 6B (13 isolates), 6A (11 isolates), 23F, 9V and 5 (7 isolates each) were the predominant serotypes causing pneumococcal meningitis, making up 50.3% of all meningeal serotypes [Table 3]. Serotypes 14, 19F, 6B, 5 and 9V were predominant in pneumococcal meningeal isolates in children <5 years of age. 19F and 6A predominated in those aged 5–16 years and were also found in meningeal isolates from those older than 16 years, along with serotypes 3, 1, 6B, 15A and 13 [Figure 2].
|Table 3: Serotype distribution and penicillin resistance in pneumococcal meningeal isolates (n=167)|
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|Figure 2: Serotype distribution of isolates of Streptococcus pneumoniae causing meningitis, by age group.|
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In this study, serotypes 14 (19 isolates), 6A and 19F (11 isolates each), 6B (10 isolates) and 23F (5 isolates) were the predominant serotypes in penicillin-resistant pneumococcal meningitis, making up 76.7% of all resistant isolates [Table 3]. 58.9% of penicillin-resistant meningeal isolates were from children younger than 5 years. Serotypes 14, 19F and 6B were the most common causes of penicillin-resistant pneumococcal meningitis in children <5 years of age, whereas serotypes 6A, 19F, 23F, 6B and 19V predominated in those older than 5 years [Figure 3].
|Figure 3: Serotype distribution of penicillin-resistant isolates of Streptococcus pneumoniae causing meningitis.|
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| ~ Discussion|| |
Although the overall prevalence of non-susceptibility to penicillin in IPD during the study period remains low at 9.3%, increasing penicillin resistance of pneumococcal meningeal isolates, from <10% in 2008 to over 40% by 2016, mirrors the rise in resistance to penicillin documented worldwide [Table 4].,,,,,,,,,,,,,,,,,,,,,,,,,, The range of documented global penicillin resistance after 2008 ranges from 20% to 30% in Brazil and Argentina through 40% in the USA to over 50% in Asia and Africa, with rates approaching or above 80% in Taiwan and China. Although factors such as the injudicious use of antibiotics could account for this increase in developing countries, international dissemination of penicillin-resistant clones such as ST 63 (Sweden 15A-25), already documented from our institution, could also contribute to rising penicillin resistance in our country.
|Table 4: Penicillin and cefotaxime non-susceptibility of invasive pneumococcal infections in other parts of the world|
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Increasing non-susceptibility to cefotaxime amongst meningeal isolates, from <5% in 2008 to over 25% in 2016 parallels the rise in penicillin resistance, with most studies documenting that cefotaxime non-susceptibility is predominantly seen amongst penicillin non-susceptible isolates., Although cefotaxime non-susceptibility is less well characterised amongst global surveillance studies, our figures are close to the over 30% cefotaxime non-susceptibility documented from Asia and Africa.,
While different penicillin susceptibility break points were formulated for meningeal and non-meningeal pneumococcal isolates based on documentation of clinical cure in non-meningeal pneumococcal infections such as pneumonia,, there are fewer studies on outcomes in pneumococcal meningitis. Cefotaxime has been proved to be efficacious in treating patients with pneumococcal meningitis with isolates resistant to penicillin but susceptible to cefotaxime. Conversely, treatment of pneumococcal meningitis with cefotaxime or ceftriaxone to which the isolates were intermediately resistant has been associated with treatment failure., Case fatality rates are usually higher with pneumococcal meningitis compared to non-meningeal infections, especially in those with non-susceptible infections. From 1995 to 2005 at a public hospital in Brazil, the case fatality rate was 37% in children with pneumococcal meningitis, of whom 17% were penicillin resistant. Mortality was significantly higher amongst children <15 years of age with penicillin resistance, which was also associated with a higher case fatality rate even when the initial treatment regimen included ceftriaxone. The case fatality rate was higher amongst those who did not receive an antibiotic to which the isolate was susceptible during the first 24 h of therapy. Amongst survivors assessed before discharge, 36% were documented to have a neurological deficit, similar to the 40% incidence of sequelae from another Brazilian study. Child survivors of pneumococcal meningitis in Bangladesh showed evidence of hearing, visual, mental, or psychomotor delay, with ≥1 type of impairment in 65% of children on short-term follow-up and in 49% on long-term follow-up after 6–24 months.
The high mortality and morbidity associated with pneumococcal meningitis has led to most recent antibiotic treatment guidelines for pneumococcal meningitis recommending the use of vancomycin along with cefotaxime or ceftriaxone to treat pneumococcal meningitis where the isolate is non-susceptible to both penicillin and cefotaxime [Table 5].,,,, The Indian Council of Medical Research's recently released guidelines on antimicrobial use in common syndromes  recommends the use of ceftriaxone with ampicillin (without vancomycin) in the treatment of acute bacterial meningitis due to the low level of penicillin resistance in pneumococcal infections. Our study is one of the first in the country to document penicillin non-susceptibility in meningeal versus non-meningeal isolates in IPD. The high level of penicillin resistance in our pneumococcal meningeal isolates leads us to believe that it would be prudent to add vancomycin to ceftriaxone for initial treatment of acute bacterial meningitis till culture reports become available, after which antibiotics can be administered based on results of susceptibility testing. Non-susceptibility to penicillin in non-meningeal pneumococcal isolates in our study being <1%, penicillin (or ceftriaxone) would continue to be appropriate therapy for such infections.
|Table 5: Various antibiotic guidelines for pneumococcal meningitis in children and adults|
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The most common serotypes 14, 19F, 6B, 6A, 9V, 23F and 5 documented in this study were the same as those documented to be the most prevalent globally., Non-susceptibility to penicillin was predominantly seen with the first six of the above-mentioned serotypes, similar to studies elsewhere., Serotypes 1 (associated with meningitis outbreaks in Africa), 3 and 15A were the next most commonly isolated serotypes. Serotype 3, commonly found in meningitis in infants and children below the age of 2 in Brazil, was only isolated from those older than 16 years in our study. The 13-valent pneumococcal conjugate vaccine (PCV-13), already available in India from private healthcare providers, would cover 86% of penicillin-resistant isolates in those <5 years of age, and 80% of resistant isolates in those aged 5 years and older [Figure 3]. This is similar to other surveillance studies that predict over 80% coverage of IPD serotypes by PCV-13.,, Serotype 19A, a significant cause of penicillin-resistant IPD after introduction of PCV-7,, was only seen in 2 isolates, both resistant, that would also be covered by PCV-13.
A limitation of our study was the use of two different methods for testing susceptibility, the agar dilution method for 198 isolates from 2008 to 2010 and since VITEK system 2 (an automated system with lesser turnaround time) was available from 2011, the VITEK system 2 to ascertain MIC for 632 isolates from 2011 to 2016. Studies comparing VITEK system with reference methods for identifying penicillin MIC for S. pneumoniae have shown excellent essential agreement with 91.8%–95% and categorical agreement with 94.2%–96%., To validate our findings with VITEK system 2, 33 isolates that were penicillin non-susceptible to S. pneumoniae by VITEK system 2 were rechecked with E-test, and we obtained 100% concordance. With the E-test also having excellent essential agreement and categorical agreement with 95%–96% and 93%–97%, respectively,, we feel that this is unlikely to have affected the validity of our results.
| ~ Conclusions|| |
Our study documents the presence of significant increase in penicillin resistance and cefotaxime non-susceptibility in pneumococcal meningitis in India. This emphasises the need to use combination therapy with vancomycin added to cefotaxime or ceftriaxone for all patients with pneumococcal meningitis until the treatment regimen can be modified using results of susceptibility testing. Penicillin is still a reliable drug for non-meningeal pneumococcal infections. The results from this study can be used to formulate treatment guidelines for pneumococcal meningitis in other parts of the country as well.
Our sincere thanks to the Centers for Disease Control and Prevention, Atlanta, USA for providing laboratory training to conduct pneumococcal surveillance in India.
Financial support and sponsorship
The World Health Organization, Geneva, and Ministry of Health and Family Welfare, for their financial support to conduct pneumococcal surveillance activities in India.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]