Antibiotic Therapy in Pyogenic Meningitis in Paediatric Patients

Transcription

1 ORIGINAL ARTICLE Antibiotic Therapy in Pyogenic Meningitis in Paediatric Patients Fauzia Tajdin 1, Muhammad Adil Rasheed 1, Muhammad Ashraf 1, Huma Rasheed 2, Hasan Ejaz 3 and Ghulam Jilany Khan 1 ABSTRACT Objective: To isolate and identify the causative pathogen, antibiotic sensitivity testing and success rate of empirical antibiotic therapy in pyogenic meningitis. Study Design: Analytical study. Place and Duration of Study: The Children s Hospital and Institute of Child Health, Lahore, Pakistan, from March to July Methodology: The study was performed on 72 culture positive meningitis cases in children less than 15 years of age. This therapy was evaluated by monitoring the patient's clinical picture for days. The collected data was analyzed by Chi-square test. Results: Seventeen different bacteria were isolated. The most commonly occurring bacteria were coagulase negative Staphylococci (25%), E. coli (12.5%), Klebsiella pneumoniae (8.3%), Streptococcus pneumoniae (8.3%) and Pseudomonas aeruginosa (8.3%). All the bacteria were sensitive to vancomycin (96.7%), meropenem (76.7%), amikacin (75%), ciprofloxacin (65.3%), chloramphenicol (46.5%), ceftazidime (44.2%), cefepime (41.9%), co-amoxiclav (38.0%), oxacillin (34.8%), cefotaxime (21.4%), penicillin (20.7%), ceftriaxone (18.6%), cefuroxime (14%) and ampicillin (6.9%). The combination of sulbactam and cefoperazone showed antimicrobial sensitivity of 81.4%. The success rate of empirical antibiotic therapy was 91.7%. Conclusion: It was found that Gram negative bacteria were the major cause of pyogenic meningitis. Mostly there were resistant strains against all commonly used antibiotics except vancomycin. All empirical antibiotic therapies were found to be most successful. Key Words: Pyogenic meningitis. Cerebrospinal fluid. Cephalosporin. Antibiotic sensitivity. Empirical therapy. INTRODUCTION Acute bacterial infection of meninges of brain is called pyogenic meningitis. 1 The population of young ages and those who live in areas where population flow is very rapid are more prone to this disease. 2 Patients who are in immunosuppressive state and developed infections like HIV, asplenia, terminal complement deficiencies and immunoglobin deficiencies are at greater risk for bacterial meningitis. 3 The Nelsseria meningitiditis is second common cause of meningitis after Streptococcus pneumoniae in Western Europe, whilst in USA, Haemophilus influenzae-b remains common. In India, the major cause of bacterial meningitis is Haemophilus influenzae-b and Streptococcus pneumoniae. In order to prevent the complications of meningitis, empirical antibiotic therapy should be started without waiting for 1 Department of Pharmacology and Toxicology / Pharmaceutical Sciences 2, University of Veterinary and Animal Sciences, Lahore. 3 Department of Microbiology, The Children's Hospital and Institute of Child Health, Lahore. Correspondence: Dr. Muhammad Aadil Rasheed, Assistant Professor, Department of Pharmacology and Toxicology, University of Veterinary and Animal Sciences, Outfall Road, Lahore. dr_aadil@hotmail.com Received: October 15, 2012; Accepted: May 16, CSF reports which comes after 48 hours. 4,5 Initially, penicillin and chloramphenicol were the agents of choice in this fatal disease in children but the advent of third generation cephalosporin has revolutionized the treatment of acute pyogenic meningitis. Third generation cephalosporins cover almost all the bacteria responsible for acute pyogenic meningitis in adults except tuberculosis and fungal meningitis, however, at the extremes of age, ampicillin is usually added with third generation cephalosporins to cover the Listeria monocytogenes infection. Vancomycin is also recommended with third generation cephalosporin as combination therapy if Gram positive organisms are seen in CSF or high incidence of penicillin resistant Streptococcus pneumoniae is known to be present in population. 6 The age of patient is an important factor for the selection of empiric antibiotic therapy as in neonates less than 28 days, therapy with third generation cephalosporin is not recommended due to risk of hyperbilirubinemia. Once the organism is identified, empiric therapy is changed with specific antibiotic therapy. Intravenous (IV) infusions of Dopamine or Dobutamine are administered in case of hypotension or shock. Steroids commonly dexamethasone is recommended as an adjuvant therapy to reduce inflammation of meninges. 7 The objective of this study was evaluation of empiric antibiotic therapy used against pyogenic meningitis in children under 15 years of age. Journal of the College of Physicians and Surgeons Pakistan 2013, Vol. 23 (10):

2 Fauzia Tajdin, Muhammad Adil Rasheed, Muhammad Ashraf, Huma Rasheed, Hasan Ejaz and Ghulam Jilany Khan METHODOLOGY Patients less than 15 years of age with meningitis were selected for this study from different wards of The Children's Hospital and Institute of Child Health, Lahore, Pakistan, who exhibited positive growth on different culture plates. Culture negative cases were excluded. CSF samples were collected in sterile containers. Six combinations of antibiotics were used as empirical therapy in children after collection of CSF samples. The combination of antibiotics used were ceftriaxone and vancomycin; second was ceftriaxone and amikacin; third was ceftriaxone and benzyl penicillin; fourth was ceftriaxone, vancomycin and benzyl penicillin; fifth was ceftriaxone, vancomycin, co-amoxiclav and sixth was ceftriaxone, vancomycin and amikacin. In patients of age less than 28 days, ceftriaxone was not given due to risk of hyperbilirubinemia and co-amoxiclav and amikacin were used. The cell count was performed with Improved Neubauer chamber (Haemocytometer) while the differential leucocyte count was performed using the Giemsa stain. 8 The glucose and protein assay was performed. The gross appearance of CSF was noted and then the sample was centrifuged at 2,000 rpm for 20 minutes. The supernatant was discarded while the sediment was mixed and the samples were further processed following the standard microbiological procedures by inoculating on blood agar, chocolate agar (prepared as instructions given by the manufacturer) and MacConkey agar plate and was incubated at C aerobically. The blood, MacConkey agar plate and chocolate agar plates were incubated by putting them in a CO 2 incubator, which provided 5-10% CO 2 concentration to create a carboxyphilic condition for fastidious bacteria. After hours of incubation, the plates were examined for the presence of bacterial colonies. Organisms were identified by standard microbiological methods, which include colony morphology, as well as staining, biochemical and serological tests, 9 and growth characteristics such as Gram's staining, catalase test, oxidase test, coagulase test, diagnostic discs, and growth enhancing factors, API 20E, API 20NE and API NH. 10,11 Antibiotic sensitivity test was conducted on pure culture isolates employing the Kirby-Bauer disc diffusion method, 12 for the fifteen commonly used antibiotics which were divided in two groups, six against Gram positive bacteria and rest were against Gram negative bacteria. The appropriate sensitivity discs as ampicillin, amikacin, oxacillin, penicillin, sulbactam and cefoparazone, vancomycin, chloramphenicol, co-amoxiclav, ceftriaxone, cefotaxime, ceftazidime, cefuroxim, meropenem, ciprofloxacin and cefepime were used for determining the in vitro susceptibility of microorganism to different antimicrobials. The diameters of growth inhibition around the discs was measured and interpreted as sensitive, intermediate or resistant as per the guidelines set by CLSI. 13 In order to check the clinical efficacy of empiric therapy, the disease selected must show proven good prognosis with the use of drug to be tested. The final decision for the success or failure of therapy was made on the basis of computerized tomography (CT) scan reports which were done on last day of follow-up. Mortality rate of patients were also observed. The variations in clinical features from day 1 to day 14 data were analyzed by Chi-square test through Statistical Package for Social Sciences (SPSS) version 16. The results were analyzed by using descriptive and inferential statistics. RESULTS Seventy two patients were culture positive. The frequency of occurrence of disease in the age group less than one month (neonates) was 10 (13.9%) while in 2nd group one month to one year was 32 (44.4%) which was the maximum number. The rate of pyogenic meningitis was twice common in males as compared to females. Turbidity of CSF samples was observed. It was found that 29 (40.3%) samples were clear while 43 (59.7%) were found turbid. WBC count was performed to determine CSF cytology. The glucose level of CSF was decreased in all cases while protein level was increased. In all cases of meningitis, cells count was raised at different rates with predominant increase in polymorphonuclear cells as described in Figure 1. Out of 72 samples of CSF analyzed in terms of isolates the majority of organisms 45 (62.5%) were Gram negative which is twice the number of Gram positive (n = 27, 37.5%). Seventeen different species of bacteria were isolated among these samples. The most commonly occurring bacteria are mentioned in Table I. The sensitivity pattern of all bacteria isolated in pyogenic meningitis is given in Table II. Figure 1: CSF cytology showing percentage of WBCs, polymorphonuclear cells and lymphocytes in children with pyogenic meningitis. 704 Journal of the College of Physicians and Surgeons Pakistan 2013, Vol. 23 (10):

3 Antibiotic therapy in pyogenic meningitis in paediatric patients Different combinations of antibiotics which were used during treatment of pyogenic meningitis patients as empirical therapy, showed improved conditions within days which showed success of these empirical therapies. The success rate of these therapies is shown in Table III. Table I: Bacteriology of CSF samples in patients of pyogenic meningitis. Organism Frequency Percent Haemophilus influenza Streptococcus pneumonia Staphylococcus aureus Coagulase negative Staphylococcus Klebsiella pneumonia Pseudomonas aeruginosa Enterobacter species E. coli Proteus species Pseudomonas stutzeri Serratia marcescens Acinetobacter baumannii Stenotrophomonas maltophilia Pseudomonas species Enterobacter colaceae Enterococcus species Pantoea species Total Out of 72 patients of pyogenic meningitis, 66 patients (91.7%) were recovered and discharged. Two patients (2.8%) were referred to other hospitals and were not followed-up while 4 patients (5.6%) died. The high ratio of discharged patients showed the success of antimicrobial therapy used in pyogenic meningitis patients. DISCUSSION Meningitis can be life-threatening because of inflammation of meninges, so this condition is considered a medical emergency. 2 The patients having high fever, altered conscious level, skin rashes, vomiting, abnormal behaviour, headache and meningeal irritation are considered to be suspected of meningitis. 4 During this study, out of 110 suspected patients of meningitis, 72 were culture positive. The maximum number of cases (44.4%) was seen in the age group of 1 month to 1 year followed by 27.8% in the age group of 1 month to 1 year with no significant difference in other age groups. The age group of 1 month to 1 year is more susceptible to disease due to lack of maternal antibodies as reported by Molyneux. 15 This age group is more susceptible to disease due to improper hygienic conditions, congested environments. The male to female ratio of pyogenic meningitis patients was 49 (68.1%) and 23 (31.9%). This showed that males suffered from pyogenic meningitis Table II: Antibiotic susceptibility pattern of various bacteria in pyogenic meningitis. Antibiotic Resistant Sensitive Intermediate sensitive Total pathogen against relative antibiotics Frequency Percentage Frequency Percentage Frequency Percentage Ampicillin % 5 6.9% Oxacillin % % Penicillin % % Ciprofloxacin % % 6 8.3% 72 Vancomycin 1 3.3% % Chloramphenicol % % 1 2.3% 43 Co-amoxiclav % % Sulbactam - Cefoparazone % % 3 7.0% 43 Ceftriaxone % % Cefotaxime % % 2 4.8% 43 Ceftazidime % % 2 4.7% 43 Amikacin % 54 75% 4 5.6% 72 Cefuroxime 37 86% 6 14% Meropenem % % Cefepime % % 1 2.3% 43 Table III: Response rates of different antibiotic combinations used in empirical therapy. Antimicrobial treatments Treatment success rate Treatment failure rate Total Frequency Percentage Frequency Percentage Ceftriaxone and Vancomycin % 1 3.7% 27 Ceftriaxone and Amikacin % % 16 Ceftriaxone and Benzyl penicillin % % 9 Co-Amoxiclav and Vancomycin 3 100% 0 0% 3 Ceftriaxone, Vancomycin and Benzyl penicillin 6 100% 0 0% 6 Ceftriaxone, Vancomycin and Co-amoxiclav % % 6 Ceftriaxone, Vancomycin and Amikacin % % 5 Journal of the College of Physicians and Surgeons Pakistan 2013, Vol. 23 (10):

4 Fauzia Tajdin, Muhammad Adil Rasheed, Muhammad Ashraf, Huma Rasheed, Hasan Ejaz and Ghulam Jilany Khan were twice as compared to females, this similar finding was also reported by others. 16,17 The CSF appearance was turbid in most of the cases (n = 43, 59.7%), which showed the presence of high number of WBCs and protein. 18 The turbid appearance of CSF was also an indication of presence of bacterial meningitis. 5 WBC count was increased in most of meningitis patients (n = 34, 47.2%) and most of them had a high percentage of polymorphonuclear cells (n = 37, 51.4%). In some cases WBC count remained normal, while lower WBC count was seen in 10 (13.9%) patients, and in those patients increased lymphocyte (n=29, 40.3%) count was observed. This could be due to the fact that their lumbar puncture was performed in the early onset of infection. 19 The CSF glucose concentration was decreased in most of the cases of acute bacterial meningitis (29, 40.3%; 14, 19.4%) that is less than 40 mg/dl which was an indicative of disease. 18 The predominance of Gram negative bacteria was also reported as major etiological agents of bacterial meningitis. 20 Coagulase negative Staphylococci followed by E. coli were the most dominant organism isolated from meningitis patients. Only one case of Haemophilus influenzae was observed and it was mainly due to inclusion of vaccine against these bacteria in child immunization programme. 21 The overall sensitivity pattern showed the most susceptible antibiotics were vancomycin, sulbactam and cefoperazone, meropenem and ciprofloxacin while intermediate sensitivity results were shown by chloramphenicol, ceftazidime, cefepime, co-amoxiclav and oxacillin. Cefotaxime, penicillin, ceftriaxone, cefuroxime and ampicillin showed the highest antimicrobial resistance. The antimicrobial resistance varied from organism to organism. The results of chloramphenicol susceptibility were observed in 46.5% of population. The level of bacterial resistance to penicillin and ampicillin was also showed by Nigerian peoples due to trend of self medication there and same is the case in our country. 1 The third generation cephalosporin was proved to be more sensitive in this study while least resistance was shown by these agents. 20 There was increasing resistance among major pathogen which cause meningitis to most of the traditionally antimicrobial agents used as initial therapy prior to the availability of bacteriological agents. Variations in clinical parameters were further evaluated for next 14 days to check that empirical therapy given to patient were appropriate or not. It was observed that all signs and symptoms of patients subsided from day 8 to day 12. Mostly patients showed successful outcome on CT scan on the last day of follow-up. Appropriate use of antibiotics, along with adjunctive therapies, such as Dexamethasone, has proved helpful in the prevention of bacterial meningitis in children. 7 The patients were evaluated for the impact of appropriate and inappropriate antibiotic therapies on mortality rate when they empirically received antibiotics. Out of 72 culture positive cases, 4 (5.6%) died before the confirmed culture report. This was due to the delayed interval between onset of illness and admission to hospital. 4,22 Despite coverage with appropriate antibiotics, morbidity and mortality was observed in the study cases. Therefore, determination of antibiotic sensitivity patterns alongside the administration of appropriate empiric antibiotic therapy could be mandatory in such cases. The indiscriminate use of antibiotics by the referring clinics/hospitals may be an underlying cause for patients. Proper antibiotic therapy should be started early in the course of disease without waiting for culture reports to reduce the risk of morbidity and mortality from this disease. CONCLUSION Coagulase negative Staphylococci followed by Gram negative bacteria were major causes of pyogenic meningitis. There was a high frequency of resistant bacteria against cefotaxime, penicillin, ceftriaxone, cefuroxime and ampicillin. Vancomycin and amikacin proved to be more sensitive and can be recommended in initiation therapy. REFERENCES 1. Akpede GO, Adeyemi O, Abba AA, Sykes RM. Pattern and antibiotic susceptibility of bacteria in pyogenic meningitis in a children's emergency room population in Maiduguri, Nigeria. Acta Paediatr 1994; 83: Telan DA, Zibulewsky J. 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