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Chloramphenicol or ampicillin plus gentamicin for the treatment of very severe pneumonia
- Dewan S. Billal, Professor Noboru Yamanaka MD, Ph.D (18 January 2008)
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Prevention: Key to Tackling Pneumonia in Developing Countries
- Des Turner, Richard Taylor (22 January 2008)
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Dewan S. Billal, Ph.D Post Doctoral Fellow, Microbiologist Department of Otolaryngology, Wakayama Medical University, Wakayama 641-8509, Japan, Professor Noboru Yamanaka MD, Ph.D
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Sir- Rai Asghar and colleagues1provided a multicenter randomized control trial comparing the efficacy of chloramphenicol versus ampicillin plus gentamicin for the treatment of community acquired very severe pneumonia among children aged 2-59 month in developing country and showed that children received injectable ampicillin plus gentamicin is superior to injectable chloramphenicol for the treatment of very severe pneumonia in low resource settings. The authors suggested WHO to updating the currently available recommendation for the treatment of very severe pneumonia regarding to global guidelines for the case management of pneumonia, which until now have recommended chloramphenicol as the treatment for the very severe pneumonia. In the Editorial, Zulfiqar A Bhutta 2 discusses the importance and limitations of this finding and emphases the trends of antibiotics resistance in causative pathogens of very severe pneumonia. In that issue, significantly more treatment failed in chloramphenicol group comparing ampicillin plus gentamicin group at day 5 (16% v 11%; relative risk 1.43, 95% confidence interval 1.03 to 1.97) which increased at day 10 (19% v 14%; relative risk 1.37, 95% confidence interval 1.03 to 1.83) and day 21 (22% v 16%; relative risk 1.34, 95% confidence interval 1.02 to 1.75). Treatment failure is most commonly associated with changing antibiotics (9% in chloramphenicol group and 5% in ampicillin plus gentamicin group) but after changing antibiotics the treatment failure rate is not increased significantly. Treatment failure not only associated with bacteraemia (27%) but also without bacteraemia (16%). Treatment failure due to bacteraemia in chloramphenicol group is much more associated with the presence of Streptococcus pneumoniae (78%vs 19% [without bacteraemia]) rather than Staphylococcus aureus (23% v 20% [without bactaeremia]). The authors did not present the exact reason of treatment failure in without bacteraemia group. Only 11.5% samples of blood and lung aspirate from sick children were positive for bacteria, with the common organisms being S. aureus (42.7%), S. pneumoniae (20%) and Haemophilus influenzae (7.3%). Overall 33.5% children reported receiving prior antibiotics in previous 24 hours which will be much more in developing countries. In a study, Tabish Hazir showed that only 21% patients reported therapy by prior antibiotics whereas 36% patient urine samples were positive for antibacterial activity3. S. pneumoniae and H. influenzae type b (Hib) are the predominant causes of meningitis and pneumonia in children in developing country and 19% of all under-5 years old children were died by pneumonia. S. aureus is still considered commensal pathogens of the upper respiratory tract. S. pneumoniae and H. influenzae isolates resistance to beta-lactam drugs has been increasing now a day4,5. However in recent years, there has been a progressive increase in resistance of Hib strains to ampicillin and chloramphenicol such that 50% of cases are now resistance to these first- line antibiotics and resistance to ampicillin of Hib isolates are due to beta-lactamase production (BLPAR; beta-lactamase positive ampicillin resistance) and penicillin binding protein genes mutation (BLNAR; beta- lactamase negative ampicillin resistance, BLPACR; beta-lactamase positive amoxicillin and clavulanate resistance)4,5. In a recent study showed that H. influenzae can metabolize chloramphenicol rapidly and converting it to reduced form that lacks antibacterial activity6. Ampicillin resistant pneumococci are still very rare (minimum inhibitory concentration to ampicillin 1-2 µg /ml) and reminded stringent but the degree of ampicillin resistance to Hib strains has been increasing (MIC to ampicillin for BLNAR and BLPACR; 16-32µg /ml and for BLPAR >256 µg/ml) day by day4,7. Treatment failure at ampicillin plus gentamicin group was lower than chloramphenicol group, might be due low prevalence of gentamicin resistance S. aureus in the community. In a study in USA showed that pneumonia due to S. aureus is associated with influenza virus, although the study group did not detect the influenza virus8. In the current issue, the authors did not perform sampling from nasopharyngeal swab before administration either chloramphenicol or ampicillin plus gentamicin which is a useful predictor for causative pathogen of invasive diseases like very severe pneumonia and interestingly, 88.5% children have very severe pneumonia due to unknown etiology. The health community can predict the resistance status of the pathogens after obtaining the susceptibility pattern of the causative pathogens from nasopharynx. In the study multivariate analysis showed that being female is an independent predictor for treatment failure. In a study, Alex Mercer et al. showed that seeking care and others from qualified (physician) providers was found to be associated with the gender of the neonate, birth order, antenatal care of the mother from trained providers, father's education and monthly expenditure of the family in Bangladesh9. As the antimicrobial resistance pattern of those organisms has been changing, the possibility remains that ampicillin, gentamicin and chloramphenicol resistance bacteria will fail to be eradicated by ampicillin, gentamicin and chloramphenicol in region where prevalence of those drug resistance causative pathogens exists. In conclusion, chloramphenicol or ampicillin plus gentamicin can be feasible to prescribe for the treatment of very severe pneumonia in regions with low prevalence of above drugs resistance pathogens after obtaining the actual status of resistance to these drugs. WHO can revise currently recommended protocol referring prescribe the drugs for treatment of very severe pneumonia on the basis of local drugs resistance pattern of causative pathogens and can introduce vaccine against Hib and conjugated S. pneumoniae in developing countries. References 1.Asghar R, Banajeh S, Egas J, Hibberd P, Iqbal I, Katep-Bwalya M, et al. Chloramphenicol versus ampicillin plus gentamicin for community acquired very severe pneumonia among children aged 2-59 months in low resource settings: multicentre randomised controlled trial (SPEAR study). BMJ 2008;336:80-4 2.Bhutta ZA. Managing severe pneumonia in children in developing countries. BMJ 2008; 336; 57-58. 3.Hazir T, Fox LM, Nisar YB, Fox MP, Ashraf YP, MacLeod WB et al., for the new Outpatient Short-course Home Oral Therapy for Severe pneumonia (NO-SHOTS) Study Group. Ambulatory short-course high-dose oral amoxicillin for treatment of severe pneumonia in children: a randomized equivalency trial. Lancet 2008; 371:49-56. 4.Hotomi M, Fujihara K, Billal DS, Suzuki K, Nishimura T, Baba S, et al. Genetic characteristics and clonal dissemination of ß-lactamase non- producing ampicillin resistant (BLNAR) Haemophilus influenzae isolated from the upper respiratory tract in Japan. Antimicrob Agents Chemother 2007; 51: 3969-76. 5.Saha SK, Darmstadt GL, Baqui AH, Islam N, Qazi S, Islam M, et al. Direct detection of the multidrug resistance genome of Haemophilus influenzae in cerebrospinal fluid of children: implication for treatment of meningitis. Pediatr infect Dis J 2008; 27: 49-53. 6.Smith AL, Erwin AL, Kline T, Unrath WCT, Nelson K, Weber A et al. Chloramphenicol is a substract for a noble nitroreductase pathway in Haemophilus influenzae. Antimicrob Agents Chemother 2007;51: 2820-2829. 7.Hotomi M, Billal DS, Shimada J, Suzumoto M, Yamauchi K, Fujihara K, et al. High prevalence of Streptococcus pneumoniae with mutations in pbp1a, pbp2x, and pbp2b genes of penicillin-binding proteins in the nasopharynx in children in Japan. ORL J Otorhinolaryngol Relat Spec 2006; 68: 139-145. 8.Centers for Disease Control and Prevention (CDC). Severe methicillin-resistant Staphylococcus aureus community-acquired pneumonia associated with influenza--Louisiana and Georgia, December 2006-January 2007. MMWR Morb Mortal Wkly Rep 2007; 56: 325-9. 9. Mercer A, Haseen F, Huq NL, Uddin N, Khan MH, Larson CP. Risk factors for neonatal mortality in rural areas of Bangladesh served by a large NGO programme. Health Policy Plan 2006;21:432-43. Competing interests: None declared |
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Des Turner, MP SW1A 0AA, Richard Taylor
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The recent study of Asghar et al., and the accompanying editorial note by Zulfi Bhutta remind all of us that much more can and must be done to control pneumonia and pneumococcal disease world wide. The work of Ashgar et al. show how treatment for very severe pneumonia among children in low resource settings could be improved by a change in antibiotic drug regimen, while Bhutta notes the findings from the study present a grim picture in the fight against pneumonia in children. The research also confirms that increasing resistance to antibiotics is making treatment more complicated and expensive. Pneumonia remains the leading infectious cause of death for children, accounting for 1.9 million child deaths each year. Significantly pneumococcal disease is the leading cause of child pneumonia deaths and is an increasingly urgent global problem, exacerbated by HIV infection. Faced with such an alarming challenge, the All Party Parliamentary Group (APPG) on Pneumococcal Disease Prevention in the developing world was formed on 23rd January 2007 to tackle the devastating impact of pneumonia on child survival. As Bhutta notes, given increasing resistance to antibiotics in the long term, the most cost effective means of reducing child mortality from pneumonia is to scale up effective preventive strategies, most notably vaccination. Pneumococcal conjugate vaccines are safe and highly effective in preventing pneumococcal pneumonia and meningitis. GAVI’s PneumoADIP is working to accelerate the introduction of these vaccines so that they can start saving lives now. The Advance Market Commitment (AMC) is an innovative financing mechanism with the potential to save millions of lives by accelerating access to vaccines that would not otherwise be available to children for many years. The UK government together with the governments of Italy, Canada, Norway, Russia and the Bill and Melinda Gates Foundation have already pledged $1.5 billion for the first AMC for pneumococcal vaccines. Through the AMC there is the potential to save the lives of 5.4 million children by 2030. The parliamentarians that constitute the APPG are committed to raising awareness of pneumococcal disease and pneumonia, vaccination strategies and sustainable financing mechanisms among MPs and peers nationally, across Europe and around the world. Dr Des Turner, MP Dr Richard Taylor MP The All-Party Parliamentary Group on Pneumococcal Disease Prevention in the Developing World Please address all correspondence to: Dr Des Turner MP, House of Commons, London, SW1A 0AA Competing interests: None declared |
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