Pneumonia is the number one killer of children in India(l). Our knowledge of this deadly disease has increased greatly in the last few years, especially regarding its etiology. The principal change has been an increase in the number and type of organisms recognized as capable of causing pneumonia. Also, the concept of "atypical" agents giving rise only to mild disease has given way to an appreciation of Mycoplasma pneumoniae and Chlamydia species as pathogens causing significant illness.

This change in knowledge has necessitated a change in therapeutic recommendations as well. Antibiotics are an essential part of the management of pneumonia, and appropriate choices could help avert much of the mortality associated with this disease. This article deals with healthy children who develop pneumonia in the community. Pneumonia acquired in the hospital setting, and pneumonia in children with immune function disorders, is a separate subject.

The etiology of pneumonia is difficult to elicit, because the seat of the infection, the lung, is not easily available for sampling. Even research studies, using specialized investigations not easily available to clinicians, are able to establish a firm diagnosis in only about 50% of cases.

In tropical countries, bacterial pneumonia is common. Indian studies have found Streptococcus pneumoniae, Hemophilus influenzae, and staphylococci to be most commonly involved in community acquired pneumonia(2,3). Staphylococcal pneumonia should be suspected in the presence of an abscess or multiple abscesses, infected scabies, and air leaks or breakdown seen on radiographs.

The old belief that "atypical" organisms like Mycoplasma pneumoniae and Chlamydia species cause only mild disease no longer holds true. These organisms are important causes of community acquired pneumonia, including serious cases. One study in adults found a 5% mortality in patients with pneumonia caused by these "atypical" pathogens(4). Indeed, the 2001 British Thoracic Society guidelines recommend that the term "atypical pneumonia" no longer be used(5).

Indian studies, too, have found a high prevalence of Mycoplasma pneumoniae and Chlamydiae pneumoniae in community acquired pneumonia in adults as well as children(6-8). There is also evidence of frequent coinfection with other organisms. These atypical organisms are more likely in older children. Chlamydia trachomatis, however, is involved in pneumonia at younger ages–3 weeks to 3 months. Gram negative organisms, especially Klebsiella and E. coli, are also common at this age(3).

Neither clinical features, nor laboratory and radiological investigations, can reliably differentiate infections owing to these so called atypical pathogens from children having pneumococcal pneumonia(9). A very high white cell count and C-reactive protein(CRP) level are more suggestive of pneumococcal pneumonia, but either may cause a lobar or interstitial picture on chest X-ray. Other investigations too, overlap to an extent that make confident differentiation impossible(10,11).

Viruses are important causes of community acquired pneumonia, especially in temperate climates, where they may be involved in 50% of cases(10,12). Respiratory syncytial virus(RSV) is the most common virus, besides influenza A and B, cyto-megalovirus, and adenoviruses. RSV causes bronchiolitis in babies, of course, but it is also a cause of classical pneumonia in older children(12).

Bacterial and viral pneumonias differ in laboratory and clinical features, but there is enough overlap to prevent reliable differ-entiation(11,13). Neither X-ray appearance, white cell count, ESR, or CRP, can reliably distinguish viral from bacterial pneumonia. CRP concentrations above 40 mg/L suggest bacterial involvement, though viral infections such as adenovirus can also induce high CRP levels.

Immunofluorescence and serology are the most useful for identifying viral infections, and their general use may help in rationalising antibiotic treatment. Blood cultures are rarely positive in children with pneumonia(12), though when they are, the disease is more severe(14).

In most clinical situations, it is not possible to diagnose viral pneumonia with confidence. Except for the very mildest cases, it is prudent to prescribe antibiotics to all children with pneumonia.

Children do not produce sputum for culture, blood cultures are rarely positive, and throat swabs are not useful because children always have bacteria colonizing the upper respiratory tract. Lung taps and broncho-alveolar lavage (BAL) are invasive investiga-tions, and not used routinely. Even when using special research protocols, an etiological diagnosis is made only in about half of cases(10,12).

We do not have reliable methods for identifying the causative agent in children before initiation of treatment, and empiric treatment is the rule. This is not as simple as covering all possible pathogens, because increasing levels of bacterial resistance are being seen allover the world. We need to consider local susceptibility and resistance data when selecting appropriate antibiotics for the treatment of bacterial pneumonia.

Empirical therapy is aimed at the organisms commonly responsible for pneumonia. Below five years, this is the pneumococcus. Children older than 5 years may have mycoplasma pneumonia, and children younger than six months may have Gram negative organisms. Beta lactamase producing bacteria are not common in the community setting, in contrast to hospital acquired infections.

Mycoplasma, Chlamydia and other "atypical" pathogens can cause severe pneumonia and death(4). These organisms do not respond to the beta lactams that we have traditionally used to treat pneumonia. The drugs of choice for these intracellular organisms are the macrolides. All children with severe pneumonia should receive initial coverage against these intracellular bacteria.

If staphylococcal pneumonia is suspected, therapy should begin with a penicillinase resistant penicillin like cloxacillin, or a beta-lactamase resistant drug like cefpodoxime, cefuroxime, or coamoxyclav. If the child does not respond, or methicilln resistant Staphylococcus aureus (MRSA) are common in the region, the drug of choice is vancomycin.

Be narrowminded. A recent prospective study in the UK found an 81% response rate to penicillin in community acquired pneumonia(10). Broad spectrum antibiotics are generally needed only in children younger than six months, whose pneumonia may be caused by Gram negative bacteria.

Amoxycillin is a good drug for outpatient treatment of children below five years with non-severe pneumonia. Even moderately resistant pneumococci will respond to it if the serum and tissue levels are high enough. Since amoxycillin can safely be given at a higher dose, it is a good first choice for pneumonia in children not sick enough to be hospitalized. It is normally given at 40-50 mg/kg a day, but in areas where resistance is common, higher doses of 80-100 mg/kg a day are more effective(15,16). This is because resistance among pneumococci is the result of alterations in the penicillin binding proteins which reduces their affinity for penicillin. Higher drug concentrations are needed for killing the bacteria(5). The drug is easy to take, well absorbed, inexpensive, and safe.

Children with pneumonia severe enough to be hospitalized should receive an intravenous beta-lactam, such as cefuroxime, ceftriaxone sodium, cefotaxime sodium, or a combination of a beta-lactam and beta lactamase inhibitor, plus a macrolide(17,18). Young infants should receive a beta lactam and an aminoglycoside, because of their tendency to get Gram negative infections.

Among the cephalosporins, cefuroxime has some advantages. Cefuroxime has a bioavailability of 50 to 60% when taken with food, and reaches peak serum concentrations of approximately 10 mg/L which remain above 1 mg/L for 8 hours. Cefuroxime penetrates well into the airway mucosa and sputum, and its clearance is slower from the sputum than from the blood. Effective concentrations at the site of infection persist long enough to permit the convenience of twice a day dosing. For respiratory infections, a dose of 50-100 mg/Kg a day would be appropriate; it has been used at much higher doses for meningitis.

Beyond the age of five years, atypical organisms are common in community acquired pneumonia, and a macrolide (erythromycin, clarithromycin, or azithro-mycin) would be a good choice. Azithro-mycin (10 mg/Kg/day once a day for 5 days) and clarithromycin (15 mg/Kg/day in 2 divided doses for 10 days) have good activity against all the major pathogens of community acquired pneumonia. Streotococcus pneumo-niae, Hemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamydia pneumoniae and even staphylococci are covered by these antibiotics. Azithromycin has good cure rates and a low incidence of side effects(19), besides the convenience of a single daily dose. Since parenteral preparations are not available in India, these agents are not suitable for severe and life threatening pneumonia. Resistance is a problem, too. Pneumococci develop resistance to macrolides by altering the antibiotic, altering the binding site, and alteration in antibiotic transport. Treatment failures have been reported with macrolides in community acquired pneumonia.

The older macrolide, erythromycin, is also effective in community acquired pneu-monia(20). However, it needs to be taken four times a day, and frequent gastrointestinal adverse effects make adherence difficult. Additionally, it is not effective against Hemophilus influenzae, an important childhood pathogen in India.

They have good oral bioavailability, the convenience of once or twice daily dosing, and a spectrum that includes Streotococcus pneu-moniae, Hemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, and Chlamydia species. The new fluoroquinolones like gatifloxacin, moxi-floxacin, and levo-floxacin seem made for respiratory infections, but unfortunately, this group of drugs is not approved for use in children.

In adults, they are at least as effective as conventional therapy with amoxy-cillin(21,22). Some comparative studies in patients with pneumonia have found the lowest mortality among patients assigned to the fluoroquinolone treatment. We urgently need safety data on these drugs among children.

Most cases can be managed with oral antibiotics. Parenteral therapy is needed only for children with severe pneumonia, disturbed consciousness, improper swallowing, frequent vomiting, and suspected drug malabsorption. Amoxycillin is a good parenteral drug for children with mild pneumonia, but children with severe pneumonia and life threatening disease should be given either a broad spectrum cephalosporin, or the amoxycillin- clavulanate combination. A macrolide should also be given, but parenteral preparations are not available in India.

Children should be switched to oral therapy as soon as they have improved sufficiently. This reduces cost of therapy, allows early discharge from hospital, and reduces the risk of nosocomial infections and complications like phlebitis. When the initial therapy is a broad spectrum parenteral cephalosporin, the change should be to oral amoxycillin-clavulanate rather than an oral cephalosporin(5).

All the major pathogens of community acquired pneumonia are developing resistance to antibiotics, but the impact on therapy is not the same for all pathogens.

Resistance in pneumococci is spreading allover the world. Pneumococci become resistant by target alteration - they change the cell wall protein that beta lactam antibiotics bind to. Higher levels of beta lactams can overcome this type of resistance in most, but not all strains. Since beta lactamase production is not the basis for resistance, adding a betalactamase antagonist (like clavulinic acid) has no effect.

Apart from beta-lactams, resistance to macrolides, lincosamides, trimethoprim-sulfamethoxazole, and the tetracyclines has been seen in pneumococci. Some strains are resistant to more than one class of antibiotic and their treatment is difficult. Patients likely to harbour resistant organisms include young children, particularly those attending day care, and children who have received recent antibiotic therapy, suffer from underlying diseases including HIV, or have nosocomial or polymicrobial pneumonia. The best drug for multi drug resistant S. pneumoniae is vancomycin; others are linezolid, teicoplanin, imipenem, and the extended spectrum cephalosporins.

Resistance in pneumococci leads to a rise in MIC (minimum inhibitory concentration). Since higher blood and tissue levels of amoxycillin and other beta lactam antibiotics can be safely achieved by giving higher doses, the presence of resistance does not usually lead to treatment failure with these drugs. In contrast, resistance to the macrolides, tri-methoprim-sulfamethoxazole, or fluoro-quinolones makes these drugs unusable for the treatment of community acquired pneumonia. Treatment failures have been reported with both macrolides and fluoroquinolones in community acquired pneumonia. Knowledge of local resistance patterns is very important in choosing the correct antibiotic in a given clinical situation.

In India, pneumococci have a very low incidence(1.3%) of resistance to penicillin(23). However, the high incidence of resistance to cotrimoxazole(56%) and chloramphenicol(17%) means that these drugs are undependable in the treatment of pneumonia(23).

Another important pathogen of serious invasive disease in childhood, Hemophilus influenzae, is often drug resistant. In India, up to 50% of isolates are resistant to chloramphenicol; resistance to ampicillin, co-trimoxazole, and erythromycin is also high (24,25). No resistance was found to the third generation cephalosporins(24,25).

Antibiotics should be given for 7-10 days, or at least for five days after the fever has subsided. However, for microbiologically undiagnosed and severe pneumonia, and pneumonia caused by Gram negative bacilli, staphylococci, or Legionella species, longer courses of 10-21 days are needed(5).

1. Indrayan A, Wysocki MJ, Kumar R, Chawla A, Singh N. Estimates of the years-of-life-lost due to the top nine causes of death in rural areas of major states in India in 1995. Natl Med J India 2002; 15: 7-13.

2. John TJ, Cherian T, Steinhoff MC, Simoes EA, John M. Etiology of acute respiratory infections in children in tropical southern India. Rev Infect Dis 1991; 13 Suppl 6: S463-469.

3. Patwari AK, Bisht S, Srinivasan A, Deb M, Chattopadhya D. Etiology of pneumonia in hospitalized children. J Trop Pediatr 1996; 42: 15-20.

4. Lim WS, Macfarlane JT, Boswell TC, Harrison TG, Rose D, Leinonen M, et al. Study of community acquired pneumonia etiology (SCAPA) in adults admitted to hospital: implications for management guidelines. Thorax 2001; 56: 296-301.

5. British Thoracic Society. Guidelines for the management of community acquired pneumonia in adults. Thorax 2001; 56 (Suppl IV): 1-64.

6. Dey AB, Chaudhry R, Kumar P, Nisar N, Nagarkar KM. Mycoplasma pneumoniae and community-acquired pneumonia. Natl Med J India 2000; 13: 66-70.

7. Mathai E, Padmavathy K, Cherian T, Inbamalar U, Varkki S. Mycoplasma antibodies in children with acute respiratory infection. Indian Pediatr 2001; 38: 157-160.

8. Chaudhry R, Nazima N, Dhawan B, Kabra SK. Prevalence of Mycoplasma pneumoniae and Chlamydia pneumoniae in children with community acquired pneumonia. Indian J Pediatr 1998 ; 65 : 717-721.

9. Esposito S, Blasi F, Bellini F, Allegra L, Principi N. Mycoplasma pneumoniae and Chlamydia pneumoniae infections in children with pneumonia. Mowgli Study Group. Eur Respir J 2001; 17: 241-245.

10. Clements H, Stephenson T, Gabriel V, Harrison T, Millar M, Smyth A, et al. Rationalised prescribing for community acquired pneumonia: A closed loop audit. Arch Dis Child 2000; 83: 320-324.

11. Wubbel L, Muniz L, Ahmed A, Trujillo M, Carubelli C, Mccoig C, et al. Etiology and treatment of community-acquired pneumonia in ambulatory children. Pediatr Infect Dis J 1999; 18: 98-104.

12. Drummond P, Clark J, Wheeler J, Galloway A, Freeman R, Cant A. Community acquired pneumonia: A prospective UK study. Arch Dis Child 2000; 83: 408-412.

13. Juven T, Mertsola J, Toikka P, Virkki R, Leinonen M, Ruuskanen O. Clinical profile of serologically diagnosed Pneumococcal pneumonia. Pediatr Infect Dis J 2001; 20: 1028-1033.

14. Waterer GW, Wunderink RG. The influence of the severity of community-acquired pneumonia on the usefulness of blood cultures. Respir Med 2001; 95: 78-82.

15. Schrag SJ, Pena C, Fernandez J, Sanchez J, Gomez V, Perez E, et al. Effect of short-course, high-dose amoxicillin therapy on resistant pneumococcal carriage: A randomized trial. JAMA 2001; 286: 49-56.

16. Pichichero ME. Recurrent and persistent otitis media. Pediatr Infect Dis J 2000; 19: 911-916.

17. Heffelfinger JD, Dowell SF, Jorgensen JH, Klugman KP, Mabry LR, Musher DM, et al. Management of community-acquired pneumonia in the era of pneumococcal resistance: a report from the drug resistant Streptococcus pneumoniae Therapeutic Working Group. Arch Intern Med 2000; 160: 1399-1408.

18. Woodhead M. Community-Acquired Pneu-monia Guidelines. An International Comparison. A view from Europe. Chest 1998; 113: 183S-187S.

19. Harris JA, Kolokathis A, Campbell M, Cassell GH, Hammerschlag MR. Safety and efficacy of azithromycin in the treatment of community-acquired pneumonia in children. Pediatrc Infect Dis J 1998; 17: 865-871.

20. Chien SM, Pichotta P, Siepman N, Chan CK. Treatment of community-acquired pneumonia. A multicenter, double-blind, randomized study comparing clarithromycin with erythromycin. Chest 1993; 103: 697-701.

21. Petitpretz P, Arvis P, Marel M, Moita J, Urueta J CAP5 Moxifloxacin Study Group. Oral moxifloxacin vs high-dosage amoxicillin in the treatment of mild-to-moderate, community-acquired, suspected pneumococcal pneumonia in adults. Chest 2001; 119: 185-195.

22. Dresser LD, Niederman MS, Paladino JA. Cost-effectiveness of gatifloxacin vs ceftriaxone with a macrolide for the treatment of community-acquired pneumonia. Chest 2001; 119: 1439-1448.

23. Invasive Bacterial Infection Surveillance (IBIS) Group, International Clinical Epidemiology Network (INCLEN). Prospective multicentre hospital surveillance of Streptococcus pneumoniae disease in India. Lancet 1999; 353: 1216-1221.

24. Steinhoff MC. Invasive Haemophilus influenzae disease in India: a preliminary report of prospective multihospital surveillance. Pediatr Infect Dis J 1998; 17: S172-175.

25. Nag VL, Ayyagari A, Venkatesh V, Ghar M, Yadav V, Prasad KN. Drug resistant Haemophilus influenzae from respiratory tract infection in a tertiary care hospital in north India. Indian J Chest Dis Allied Sci 2001; 43: 13-17.