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Three randomized open-label clinical trials Simplified Antibiotic Therapy Trial (SATT) Bangladesh, SATT Pakistan and African Neonatal Sepsis Trial (AFRINEST) were developed to test the equivalence of simplified antibiotic regimens compared with the standard regimen of 7 days of parenteral antibiotics. These trials were originally conceived and designed separately; subsequently, significant efforts were made to develop and implement a common protocol and approach. Previous articles in this supplement briefly describe the specific quality control methods used in the individual trials; this article presents additional information about the systematic approaches used to minimize threats to validity and ensure quality across the trials.

Invasive meningococcal disease (IMD) is under-reported in countries that do not employ polymerase-chain reaction for surveillance because culture-negative cases are omitted. To evaluate a clinically based, case-finding method, we developed case definitions for “probable,” “compatible with,” and “possible, but unlikely” IMD, respectively, based on supportive documentation (e.g., discharge diagnosis of meningococcal infection, culture-negative bacterial meningitis, petechiae/purpura, Gram-negative diplococci on Gram stain) and weight of clinical evidence, which we then applied to electronic health records for all children aged ≤5 y who were admitted to approximately 100 US hospitals between January 2000 and June 2009. Among 47,863 qualifying admissions, 16 children had culture-positive IMD, 5 had “probable” IMD, and 5 had illness “compatible with” IMD. Five additional children had disease considered “possible but unlikely” IMD. Our case-finding methods suggest that culture-based ascertainment may underestimate the number of IMD cases by 31–63%, supporting findings in other nations that culture-based reporting provides incomplete information on disease incidence and therefore underestimates the potential benefits of routine vaccination of young children against meningococcal disease.

Chemical synthesis of the penicillin nucleus in the 1950s made introduction of a broad array of new and important antimicrobials, including ampicillin and amoxicillin, possible. Ampicillin was introduced in 1962 in oral and parenteral forms as the first of the semisynthetic penicillins to provide increased activity against Gram-negative bacteria. Amoxicillin replaced oral ampicillin beginning in 1974 because amoxicillin resulted in higher and more prolonged serum concentrations than did equivalent doses of ampicillin. Amoxicillin/clavulanate (Augmentin) was introduced in the United States in 1984 to enhance the activity of amoxicillin by addition of the beta-lactamase inhibitor, clavulanic acid. During the past 20 years, amoxicillin/clavulanate has proven effective for a variety of pediatric infectious diseases, particularly acute otitis media (AOM). In 2001, a new pediatric formulation, high dose amoxicillin/clavulanate (Augmentin ES-600) was approved for use in the United States. The high dose preparation addressed the needs of pediatricians by providing greater amounts of amoxicillin while maintaining the same daily dose of clavulanic acid as the regular strength formulation. Doubling the dose of amoxicillin for management of recurrent and persistent AOM was recommended in 1999 by the Centers for Disease Control and Prevention because of concern about the increased incidence of nonsusceptible strains of Streptococcus pneumoniae.The original formulation combined amoxicillin/clavulanate in a 4:1 ratio and was followed by a 7:1 ratio formulation. The high dose formulation (600 mg of amoxicillin per 5 ml) provides a 14:1 ratio of amoxicillin to clavulanate. Although management of AOM will likely undergo changes in the coming years, amoxicillin is expected to remain first line therapy for AOM. For children who fail initial therapy with amoxicillin, high dose amoxicillin/clavulanate, an oral cephalosporin or parenteral ceftriaxone is recommended.

Acute otitis media is the most common diagnosis in children seeking treatment for an illness rather than for a healthy child visit. The finding that a limited number of Streptococcus pneumoniaeserotypes cause a substantial proportion of otitis media has led to the development of conjugate vaccines designed to induce immunity to those serotypes known to be the most common causative agents or associated with antibiotic resistance. The heptavalent vaccine approved by the Food and Drug Administration in February 2000 has been shown to significantly reduce the incidence of invasive pneumococcal disease. However, the long-term effect of vaccination on the incidence of otitis media has yet to be determined. Several recent studies suggest that although vaccination leads to a decreased incidence of disease due to vaccine serotypes, there is an increased incidence of otitis media due to nonvaccine serotypes. However, the number of children with multiple episodes of otitis media and the number of those requiring tympanostomy tube placement are reduced by the vaccine.

Should strategies of management of invasive disease in the febrile child without focus of infection (occult bacteremia) be reconsidered in communities with universal immunization of infants with the conjugate vaccines for Haemophilus influenzaetype b and Streptococcus pneumoniae(PCV7)? The incidence of occult bacteremia is likely to decrease with the virtual elimination of H. influenzaetype b and vaccine serotype pneumococcal invasive diseases. The number of children with fever coming to physicians’ offices, however, is unlikely to change. The challenge of distinguishing the febrile child with invasive bacterial disease who requires aggressive therapy from the febrile child who has a viral infection and requires only symptomatic therapy will persist. The bacteriology of invasive disease in infants and young children in 2002 will include pneumococcal serotypes not in PCV7; serotypes in PCV7 that occur in the unimmunized, partially immunized or fully immunized child (vaccine failures);Neisseria meningitidis;Salmonellaspp., group A Streptococcus, Staphylococcus aureusand Gram-negative enteric bacilli. Management plans published in the 1990s suggested an aggressive diagnostic approach to the febrile child 3 to 36 months old who was toxic or had a temperature of >39°C. Diagnostic tests included white blood cell counts, cultures of blood and urine and chest radiograph and lumbar puncture as indicated by clinical signs and administration of parenteral ceftriaxone. Although PCV7 was extraordinarily effective in prevention of serotype-specific invasive pneumococcal disease in clinical trials, pediatricians need to know whether the results based on 38 000 enrollees will be maintained as millions of children are immunized. In addition questions about change in serotype of pneumococci causing invasive disease (serotype switching), herd immunity and durability of protection after immunization need to be answered. Until more experience is available to answer these questions, the febrile child without focus of infection should be managed without consideration of immunization with PCV7. Evaluation of the organism (serotype) and the host (acute and convalescent sera) should be undertaken for each case of invasive pneumococcal disease in this era of universal pneumococcal immunization.

In the next few years what will alter our modes of diagnosis, choice of therapies and strategies for prevention of acute otitis media (AOM)? These issues, as well as whether antibiotic resistance will continue to threaten the efficacy of currently available antimicrobial agents, whether industry and academia will be able to respond to bacterial resistance with effective new antimicrobial drugs and whether the pneumococcal conjugate vaccine will substantially reduce the incidence of AOM provide a basis for discussing the problems and possible solutions related to AOM.

Otitis media is one of the most common office diagnoses among children in the US and the leading reason for the use of antimicrobials in pediatric practice. We undertook this study to characterize medical and surgical management of otitis media.

There has been little apparent change in the overall incidence of systemic bacterial infection in newborns, though rates of disease differ among institutions and countries and patterns of causative organisms have shifted. Selected aspects of the clinical pharmacology of antimicrobials in newborns, present usage of agents for suspected systemic infection, the potential value of new therapies including a new generation of cephalosporins, and adjunctive therapies such as granulocyte transfusion, exchange transfusion, and immune globulins, are discussed.

In the field of infectious diseases, the emergence of new pathogens or old diseases in newly recognized forms; changing virulence of pathogens; changing patterns of antimicrobial susceptibility; new diagnostic techniques, drugs or vaccines; changing concepts of chemoprophylaxis; controversies about medical vs. surgical techniques; and the challenge of care of children with infectious diseases within new guidelines of managed care are recently identified areas of change. The increased resistance of Streptococcus pneumoniaeto many commonly used antimicrobials and the increased proportion of beta-lactamase-producing nontypable Haemophilus influenzaeand Moraxella catarrhalisconcern many practitioners. The decreased antibiotic susceptibility of S. pneumoniaeis a relatively new phenomenon in the United States. Optimal therapy for mild, moderate or severe pneumococcal disease is dependent on current local susceptibility patterns. Group A streptococci are uniformly susceptible to readily achieved concentrations of all penicillins and cephalosporins. However, recent clusters of cases of rheumatic fever, increased recognition of toxic shock syndrome and bacteremic and localized severe pneumococcal disease have increased concern about the changing ecology of the Streptococcusand the implications for therapy. Finally recognition that many children with acute bacterial otitis media have resolution of disease without use of antimicrobial agents has led to more rigorous study designs for evaluating new drugs. Criteria for choice of antimicrobial agents for acute otitis media in children are based on clinical efficacy determined from studies of sufficient sample size to show differences among the products evaluated, microbiologic efficacy with aspirates of middle ear fluid before therapy and subsequent evaluation based on clinical criteria or repeat aspiration of middle ear fluid to define sterilization by the drug, side effects and toxicity, administrative advantages, acceptability and costs of illness.

Antibiotic resistance to available antimicrobial agents has been constant since the introduction of the sulfonamides in the 1930s. Multidrug-resistant Streptococcus pneumoniaeand beta-lactamase-producing Haemophilus influenzaeare a concern now because of the importance of these pathogens in infections of the respiratory tract in infants and children. Amoxicillin remains the drug of choice for initial episodes of acute otitis media (AOM) although increase of the dosage schedule to 80 mg/kg/day has been recommended by some investigators. There are 15 additional antimicrobial agents approved by the Food and Drug Administration for the indication of AOM. All approved drugs are clinically effective but some have been suggested to have priority for patients who fail amoxicillin: amoxicillin-clavulanate; an oral cephalosporin such as cefuroxime axetil; and intramuscular ceftriaxone. Management of the child with severe and recurrent disease should include antibiotic prophylaxis but the increased incidence of resistance requires selective use. Prevention of infection may be achieved by innovative techniques for interference with attachment of bacteria to the nasal mucosa such as administration of oligosaccharides in a nasal spray. The currently available polysaccharide pneumococcal vaccines have limited immunogenicity in infants, but the vaccine is useful in children 2 years of age and older who still have recurrent AOM. Children with frequent AOM during the prior respiratory season are candidates also for influenza virus vaccine. If medical management fails to prevent new episodes of AOM in children with severe and recurrent disease, placement of tympanostomy tubes and possible adenoidectomy should be considered.

Erythromycin, the prototypical macrolide, has been widely used since the 1950s in the management of pediatric infections. Erythromycin is the drug of choice for infants and children with Legionnaire's disease, pertussis, diphtheria, lower respiratory tract infections caused by Mycoplasma pneumoniae, Chlamydia pneumoniaeand Chlamydia trachomatisand enteritis caused by Campylobacter jejuni.It is also indicated for treatment of syphilis; for streptococcal, staphylococcal and pneumococcal infections; genital infections caused by Ureaplasma urealyticum;and for the prevention of rheumatic fever and endocarditis in patients who are allergic to beta-lactam antibiotics. The new macrolides azithromycin and clarithromycin are also active against Borrelia burgdorferi, Helicobacter pylori, Mycobacterium avium-intracellularecomplex, Cryptosporidiumspp. and Toxoplasma gondii.Erythromycin is associated with a low risk of serious side effects, although gastric distress occurs in a significant proportion of patients. Drug interactions with theophylline, carbamazepine, warfarin, cyclosporine, terfenadine and digoxin limit erythromycin use. The newer macrolides azithromycin and clarithromycin are more stable, better absorbed and better tolerated than erythromycin. Azithromycin is more active than erythromycin against Haemophilus influenzae.

To determine the risk of urinary tract infections in acutely ill febrile children younger than 5 years of age we obtained a urine culture from 664 children presenting to our walk-in clinic with an acute febrile episode. Only 11 children (1.7) had significant bacteriuria. This figure is similar to the number of children who would be expected to have asymptomatic bacteriuria. These results suggest that pediatricians are not missing the diagnosis of urinary tract infection in febrile children.

Acute otitis media (AOM) is thought to occur frequently in children infected with human immunodeficiency virus (HIV). We compared experience with AOM of 28 HIV-infected children with that of 33 children who seroreverted to HIV antibody negative status by age 18 months. The mean number of episodes/year of AOM for children who seroreverted decreased from 1.33 in the first year of life to 0.13 in the third year, whereas the mean number of episodes/year in HIV-infected children increased from 1.89 to 2.40. By age 3 years, all HIV-infected children had experienced 1 or more episodes of AOM, and 80 had experienced 6 or more, whereas 75 of children who seroreverted had experienced 1 or more episodes, and none had had 6 or more. HIV-infected children with normal T4 lymphocyte counts had a mean of 1.18 episodes of AOM in the first year of life compared with 2.35 episodes in HIV-infected children with decreased counts (P = 0.023). HIV-infected children with low counts had a nearly 3-fold increased risk of recurrent AOM (17 vs. 18).

Appropriate choice of antimicrobial agents for therapy of otitis media (OM) is based on an understanding of the microbiology of the acute and chronic diseases. The results of studies of bacteriology of OM are very similar: Streptococcus pneumoniaeand Hemophilus in fluenzaeare the most important pathogens; Gram-negative enteric bacilli are isolated from middle ear fluids (MEF) of approximately 20% of infants to 6 weeks of age; group A β-hemolytic Streptococcusand Staphylococcus aureusare infrequent causes of otitis. Preliminary results suggest that anaerobic bacteria are responsible for some episodes of OM. Viruses and mycoplasma are infrequently isolated from MEF but Chlamydia trachomatisappears to be a significant cause of OM in young infants. Recent studies of asymptomatic children with persistent MEF indicate that bacterial pathogens are present in some of these fluids. The significance of these results is uncertain, but they suggest that the persistent effusion may be a result of prolonged infection or may be an immune response to bacterial antigens. Based on the bacteriology, amoxicillin or ampicillin are the currently preferred drugs for initial treatment of otitis media. For the child who is allergic to penicillins, cefaclor or erythromycin combined with a sulfonamide or trimethoprim-sulfamethoxazole are satisfactory alternatives. The current incidence of ampicillin-resistant H influenzaeresponsible for OM is low but if the patient does not respond to initial therapy with ampicillin or amoxicillin, infection with a resistant strain of H influenzaeshould be considered and a change in therapy to include a sulfonamide, trimethoprim-sulfamethoxazole or cefaclor is appropriate.

We evaluated the inhibitory effect of trimethoprim (TMP) and sulfamethoxazole (SMZ), alone and in combination, against 34 strains of Haemophilus influenzae. Growth inhibition was determined after incubation for 18 h by comparing viable counts of cultures in drug-containing medium with corresponding counts of control cultures in drug-free medium. In a modified, thymidine-deficient Levinthal broth, the numbers of colony-forming units of all the isolates tested were reduced 100-fold or more by TMP/SMZ (1.25/25 μg/ml) as compared with growth without drug. Inhibition was significantly greater with TMP/SMZ than with either TMP or SMZ alone. Ampicillin-susceptible and ampicillin-resistant strains were equally susceptible to TMP/SMZ. Growth of nontypable strains was inhibited more than growth of type b organisms.

Thirty-five strains each of Klebsiellaand Proteuswere tested for susceptibility to mecillinam alone and in combination with ampicillin, carbenicillin, cephalothin, and cefazolin. Antibiotics were considered to be synergistic when there was a ≥fourfold reduction in minimum inhibiting concentration of both antibiotics in the combination as compared with that of each antibiotic alone. Synergy of mecillinam with ampicillin, carbenicillin, cephalothin, and cefazolin was demonstrated against 2, 3, 7, and 8 of the 35 strains of Klebsiellaand against 14, 14, 19, and 24 of the 35 strains of Proteus, respectively. Synergy against the isolates of Proteuswas related to species, whereas against Klebsiellait was related to susceptibility of the isolates to mecillinam. Tests of combinations of mecillinam with other antibiotics on the same and different species indicated that synergy was related to the antibiotic, the species, and the strains of organisms tested.

The emergence of pneumococci resistant to penicillin has prompted an examination of the role of resistant organisms in the response to treatment for acute otitis media (AOM). At this time, antibiotic-resistant organisms play a small role in the number of episodes of AOM that do not respond to initial therapy. Amoxicillin remains the drug of choice for treatment of AOM. For children who do not respond, assessment of clinical status is important. Children who are well-appearing may respond to a β-lactamase-stable oral agent. Children who are ill may require tympanotomy and presumptive therapy for infection due to resistant organisms.

Bacteremia is a relatively common disease in young, apparently mildly ill febrile children. It resolves spontaneously in some, but many remain ill. Therefore, physicians should use cultures of blood of young children who are well enough to be treated as outpatients. The authors suggest that patients at increased risk of developing bacteremia receive presumptive treatment with antimicrobial agents.