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PRIORITY PRESS - 88th Canadian Paediatric Society Annual Conference

Québec City, Québec / June 15-18, 2011

Medical Editor: Dr. Julie Frère, Montréal, Quebec

Antibiotic resistance directly affects the health of Canadian children and physicians who care for them have a duty to prescribe the appropriate antibiotic at the right dose for the correct duration of time to minimize the perpetuation of antibiotic resistance among organisms that cause common childhood infections.

Pathophysiology of Antibiotic Resistance

There are a number of different mechanisms by which bacteria acquire resistance, as noted here at the CPS by Dr. François Boucher, Associate Professor of Paediatrics, Université Laval, Québec City, and each of the mechanisms employed by bacteria variously affects different antibiotics. “However, beta-lactamase is the most common mechanism of resistance that affects bacterial infections in children,” Dr. Boucher observed.

Resistance spreads under direct selective antimicrobial pressure which causes bacteria to either mutate or acquire new resistance genes by direct DNA transfer. Alternatively, resistant bacterial clones can be transmitted from person to person. Factors that promote the development of antibiotic resistance are widely known to physicians and include inappropriate use of antibiotics; use of inappropriate doses and subtherapeutic exposure; and frequent exposure to the same class of antibiotics.

Macrolide-resistant pneumococci are not a real issue in childhood infections, Dr. Boucher observed. As for penicillin-resistant Streptococcus pneumoniae (PRP), Dr. Boucher noted that pneumococcal serotypes contained in the 7-valent pneumococcal vaccine (PCV7) were responsible for most PRP infections in children. Prior to the introduction of the PCV7 vaccine, “intermediate to high resistance was very marked in the 1990s,” Dr. Boucher told delegates.

Following the introduction of the PCV7 program, “there was some plateau in the prevalence of resistant strains of pneumococci and some decrease in high level resistance,” he added. Québec launched the PCV7 vaccination program in 2005 and they, too, have witnessed a similar phenomenon, he added. Indeed, according to Québec data, the vaccine prevented approximately 85% of pneumococcal infections caused by the 7 serotypes in the PCV7 vaccine in children and 94% of resistant infections.

“After the introduction of the PCV7 vaccine, the incidence of pneumococcal infections decreased in all target groups—not only in children who were immunized but also in their grandparents,” Dr. Boucher reported.

Patterns of PRP in the US have mirrored those in Canada; unfortunately, replacement serotypes, especially serotype 19A in the US, is causing very aggressive infections in children. “The PCV13 vaccine adds 6 serotypes over the serotypes provided by the PCV7 vaccine, [including] serotypes 3, 6A and, most importantly, 19A infections,” Dr. Boucher noted. “I think it is a good decision to change to the PCV13 vaccine in order to prevent these infections.”

Treatment Strategies

“At least 95% of the time, you do not have susceptibility data when choosing an antibiotic,” as Dr. Joan Robinson, Professor of Paediatrics, University of Alberta, Edmonton, reminded CPS delegates. She discussed empiric therapy with the appropriate antibiotics for the most common childhood infections. “When treating infections due to pneumococcus, think about penicillin resistance because penicillin resistance is here to stay,” she stated. For acute otitis media (AOM) infections, the Canadian Paediatric Society recommends “expectant” symptomatic treatment of AOM, reserving antibiotics only for children who do not improve without them. For these children, “I still think oral amoxicillin is the best antibiotic for possible penicillin-resistant pneumococcal infections and if you give 75 to 90 mg/kg/day, you can overcome intermediate resistance,” Dr. Robinson indicated.

The main organism behind sinusitis is also pneumococcus and the same regimen may be used to treat sinusitis in children in whom PRP is suspected. Amoxicillin-clavulanic acid covers AOM infections due to Haemophilus influenzae and Moraxella catarrhalis but as Dr. Robinson noted, “it is a laxative.” For pneumonia, “amoxicillin is usually the drug of choice for oral therapy unless the child has prominent features of atypical pneumonia, with high doses being recommended as with AOM,” Dr. Robinson confirmed.

There is “no simple answer” as to which intravenous (i.v.) antibiotics are best for possible PRP infections. High doses of penicillin (250,000 units/kg/day) will probably cure even fully PRP infections outside of those in the central nervous system (CNS); for CNS disease, cefotaxime is an effective choice, she added. Until about 2004, most cases of methicillin-resistant Staphylococcus aureus (MRSA) in Canada were hospital-acquired. “Now, most MRSA is community-acquired,” she noted, “and every patient with suspected S. aureus infection could have MRSA.”

Boils are the most common source of MRSA infection in children and they often recur on the buttocks. “Whether the boil drains spontaneously, or you drain it, or if you need to wait for it to ripen, then drain it, all you need to do is get the pus out,” Dr. Robinson noted, “because antibiotics have limited benefit in these infections.” Pending culture, the usual choice of oral antibiotic for subcutaneous abscesses would be trimethoprim/sulfamethoxazole (TMP/SMX). For any serious infection where MRSA is a possibility, vancomycin covers almost all MRSA strains.

Cellulitis without boils is significantly more likely to be due to group A streptococcus than to S. aureus and most cellulitis will respond to oral cephalexin or to i.v. cefazolin. Cefixime by mouth is a good choice for uncomplicated urinary tract infections in previously well children 3 months of age or older not on antibiotic prophylaxis and not known to be colonized with a multiresistant gram-negative organism. “If admitted for suspected pyelonephritis, i.v. gentamicin remains the drug of choice,” Dr. Robinson noted.

Dr. Robinson stressed that routine immunization with the PCV7 vaccine may reduce the incidence of PRP disease and help stop the spread of antibiotic resistance. Now with the PCV13 vaccine, “we may continue to battle the problem of PRP disease,” she added. Physicians also should promote routine influenza vaccination in children and good hand hygiene can prevent transmission. Watchful waiting rather than initiation of antibiotics is appropriate for both AOM and sinusitis, as is a shorter course of antibiotic therapy (5 days) for their treatment.

Catch-up Vaccination

In 2010, the National Advisory Committee on Immunization (NACI) recommended the PCV13 vaccine for routine infant vaccination. In addition, they recommended a catch-up dose for children between the ages of 14 and 59 months who had been previously fully vaccinated with the PCV7 vaccine.

In a presentation by Strutton et al. at the European Society for Paediatric Infectious Diseases (ESPID) conference last week, researchers estimated the number of pneumococcal-related cases that would occur over the next 10 years in a group of children up to 59 months of age who were not covered by a catch-up program.

With no catch-up, researchers estimated there would be 22,261 cases of invasive pneumococcal disease (IPD) over 10 years in this age group. They also estimated there would be 14,977,794 cases of pneumonia, 144,731,659 cases of AOM and 3141 deaths.

With 39% of the target age group covered by the catch-up program, there would be 20,148 cases of IPD over the next 10 years in the target age group, 14,874,651 cases of pneumonia, 143,125,025 cases of OAM and 3051 deaths. With 87% of the target age group covered by the catch-up program, there would be 18,822 cases of IPD, 14,806,341 cases of pneumonia, 142,466,963 AOM and 3020 deaths.

“Assuming no herd effect acceleration, the current catch-up program is estimated to prevent an additional 593,669 cases of disease and 26 deaths compared with no catch-up program,” researchers stated, “and our analysis continues to predict an important decline in IPD, pneumonia and AOM in children under 5 years of age.”

Currently, the catch-up vaccination dose is publicly funded in certain Canadian provinces for children up to 59 months of age.

Summary

Control of antibiotic resistance is critical in the management of paediatric infections and good antimicrobial stewardship is key to containing its spread. Appropriate use of antibiotics when necessary is clearly important as is appropriate childhood vaccination to prevent infectious disease. By offering broader coverage against pneumococcal infections, the PCV13 vaccine may further reduce antibiotic resistance and help preserve important treatment options for those infections which do require antibiotics.