Pediatric Annals

Mechanisms of Pneumococcal Antibiotic Resistance and Treatment of Pneumococcal Infections in 2002

Sheldon L Kaplan, MD; Edward O Mason, Jr, PhD

Abstract

Streptococcus pneumoniae is one of the most common pathogens causing upper respiratory tract, lower respiratory tract, and other serious invasive infections in children. During the past 15 years, antibiotic resistance among pneumococcal isolates has continued to increase and has impacted the management of pneumococcal infections. In this article, the mechanisms by which S. pneumoniae evade the actions of antibiotics and the antimicrobial approach to treating pneumococcal infections in the era of antibiotic resistance are discussed.

MECHANISMS OF RESISTANCE

β-Lactam Antibiotics

Penicillin-binding proteins (PBPs) are enzymes that are important in the production of the bacterial cell wall and are inhibited by the binding of β-lactam antibiotics such as penicillin or extended-spectrum cephalosporins. Susceptible strains of S. pneumoniae have six PBPs (1a, 1b, 2x, 2a, 2b, and 3) of different molecular weights.1 Alterations in the PBPs (PBP 2b most commonly) lead to a decrease in affinity for β-lactam antibiotics and thus decreased susceptibility to the antibiotic. Nucleotide changes in the PBP genes are thought to have originated through horizontal transfer of genetic material between different streptococcal species, including alpha-streptococci with pneumococci. Continual changes in the PBP genes result in stepwise alterations in the affinity of PBPs for, and thus increasingly greater resistance to, β-lactam antibiotics. Exposure to antibiotics, young age, and day care attendance are associated with a greater likelihood of being colonized or infected with a penicillin-resistant S. pneumoniae strain.

The National Committee for Clinical Laboratory Standards (NCCLS) establishes the interpretive standards for determining the susceptibility of bacteria to antibiotics. In vitro susceptibility, pharmacokinetic and pharmacodynamic data, and clinical data are considered in developing these standards and standards may be modified as new information becomes available. For example, early on, pneumococci with a minimum inhibitory concentration (MIC) of greater than 0.1 µg/mL were considered nonsusceptible to penicillin primarily because several patients with pneumococcal meningitis failed treatment with penicillin and their isolates demonstrated this degree of susceptibility. The 2001 NCCLS interpretive guidelines for selected antibiotics are outlined in Table 1.2

In the United States, up until the late 1980s, only 5% to 8% of pneumococcal isolates were nonsusceptible (intermediate and resistant categories combined equal total nonsusceptible) to penicillin. Furthermore, most of the decreased susceptibility was in the intermediate category. However, since that time there has been a steady increase in the proportion of isolates nonsusceptible to penicillin, especially in the resistant category.3 Clonal spread of a relatively few strains of pneumococci resistant to ß-lactam antibiotics may explain this rapid increase in resistance. Although there are more than 90 S. pneumoniae serotypes, 7 (6A, 6B, 9V, 14, 19A, 19F, and 23F) account for more than 90% of penicillin-resistant strains.

In a national survey conducted from November 1, 1999, through April 30, 2000, among 1,531 isolates collected from 33 U.S. medical centers, 34.2% were penicillin nonsusceptible (resistant, 21.5%; intermediate, 12.7%).4 Similarly, the nonsusceptibilty rate to ceftriaxone has been increasing steadily, and in this survey 13.3% of isolates were intermediate (MIC = 1.0 µg/mL) and 14.4% were resistant (MIC > 2.0 µg/ mL) to ceftriaxone. As in most studies, isolates obtained from children had rates of penicillin resistance greater than those collected from adults and strains associated with upper respiratory tract infections were associated with higher rates of resistance than those from normally sterile sites. Among 8 children's hospitals surveying invasive pneumococcal infections since 1993, rates of resistance to penicillin and ceftriaxone increased significantly during a 6year period.5 In the sixth year of the study, 37% and 11% were nonsusceptible to penicillin or ceftriaxone, respectively.

Macrolide, Lincosomide, and Streptogramin Antibiotics

Resistance to the macrolide group of antibiotics (erythromycin, clarithromycin, and azithromycin) can occur by two…

Streptococcus pneumoniae is one of the most common pathogens causing upper respiratory tract, lower respiratory tract, and other serious invasive infections in children. During the past 15 years, antibiotic resistance among pneumococcal isolates has continued to increase and has impacted the management of pneumococcal infections. In this article, the mechanisms by which S. pneumoniae evade the actions of antibiotics and the antimicrobial approach to treating pneumococcal infections in the era of antibiotic resistance are discussed.

MECHANISMS OF RESISTANCE

β-Lactam Antibiotics

Penicillin-binding proteins (PBPs) are enzymes that are important in the production of the bacterial cell wall and are inhibited by the binding of β-lactam antibiotics such as penicillin or extended-spectrum cephalosporins. Susceptible strains of S. pneumoniae have six PBPs (1a, 1b, 2x, 2a, 2b, and 3) of different molecular weights.1 Alterations in the PBPs (PBP 2b most commonly) lead to a decrease in affinity for β-lactam antibiotics and thus decreased susceptibility to the antibiotic. Nucleotide changes in the PBP genes are thought to have originated through horizontal transfer of genetic material between different streptococcal species, including alpha-streptococci with pneumococci. Continual changes in the PBP genes result in stepwise alterations in the affinity of PBPs for, and thus increasingly greater resistance to, β-lactam antibiotics. Exposure to antibiotics, young age, and day care attendance are associated with a greater likelihood of being colonized or infected with a penicillin-resistant S. pneumoniae strain.

The National Committee for Clinical Laboratory Standards (NCCLS) establishes the interpretive standards for determining the susceptibility of bacteria to antibiotics. In vitro susceptibility, pharmacokinetic and pharmacodynamic data, and clinical data are considered in developing these standards and standards may be modified as new information becomes available. For example, early on, pneumococci with a minimum inhibitory concentration (MIC) of greater than 0.1 µg/mL were considered nonsusceptible to penicillin primarily because several patients with pneumococcal meningitis failed treatment with penicillin and their isolates demonstrated this degree of susceptibility. The 2001 NCCLS interpretive guidelines for selected antibiotics are outlined in Table 1.2

In the United States, up until the late 1980s, only 5% to 8% of pneumococcal isolates were nonsusceptible (intermediate and resistant categories combined equal total nonsusceptible) to penicillin. Furthermore, most of the decreased susceptibility was in the intermediate category. However, since that time there has been a steady increase in the proportion of isolates nonsusceptible to penicillin, especially in the resistant category.3 Clonal spread of a relatively few strains of pneumococci resistant to ß-lactam antibiotics may explain this rapid increase in resistance. Although there are more than 90 S. pneumoniae serotypes, 7 (6A, 6B, 9V, 14, 19A, 19F, and 23F) account for more than 90% of penicillin-resistant strains.

In a national survey conducted from November 1, 1999, through April 30, 2000, among 1,531 isolates collected from 33 U.S. medical centers, 34.2% were penicillin nonsusceptible (resistant, 21.5%; intermediate, 12.7%).4 Similarly, the nonsusceptibilty rate to ceftriaxone has been increasing steadily, and in this survey 13.3% of isolates were intermediate (MIC = 1.0 µg/mL) and 14.4% were resistant (MIC > 2.0 µg/ mL) to ceftriaxone. As in most studies, isolates obtained from children had rates of penicillin resistance greater than those collected from adults and strains associated with upper respiratory tract infections were associated with higher rates of resistance than those from normally sterile sites. Among 8 children's hospitals surveying invasive pneumococcal infections since 1993, rates of resistance to penicillin and ceftriaxone increased significantly during a 6year period.5 In the sixth year of the study, 37% and 11% were nonsusceptible to penicillin or ceftriaxone, respectively.

Macrolide, Lincosomide, and Streptogramin Antibiotics

Resistance to the macrolide group of antibiotics (erythromycin, clarithromycin, and azithromycin) can occur by two major mechanisms. The most common, known as M phenotype, is mediated through an efflux pump that effectively removes macrolide antibiotics from the cell. This form of resistance is encoded by the mefE gene and is associated with erythromycin MICs ranging from 1 to 32 µg/mL. There is some evidence that infections caused by pneumococcal isolates with the M phenotype can still be successfully treated with high doses of macrolides. Isolates with the M phenotype are typically susceptible to clindamycin.

Table

TABLE 1Selected MIC Interpretive Standards for Streptococcus pneumoniae, National Committee for Clinical Laboratory Standards- 2001

TABLE 1

Selected MIC Interpretive Standards for Streptococcus pneumoniae, National Committee for Clinical Laboratory Standards- 2001

The second major resistant phenotype is known as MLSB and is associated with a methylase that blocks the binding of macrolides, clindamycin, and streptogramins to the bacterial 23S ribosomal RNA. This form of resistance is encoded by the ermAM gene. With the MLSB phenotype, the organisms are resistant to macrolides at high levels (erythromycin MICs are > 64 /¿g/mL) and to clindamycin and streptogramin antibiotics.

Resistance to macrolides has also been increasing in the United States during the past several years. In Centers for Disease Control and Prevention (CDC) surveillance studies conducted in 8 states, macrolide resistance increased from 10.6% in 1995 to 20.4% in 1999.6 The proportion of isolates with the M phenotype increased from 7.4% to 16.5%, whereas the proportion with the MLSB phenotype remained stable at 3.4% to 3.7% during the study periods. In 1999, macrolide resistance was found to be higher among children younger than 5 years (30.6%) than among individuals older than 5 years (16%). Eighty-seven percent of the macrolide-resistant isolates from children younger than 5 years were serotypes 4, 9V, 14, 19F, 23F, 18C, or 6B; serotype 14 accounted for 44.5% of resistant strains.

In a multicenter study by Doern et al.4 from November 1, 1999, through April 30, 2000, 25.7% of pneumococcal isolates were erythromycin resistant. Among these isolates, the efflux mechanism of resistance accounted for approximately 70%. Erythromycin resistance was found in 43% and 78% of isolates intermediate or resistant to penicillin, respectively. Clindamycin resistance was found in 20% to 25% of penicillin-nonsusceptible pneumococcal strains. As in the CDC study, isolates from children younger than 5 years had the highest rate of resistance to erythromycin (33%).

Trimethoprim-Sulfamethoxazole

Resistance to sulfonamide is thought to be by a change in the enzyme dihydropteroate such that the sulfonamide no longer blocks folate synthesis. Resistance to trimethoprim is mediated by changes in the dihydrofolate reductase, of which many have been described.7 In the study by Doern et al., 36% of isolates were resistant to trimethoprim-sulfamethoxazole (TMP-SMX) in 1999 to 2000 compared with 9.1% from 1994 to 1995.4 TMP-SMX resistance was found in 13%, 49%, and 98% of isolates susceptible, intermediate, or resistant to penicillin, respectively. The CDC surveillance reported slightly lower percentages among invasive isolates in the United States in 1998.3

Fluoroquinolones

Although fluoroquinolones are not recommended routinely for children younger than 17 years, in selected cases these agents may be important options for treating infections caused by pneumococci resistant to multiple antibiotics. The newer fluoroquinolones (eg, gemifloxacin, moxifloxacin, gatifloxacin, and levofloxacin [in order of most active]) have improved in vitro activity against pneumococci. Resistance to fluoroquinolones is due to mutations in the genes encoding subunits of topoisomerase IV (parC) and DNA gyrase A (gyrA).8 Isolates that have mutations in both parC and gyrA have higherlevel resistance to the fluoroquinolones and are cross-resistant to all agents in this class. In the 1998 CDC surveillance of invasive pneumococcal isolates, low levels of resistance to levofloxacin (0.1% to 0.7%) were found among pneumococcal isolates regardless of susceptibility to penicillin.3 All of the levofloxacin-resistant isolates were recovered from adults. In the 1999-2000 study by Doern et al., 1% to 1.2% of isolates were intermediate or resistant to levofloxacin; slightly fewer were nonsusceptible to gatifloxacin.4

Vancomycin

Although resistance to vancomycin has not been described for pneumococci, strains found to be tolerant of vancomycin have been reported. Vancomycin-tolerant pneumococci are inhibited but not killed by vancomycin.910 It is thought that the tolerance results from the lack of triggering autolysins, enzymes that degrade the bacterial cell wall. A time-kill curve is the definitive laboratory technique to detect vancomycin tolerance. In the one study that examined vancomycin tolerance among pneumococcal isolates, less than 2 log kill during 4 hours was defined as tolerance.9 Among 116 clinical isolates, 3 (3%) were tolerant to vancomycin. All were serotype 9V. The clinical significance of vancomycin tolerance remains to be determined.

TREATMENT OF PNEUMOCOCCAL INFECTIONS

The treatment of invasive or local infections caused by S. pneumoniae has become more complicated during the past decade because of the increasing and multiple antibiotic resistance among pneumococcal isolates. Recommendations for treatment are evolving and are based primarily on case series from around the world and not on randomized trials.11 The effectiveness of certain antibiotics (eg, penicillin or ampicillin) is difficult to assess in the United States, where these antibiotics are rarely used in the initial empiric therapy of serious infections that might be caused by S. pneumoniae.

As clinical outcome data have become available, new breakpoints recently have been recommended for the extended-spectrum cephalosporins that are dependent on the site of infection and the achievable concentrations of the cephalosporins at the site. For isolates associated with bacterial meningitis, the MIC breakpoints for cefotaxime or ceftriaxone remain the same (susceptible, < 0.5 pg/ mL; intermediate, 1.0 µg /mL; resistant, > 2.0 µg /mL). However, for isolates associated with infections outside the central nervous system, the MIC breakpoints have been increased (susceptible, < 1.0 µg /mL; intermediate, 2.0 µg /mL; resistant, 2* 4.0 µg/ mL). These new recommendations represent the first time that interpretation of the MIC breakpoints has been dependent on the site of infection and will require physician education to avoid confusion.

Bacterial Meningitis

The guidelines for treating pneumococcal meningitis have been based to a large degree on case reports of treatment failure and the associated MIC of the pneumococcal isolate for the antibiotic the patient was receiving.11 Several reports in the 1970s indicated that microbiologic and clinical failure of treatment with penicillin was likely when the penicillin MIC of the pneumococcal isolate was greater than 0.1 ^g/ mL. Routine doses of penicillin did not achieve high enough concentrations in the cerebrospinal fluid (CSF) of patients to reliably eradicate pneumococcal isolates with MICs of 0.1 µg /mL or greater. Chloramphenicol is not an acceptable alternative for treating meningitis caused by isolates nonsusceptible to penicillin. Penicillinnonsusceprible isolates have increased chloramphenicol MICs compared with penicillin-susceptible isolates, and this likely results in lower bactericidal activity in the CSF.

By the mid 1980s, monotherapy with cefotaxime or ceftriaxone was the most commonly recommended empiric treatment for children with suspected bacterial meningitis. However, beginning in 1989 a series of case reports of patients continuing to have positive results on CSF cultures despite therapy with an extendedspectrum cephalosporin appeared (Table 2). Most of the treatment failures were associated with MICs for cefotaxime or ceftriaxone of 2.0 /¿g /mL or greater, although 3 had isolates with cefotaxime MICs of 1.0 ¿g /mL. Most of these patients were successfully treated with the addition of vancomycin. Other investigators reported successful treatment with cefotaxime or ceftriaxone when the MIC for these agents was 1.0 µg /mL.

Several antibiotics have been evaluated in the rabbit model of pneumococcal meningitis using strains resistant to cefotaxime or ceftriaxone. In one study, high doses of ceftriaxone did not result in effective killing and bactericidal activity in the CSF for a pneumococcal isolate with a ceftriaxone MIC of 2 to 4 µg /mL.12 However, when vancomycin was added to the ceftriaxone, the combination was synergistic and superior to vancomycin alone. In this model, meropenem is not significantly different from ceftriaxone. In other studies, the adjunctive administration of dexamethasone impaired the penetration of vancomycin into the CSF and diminished the bactericidal activity of CSF. When the dose of vancomycin was doubled, the effect of the steroid was circumvented. A similar concern regarding the effect of dexamethasone administration on vancomycin penetration has been raised for adults with meningitis. In the only study that has measured vancomycin concentrations in the CSF of children with bacterial meningitis who were receiving vancomycin (60 mg/kg/d in 4 divided doses) and dexamethasone (0.6 mg/kg/d in 4 divided doses), the mean concentration of vancomycin in the CSF was 3.3 ± 1.1 µg/mL 2 to 3 hours after a dose, following 1 to 2 days of treatment.13 This concentration is comparable to that reported in children who did not receive dexamethasone.

Table

TABLE 2Failure of Extended-Spectrum Cephalosporins to Treat Pneumococcal Meningitis*

TABLE 2

Failure of Extended-Spectrum Cephalosporins to Treat Pneumococcal Meningitis*

Besides the addition of vancomycin to an extended-spectrum cephalosporin, another approach has been to increase the dose of cefotaxime. Most of the treatment failures in children occurred with a cefotaxime dose of 200 mg/kg/d. Two groups measured bactericidal activity in the CSF of children with bacterial meningitis following 300 mg / kg / d of cefotaxime. In one study, children also received dexamethasone; in the other, vancomycin was also administered. In both studies, the concentration of vancomycin in the CSF did not correlate well with bactericidal activity in the CSF. In both studies, the higher dose of cefotaxime did not result in increased bactericidal activity in the CSF, although additive activity between cefotaxime and vancomycin was noted by one group.

On the basis of these case reports, the CSF studies, and information derived from the rabbit model of pneumococcal meningitis, most experts and the Committee of Infectious Diseases of the American Academy of Pediatrics recommend that the combination of cefotaxime or ceftriaxone plus vancomycin be administered empirically for infants and children older than 1 month with suspected bacterial meningitis.14 The recommended doses and modifications in therapy based on the in vitro susceptibility of the pneumococcal isolate are outlined in Table 3. In children, these recommendations are not altered if dexamethasone is also administered. Adjunctive therapy with dexamethasone remains somewhat controversial for pneumococcal meningitis and each physician must weigh the potential risks and benefits in his or her decision to administer it.

Table

TABLE 3Treatment of Pneumococcal Meningitis In Children: Modifications Based on Antibiotic Susceptibilities

TABLE 3

Treatment of Pneumococcal Meningitis In Children: Modifications Based on Antibiotic Susceptibilities

It is unclear at what point rifampin might be added to the treatment regimen. The Red Book states that the addition of rifampin should be considered if the isolate is susceptible to rifampin and (1) the patient's condition continues to deteriorate after 24 to 48 hours of cefotaxime or ceftriaxone and vancomycin; (2) a repeat culture demonstrates continued growth or the Gram stain of CSF does not show a substantial reduction in the number of organisms; or (3) the pneumococcal isolate has a cefotaxime or ceftriaxone MIC of 4.0 ^g /mL or greater.14

Repeat lumbar puncture to document the sterility of the CSF after 36 to 48 hours of therapy is recommended for any patient who is not improving as expected or who has a pneumococcal isolate for which the cefotaxime or ceftriaxone MIC is greater than 2.0 ^g/ mL. This is especially important for patients who are receiving adjunctive dexamethasone because they may appear to be responding to antibiotic therapy with a decrease in fever despite continued positive results on CSF culture. Although not common, isolates that are tolerant to vancomycin have been reported and associated with treatment failure in one patient.10 Time-kill curves to detect vancomycin tolerance should be considered for isolates from the patient who has persistently positive results on CSF cultures without another reasonable explanation.

There is little evidence that other available antibiotics offer any advantage in treating pneumococcal meningitis caused by strains resistant to the extended-spectrum cephalosporins. Cefepime has activity equivalent to cefotaxime or ceftriaxone against penicillin-resistant pneumococci in vitro and in the rabbit model. In clinical trials comparing cefepime with cefotaxime for treating pneumococcal meningitis, no cefotaxime-resistant isolates were encountered and so the efficacy of cefepime in this situation is untested. Meropenem is approved for the treatment of meningitis in infants and children. The in vitro activity of meropenem against pneumococcal isolates resistant to cefotaxime or ceftriaxone is not well established. Meropenem has been compared with cefotaxime in two randomized trials in children with bacterial meningitis. In one of the studies, the dose of cefotaxime was 180 mg/kg/d, a dose lower than that generally recommended.15 Among the évaluable patients in the two studies combined, 173 children received cefotaxime and 177 received meropenem; at least 49 patients had S. pneumoniae isolated. Only 2 children with pneumococcal meningitis caused by isolates with cefotaxime MICs of 0.5 µ%1 mL or greater received meropenem. Additional experience with meropenem for the treatment of pneumococcal meningitis caused by strains nonsusceptible to the extended-spectrum cephalosporins is required.

Trovafloxacin was among the newer formulations of quinolones with improved activity against S. pneumoniae and was the first fluoroquinolone to be evaluated in a randomized, controlled trial for the treatment of bacterial meningitis in children. Unfortunately, in the middle of this pediatric study liver toxicity developed in several adults receiving trovafloxacin and the pediatric trial was halted. In the rabbit model of pneumococcal meningitis using a cephalosporinresistant isolate, gatifloxacin was equivalent to ceftriaxone and vancomycin.16 Gatifloxacin is the second quinolone to reach clinical trials in children with bacterial meningitis. Selected fluoroquinolones may become important treatment options for serious pneumococcal infections caused by antibiotic-resistant strains.

Currently in the United States, antibiotic resistance in S. pneumoniae has not affected the outcome of pneumococcal meningitis in children or adults.1718 One explanation for this is that physicians have been aware of the resistance problem and have modified their initial empiric treatment. Therefore, most patients receive vancomycin along with a cephalosporin initially and are being treated adequately even if the pneumococcal isolate is not susceptible to cefotaxime or ceftriaxone.

Bacteremia

The most common invasive infection caused by S. pneumoniae in children is bacteremia.19 In early reports from 1984 to 1995 in the United States, most of the patients with antibiotic-resistant pneumococcal bacteremia had penicillinintermediate strains. Rarely were treatment failures observed when therapy consisted primarily of second-generation or third-generation cephalosporins and not penicillin.11 Breakthrough bacteremia and meningitis were reported in a normal 18-month-old child who had received cefotaxime (180 mg/kg/d) for 2 days followed by intravenous cefuroxime (200 mg/kg/d) for 4 days. The MICs of cefotaxime and cefuroxime for the pneumococcal isolate were 2.0 and 8.0 ^g /mL, respectively. Breakthrough bacteremia, meningitis, or both have been reported in several children and adults primarily receiving a macrolide antibiotic and with pneumococcal isolates resistant to the macrolide.20"24 Most of these isolates had the M phenotype of macrolide resistance.

Among 8 children's hospitals involved in a multicenter surveillance study of pneumococcal infections, 100 children were encountered with invasive infections caused by isolates nonsusceptible to cefotaxime or ceftriaxone and were treated primarily with a ß-lactam antibiotic.25 Bacteremia caused by pneumococcal isolates with a MIC of 1.0 ^g /mL was found in 71 children and a MIC of 2.0 ^g /mL or greater in 6 children. Ten (13%) of the 77 had an underlying condition that could predispose to invasive pneumococcal infection. All but one was successfully treated with parenteral or oral ß-lactam antibiotics or both. The one treatment failure occurred in a child with severe combined immune deficiency who remained febrile after a single dose of ceftriaxone followed by cefprozil for 12 days. Silverstein et al.26 also reported that reduced susceptibility to penicillin did not negatively impact the outcome of children with pneumococcal bacteremia when treated in a similar manner as in the multicenter study.

Because cefuroxime, cefotaxime, and ceftriaxone reach serum concentrations of greater than 4.0 ^g /mL for a large portion of the dosing interval, successful treatment is expected for isolates with MICs up to 4.0 µ% /mL.27 In the otherwise healthy child with suspected occult pneumococcal bacteremia, the current common approach of administering a single dose of ceftriaxone followed by an oral ß-lactam antibiotic remains appropriate. For the child with suspected bacteremia who appears more ill and is to be admitted to the hospital, cefotaxime or ceftriaxone should be included in the empiric antibiotic selection. For the child in septic shock, we suggest vancomycin and cefotaxime or ceftriaxone for empiric treatment. Once an organism is isolated, penicillin is adequate for isolates with MICs of 1.0 µg /mL or less; high-dose penicillin is probably adequate for treating isolates with MICs up to 2.0 µg/ mL based on experience in children and adults for pneumococcal pneumonia with similar susceptibility results. For pneumococcal isolates with penicillin MICs of greater than 2.0 µg/mL and cefotaxime and ceftriaxone MICs of 2.0 µg/mL or less, cefotaxime or ceftriaxone is suggested. Because these isolates are generally susceptible to clindamycin, this antibiotic is an important alternative, especially for children with hypersensitivity reactions to ß-lactam antibiotics. Vancomycin can be avoided in most circumstances. There is essentially no information available on the macrolide group of antibiotics for the treatment of pneumococcal bacteremia in children. Macrolides would be an option only when the organism is known to be macrolide susceptible.

Pneumonia

Almost all studies have found that high-dose penicillin is adequate treatment for pneumococcal pneumonia caused by strains with penicillin MICs up to 2.0 ,wg/ ml. Furthermore, except for one study, pneumonia caused by antibiotic-resistant isolates was found to be no more likely to be complicated by an empyema or require chest tube drainage than that caused by susceptible strains.28 Although most of the clinical outcome information is related to mortality in adults, the pediatric studies have come to the same conclusion. In a population-based active surveillance study by the CDC from 9 geographic areas in North America, deaths from pneumococcal pneumonia after the fourth hospital day were significantly associated with isolates having a penicillin MIC of 4.0 Wg/mL or greater; only 7% of these patients were younger than 18 years.29 In a subsequent CDC study conducted in 3 metropolitan areas, death or the requirement for intensive care treatment was not more likely to occur among those whose isolates were penicillin or cefotaxime nonsusceptible or among those treated with antibiotics to which their pneumococcal isolate was not susceptible.30

In the first relatively large pediatric study to address the outcome of treatment of pneumococcal pneumonia caused by antibiotic-nonsusceptible S. pneumoniae, 25 children with isolates intermediate to penicillin were compared with 53 children with penicillin-susceptible isolates.31 The duration of fever, respiratory distress, oxygen requirements, rates of improvement, and mortality were no different between the groups. Most children were treated with a penicillin antibiotic. Among children with pneumococcal pneumonia in Korea and Uruguay, penicillin or ampicillin was just as effective in treating patients with penicillin-nonsusceptible isolates as it was for penicillin-susceptible strains.32,33

In studies conducted in the United States among 8 children's hospitals. Tan et al.34 did not find any differences in the clinical presentation or outcome of therapy between children with penicillin-susceptible isolates and those with penicillin-nonsusceptible isolates of S. pneumoniae: These patients were treated in the hospital primarily with second-generation and third-generation cephalosporins. In another study. Hardie et al.35 compared the clinical features of children with complicated parapneumonic effusions between 6 children with infection caused by pneumococcal isolates not susceptible to penicillin and 17 children whose isolates were penicillin susceptible. Thoracoscopy or urokinase treatment was undertaken for 5 children in the nonsusceptible group and 5 in the susceptible group. Other features of the hospital course or outcome were no different.

In the report from the pediatric multicenter surveillance study, 14 and 5 children had pneumonia caused by pneumococcal isolates with a ceftriaxone MIC of 1.0 Wg /mL and 2.0 wg/ mL or greater, respectively.25 Five of these children had underlying conditions. AU were treated successfully with a ß-lactam antibiotic primarily.

On the basis of these studies, in normal hosts, penicillin, ampicillin, or cefuroxime should be adequate to treat children hospitalized with pneumococcal pneumonia due to isolates for which penicillin MICs are 2.0 Wg /mL or less. Although two retrospective studies among adults with bacteremic pneumococcal pneumonia have shown lower mortality for patients treated with a cephalosporin and macrolide antibiotic combination, there are no similar data for children.36'37 Because the mortality rate for pneumococcal pneumonia in children in the United States is less than 1%, it is unlikely that a dual regimen could be shown to be more effective in reducing mortality than single-agent treatment. Oral therapy with amoxicillin, cefuroxime, or cefdinir should also be effective for initial outpatient management or when completing therapy following parenteral treatment. Macrolides should also be efficacious for outpatient therapy for pneumococcal pneumonia due to susceptible strains. Cefotaxime, ceftriaxone, and clindamycin are effective antibiotics for treating pneumococcal pneumonia caused by susceptible isolates (MIC ^ 2.0 Wg /mL for the cephalosporins). Quinolones are major agents for treating pneumococcal pneumonia in adults but currently have a limited role in children.

Table

TABLE 4Authors' Considerations for Treating Acute Otitis Media In an Era of Antibiotic-Resistant Streptococcus pneumoniae

TABLE 4

Authors' Considerations for Treating Acute Otitis Media In an Era of Antibiotic-Resistant Streptococcus pneumoniae

When a pneumococcal isolate has a MIC of greater than 4.0 Wg/mL for cefotaxime or ceftriaxone, clindamycin or vancomycin is recommended. It may be in this situation that one of the newer quinolones (eg, gatifloxacin or moxifloxadn) or the oxazolidinone linezolid could be considered for selected children. For the critically ill child or the child with an immunocompromising condition who is to be hospitalized, including vancomycin or clindamycin in the initial empiric therapy for pneumonia is reasonable. Although several groups have proposed guidelines for the management of community-acquired pneumonia, none address the approach to children in detail.38

Acute Otitis Media

Acute otitis media (AOM) and acute sinusitis are the two most common infections caused by S. pneumoniae. As with invasive infections, antibiotic resistance has complicated the treatment of these common upper respiratory tract infections (Table 4). Presumably, data for the treatment of AOM caused by penicillin-resistant S. pneumoniae with a particular antibiotic will also be true for acute sinusitis.

In 1999, the CDC, the American Academy of Pediatrics, and other organizations published consensus recommendations for the management of AOM in an era of antibiotic resistance among pneumococcal isolates.39 The Drug-resistant Streptococcus pneumoniae Therapeutic Working Group examined in vitro susceptibility data, pharmacokinetic and pharmacodynamic information, and, most importantly, the results of clinical trials to develop these recommendations. The recommended antibiotics and dose were based, in part, on whether a child had received an antibiotic in the month before the current episode of AOM, perhaps the most important risk factor for antibiotic-resistant pneumococci. Amoxicillin (45 or 90 mg/kg/d), high-dose amoxicillin-clavulanate (90 mg/kg/d of the amoxicillin component), and cefuroxime axetil and ceftriaxone (three daily doses if administered for a treatment failure) were the agents recommended. Clindamycin was suggested only if a pneumococcal etiology for AOM was known.

In several studies, amoxicillin was shown to remain an effective therapy even when treating penicillin MICs up to 2.0 wg/mL. During the time period that these studies were conducted, the dose of amoxicillin was increased in several studies to achieve higher blood levels and thus greater concentrations in the middle ear fluid.

In the initial guideline mentioned earlier, highdose amoxicillin was 90 mg/kg/d. If high-dose amoxicillin-clavulanate was to be administered, two prescriptions were required, one for amoxicillin and another for amoxicillin-clavulanate, each to deliver 45 mg/kg/d of amoxicillin. A formulation of amoxicillin-clavulanate is now available that allows adrninistration of 90 mg /kg/ d of amoxicillin and 6.4 mg/kg/d of clavulanate. In a double-tap study, this high-dose formulation eradicated 91% of pneumococcal isolates with penicillin MICs of 2 to 4 /¿g/ mL from middle ear cultures and thus supported the use of high-dose amoxicillin for treating AOM caused by resistant pneumococci.40

Cefdinir is an oral extended-spectrum cephalosporin with in vitro activity for S. pneumoniae comparable to cefuroxime. In comparative taste tests, cefdinir has been found to be acceptable to children. In AOM studies, cefdinir was associated with a 73% cure rate for children with pneumococcal isolates intermediate to penicillin, which is similar to what has been reported for cefuroxime axetil.41 In our opinion, cefdinir should be added to the list of antibiotics mat have been recommended for treating children with AOM in the era of antibiotic-resistant pneumococci. When given as a single (30 mg/kg) or triple (10 mg/kg once daily for 3 days) dose, azithromycin has been found to be as effective as amoxicillin-clavulanate for 10 days in the treatment of AOM in children. In these studies, 12 (75%) of 16 children with penicillin-intermediate isolates and 6 (67%) of 9 children with penicillinresistant isolates were considered cured. One concern with single-dose azithromycin therapy is what effect the onset of vomiting has on the need for redosing. With time, the role of single-dose and triple-dose azithromycin in the treatment of AOM will become clearer. All of these agents are among those recommended by an American Academy of Pediatrics task force for the treatment of acute sinusitis in children.42

REFERENCES

1. Klugman KP. Pneumococcal resistance to antibiotics. Clin Microbiol Rev. 1990,3:171-196.

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TABLE 1

Selected MIC Interpretive Standards for Streptococcus pneumoniae, National Committee for Clinical Laboratory Standards- 2001

TABLE 2

Failure of Extended-Spectrum Cephalosporins to Treat Pneumococcal Meningitis*

TABLE 3

Treatment of Pneumococcal Meningitis In Children: Modifications Based on Antibiotic Susceptibilities

TABLE 4

Authors' Considerations for Treating Acute Otitis Media In an Era of Antibiotic-Resistant Streptococcus pneumoniae

10.3928/0090-4481-20020401-09

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