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Current needs for new beta-lactam antibiotics in pediatrics
Current Needs for New Beta-Lactam Antibiotics in Pediatrics
JOHN D. NELSON, M.D. Dallas,
Six common clinical situations in infants and children are discussed from the point of view of standard therapeutic regimens: neonatal sepsis and meningitis; febrile episodes in neutropenia; bacterial meningitis; acute pulmonary exacerbations of cystic fibrosis; pneumbnia, bone and joint infections, and ceiiuiitis in patients less than four years of age; and intra-abdominai sepsis. Potential or actual problems with these therapeutic regimens and newer therapeutic options are outlined.
Texas
From the Department of Pediatrics, University Health Science Center at Dallas, Dallas, Texas. Requests for reprints should be addressed to Dr. John D. Nelson, Department of Pediatrics, University of Texas Health Science Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235.
The variety of bacteria that cause infection in infants and children is strongly: influenced by the age and altered status of the host. Customarily, many serious infections in hospitalized children are treated initially with two or more antibiotics until the precise etiologic agent is known; the best therapeutic regimen is then tailored to the infectious agent and its antimicrobial susceptibilities. In many clinical situations, certain regimens using combinations of antibiotics have become standard therapy, but none is ideal. For example, neonatal sepsis and meningitis are usually treated with a penicillin and an aminoglycoside, such as ampicillin and gentamicin. Febrile patients with neutropenia may receive an antipseudomonal penicillin and an aminogly coside, with or without an antistaphylococcal penicillin. Bacterial meningitis is often treated with a combination of ampicillin and chloramphenicol. For acute pulmonary exacerbations of cystic fibrosis, an antipseudomonal penicillin and an aminoglycoside are usually administered. Pneumonia, infections of the bone and joint, and cellulitis in children younger than four years of age are most often treated with a combination of an antistaphylococcal penicillin and a drug active against Hemophilus species. Clindamycin and gentamicin are usually given in combination to treat intra-abdominal sepsis. Each of these six disease states and their current standard therapeutic regimens have potential or actual problems that new antibiotics might be able to overcome. The specific problems and therapeutic options associated with newer antibiotics are the focus of this article; the desired characteristics of future beta-lactam antibiotics are also detailed. The role of beta-lactam antibiotics in the treatment of infections in the pediatric population is expanding. Only in recent years, when the secondand third-generation cephalosporins were introduced, have pediatricians become familiar with that class of drug; even now, first-generation cephalosporins are used only infrequently in treating infections in pediatric patients. Similarly, pediatricians are becoming more familiar with the ureidopenicillins and beta-lactamase inhibitors. It is important for other physicians to bear in mind that children are not merely tittle adults and that children with infectious diseases present some special and unique problems.
174
of Medldne
Novsmber
29,1985
The
American
Journal
Volume
79 (suppl56)
SYMPOSIUM
INHIBITION-NELSON
MICROBIOLOGY
FEBRILE
The major bacterial pathogen causing serious systemic infection in neonates is the group B streptococcus, and the major bacterium causing disease in infants and toddlers is Hemophilus influenzae type b. Both of these microorganisms are uncommon causes of invasive disease in adults.
Febrile neutropenic pediatric patients are not unlike febrile neutropenic adults in terms of the severity of disease; however, group A streptococcal sepsis and pneumococcal sepsis occur more frequently among infants and children. For a number of years, many pediatricians have instituted two-drug therapy, with ticarcillin and tobramycin being prescribed most often; many hospitals also add an antistaphylococcal agent, such as nafcillin, to the regi‘men. Substituting the penicillin with one of the new cephalosporins would provide some intermediate antistaphylococcal coverage and activity against aminoglycoside-resistant coliforms, but would sacrifice antipseudomonal activity. If a regimen of vancomycin and an aminoglycoside was used, activity against staphylococci would be excellent; however, in patients with neutropenia, one should not rely on an aminoglycoside alone for antipseudomonal activity. The optimal combination to date is probably vancomycin and ceftazidime, which provides antipseudomonal, antistaphylococcal, &nd coliform coverage. The only drawback is the lack of extensive clinical experience, although results thus far have been gratifying.
PHARMACOKINETICS
The pharmacodynamics and pharmacokinetics of antibiotics are dependent on age to a great degree. In infants, the volume of distribution is larger per unit of body weight or even per surface area than it is in adults. Therefore, infants should usually receive larger dosages, based on body weight, in order to achieve serum concentrations comparable to those in adults. Drug kinetics are often altered in neonates because of immature renal or hepatic function or both, depending on the metabolic pathway of the drug. Drug toxicity in pediatric patients is often very different from that in adults because of deficient enzyme systems or the effects of drugs on developing tissues. Some classic examples are the gray syndrome of neonates associated with chloramphenicol administration, and the problems of tooth discoloration and deposition in the bones after administration of tetracycline. NEONATAL
SEPSIS
BACTERIAL
The two major pathogens causing neonatal sepsis and meningitis are the group B streptococcus and Escherichia coli; however, 15 to 20 percent of these cases are caused by other enteric organisms and Listeria monocytogenes, staphylococci, or Pseudomonas species. For many years, the combination of ampicillin and gentamicin has been a popular choice, except in situations in which nosocomial problems with Pseudomonas species or the presence of staphylococci within the intensive-care unit necessitate a change in the initial empiric therapy. Aminoglycoside-resistant coliforms also present problems in nearly every extended-carehewborn unit, whereas species of Bacteroides are uncommon except in infants who remain in such units for more than a week. The substitution of ticarcillin for ampicillin in this regimen would be sensible. The antimicrobial spectrum of ticarcillin is similar to that of ampicillin and, in addition, it has more activity against Pseudomonas species. The substitution of a new cephalosporin for gentamicin would provide antibacterial activity against aminoglycoside-resistant coliforms; it could also provide some degree of antistaphylococcal activity, as well as antipseudomonal activity, depending on the particular agent selected. Vancomycin would certainly provide excellent antistaphylococcal coverage but would also introduce many other problems.
29,1995
WITH NEUTROPENIA
MENINGITIS
Since 1974, ampicillin and chloramphenicol have been the standard initial therapy for meningitis in patients beyond the newborn period and up to five or 10 years of age. In most cases, this regimen is very effective. About 5 to 10 percent of all pneumococci are relatively resistant to penicillin and ampicillin but are usually susceptible to chloramphenicol. The strains of Hemophilus species that are resistant to both ampicillin and chloramphenicol have become of greater concern lately, particularly in Spain, where they have recently accounted for approximately 20 percent of all isolates of Hemophilus species causing systemic diseases in children. It is possible for these betalactamase- and acetyltransferase-producing strains to become a serious clinical problem. Experimental animal models have demonstrated that some of the new cephalosporins are effective against these strains and, although the clinical experience in this area is limited, the results in animals are encouraging. Ticarcillin plus clavulanate potassium would have poor activity against resistant pneumococci but should be effective against resistant isolates of Hemophilus species.
AND MENINGITIS
November
PATIENTS
ON BETA-IACTAMASE
ACUTE PULMONARY FIBROSIS
EXACERBATIONS
OF CYSTIC
Because of the excellent medical attention given to patients with cystic fibrosis and the resultant longer life span, the problem of acute exacerbation of this disease has increased in number and frequency year after year. Furthermore, the cause of the exacerbation remains unclear. The isolates found in sputum samples during the exacerbation
The
Amerlcan
Journal
of Medicine
Volume
79 (suppl5B)
175
are usually the same as those found between exacerbations; after treatment, patients show a clinical response although the same organisms remain. Ticarcillin and tobramycin have been the most popular regimens, but they are suboptimal in eradicating staphylococci and beta-lactamase-producing strains of Hemophilus species, as well as resistant strains of Pseudomonas aeruginosa or Pseudomonas cepacia. The use of piperacillin has no additional benefit, although ceftazidime shows promise in this area. Its only disadvantages are its limited clinical expo-. sure and its intermediate effectiveness against staphylococci. This is a disease entity in which ticarcillin plus clavulanate potassium may show promise because of its broader spectrum. MISCELLANEOUS INFECTIONS IN PATIENTS LESS THANFOURYEARSOFAGE Community-acquired infections in infants and toddlers, including pneumonia, infections of the bone and joint, and buccal or periorbital cellulitis, affect a greater number of patients than the infections discussed previously. In these usually routine cases, Hemophilus species, pneumococci, and staphylococci are often isolated. The most common initial empiric therapy has been nafcillin and chloramphenicol or methicillin and chloramphenicol. Currently, cefuroxime is used frequently at the hospital affiliated with the University of Texas Health Science Center, because it is effective and does not require the strict monitoring for
179
Nov6mb6r29,1995
m6Amsrksn
.burn6l
ot M6dldn6
toxicity required with the other agents. Since the new cephalosporins lack sufficient antistaphylococcal activity, ticarcillin plus clavulanate potassium may be useful in this area. INTRA-ABDOMINAL SEPSIS Among pediatric surgeons, one of the more popular regimens in the treatment of intra-abdominal sepsis is clindamycin and gentamicin. However, no two drugs are ideal in every case, and this type of infection is no exception. Cefoxitin has not been used extensively, and the exact dosage for newborns has not been determined. A combination of clindamycin and a new cephalosporin would provide coverage against some of the aminoglycosideresistant coliforms that are isolated occasionally. THE IDEAL BETA-LACTAM ANTIBIOTIC FOR PEDIATRIC USE What is needed for treating serious infections in pediatric patients is a drug that is well tolerated, safe, and inexpensive. Ideally, this drug would not require administration of a second drug for synergistic activity and could be used alone against aminoglycoside-resistant coliforms, betalactamase-producing organisms, Pseudomonas species, and Bacteroides species. It should also be a drug that is effective against the most frequently isolated pathogens in sepsis and meningitis.
VOkUn6
79
(SU+t@
58)
JOHN D. NELSON, M.D. Dallas,
Six common clinical situations in infants and children are discussed from the point of view of standard therapeutic regimens: neonatal sepsis and meningitis; febrile episodes in neutropenia; bacterial meningitis; acute pulmonary exacerbations of cystic fibrosis; pneumbnia, bone and joint infections, and ceiiuiitis in patients less than four years of age; and intra-abdominai sepsis. Potential or actual problems with these therapeutic regimens and newer therapeutic options are outlined.
Texas
From the Department of Pediatrics, University Health Science Center at Dallas, Dallas, Texas. Requests for reprints should be addressed to Dr. John D. Nelson, Department of Pediatrics, University of Texas Health Science Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235.
The variety of bacteria that cause infection in infants and children is strongly: influenced by the age and altered status of the host. Customarily, many serious infections in hospitalized children are treated initially with two or more antibiotics until the precise etiologic agent is known; the best therapeutic regimen is then tailored to the infectious agent and its antimicrobial susceptibilities. In many clinical situations, certain regimens using combinations of antibiotics have become standard therapy, but none is ideal. For example, neonatal sepsis and meningitis are usually treated with a penicillin and an aminoglycoside, such as ampicillin and gentamicin. Febrile patients with neutropenia may receive an antipseudomonal penicillin and an aminogly coside, with or without an antistaphylococcal penicillin. Bacterial meningitis is often treated with a combination of ampicillin and chloramphenicol. For acute pulmonary exacerbations of cystic fibrosis, an antipseudomonal penicillin and an aminoglycoside are usually administered. Pneumonia, infections of the bone and joint, and cellulitis in children younger than four years of age are most often treated with a combination of an antistaphylococcal penicillin and a drug active against Hemophilus species. Clindamycin and gentamicin are usually given in combination to treat intra-abdominal sepsis. Each of these six disease states and their current standard therapeutic regimens have potential or actual problems that new antibiotics might be able to overcome. The specific problems and therapeutic options associated with newer antibiotics are the focus of this article; the desired characteristics of future beta-lactam antibiotics are also detailed. The role of beta-lactam antibiotics in the treatment of infections in the pediatric population is expanding. Only in recent years, when the secondand third-generation cephalosporins were introduced, have pediatricians become familiar with that class of drug; even now, first-generation cephalosporins are used only infrequently in treating infections in pediatric patients. Similarly, pediatricians are becoming more familiar with the ureidopenicillins and beta-lactamase inhibitors. It is important for other physicians to bear in mind that children are not merely tittle adults and that children with infectious diseases present some special and unique problems.
174
of Medldne
Novsmber
29,1985
The
American
Journal
Volume
79 (suppl56)
SYMPOSIUM
INHIBITION-NELSON
MICROBIOLOGY
FEBRILE
The major bacterial pathogen causing serious systemic infection in neonates is the group B streptococcus, and the major bacterium causing disease in infants and toddlers is Hemophilus influenzae type b. Both of these microorganisms are uncommon causes of invasive disease in adults.
Febrile neutropenic pediatric patients are not unlike febrile neutropenic adults in terms of the severity of disease; however, group A streptococcal sepsis and pneumococcal sepsis occur more frequently among infants and children. For a number of years, many pediatricians have instituted two-drug therapy, with ticarcillin and tobramycin being prescribed most often; many hospitals also add an antistaphylococcal agent, such as nafcillin, to the regi‘men. Substituting the penicillin with one of the new cephalosporins would provide some intermediate antistaphylococcal coverage and activity against aminoglycoside-resistant coliforms, but would sacrifice antipseudomonal activity. If a regimen of vancomycin and an aminoglycoside was used, activity against staphylococci would be excellent; however, in patients with neutropenia, one should not rely on an aminoglycoside alone for antipseudomonal activity. The optimal combination to date is probably vancomycin and ceftazidime, which provides antipseudomonal, antistaphylococcal, &nd coliform coverage. The only drawback is the lack of extensive clinical experience, although results thus far have been gratifying.
PHARMACOKINETICS
The pharmacodynamics and pharmacokinetics of antibiotics are dependent on age to a great degree. In infants, the volume of distribution is larger per unit of body weight or even per surface area than it is in adults. Therefore, infants should usually receive larger dosages, based on body weight, in order to achieve serum concentrations comparable to those in adults. Drug kinetics are often altered in neonates because of immature renal or hepatic function or both, depending on the metabolic pathway of the drug. Drug toxicity in pediatric patients is often very different from that in adults because of deficient enzyme systems or the effects of drugs on developing tissues. Some classic examples are the gray syndrome of neonates associated with chloramphenicol administration, and the problems of tooth discoloration and deposition in the bones after administration of tetracycline. NEONATAL
SEPSIS
BACTERIAL
The two major pathogens causing neonatal sepsis and meningitis are the group B streptococcus and Escherichia coli; however, 15 to 20 percent of these cases are caused by other enteric organisms and Listeria monocytogenes, staphylococci, or Pseudomonas species. For many years, the combination of ampicillin and gentamicin has been a popular choice, except in situations in which nosocomial problems with Pseudomonas species or the presence of staphylococci within the intensive-care unit necessitate a change in the initial empiric therapy. Aminoglycoside-resistant coliforms also present problems in nearly every extended-carehewborn unit, whereas species of Bacteroides are uncommon except in infants who remain in such units for more than a week. The substitution of ticarcillin for ampicillin in this regimen would be sensible. The antimicrobial spectrum of ticarcillin is similar to that of ampicillin and, in addition, it has more activity against Pseudomonas species. The substitution of a new cephalosporin for gentamicin would provide antibacterial activity against aminoglycoside-resistant coliforms; it could also provide some degree of antistaphylococcal activity, as well as antipseudomonal activity, depending on the particular agent selected. Vancomycin would certainly provide excellent antistaphylococcal coverage but would also introduce many other problems.
29,1995
WITH NEUTROPENIA
MENINGITIS
Since 1974, ampicillin and chloramphenicol have been the standard initial therapy for meningitis in patients beyond the newborn period and up to five or 10 years of age. In most cases, this regimen is very effective. About 5 to 10 percent of all pneumococci are relatively resistant to penicillin and ampicillin but are usually susceptible to chloramphenicol. The strains of Hemophilus species that are resistant to both ampicillin and chloramphenicol have become of greater concern lately, particularly in Spain, where they have recently accounted for approximately 20 percent of all isolates of Hemophilus species causing systemic diseases in children. It is possible for these betalactamase- and acetyltransferase-producing strains to become a serious clinical problem. Experimental animal models have demonstrated that some of the new cephalosporins are effective against these strains and, although the clinical experience in this area is limited, the results in animals are encouraging. Ticarcillin plus clavulanate potassium would have poor activity against resistant pneumococci but should be effective against resistant isolates of Hemophilus species.
AND MENINGITIS
November
PATIENTS
ON BETA-IACTAMASE
ACUTE PULMONARY FIBROSIS
EXACERBATIONS
OF CYSTIC
Because of the excellent medical attention given to patients with cystic fibrosis and the resultant longer life span, the problem of acute exacerbation of this disease has increased in number and frequency year after year. Furthermore, the cause of the exacerbation remains unclear. The isolates found in sputum samples during the exacerbation
The
Amerlcan
Journal
of Medicine
Volume
79 (suppl5B)
175
are usually the same as those found between exacerbations; after treatment, patients show a clinical response although the same organisms remain. Ticarcillin and tobramycin have been the most popular regimens, but they are suboptimal in eradicating staphylococci and beta-lactamase-producing strains of Hemophilus species, as well as resistant strains of Pseudomonas aeruginosa or Pseudomonas cepacia. The use of piperacillin has no additional benefit, although ceftazidime shows promise in this area. Its only disadvantages are its limited clinical expo-. sure and its intermediate effectiveness against staphylococci. This is a disease entity in which ticarcillin plus clavulanate potassium may show promise because of its broader spectrum. MISCELLANEOUS INFECTIONS IN PATIENTS LESS THANFOURYEARSOFAGE Community-acquired infections in infants and toddlers, including pneumonia, infections of the bone and joint, and buccal or periorbital cellulitis, affect a greater number of patients than the infections discussed previously. In these usually routine cases, Hemophilus species, pneumococci, and staphylococci are often isolated. The most common initial empiric therapy has been nafcillin and chloramphenicol or methicillin and chloramphenicol. Currently, cefuroxime is used frequently at the hospital affiliated with the University of Texas Health Science Center, because it is effective and does not require the strict monitoring for
179
Nov6mb6r29,1995
m6Amsrksn
.burn6l
ot M6dldn6
toxicity required with the other agents. Since the new cephalosporins lack sufficient antistaphylococcal activity, ticarcillin plus clavulanate potassium may be useful in this area. INTRA-ABDOMINAL SEPSIS Among pediatric surgeons, one of the more popular regimens in the treatment of intra-abdominal sepsis is clindamycin and gentamicin. However, no two drugs are ideal in every case, and this type of infection is no exception. Cefoxitin has not been used extensively, and the exact dosage for newborns has not been determined. A combination of clindamycin and a new cephalosporin would provide coverage against some of the aminoglycosideresistant coliforms that are isolated occasionally. THE IDEAL BETA-LACTAM ANTIBIOTIC FOR PEDIATRIC USE What is needed for treating serious infections in pediatric patients is a drug that is well tolerated, safe, and inexpensive. Ideally, this drug would not require administration of a second drug for synergistic activity and could be used alone against aminoglycoside-resistant coliforms, betalactamase-producing organisms, Pseudomonas species, and Bacteroides species. It should also be a drug that is effective against the most frequently isolated pathogens in sepsis and meningitis.
VOkUn6
79
(SU+t@
58)