Journal of Clinical Pharmacy and Therapeufics (1992)17,141-146
COMMENTARY
Advances in paediatric pharmacotherapy M. C. Nahata Colleges of Pharmacy and Medicine, The Ohio State University and Wexner lnstitute for Pediatric Research Children’s Hospital, Columbus, Ohio, U.S.A.
SUMMARY
Marked differences in body composition and organ function development have been demonstrated among neonates, infants, and children versus adults. Specific dosage guidelines for the paediatric population, however, are still not available for the majority of marketed drugs. Much needs to be learned about the pharmacokinetics, pharmacodynamics, comparative efficacy and safety of drugs in infants and children. Recent developments in paediatric therapeutics include the availability of several new antibiotics for the treatment of infections including, streptococcal pharyngitis, otitis media, bacterial meningitis, herpes encephalitis, neonatal herpes, and AIDS. Corticosteroids and intravenous inmunoglobulin have become important adjunctive treatments for certain infections. A variety of drugs are available to treat asthma but the mortality due to this disease is still increasing. The identification of a gene defect in patients with cystic fibrosis could lead to more effective treatment in the future. Qndansetron, marketed for use in adults only, shows promise as a more effective and safer antiemetic in children receiving cancer chemotherapy. Numerous drugs are not available in suitable dosage forms for paediatric use and extemporaneous formulations are required. Documentation on the stability of the reformulated drugs is therefore needed. Studies have shown that the methods used for intravenous delivery can influence the serum concentrations of drugs in infants and children. Large numbers of children could be saved worldwide solely with improved vaccination and Correspondence: Dr M. C. Nahata, College of Pharmacy, Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, U.S.A.
control of diarrhoea. Despite this, it is encouraging to witness the continued advances being made in paediatric pharmacotherapy. INTRODUCTION
Although children comprise about 30% of the population, they will shape 100% of our future. Insufficient emphasis and resources are given, however, to prevent and treat diseases of childhood. It is widely known that body composition and organ function differ substantially not only between an adult and a paediatric patient, but also among patients within the paediatric age group (birth-18 years). Note, however, that specific dosage guidelines for the paediatric population are not available for the majority of marketed drugs. The inappropriate use of drugs can lead to the occurrence of adverse effects or poor efficacy. Over the last two decades, enormous progress has been made in the areas of pharmacokinetics and in the evaluation of the efficacy and safety of drugs in infants and children. This progress, together with advances in technology, has led to improved diagnosis and treatment for many diseases of childhood. The purpose of this article is to highlight some of the recent developments and current challenges in paediatric pharmacotherapy. STREPTOCOCCAL PHARYNGITIS
Streptococcal pharyngitis is one of the most common infections affecting children. A variety of antibiotics are available to treat this infection but these must be given several times daily for a 10-day period. As most patients improve after the first few days, they may only be partially compliant with antibiotic therapy during the later part of therapy. Preliminary data suggest that a new macrolide antibiotic, azithromycin, given once daily for 5 days, appears to be as effective as penicillin
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V. Azithromycin has a long elimination half-life, and distributes well into the tissues. Thus, it is detectable for several days in tissues after the last dose on day 5.It may also cause less adverse effects than erythromycin (I). The use of this antibiotic and other investigational macrolides, such as clarithromycin, may simplify the treatment of streptococcal pharyngitis. OTITIS MEDIA
Otitis media occurs very frequently in infants and children. Amoxicillin is the drug of choice for /?-lactamase negative micro-organisms while amoxicillin with clavulanate, erythromycin with sulphisoxazole, himethoprim with sulphamethoxazole cefaclor, cefuroxime axetil or cefixime can be used for the/?-lactamase positive pathogens. Cefuroxime axetil is available only in a tablet dosage form and it is not easy to prepare a palatable suspension from crushed tablets. Three important developments are (i) a new liquid formulation of cefuroxime axetil (not yet marketed in the U.S.),which appears to be effective, safe and well tolerated; (ii) cefixime which can be given once daily to improve compliance in certain patients; and (iii) preliminary data suggesting that adjunctive prednisone treatment for 1-2 weeks may provide benefit in patients older than 3 years, with persistent otitis media and effusion of at least 6 weeks' duration (2). The high cost of new drugs, however, should be weighed against the potential therapeutic advantages when making a drug selection. A major challenge in the development of a safe and effective vaccine is to reduce the incidence of recurrent otitis media. A forthcoming article in this Journal will cover the topic in greater detail. BACTERIAL MENINGITIS
Bacterial meningitis causes serious morbidity and mortality in infants and children. It has been estimated that nearly 20,000patients develop the infection, and 800-1,000 die annually from this disease in the U.S. alone. Although the use of antibiotics has reduced the associated mortality, a disturbing number of patients continue to suffer from long-term neurological or audiological sequelae. Recent studies have shown that the cytokines, interleukin-lp and tumour necrosis factor a (TNF-a) play an important role in meningeal inflammation, which may cause alterations in the blood-brain barrier, cerebrovascular autoregulation, cerebrospinal fluid dynamics and brain metabolism. Dexamethasone has
been shown to reduce meningeal inflammation and patient outcome (3). Thus, it has become a common practice to administer adjunctive dexamethasone, 0.15 mg/kg of body weight every 6 h during the first four days of therapy. The first dose of dexamethasone should be given before the first dose of antibiotics. Hearing loss and neurological abnormalities occurred less frequently in patients receiving dexamethasone plus cefuroxime or cefotaxime compared with cefuroxime or cefotaxime alone (4-5). Some reports of delayed sterilization of the cerebrospinal fluid have appeared in patients receiving cefuroxime; therefore, this drug is not used for the treatment of bacterial meningitis in most hospitals. Ceftriaxone is used widely in infants and children, and cefotaxime is indicated in neonates with bacterial meningitis. The third-generation cephalosporins have largely replaced chloramphenicol for the treatment of ampicillin-resistant Haemophilw influenme type b. One of the most important recent advances is the availability of an approved vaccine against the most common pathogen, H. influenme type b. It has been shown to prevent the disease in infants and children, and can be initiated at 2 months of age (6).The challenge will be to vaccinate all infants and children as required. IMMUNIZATIONS
Immunization has been termed the greatest public health success story of the last decade. Just over 10 years ago, less than 20% of the developing worlds children were adequately immunized. The WHO'S goal of immunizing 80% of the children in the developing world by 1990 has been met. Far too many children, however, still die from preventable diseases. In 1990 the number of deaths were from measles (1.5 million), tetanus (0.8million) and pertussis (0.5million) (7). Efforts are needed to assure improved uptake of immunization worldwide. This is not a problem confined to the developing world. Nearly 50% of inner-city children younger than 2 years of age in the U.S.may not receive recommended immunizations. Disease prevention should receive a greater attention than is hitherto the case. ACQUIRED. I MM U N 0DEFICIENCY SYNDROME (AIDS)
AIDS poses a serious threat, both directly and indirectly, to the future of children. The WHO estimated that by 1989, nearly 3 million women, including
Advances in paediatric pharmacofherapy 143 2 5 million in sub-Saharan Africa were infected with
human immunodeficiency virus (HIV), and some 500,000 infants had acquired the virus from their mothers. It is expected that by 1992, 1 million babies will be born with HIV, of whom 600,000 will develop AIDS in Africa alone. Escalating numbers of patients in Asia have led WHO to project that the AIDS may become more prevalent in Asia than Africa at the end of this decade. WHO predicts that over 10 million children uninfected with HIV will be orphaned as a result of AIDS during the 1990s. Zidovudine (AZT) is effective in the treatment of HIV disease and, is now available as a syrup for use in infants and children with HIV or AIDS. Haematologic toxicity (e.g. anaemia, neutropenia) due to AZT may occur in about 60% of patients, and nearly one-third may require modification of dose or blood transfusions (8).Studies are underway to evaluate (i) the efficacy of dideoxyinosine ( d d ) in children
who are either intolerant or unresponsive to AZT; (ii) the phmacokinetics and safety of ddI administered twice daily to infants and children with symptomatic HIV or AIDS; (iii) the efficacy of adjunctive intravenous immunoglobulin in children with symptomatic HIV infection receiving AZT; (iv) the pharmacokinetics and safety of recombinant CD4 in infants and children infected with or at risk of HIV infection; (v) the efficacy of AZT versus ddI in HIV-infected children; and (vi) the efficacy and safety of oral AZT versus placebo in pregnant HIV infected women and their infants. Education is the best method to prevent AIDS. It is hoped that an effective vaccine will be available in the 1990s.The patients develop a variety of opportunistic infections, e.g. cytomegalovirus infections to be treated with ganciclovir, and Pneurnocystis curinii with trimethoprim/sulphamethoxazoleor pentamidine. An article in a future issue of this Journal will address the treatment of HIV disease. HERPES SIMPLEX VIRUS INFECTIONS
Herpes encephalitis and neonatal herpes are also serious viral infections. Acyclovir has proved to be a drug of choice for paediatric patients with these infections (9).
SYSTEMIC FUNGAL INFECTIONS
The rising incidence of fungal infections is of major concern (10).Amphotericin B is the most effective drug for systemic infections but frequently causes toxicity. Fluconazole may prove to be an alternative to amphotericin B for the treatment of certain systemic fungal infections. Fluconazole can be given orally due to its excellent bioavailability, and appears to be much safer than amphotericin B. BIOTECHNOLOGY-BASED DRUGS
Drugs in development include adjunctive monoclonal antibodies against endotoxins to improve survival in patients with Gram-negative bacteremia (II); colony stimulating factors (G-CSF and GM-CSF) to stimulate bone marrow progenitor cells and thus, reduce neutropenia and infection; and erythopoietin to stimulate red blood cell production and thus decrease anaemia associated with chronic renal failure. These drugs have not been evaluated suHiciently in paediatric patients to enable the development of optimal dosage guidelines. NEONATAL RESPIRATORY DISTRESS SYNDROME
Respiratory distress syndrome (RDS)is a major cause of morbidity and mortality, accounting for nearly half of all neonatal deaths. The use of exogenous surfactants (e.g. Exosurf, Survanta and Curosurf) has produced marked improvement in lung function and decreased some acute complications (pulmonary air leaks). Although exogenous surfactant improves survival, it may not influence complications, such as intracranial haemorrhage, patent ductus arteriosus, retinopathy of prematurity, and bronchopulmonary dysplasia. Thus, a larger number of premature infants are surviving but with an increased rate of complications. Although there are about 10 different exogenous surfactan t preparations (human amniotic fluid surfactant, organic solvent extracts, modified lipid extracts, and synthetic preparations), which have been studied in neonates, no comparative studies are available (12). An important question is: who would benefit most from surfactant therapy? For example: (i) should all newborns less than 28 weeks of gestational age be treated although up to one-third will never develop RDS?; and (ii) should all neonates older than 32 weeks be treated although they rarely die from RDS or its complications?
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It is important to find answers to these questions in order to target pharmacotherapy and minimize costs. At our hospital, surfactant preparations account for the largest share of the drug budget this year. CYSTIC FIBROSIS
Cystic fibrosis (CF) is the most common serious autosoma1 recessive disorder in the Caucasian population. CF affects a number of organs. Although supportive therapy, pancreatic enzyme supplements and antimicrobial therapy have improved patient outcome, most patients still do not survive beyond their thirtieth birthday. Recently, the major gene defect that causes CF has been identified. Nearly 70% of the gene mutations in CF are known to be caused by the loss of a single, specific trinucleotide codon, and the protein lacks only one amino acid, phyenylalanine, at position 508 (13). Gene therapy may offer the ultimate solution to CF. While it may be possible to introduce the normal gene into the living and intestinal cells, the widespread tissue defect that causes CF make this option difficult. It may be more feasible to develop drugs that act through the altered protein to restore normal chloride transport. Children with adenosine deaminase (ADA) deficiency are being treated with gene therapy by transfusing lymphocytes carrying the ADA-producing gene to produce ADA. Gene therapy may be developed for patients with many other diseases including AIDS and emphysema in the future (13). ASTHMA
Unlike the case with many other chronic diseases, the incidence of asthma and the associated number of hospitalizations and deaths are all rising. The use of inhaled albuterol, cromolyn, and corticosteroids has increased substantially but many patients as well as pharmacists may be inadequately informed about the proper use of inhalation devices (14). Optimal use of these drugs and monitoring of theophylline serum concentration will help in better control of asthma. Pharmacists can play an important role in patient education about optimal use of such drugs. The peak flow meter is a simple and relatively inexpensive home monitoring device to measure air flow obstruction. This can assist patients to identify factors that worsen asthma, and alert them to the need to adjust their therapy. The trend of increasing morbidity and mortality can be reversed in part by appropriate
pharmacotherapy. A future article in this Journal will discuss the topic. ANTI-EMETIC THERAPY IN CANCER PATIENTS
Nearly all patients receiving chemotherapy with cisplatin develop nausea and vomiting. Other drugs, such as cydophosphamide, also induce emesis. This may be so severe that patients refuse to continue chemotherapy. Metoclopramide and prochlorperazine have been used in paediatric patients; the former is more effective but also more toxic. A new anti-emetic, ondansetron (serotonin receptor antagonist), has been found to be at least as effective as, and less toxic than, metoclopramide in adult patients (15). Limited experience in paediatric patients suggests similar results. Thus, ondansetron can be used in cancer patients receiving emetogenic chemotherapy, with a past history of toxicity or inadequate response to metoclopramide. SEDATION FOR DIAGNOSTIC PROCEDURES
Paediatric pa tients undergoing diagnostic procedures such as endoscopy, biopsy, and computer tomography require sedation. There are, however, limited data about the use of effective and safe sedatives. Our comparative studies have shown that meperidine alone may be preferred over meperidine plus diazepam in patients undergoing endoscopy (16). We are comparing meperidine with meperidine plus midazolam, as midazolam may provide amnesia. We have discontinued the use of the common combination product containing meperidine, promethazine and chlorpromazine (DPT or MPC), as this can produce severe adverse effects in some infants and children. LACK QF APPROPRIATE DOSAGE FORMS
Many drugs used in paediatric patients are not available in suitable dosage forms. This often requires dilution of highly concentrated drugs intended for adults, e.g. atropine, diazepam, digoxin, morphine, phenobarbital, and phenytoin. The dilution of these products can reduce errors in measurement and prevent subtherapeutic response or toxicity. Similarly,drugs like acetazolamide, spironolactone and rifampicin are not available in suitable liquid dosage forms for accurate measurement of doses based on body weight and for safe administration
Advances in paediatric phamacotherapy
to young infants unable to swallow tablets or capsules. It is important to note that the stability of reformulated drugs must be confirmed to assure potency during preparation, storage and administration (17, 18). A book which provides 63 paediatric formulations has recently been published but specific references to document product stability are still not available for many products (18).Resources to conduct such studies are often limited. THERAPEUTIC DRUG MONITORING
Therapeutic drug monitoring (TDM) should be carried out to assure optimal use of drugs in our patients. This should include monitoring of drug administration, serum concentration measurement, if needed, and assessment of therapeutic outcome. There are numerous studies to show that the intravenous drug delivery system (e.g. flow rate, injection site, tubing diameter, and type of device) can directly influence the amount of drug received and the serum concentrations of drugs achieved in patients. For example, administration of drugs through an intravenous site closer to patients results in a higher aminoglycoside peak concentration and the peak occurs earlier than when the drug injection is made from a more distant site on an IV tubing. It is important to understand the impact of drug delivery systems on the pharmacokinetics, pharmacodynamics and therapeutic response to ensure that the desired outcomes are achieved (17). Serum concentrations of drugs including digoxin, theophylline, aminoglycosides, chloramphenicol, vancomycin, and anticonvulsants are routinely monitored. The concentrations, however, should be correlated with therapeutic response and consideration given to potential toxicity, patient and disease status and concomitant drugs so that appropriate dosage adjustments may be made when required. Collaborative efforts among pharmacists, physicians, nurses, intravenous therapists, and laboratory staff are needed to assure optimal outcomes. DRUG UTILIZATION REVIEW A N D FORMULARY An effective fomiulary can be important to promote the
appropriate use of drugs. Drug utilization reviews should be conducted in a concurrent, prospective and retrospective manner to describe patterns of usage, and develop strategies to improve drug use. These efforts
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should be focused on the most important therapeutic problems and/or high cost drugs. Education, selective formulary, drug order forms, including the rationale for therapy, direct consultation, and chart notes have been used with some success to optimize drug use in patients. Success is most likely with collaborative efforts among departments including pharmacy, medicine and nursing. GLOBAL PERSPECTIVE
Although childhood mortality continues to fall worldwide, nearly 14 million children under 5 years of age still die annually in the developing countries. The mortality among children under 5 years of age is still too high. In 1989, it ranged from 143 to 297 per 1,000live births in 38 countries, 72-139 per 1,000 in 31 countries, 21-66 per 1,000in 28 countries, and 6-20 per 1,000 in 32 countries. Diarrhoea and pneumonia each claims 4 million lives annually. It has been estimated that parents in the developing world spend over $1billion per year, primarily on ineffective remedies and medicines for diarrhoea1disease and respiratory infections (7). Diarrhoea, measles, tetanus, pertussis, pneumonia, malnutri tion and acquired immunodeficiencysyndrome are all preventable or treatable and yet cause the majority of deaths. It is encouraging that the WHO'S goal of immunizing 80% of all children in the developing world has been met. Increased vaccination has reduced the morbidity and mortality due to those diseases. Recent data suggest that the administration of vitamin A can reduce mortality in malnourished populations. New goals to be attained by the year 2000 have been developed (7). The agencies of the United Nations realize that although additional resources will be difficult to obtain, much can be gained by shifting priorities. The total cost of achieving the goals set for world-wide health has been reported to be the same as the amount currently spent on the military every 10 days. At the global level, military expenditure accounts for 5.4% of the Gross National Product (GNP) compared with 4.2% on health. Developing countries, where 85% of children under 5 years live, spend 5.6% of their GNP on the military and 1.4% on health. Other useful shifts in priorities include the training of more community health workers (training cost $500 each), rather than training only physicians, to reach more people; opening more community health clinics rather than only a few hospitals; and emphasizing primary and secondary education to everyone rather than higher education to only a few (7).
146 M. C. Nahata Vitamin A deficiency causes clinically significant ocular disease in some 5-10 million children annually in the developing countries, and many more have subclinical deficiency. Supplementation with vitamin A has produced more than a 50% decline in mortality in Southern India. The benefits were most striking in children below 3 years of age and among those chronically malnourished (19). The problems of childhood diseases are not confined to developing countries. The industrialized world has its share of problems. Despite rising prosperity in general, the number of children living below their nation’s poverty line has increased in most of the western countries (e.g. Canada, Germany, Ireland, U.K.and U.S.) over the last decade. Poor prenatal care and drug abuse during pregnancy are major health risks for the newborn. In conclusion, although substantial progress has been made, much needs to be done to improve drug therapy for infants and children. Disease prevention should receive greater emphasis. The advances in science and technology, coupled with a strong commitment by health professionals, governmental and nongovernmental agencies should ensure that the well-being of our children world-wide is improved.
REFERENCES 1. Bahal N, Nahata MC. (1992)The new macrolides: azithro-
mycin, clarithromycin,dirithromycin,and roxithromycin. DICP Annals of Pharmacotherapy, 26,46-55. 2. Podoshin L, Fradis M, Ben-David Y, Faraggi D. (1990) The efficacy of oral steroids in the treatment of persistent otitis media with effusion. Archives of Otolaryngology Head and Neck Surgery, 116,1404-1406. 3. Saez-Llorens X, Romilo 0, Mustafa M, Mertsola J, McCracken CH Jr.(1990)Molecular pathophysiology of bacterial meningitis current concepts and therapeutic implications. ]ournu1 of Pediatrics, 116,671-684. 4. Odio CM, Faingezicht I, Paris M, et al. (1991)The beneficial effects of early dexamethasome administration in infants and children with bacterial meningitis. New England]oumal of Medicine, 22,1525-1531. 5. Bahal N, Nahata MC. (1991)The role of corticosteroids in infants and children with bacterial meningitis. DICP Annals of Pharmacotherapy 25,542-545.
6. Eskola J, Kaythy H, Takala A#, et al. (1990)Randomized prospective field trial of a conjugate vaccine in the protection of infants and young children against invasive Haemophilus influenzae type b disease. New England ]ournaJ of Medicine, 323, 1381-1387. 7. United Nations Children’s Fund (UNICEF) (1991)The State of the Worlds Children. Oxford University Press, Oxford. 8. McKinney RE, Maha MA, Connor EM, et al. (1991)A multicenter trial of oral zidovudine in children with advanced human immunodeficiency virus disease. New England]ournal of Medicine, 324, 1018-1025. 9. Nahata MC. (1992) Viral infections. In: Applied Therapeutics:The Clinical Use of Drugs, 5th edn. eds Young LY, Koda-Kimble MA. pp. 1-11. Applied Therapeutics, Vancouver, WA (USA). 10. Benson JM, Nahata MC. (1988)Clinical use of systemic antifungal agents. Clinical Pharmacy, 7,424-438. 11. Ziegler EJ, Fisher CJ, Sprung CL, Straube RC, Sadoff JC, Foulke GE. (1991)Treatment of Gram-negative bacteremia and septic shock with HA-IA human monoclonal antibody against endotoxin. New England Journal of Medicine, 324,429-436. 12. Shapiro DL. (1988) Surfactant replacement therapy. Seminars in Perinatology, 12,173-260. 13. Nahata MC. (1990)Discovery of gene defect in cystic fibrosis: Implications for diagnosisand treatment. Clinical Pharmacy, 9,716-717. 14. Kelly HW. (1991) Asthma, aerosols, and patient education. DICP Annals of Pharmacotherapy, 25, 668-669. 15. Marty M, Pouillart P, Scholl S, et al. (1990)Comparison of the 5-hydroxytryptamine3 (serotonin) antagonist ondansetron (GR 38032F) with high-dose metoclopramide in the control of cisplatin-induced emesis. New England]oumal of Medicine 322,816-821. 16. Bahal N, Nahata MC, Murray RD, et al. (1992) Comparative evaluation of meperidine and diazepam for sedation in pediatric patients undergoing gastrointestinal endoscopy (Abstract).Pharmacotherapy, 11,43. 17. Nahata MC. (1992)Pediatrics. In: Pharmacotherapy, eds DiPiro et al. pp. 1-8. Elsevier, New York. 18. Nahata MC, Hipple TF. (1990)PediatricDrug Formulations. 1stedn.pp. 1-89.Harvey Whitney Books Co., Cincinnati, OH. 19. Rahmathullah L, Underwood BA, Thulasiraj RD, et al. (1990)Reduced mortality among children in Southern India receiving a small weekly dose of vitamin A. New England]oumal of Medicine, 323.929-935.
COMMENTARY
Advances in paediatric pharmacotherapy M. C. Nahata Colleges of Pharmacy and Medicine, The Ohio State University and Wexner lnstitute for Pediatric Research Children’s Hospital, Columbus, Ohio, U.S.A.
SUMMARY
Marked differences in body composition and organ function development have been demonstrated among neonates, infants, and children versus adults. Specific dosage guidelines for the paediatric population, however, are still not available for the majority of marketed drugs. Much needs to be learned about the pharmacokinetics, pharmacodynamics, comparative efficacy and safety of drugs in infants and children. Recent developments in paediatric therapeutics include the availability of several new antibiotics for the treatment of infections including, streptococcal pharyngitis, otitis media, bacterial meningitis, herpes encephalitis, neonatal herpes, and AIDS. Corticosteroids and intravenous inmunoglobulin have become important adjunctive treatments for certain infections. A variety of drugs are available to treat asthma but the mortality due to this disease is still increasing. The identification of a gene defect in patients with cystic fibrosis could lead to more effective treatment in the future. Qndansetron, marketed for use in adults only, shows promise as a more effective and safer antiemetic in children receiving cancer chemotherapy. Numerous drugs are not available in suitable dosage forms for paediatric use and extemporaneous formulations are required. Documentation on the stability of the reformulated drugs is therefore needed. Studies have shown that the methods used for intravenous delivery can influence the serum concentrations of drugs in infants and children. Large numbers of children could be saved worldwide solely with improved vaccination and Correspondence: Dr M. C. Nahata, College of Pharmacy, Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, U.S.A.
control of diarrhoea. Despite this, it is encouraging to witness the continued advances being made in paediatric pharmacotherapy. INTRODUCTION
Although children comprise about 30% of the population, they will shape 100% of our future. Insufficient emphasis and resources are given, however, to prevent and treat diseases of childhood. It is widely known that body composition and organ function differ substantially not only between an adult and a paediatric patient, but also among patients within the paediatric age group (birth-18 years). Note, however, that specific dosage guidelines for the paediatric population are not available for the majority of marketed drugs. The inappropriate use of drugs can lead to the occurrence of adverse effects or poor efficacy. Over the last two decades, enormous progress has been made in the areas of pharmacokinetics and in the evaluation of the efficacy and safety of drugs in infants and children. This progress, together with advances in technology, has led to improved diagnosis and treatment for many diseases of childhood. The purpose of this article is to highlight some of the recent developments and current challenges in paediatric pharmacotherapy. STREPTOCOCCAL PHARYNGITIS
Streptococcal pharyngitis is one of the most common infections affecting children. A variety of antibiotics are available to treat this infection but these must be given several times daily for a 10-day period. As most patients improve after the first few days, they may only be partially compliant with antibiotic therapy during the later part of therapy. Preliminary data suggest that a new macrolide antibiotic, azithromycin, given once daily for 5 days, appears to be as effective as penicillin
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M. C. Nahafa
V. Azithromycin has a long elimination half-life, and distributes well into the tissues. Thus, it is detectable for several days in tissues after the last dose on day 5.It may also cause less adverse effects than erythromycin (I). The use of this antibiotic and other investigational macrolides, such as clarithromycin, may simplify the treatment of streptococcal pharyngitis. OTITIS MEDIA
Otitis media occurs very frequently in infants and children. Amoxicillin is the drug of choice for /?-lactamase negative micro-organisms while amoxicillin with clavulanate, erythromycin with sulphisoxazole, himethoprim with sulphamethoxazole cefaclor, cefuroxime axetil or cefixime can be used for the/?-lactamase positive pathogens. Cefuroxime axetil is available only in a tablet dosage form and it is not easy to prepare a palatable suspension from crushed tablets. Three important developments are (i) a new liquid formulation of cefuroxime axetil (not yet marketed in the U.S.),which appears to be effective, safe and well tolerated; (ii) cefixime which can be given once daily to improve compliance in certain patients; and (iii) preliminary data suggesting that adjunctive prednisone treatment for 1-2 weeks may provide benefit in patients older than 3 years, with persistent otitis media and effusion of at least 6 weeks' duration (2). The high cost of new drugs, however, should be weighed against the potential therapeutic advantages when making a drug selection. A major challenge in the development of a safe and effective vaccine is to reduce the incidence of recurrent otitis media. A forthcoming article in this Journal will cover the topic in greater detail. BACTERIAL MENINGITIS
Bacterial meningitis causes serious morbidity and mortality in infants and children. It has been estimated that nearly 20,000patients develop the infection, and 800-1,000 die annually from this disease in the U.S. alone. Although the use of antibiotics has reduced the associated mortality, a disturbing number of patients continue to suffer from long-term neurological or audiological sequelae. Recent studies have shown that the cytokines, interleukin-lp and tumour necrosis factor a (TNF-a) play an important role in meningeal inflammation, which may cause alterations in the blood-brain barrier, cerebrovascular autoregulation, cerebrospinal fluid dynamics and brain metabolism. Dexamethasone has
been shown to reduce meningeal inflammation and patient outcome (3). Thus, it has become a common practice to administer adjunctive dexamethasone, 0.15 mg/kg of body weight every 6 h during the first four days of therapy. The first dose of dexamethasone should be given before the first dose of antibiotics. Hearing loss and neurological abnormalities occurred less frequently in patients receiving dexamethasone plus cefuroxime or cefotaxime compared with cefuroxime or cefotaxime alone (4-5). Some reports of delayed sterilization of the cerebrospinal fluid have appeared in patients receiving cefuroxime; therefore, this drug is not used for the treatment of bacterial meningitis in most hospitals. Ceftriaxone is used widely in infants and children, and cefotaxime is indicated in neonates with bacterial meningitis. The third-generation cephalosporins have largely replaced chloramphenicol for the treatment of ampicillin-resistant Haemophilw influenme type b. One of the most important recent advances is the availability of an approved vaccine against the most common pathogen, H. influenme type b. It has been shown to prevent the disease in infants and children, and can be initiated at 2 months of age (6).The challenge will be to vaccinate all infants and children as required. IMMUNIZATIONS
Immunization has been termed the greatest public health success story of the last decade. Just over 10 years ago, less than 20% of the developing worlds children were adequately immunized. The WHO'S goal of immunizing 80% of the children in the developing world by 1990 has been met. Far too many children, however, still die from preventable diseases. In 1990 the number of deaths were from measles (1.5 million), tetanus (0.8million) and pertussis (0.5million) (7). Efforts are needed to assure improved uptake of immunization worldwide. This is not a problem confined to the developing world. Nearly 50% of inner-city children younger than 2 years of age in the U.S.may not receive recommended immunizations. Disease prevention should receive a greater attention than is hitherto the case. ACQUIRED. I MM U N 0DEFICIENCY SYNDROME (AIDS)
AIDS poses a serious threat, both directly and indirectly, to the future of children. The WHO estimated that by 1989, nearly 3 million women, including
Advances in paediatric pharmacofherapy 143 2 5 million in sub-Saharan Africa were infected with
human immunodeficiency virus (HIV), and some 500,000 infants had acquired the virus from their mothers. It is expected that by 1992, 1 million babies will be born with HIV, of whom 600,000 will develop AIDS in Africa alone. Escalating numbers of patients in Asia have led WHO to project that the AIDS may become more prevalent in Asia than Africa at the end of this decade. WHO predicts that over 10 million children uninfected with HIV will be orphaned as a result of AIDS during the 1990s. Zidovudine (AZT) is effective in the treatment of HIV disease and, is now available as a syrup for use in infants and children with HIV or AIDS. Haematologic toxicity (e.g. anaemia, neutropenia) due to AZT may occur in about 60% of patients, and nearly one-third may require modification of dose or blood transfusions (8).Studies are underway to evaluate (i) the efficacy of dideoxyinosine ( d d ) in children
who are either intolerant or unresponsive to AZT; (ii) the phmacokinetics and safety of ddI administered twice daily to infants and children with symptomatic HIV or AIDS; (iii) the efficacy of adjunctive intravenous immunoglobulin in children with symptomatic HIV infection receiving AZT; (iv) the pharmacokinetics and safety of recombinant CD4 in infants and children infected with or at risk of HIV infection; (v) the efficacy of AZT versus ddI in HIV-infected children; and (vi) the efficacy and safety of oral AZT versus placebo in pregnant HIV infected women and their infants. Education is the best method to prevent AIDS. It is hoped that an effective vaccine will be available in the 1990s.The patients develop a variety of opportunistic infections, e.g. cytomegalovirus infections to be treated with ganciclovir, and Pneurnocystis curinii with trimethoprim/sulphamethoxazoleor pentamidine. An article in a future issue of this Journal will address the treatment of HIV disease. HERPES SIMPLEX VIRUS INFECTIONS
Herpes encephalitis and neonatal herpes are also serious viral infections. Acyclovir has proved to be a drug of choice for paediatric patients with these infections (9).
SYSTEMIC FUNGAL INFECTIONS
The rising incidence of fungal infections is of major concern (10).Amphotericin B is the most effective drug for systemic infections but frequently causes toxicity. Fluconazole may prove to be an alternative to amphotericin B for the treatment of certain systemic fungal infections. Fluconazole can be given orally due to its excellent bioavailability, and appears to be much safer than amphotericin B. BIOTECHNOLOGY-BASED DRUGS
Drugs in development include adjunctive monoclonal antibodies against endotoxins to improve survival in patients with Gram-negative bacteremia (II); colony stimulating factors (G-CSF and GM-CSF) to stimulate bone marrow progenitor cells and thus, reduce neutropenia and infection; and erythopoietin to stimulate red blood cell production and thus decrease anaemia associated with chronic renal failure. These drugs have not been evaluated suHiciently in paediatric patients to enable the development of optimal dosage guidelines. NEONATAL RESPIRATORY DISTRESS SYNDROME
Respiratory distress syndrome (RDS)is a major cause of morbidity and mortality, accounting for nearly half of all neonatal deaths. The use of exogenous surfactants (e.g. Exosurf, Survanta and Curosurf) has produced marked improvement in lung function and decreased some acute complications (pulmonary air leaks). Although exogenous surfactant improves survival, it may not influence complications, such as intracranial haemorrhage, patent ductus arteriosus, retinopathy of prematurity, and bronchopulmonary dysplasia. Thus, a larger number of premature infants are surviving but with an increased rate of complications. Although there are about 10 different exogenous surfactan t preparations (human amniotic fluid surfactant, organic solvent extracts, modified lipid extracts, and synthetic preparations), which have been studied in neonates, no comparative studies are available (12). An important question is: who would benefit most from surfactant therapy? For example: (i) should all newborns less than 28 weeks of gestational age be treated although up to one-third will never develop RDS?; and (ii) should all neonates older than 32 weeks be treated although they rarely die from RDS or its complications?
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It is important to find answers to these questions in order to target pharmacotherapy and minimize costs. At our hospital, surfactant preparations account for the largest share of the drug budget this year. CYSTIC FIBROSIS
Cystic fibrosis (CF) is the most common serious autosoma1 recessive disorder in the Caucasian population. CF affects a number of organs. Although supportive therapy, pancreatic enzyme supplements and antimicrobial therapy have improved patient outcome, most patients still do not survive beyond their thirtieth birthday. Recently, the major gene defect that causes CF has been identified. Nearly 70% of the gene mutations in CF are known to be caused by the loss of a single, specific trinucleotide codon, and the protein lacks only one amino acid, phyenylalanine, at position 508 (13). Gene therapy may offer the ultimate solution to CF. While it may be possible to introduce the normal gene into the living and intestinal cells, the widespread tissue defect that causes CF make this option difficult. It may be more feasible to develop drugs that act through the altered protein to restore normal chloride transport. Children with adenosine deaminase (ADA) deficiency are being treated with gene therapy by transfusing lymphocytes carrying the ADA-producing gene to produce ADA. Gene therapy may be developed for patients with many other diseases including AIDS and emphysema in the future (13). ASTHMA
Unlike the case with many other chronic diseases, the incidence of asthma and the associated number of hospitalizations and deaths are all rising. The use of inhaled albuterol, cromolyn, and corticosteroids has increased substantially but many patients as well as pharmacists may be inadequately informed about the proper use of inhalation devices (14). Optimal use of these drugs and monitoring of theophylline serum concentration will help in better control of asthma. Pharmacists can play an important role in patient education about optimal use of such drugs. The peak flow meter is a simple and relatively inexpensive home monitoring device to measure air flow obstruction. This can assist patients to identify factors that worsen asthma, and alert them to the need to adjust their therapy. The trend of increasing morbidity and mortality can be reversed in part by appropriate
pharmacotherapy. A future article in this Journal will discuss the topic. ANTI-EMETIC THERAPY IN CANCER PATIENTS
Nearly all patients receiving chemotherapy with cisplatin develop nausea and vomiting. Other drugs, such as cydophosphamide, also induce emesis. This may be so severe that patients refuse to continue chemotherapy. Metoclopramide and prochlorperazine have been used in paediatric patients; the former is more effective but also more toxic. A new anti-emetic, ondansetron (serotonin receptor antagonist), has been found to be at least as effective as, and less toxic than, metoclopramide in adult patients (15). Limited experience in paediatric patients suggests similar results. Thus, ondansetron can be used in cancer patients receiving emetogenic chemotherapy, with a past history of toxicity or inadequate response to metoclopramide. SEDATION FOR DIAGNOSTIC PROCEDURES
Paediatric pa tients undergoing diagnostic procedures such as endoscopy, biopsy, and computer tomography require sedation. There are, however, limited data about the use of effective and safe sedatives. Our comparative studies have shown that meperidine alone may be preferred over meperidine plus diazepam in patients undergoing endoscopy (16). We are comparing meperidine with meperidine plus midazolam, as midazolam may provide amnesia. We have discontinued the use of the common combination product containing meperidine, promethazine and chlorpromazine (DPT or MPC), as this can produce severe adverse effects in some infants and children. LACK QF APPROPRIATE DOSAGE FORMS
Many drugs used in paediatric patients are not available in suitable dosage forms. This often requires dilution of highly concentrated drugs intended for adults, e.g. atropine, diazepam, digoxin, morphine, phenobarbital, and phenytoin. The dilution of these products can reduce errors in measurement and prevent subtherapeutic response or toxicity. Similarly,drugs like acetazolamide, spironolactone and rifampicin are not available in suitable liquid dosage forms for accurate measurement of doses based on body weight and for safe administration
Advances in paediatric phamacotherapy
to young infants unable to swallow tablets or capsules. It is important to note that the stability of reformulated drugs must be confirmed to assure potency during preparation, storage and administration (17, 18). A book which provides 63 paediatric formulations has recently been published but specific references to document product stability are still not available for many products (18).Resources to conduct such studies are often limited. THERAPEUTIC DRUG MONITORING
Therapeutic drug monitoring (TDM) should be carried out to assure optimal use of drugs in our patients. This should include monitoring of drug administration, serum concentration measurement, if needed, and assessment of therapeutic outcome. There are numerous studies to show that the intravenous drug delivery system (e.g. flow rate, injection site, tubing diameter, and type of device) can directly influence the amount of drug received and the serum concentrations of drugs achieved in patients. For example, administration of drugs through an intravenous site closer to patients results in a higher aminoglycoside peak concentration and the peak occurs earlier than when the drug injection is made from a more distant site on an IV tubing. It is important to understand the impact of drug delivery systems on the pharmacokinetics, pharmacodynamics and therapeutic response to ensure that the desired outcomes are achieved (17). Serum concentrations of drugs including digoxin, theophylline, aminoglycosides, chloramphenicol, vancomycin, and anticonvulsants are routinely monitored. The concentrations, however, should be correlated with therapeutic response and consideration given to potential toxicity, patient and disease status and concomitant drugs so that appropriate dosage adjustments may be made when required. Collaborative efforts among pharmacists, physicians, nurses, intravenous therapists, and laboratory staff are needed to assure optimal outcomes. DRUG UTILIZATION REVIEW A N D FORMULARY An effective fomiulary can be important to promote the
appropriate use of drugs. Drug utilization reviews should be conducted in a concurrent, prospective and retrospective manner to describe patterns of usage, and develop strategies to improve drug use. These efforts
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should be focused on the most important therapeutic problems and/or high cost drugs. Education, selective formulary, drug order forms, including the rationale for therapy, direct consultation, and chart notes have been used with some success to optimize drug use in patients. Success is most likely with collaborative efforts among departments including pharmacy, medicine and nursing. GLOBAL PERSPECTIVE
Although childhood mortality continues to fall worldwide, nearly 14 million children under 5 years of age still die annually in the developing countries. The mortality among children under 5 years of age is still too high. In 1989, it ranged from 143 to 297 per 1,000live births in 38 countries, 72-139 per 1,000 in 31 countries, 21-66 per 1,000in 28 countries, and 6-20 per 1,000 in 32 countries. Diarrhoea and pneumonia each claims 4 million lives annually. It has been estimated that parents in the developing world spend over $1billion per year, primarily on ineffective remedies and medicines for diarrhoea1disease and respiratory infections (7). Diarrhoea, measles, tetanus, pertussis, pneumonia, malnutri tion and acquired immunodeficiencysyndrome are all preventable or treatable and yet cause the majority of deaths. It is encouraging that the WHO'S goal of immunizing 80% of all children in the developing world has been met. Increased vaccination has reduced the morbidity and mortality due to those diseases. Recent data suggest that the administration of vitamin A can reduce mortality in malnourished populations. New goals to be attained by the year 2000 have been developed (7). The agencies of the United Nations realize that although additional resources will be difficult to obtain, much can be gained by shifting priorities. The total cost of achieving the goals set for world-wide health has been reported to be the same as the amount currently spent on the military every 10 days. At the global level, military expenditure accounts for 5.4% of the Gross National Product (GNP) compared with 4.2% on health. Developing countries, where 85% of children under 5 years live, spend 5.6% of their GNP on the military and 1.4% on health. Other useful shifts in priorities include the training of more community health workers (training cost $500 each), rather than training only physicians, to reach more people; opening more community health clinics rather than only a few hospitals; and emphasizing primary and secondary education to everyone rather than higher education to only a few (7).
146 M. C. Nahata Vitamin A deficiency causes clinically significant ocular disease in some 5-10 million children annually in the developing countries, and many more have subclinical deficiency. Supplementation with vitamin A has produced more than a 50% decline in mortality in Southern India. The benefits were most striking in children below 3 years of age and among those chronically malnourished (19). The problems of childhood diseases are not confined to developing countries. The industrialized world has its share of problems. Despite rising prosperity in general, the number of children living below their nation’s poverty line has increased in most of the western countries (e.g. Canada, Germany, Ireland, U.K.and U.S.) over the last decade. Poor prenatal care and drug abuse during pregnancy are major health risks for the newborn. In conclusion, although substantial progress has been made, much needs to be done to improve drug therapy for infants and children. Disease prevention should receive greater emphasis. The advances in science and technology, coupled with a strong commitment by health professionals, governmental and nongovernmental agencies should ensure that the well-being of our children world-wide is improved.
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6. Eskola J, Kaythy H, Takala A#, et al. (1990)Randomized prospective field trial of a conjugate vaccine in the protection of infants and young children against invasive Haemophilus influenzae type b disease. New England ]ournaJ of Medicine, 323, 1381-1387. 7. United Nations Children’s Fund (UNICEF) (1991)The State of the Worlds Children. Oxford University Press, Oxford. 8. McKinney RE, Maha MA, Connor EM, et al. (1991)A multicenter trial of oral zidovudine in children with advanced human immunodeficiency virus disease. New England]ournal of Medicine, 324, 1018-1025. 9. Nahata MC. (1992) Viral infections. In: Applied Therapeutics:The Clinical Use of Drugs, 5th edn. eds Young LY, Koda-Kimble MA. pp. 1-11. Applied Therapeutics, Vancouver, WA (USA). 10. Benson JM, Nahata MC. (1988)Clinical use of systemic antifungal agents. Clinical Pharmacy, 7,424-438. 11. Ziegler EJ, Fisher CJ, Sprung CL, Straube RC, Sadoff JC, Foulke GE. (1991)Treatment of Gram-negative bacteremia and septic shock with HA-IA human monoclonal antibody against endotoxin. New England Journal of Medicine, 324,429-436. 12. Shapiro DL. (1988) Surfactant replacement therapy. Seminars in Perinatology, 12,173-260. 13. Nahata MC. (1990)Discovery of gene defect in cystic fibrosis: Implications for diagnosisand treatment. Clinical Pharmacy, 9,716-717. 14. Kelly HW. (1991) Asthma, aerosols, and patient education. DICP Annals of Pharmacotherapy, 25, 668-669. 15. Marty M, Pouillart P, Scholl S, et al. (1990)Comparison of the 5-hydroxytryptamine3 (serotonin) antagonist ondansetron (GR 38032F) with high-dose metoclopramide in the control of cisplatin-induced emesis. New England]oumal of Medicine 322,816-821. 16. Bahal N, Nahata MC, Murray RD, et al. (1992) Comparative evaluation of meperidine and diazepam for sedation in pediatric patients undergoing gastrointestinal endoscopy (Abstract).Pharmacotherapy, 11,43. 17. Nahata MC. (1992)Pediatrics. In: Pharmacotherapy, eds DiPiro et al. pp. 1-8. Elsevier, New York. 18. Nahata MC, Hipple TF. (1990)PediatricDrug Formulations. 1stedn.pp. 1-89.Harvey Whitney Books Co., Cincinnati, OH. 19. Rahmathullah L, Underwood BA, Thulasiraj RD, et al. (1990)Reduced mortality among children in Southern India receiving a small weekly dose of vitamin A. New England]oumal of Medicine, 323.929-935.
