Antimicrobial therapy in infants and children. Part II. Therapy of infectious conditions.

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Antimicrobial therapy. Part II. Therapy

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Part II. Therapy of infectious conditions

George H. McCracken, Jr., M.D., and Heinz F. Eichenwald, M.D., Dallas, Texas

SEPTICEMIA septicemia is most commonly caused by bacteria acquired from th e maternal genitourinary or gastrointestinal tracts. The etiologic agents recovered from 191 neonates with sepsis treated at Parkland Memorial Hospital in Dallas from 1973 to 1977 were the following: group B streptococcus, 39%; group D streptococcus, 20%; Escherichia . coli, 17%; KlebsiellaEnterobacter, 70%; Staphylococcus aureus, 5%; and miscellaneous organisms, 12%. Anaerobic bacteria accounted for only 3% of cases. After the neonatal period, sepsis may be caused by Streptococcus pneumoniae, Neisseria meningitldls, and Hemophilus influenzae; coliform bacteria are occasionally encountered in children with infection and abnormalities of the genitourinary tract. Septicemia in older children is rare and is usually associated with infections of the urinary or skeletal system. Staphylococcus aureus and group A beta hemolytic streptococci are cultured from blood of approximately 50% of children older than two years who have septic arthritis or osteomyelitis. Occasionally staphylococcal bloodstream infection is associated with disseminated disease involving many organs. Patients with malignancy or other chronic illnesses treated with immunosuppressive drugs are at increased risk of developing septicemia, as well as deep tissue infections caused by the usual bacterial agents or by uncommon pathogens such as coliform bacilli, Pseudomonas species , Candida albicans, and other fungi. Prolonged venous cannulation for the purpose of administering nutrients, fluids, or drugs may result in bloodstream infection with organisms such as Klebsiella or Serratia. Phlebitis may be chemically produced by infusion of improperly diluted antibiotics or may be caused by bacteria introduced on insertion of the needle or catheter. Sepsis neonatorum. A knowledge of the epidemiologic experience of a specific nursery or intensive care unit is important in the selection of therapy. For example, some IN

THE

NEW BORN

INFA NT,

units have far greater infection rates than others with Pseudomonas or Klebsiella-Eruerobacter species. Cultures of blood, urine, and cerebrospinal fluid should be obtained prior to initiation of therapy. Cultures and stained smears of material from superficial sites or from gastric aspirates are usually not helpful and may be misleading in determining the cause of disease . N eutropenia with an increased number of immature cells is frequently found in the early-onset form of sepsis.' Abbreviations used CIE: INH: PAS:

counterimmunoelectrophoresis

isoniazid para-aminosalicylic acid

Infants have a higher rate of bloodstream and tissue infections when housed in intensive care units for therapy of noninfectious conditions, particularly if assisted ventilation procedures andlor blood gas monitoring are required. These in-dwelling devices can act as fomites for relatively nonpathogenic organisms. Clinical diagnosis of septicemia is often delayed because of the patient's underlying condition; the use of "pro phylactic" antibiotics may inhibit growth of bacteria from blood and other body fluid cultures and thus obscure the clinical picture. Ampicillin combined with either kanamycin or gentamicin provide bactericidal act ivity against most potential pathogens. Ampicillin is given intravenously in a dosage of 50 rug/kg/day divided in two doses to all infants under seven days of age, and of 100 to 150 mg/kg/day divided in three equal doses to older neonates. Selection of the aminoglycosidic drug must be based on the susceptibilities of coliform bacteria commonly encountered in a specific nursery. If Escherichia coli and Klebsiella species are susceptible to kanamycin, this drug is used in a dosage . of 15 to 30 mg/kg/day given in two or three doses (for specific details on dosage, see page 339 of previous section). In nurseries where kanamycin-resistant coliform organisms or Pseudomonas species are common, gentami-

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The Journal of Pediatrics September 1978

McCracken and Eichenwald

Table II. Preferred antimicrobial therapy of selected pathogens Antimicrobial agent" Microorganism Acineiobacter (mirna, herellea) Actinomyces israelii Bacteroides sp. (non-fragilis) Bacteroides jragilis

Bordetella sp. Borrelia sp. Brucella sp. Chlamydia sp.

Clostridium perfrigens Clostridium tetani Corynebacterium diphtherlae Escherichia coli

Francisella tularensis HB organisms (Eikenella corrodens, Hemophilus aphrophilus, Actinobacillus octlnomycetemcomitans) Hemophilus infiuenzae

Klebsiella-Enterobacter Serratis sp. Leptospira sp. Listeria monocytogenes

I

Alternate

Clinical illness

Drug of choice

Sepsis, meningitis Actinomycosis Lung abscess Abscesses, peritionitis, septicemia Pertussis Relapsing fever Burcellosis Inclusion blenorrhea, pertussoid pneumonia, psittacosis Gas gangrene Tetanus Diphtheria Urinary tract infection, septicemia, pneumonia Meningitis Tularemia Abscesses

Gentamicin or kanamycin Penicillin Penicillin Chloram phenicol

Arnikacin.j chloramphenicol Tetracycline Tetracycline Clindamycin or carbenicillin

Erythromycin Tetracycline Tetracycline Erythromyein

Ampicillin Chloramphenicol Penicillin Tetracycline (topical conjunctivitis)

Penicillin Penicillin Penicillin Sulfisoxazole Gentamicin or .kanamycin

Tetracycline Tetracycline Erythromycin Ampicillin Arnikacin]

Streptomycin Tetracycline

Tetracycline Ampicillin

Ampicillin or amoxicillin

Sulfisoxazole

Ampicillin Sulfisoxazole Gentamicin or kanamycin

Chloramphenicol Nitrofurantoin or cephalexin Amikacin]

Penicillin Ampicillin

Tetracycline Tetracycline

Otitis media, pneumonia, sepsis Arthritis, Meningitis Urinary tract infection Septicemia, meningitis, pneumonia Leptospirosis Septicemia, meningitis

'Dosages are presented in text and in our previous article (J PSDTATR 75:923, 1969). tSee text. trrimethoprim-sulfamethoxazo!e .investigarional use only.

cin is recommended in a dosage of 5 rug/kg/day in two doses for infants under one week of age and 7.5 mgt kg/day in three doses for older neonates. The aminoglycosides may be administered intramuscularly or as a constant intravenous infusion given over a 20-minute period.' Because absorption of aminoglycosides may be erratic in some neonates, whenever possible serum concentrations should be monitored to assure adequate antimicrobial activity without toxicity. Experience with two new aminoglycosides (tobramycin and amikacin) is too limited to warrant their routine use. Amikacin is not inactivated by many of the R-factor-related enzymes that destroy the other members of this class of drugs. Thus, an organism resistant to kanamycin and gentamicin may be susceptible toamikacin, but this should be demonstrated in vitro prior to use. The provisional dosage of amikacin is 7.5 rug/kg every 12 hours to

all neonates with the possible exception of infants > 7 days of age and > 2,000 gm at birth. It is possible that these older and larger infants should receive the same dose every 8 hours for a total of22.5 mg/kg/day. Further studies are necessary before definitive recommendations are possible. Once the pathogen is identified and susceptibilities are known, the most appropriate drug or drugs are used. For groups Band nonenterococcal D streptococci, penicilJin G in a dosage of 50,000 to lOO,DOO units/kg/day in two or three doses is preferred therapy. Ampicillin represents optimal therapy for infections caused by Listeria monocytogenes, Proteus mirabilis, and enterococci. Coliform bacilli should be treated with either kanamycin or gentamicin depending on the results of susceptibility studies. Pseudomonas aeruginosa and indole-positive Proteus species are best treated with ticarcillin or carbeni-

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Antimlcrobal therapy. Part II. Therapy

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Table II. Cont'd Antimicrobial agent" M icroorganism Mycoplasma pneumon iae Mycoba cterium tuberculosis Neisseria meningitiodis Neisseria gonorrhoeae Nocardia Proteus mirabllis Proteus sp_(Indole positive) Pseudomonas aeruginosa Rickeusia Salmonella sp, Serratia Shigella sp. Staphylococcus aureus

Staphylococcus epidermidis

Group A streptococci Group B streptococci Group D Streptococci (enterococci)

Clinical illness

Pneumonia See Table IX Septicemia, meningitis Genital, arthritis. bacteremia Nocardiosis Urinary tract infection, septicemia, meningitis Urinary tract infection, septicemia, meningitis Urinary tract infection, septicemia, meningitis Rocky Mountain spotted fever, etc. Focal infection, septicemia, typhoid fever Septicemia, meningitis Gastroenteritis Abscesses, skin infections Pneumonia, arthritis, osteomyelitis, septicemia Bacteremia, ventriculitis Pharyngitis, impetigo Septicemia, meningitis Septicemia, meningitis

Streptococcus pneumoniae

Otitis media

Streptococcus viridans group Treponema pal/idum Vibrio cholera Yersinia pestis

Pneumonia Meningitis Endocardit is Syphilis Cholera Plague

cillin an d gentamicin. The dosage schedule for carbenicillin is as follows: 100 rng/kg every 12 hours during the first week of life, then every 8 hours for infants 2,000 gm. Ticarcillin is administered in about one-half this dosage. Guidelines for determining duration of therapy in the neonatal period are often Jacking because objective evidence of illness may be minimal. Blood culture-should be repeated 24 to 48 hours after initiation of therapy to assure bacteriologic cure . In the absence of deep tissue involvement or abscess formation , therapy is usually continued for five to seven days after clinical improvement. When multiple organs are involved or when the clinical response is slow, therapy may need to be continued for two to three weeks or even longer. Septicemia beyond the newborn period. Clues to the

Drug of choice

I

Alternate

Erythromycin See Table IX Penicillin Penicillin A sulfonamide Ampicillin

Tetracycline See Table IX Ampicillin or chloramphenicol Ampicillin or tetracycline TMP/S?v\X:j: Gentam icin

Carben icillin

Gentamicin

Carbenicillin

Gentamicin

Tetracycline

Chloramphenicol

Chloramphenicol

Ampicillin

Gentamicin or kanamycin Ampicillin Cloxaci!lin Nafcillin

TMP/SMXt Cephalcx in A cephalosporin

Penicillin Penicillin Penicillin Ampicillin Penicillin Penicillin Penicillin Penicillin and streptomycin Pen icillin

Tetracycline Streptomycin

Amikacin]

N afcl1lin or a cephalosporin

Erythromycin Ampicillin Penicillin or streptomycin Erythromycin A cephalosporin Chloramphenicol Penicillin Tetracycline TMP /SMXt Tetracycline

bacteriologic diagnosis of septicemia can often be obtained from clinical history and physical examination. MUltiple petechial lesions of the skin and mucous membranes suggest meningococcal infection , although pneumococci, Hemophilus. streptococci, staphylococci, rickettsiae, and viruses may produce a similar rash . Patients with an antecedent splenectomy are prone to overwhelming pneumococcal infections. Diseases or therapy which suppress immunologic responsiveness predispose to bacterial, fungal, viral, or protozoan disease, or to mixed infections. Leukemic patients with neutropenia from bone marrow replacement by tumor or depression secondary to therapy tend to develop pyogenic (staphylococcal or streptococcal) or Pseudomonas infections, whereas patients in remission frequently have disease due to opportunistic organisms such as Pneumocystis carinii and cytomegalovirus. Streptococci and staphylococci are

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Table m. Etiology and therapy of central nervous system infections Clini cal condition

Neonatal meningitis Unknown etiology

Escherichia coli Group B streptococcus Listeria monocytogenes and enterococci Pseudomonas aeruginosa

Initial therapy'

Ampicillin 100 to 200 mg/kg/ day iv 2 or J doses and gentamicin 5 to 7.5 rug/kg/ . day im in 2 or 3 doses Ampicillin and gentamicin, as above Penicillin G 150,000-250,000 units/kg iv in 2 to 4 doses Ampicillin as above

Carbenicillin 400 mg/kg/day iv in 4 doses with or without gentamicin Meningitis beyond 2 mo of nge Ampicill in 200 to 300 mg/kg/ Unknown etiology day iv in 4 doses and chloramphenicol 100 mg/kgl day iv in 4 doses H. influenzae Ampicillin (beta lactamase negative) Dr chloramphenicol (beta lactamase positive) as above Pneumococcus Penicillin G 250,000 units/kg/ day iv in 4 10 6 doses Meningococcus Penicillin G as above Brain abscess Pen icillin G 250,000-500,000 un its/kg/day in 4 to 6 doses and chloramphenicol 100 mgt kg/day in 4 doses until culture results available ·See text for specific dosage recornrnendauons in neonates.

. often found in the bloodstream of children with extensive lesions of the skin, as occur with burns and epidermolysis bullosa. Pseudomonas may produce disease in this latter group following therapeutic or prophylactic admin istration of antimicrobial agents. Considerable attention has been focused recently on the occurrence of pneumococcemia in infants less than two years of age. 3,. These patients usually have fevers greater than 103°F and white blood cell counts exceeding 20~OOO/mn3 . A focus of infe ction (otitis media or pneumonia) is recognized in 75% of these children. Although rrianagement must be individualized, close follow-up is necessary to assure that infection is eradicated before spread occurs to other tissues, particularly .the meninges. When no firm bacteriologic diagnosis is established in older infants and children, but bacterial septicemia seems likely, ampicillin is administered in a dosage of 150 to 200 rag/kg/day in four doses along with either kanamycin or


gentamicin. If coliform organ isms commonly encountered in a specific geographic area are suscept ible to kanamycin, this agent is preferred in a dosage of 30 rng/kg/ day in three divided doses. If kanamycin-resistant coliform bacteria or Pseudomonas species are suspected, gentamicin is administered in a dosage of 6107.5 rug/kg/day in three divided doses. Monitoring of seru m kanamycin or gentamicin concentrations in advisable in patients with proved gram-negative septicemia, particularly if renal function is compromised. If the pathogen is subsequently identified as a pneumococcus, streptococcus, meningococcus, or penicillinsusceptible staphylococcus, penicillin G 100,000 to 150,000 units/kg/day is given intravenously in four divided doses. Suspected or proved penicillin-resistant staphylococcal infection is best trea ted with methicillin (200 rug/kg/day in four doses) or nafcillin (150 mg/kgl day in four doses) by intra venous infusion. We prefer nafcillin over methicillin because of less risk of nephrotoxicity. For Pseudomonas infections carbenicillin 400 to 600 rug/kg/day in four doses (or ticarcillin in one-half this dosage) is given alone or in combination with gentamiem. When septicemia is suspected in patients with altered immunologic responsiveness , a comb ination of carbenicillin (or ticarcillin) and gentam icin should be administered until the offending pathogen is identified and results of susceptibility studies are available. If blood cultures are negative for bacterial pathogens, special cultures should be obtained for identification of anaerobes as well as fungal, protozoan, or viral agents. Broad-spectrum antibiotic treatment should not be continued in the absence of proved bacterial disease because overgrowth of resistant bacteria in the gastrointestinal and respiratory tracts is likely. CENTERAL NERVOUS SYSTEM INFECTIONS (TABLE III) Meningitis. Because bacteria most commonly invade the meninges from the bloodstream, the etiologic agents in meningitis are often the same organisms responsible for septicemia in the vari ous age groups. During the four-year period from 1973 to 1976, group B streptococci accounted for 52% of 70 cases of neonatal meningitis, E. coli 14%, other gram-negative bacilli 13%, Listeria monocytogenes 6%, and miscellaneous bacteria 14%. Beyond the neonatal period, Hemophilus influenzae type B is the principal etiologic agent in the United States , causing 60 to 70% of cases, followed in incidence by meningococci and pneumococci. The diagnosis of bacterial meningitis is made by examination and cultures of cerebrospinal fluid. A gramand methylene blue-stained smear of spinal fluid is

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carefully examined for the presence of extracellular and intracellular bacteria. If findings are equivocalin a patient with mild clinical illness, therapy can be withheld for several hours and the lumbar puncture repeated. If the patient has bacterial meningitis, this second examination will usually show changes characteristic of this disease. Therapy should not be withheld in a patient more than mildly ill; rather, antibiotics are started after appropriate cultures have been obtained. Duration of therapy is based on results of blood and cerebrospinal fluid cultures and on the clinical condition of the patient. During recent years a number of screening tests have been suggested to help differentiate viral from bacterial disease. Measurement of cerebrospinal fluid lactic acid dehydrogenase and lactic acid concentrations may be useful but are not readily available. Detection of bacterial antigen in spinal fluid, serum, or urine by counterimmunoelectrophoresis rapidly identifies many patients with bacterial meningitis." A positive CIE reaction provides a specific etiologic diagnosis; a negative test does not rule out bacterial disease. Measurement of antigen should be considered an adjunct to the usual studies for diagnosing bacterial meningitis. In the ne~bom infant, initial therapy for suspected or proved purulent meningitis consists of ampicillin and gentamicin. Ampicillin is administered intravenously in a dosage of 100 rug/kg/day in two divided doses in infants under seven days of age and in a dosage of 200 rug/kg/ day in three doses beyond the first week of life. The dosage of gentamicin is the same as for septicemia. All infants should have a repeat spinal fluid examination and culture at 24 to 36 hours after initiation of therapy. As a rule, group B streptococci and L. monocytogenes are killed in 12 to 24 hours, but coliform bacilli are not eradicated for an average of three to four days after start of therapy. If organisms are observed on stained smears of spinal fluid on repeat examinations, direct instillation of drug into CSF should be considered. The purpose of this mode of therapy is to achieve levels of antibiotic in spinal fluid that exceed the minimal inhibitory concentration of the pathogen by at least five- to tenfold. A controlled trial of lumbar intrathecal therapy with I mg gentamicin injected daily for at least three days combined with systemic antibiotics demonstrated no beneficial effect on mortality and morbidity compared to systemically administered drugs only." It was observed, however, that ventriculitis was usually present in those infants who had persistent bacteriachia despite lumbar intrathecal therapy, indicating that locally instilled antibiotics into the lumbar CSF do not diffuse adequately into the ventricles. The Neonatal Meningitis Cooperative Study group is presently assessing the benefits and hazards of intraventricular

Antimicrobal therapy. Part II. Therapy

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therapy. Preliminary results indicate that direct administration of gentamicin into the ventricles results in high concentrations of dru g that rapidly and uniformly distribute throughout the CSF space. Ventriculitis was already present in 75%of infants at the time when the diagnosis of meningitis was first made. It is not yet known if intraventricular therapy will improve the prognosis of neonatal meningitis caused by coliform bacilli. In the absence of specific information, we are presently recommending a ventricular tap by a neurosurgeon in all infants who have organisms on stained smears of CSF 24 to 36 hours after initiation of therapy. If ventriculitis is found (5 50 WBC/ mm- and/or positive smear), intraventricular therapy should be started using 2 to 3 mg gentamicin daily. The specific method of administration (daily ventricular taps versus use of a reservoir) should be determined by the neurosurgeon. The duration of intraventricular therapy is dependent on the clinical course, on the etiologic agent, and on the time necessary to sterilize ventricular fluid cultures. Chloramphenicol therapy is not recommended for neonatal meningitis. The drug is bacteriostatic only for gram-negative bacilli and resistance develops during therapy in as many as a third ofpatients. Further, dosage must be individualized. The infant's maturity and clinical condition, as well as coadministration of phenobarbital and perhaps other drugs, may profoundly affect concentrations of chlorphenicol in body fluids. Thus, antibiotic can be administered safely only when serum concentrations can be monitored to assure peak values in the therapeutic and safe range of 15 to 25 pg/ml. After the organism has been identified and appropriate antibiotic susceptibilities determined, systemic therapy may need to be changed. Penicillin G 150,000 to 250,000 units/kg/day in two to four doses is preferred for group B and nonenterococcal group D streptococcal disease; ampicillin alone is continued for meningitis caused by L. monocytogenes or by enterococcal group D streptococci. Meningitis caused by coliform organisms is treated with a combination of ampicillin and either kanamycin or gentamicin, depending on the results of susceptibility tests. Pseudomonas aeruginosa is best treated with carbenicillin (or ticarcillin) and gentamicin. The dosages of carbenicillin or ticarcillin are the same as those recommended for septicemia. Duration of systemic therapy is based on the clinical condition of the infant and the duration of positive cerebrospinal fluid cultures. In general, meningitis caused by gram-positive organisms is treated for two weeks after bacteria can no longer be grown from spinal fluid, and gram-negative meningitis is treated for a minimum of three weeks or for at least two weeks after sterilization of spinal fluid.

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Bacterial meningitis of unknown etiology occurring beyond the newborn period is treated initially with a combination of ampicillin and chloramphenicol. Whereas ampicillin was formerly used alone, the emergence of beta lactamase-producing H. infiuenzae (currently 5 to 10% of strains) has made it necessary to add chloramphenicol to the starting regimen.' Although a single patient with chloramphenicol-resistant H. influenzae meningitis has been reported recently," this strain was susceptible to ampicillin. Ampicillin is administered in an initial dose of 100 mg/ kg by rapid intravenous infusion, followed by 50 mg/kg intravenously in a 15- to 20-minute infusion every six hours. This dosage regimen produces peak cerebrospinal fluid ampicillin concentrations of 5 to 20 jLg/ml. These values are at least ten- to laO-fold greater than the MIC values for susceptible H. infiuenzae strains and at least lOO-fold greater than the MIC values for meningococci and pneumococci. Although spinal fluid ampicillin levels are lower on the tenth day of therapy, when meningeal inflammation is reduced, peak concentrations still are at least tenfold greater than the MIC values, and spinal fluid bactericidal activity is readily demonstrated against these pathogens. There is no evidence that larger dosages of ampicillin are more efficacious than the recommended 200 mg/kg/day, Chloramphenicol is given intravenously in a dosage of 100 rug/kg/day in four divided doses. Although reversible suppression of one or more bone marrow elements may be observed in a few infants, idiosyncratic, irreversible aplasia is rare (incidence, one case per 30,000 to 50,000 treated patients). If the pathogen is identified as Hemophilus infiuenzae type b, the strain should be tested for beta lactamase production. Continuation of either ampicillin or chloramphenicol is dependent on the results of this test. As a rule, ampicillin is used for beta lactamase-negative strains, but chloramphenicol must be used for positive organisms. A recent study has shown comparable efficacy of these two drugs in the treatment of meningitis caused by susceptible H. infiuenzae strains." If the etiologic agent is a meningococcus or pneumococcus, penicillin G (250,000 units/kg/day in four or six doses) is the preferred drug. Recently, penicillin-insensitive (MIC 0.1 to 0.5 I-tg/ml) pneumococcal strains have been recovered from pediatric patients with meningitis in the United States." These insensitive strains usually do not respond satisfactorily to penicillin even when administered in dosages several-fold greater than those generally recommended. Chloramphenicol is effective in such patients. The multiply resistant organisms principally

The Journal oj Pediatrics September 1978

identified in South Africa are not susceptible to penicillin, chloramphenicol, the cephalosporins, and lincomycin antibiotics." Vancomycin, bacitracin, and rifampin are effective in vitro against these strains. Similarly resistant pneumococci have not yet been isolated from patients in North America. Parenteral therapy is continued for seven to ten days in complicated cases. No specific spinal fluid finding is useful in determining the optimal duration of therapy. The patient should be observed for several days after treatment is stopped. In infants and children with immunologic deficits, or when prior neurosurgical invasion results in central nervous system infection, the bacterial agents causing meningitis are often different from those encountered in normal patients. Pseudomonas, Listeria, staphylococci, enteric bacteria, anaerobes, and occasionally fungi are found and therapy must be adjusted accordingly. Brain abscess. Brain abscesses in children are frequently associated with antecedent otitic and paranasal sinus infections, congenital heart disease, trauma, or previous surgery. When brain abscess is suspected, an immediate electroencephalogram and brain scan should be performed. If these procedures suggest or indicate intracranial tumor, a carotid arteriogram is obtained. Antimicrobial therapy with prompt excision or. drainage of the intracranial abscess are essential aspects of treatment. The importance of surgical intervention is emphasized by the observation that the mortality rate of brain abscess in patients treated with antimicrobial agents without surgery has not changed significantly from that noted in the preantibiotic era. The bacterial pathogens most commonly associated with brain abscesses are aerobic and anaerobic streptococci, staphylococci, and Bacteroides species. Less commonly encountered bacteria are the HB organisms, coliforms, pneumococci, and mixed infections. As initial therapy, before bacteriologic confirmation, penicillin G 250,000 to 500,000 units/kg/day given intravenously in four or six doses and chloramphenicol 100rug/kg/day given intravenously in four doses should be administered. Once the abscess has been drained or surgically removed and the pathogen identified, the appropriate drug or drugs should be given for a period of approximately seven to ten days after surgery. Chloramphenicol is the preferred drug for brain abscess caused by Bacteroidesfragilis. Carbenicillin, ticarcillin, or metronidazole should be tried in those patients not responding to chloramphenicol therapy. Clindamycin does not attain sufficiently high brain and cerebrospinal fluid levels to be useful in central nervous system infections caused by B. fragilis.

Volume 93 Number 3

INFECTIONS OF THE RESPIRATORY TRACT The great majority of respiratory tract infections are viral in origin and are not affected by antimicrobial therapy. Bacterial infection is commonly preceded or accompanied by a viral illness; clear etiologic differentia tion may thus be difficult. When antimicrobial therapy is indicated , only a few drugs are useful. The penicillins are used most commonly in pediatric respiratory tract infections. In patients with penicillin hypersensitivity, erythromycin is a suitable oral preparation for upper tract infections, and the cephalosporins are acceptable alternatives for parenteral administration. An occasional pediatric patient will have cross-hypersensitivity to penicillins and cephalosporins. Otitis media and sinusitis. Pneumococci and H. influenzae are the most common etiologic agents of otitis media in pediatric patients. Whereas formerly it was thought that H. influenzae did not play an important role in this condition beyond early childhood, it is now recognized that these strains account for 10 to 20% of cases in the 5- to lO-year-old age group." The only certain way of establishing a bacteriologic diagnosis is by needle aspiration of middle ear pus. This procedure is both diagnostic and therapeutic in the patient with a bulging tympanic membrane. Penicillin is the drug of choice for pneumococcal and streptococcal infections; ampicillin, amoxicillin, or combinations of penicillin and a sulfonamide or erythromycin and a sulfonamide are preferred for Hemophilus in~ections. The daily dosage schedules are the following: Penicillin V, 50,000 units/kg; ampicillin, 100 mg/kg; amoxicillin, 50 mg/kg: erythromycin, 30 mg/kg; and sulfasornizole or trisulfapyrimidines, 120 to 150 mgt kg. These drugs are optimally absorbed on an empty stomach and may be given in three or four divided doses. Therapy should be continued for ten days or until signs of infection have completely disappeared . Beta lactamase production is found in 5 to 10% of Hemophilus strains. Because otitis media caused by these organisms does not respond satisfactorily to ampicillin or amoxicillin therapy, a sulfonamide combined with penicillin or erythromycin should be used: A less suitable alternative would be trimethoprim and sulfamethoxazole, which has been approved for use in such cases. In recurrent otitis media, Staphylococcus aureus and Hemophilus influenzae are more commonly encountered than are Diplococcus pneumoniae and group A streptococcus. A needle aspiration of the middle ear is helpful in identifying the pathogen and in selecting appropriate antimicrobial therapy. If the etiology is unknown, ampicillin or amoxicillin is preferred for recurrent otitis media

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in infants and young children; in older children, an oral antistaphylococcal penicillin such as cloxacillin (50 mg/ kg/day) or dicloxacillin (25 to 50 mg/kg/day) is used. Chronic otitis media represents a difficult medical problem. These patients should be managed by otolaryngologists to assure proper drainage and to prevent extension of infection to adjacent tissues. Pseudomonas or Proteus species are frequently cultured from the ear drainage of patients with chronic otitis media. Therapy directed specificallyat these agents is relatively ineffective without proper drainage and should be used principally for acute exacerbations of infection rather than in an attempt to eradicate the organism. Acute sinusitis in children is usually caused by the pneumococcus and is treated with penicillin V 50,000 to 75,000 units/kg/day for five to seven days. Acute ethmoiditis in some infants and young children may be due to Hemophilus infi uenzae type b; amp icillin and/or chloramphenicol is used until cultures of blood and nasal discharge are available. The young infant with acute ethmoiditis should have a spinal fluid examination and culture. Patients with acute mastoiditis should be hospitalized and cultures of blood, cerebrospinal fluid, and middle ear pus, if present, obtained prior to therapy . Although pneumococcus is the common causative agent, H. influenzae or staphylococci may occasionally be encountered. Nafcillin (150 rug/kg/day in four doses) and chloramphenicol are usually started in infants, whereas penicillin G (100,000 units/kg/day in four or six doses) is used in children; larger doses of penicillin (250,000 units/kg/day) are indicated for associated meningitis. In acute suppurative mastoiditis surgery should be performed promptly. Chronic otitis media with mastoiditis usually does not require antimicrobial therapy unless acute superinfection occurs or when surgery is anticipated. For Pseudom onas infection, carbenicillin 400 to 600 mg/kg/day in four doses (or ticarcillin in half that amount) is administered for approximately three days after mastoidectomy and tympanoplasty, and for five days after surgery. Orbital cellulitis. Inflammation and swelling of tissues around the eye may be associated with bacterial conjunctivitis, orbital, or periorbital cellulitis or ethmoid or maxillary sinusitis. Clinical features, roentgenograms of the sinuses, and computerized axial tomography of the orbit help to differentiate these conditions . The etiology is dependent on the age and the tissues involved; S. pneumoniae and S. aureus are the common pathogens, but H . influenzae type b may be causative in some infants ... Cultures of blood and of material obtained from aspiration of the infected site are important in guiding therapy.

364



Table IV. Etiology and initial therapy of lower respiratory tract diseases Clinica l condition

Principal etiologic agents

Lobar pneumonia

S. pneumoniae

Bronchopneumonia Empyema , infancy

Mainly viral (consider mycoplasma) S. aureus, H . influenzae

Empyema, childhood

S. pneumoniae, S. aureus

Lung abscess Putrid

Anaerobic streptococci, Bacteroides

Nonputrid Interstitial

S. pneumoniae, S. aureus Ma inly viral, consider chlam ydia in young infants

NafcUlin (150 rug/kg/day) and chloramphenicol (100 mg/kg/day) are used initially in infants and young children; nafcillin alone is recommended for older children . It may be necessary to drain the infected sinuses. Pharyngitis and epiglottitis. The majority of cases of pharyngitis are caused by viruses. When group A streptococcal pharyngitis is suspected or proved by cultu re, penicillin is the drug of choice. Of the two oral formulations, penicillin V is absorbed nearly twice as well as penicillin G, but both are adversely affected by concurrent administration of food. A dosage of 50,000 units/kg/ day in four doses is recommended. When penicillin is contraindicated, erythromycin is the preferred alternative. Lincomycin, clindamycin, and cephalosporins are also effective, but should not be used routinely for treatment of streptococcal pharyngitis. Sulfonamides do not represent acceptable therapy. Membranous pharyngitis may be seen with diphtheria, infectious mononucleosis, and occasionally in streptococcal and viral illnesses. In d iphtheria, either penicillin or erythromycin will eradicate the bacteria, but these drugs have no effect on toxic manifestations. Acute infectious croup (laryngotracheobronchitis) is caused almost exclusively by viral agents, and antimicrobial therapy is neither necessary nor desirable. Another form of croup, epiglottitis, is caused by H. infiuenzae type b. These patients are usually older than those with laryngotracheobronchitis and are considerably more febrile and toxic. Parenteral ampicillin and/or chloramphenicol , each in a dosage of 100 rug/kg/day in four doses, is administered parenterally, and airway management is usually required in addition. Therapy should be changed to one or the other of these drugs after the

Initial therapy

Penicillin 25.000- 50,000 units /kg/day iv or im or 50,000 units/ kg /day. orally in 4 doses See text Based on Gram stain of pleural fluid: Gram-positive baclerianafcillin 150 mg/kg/day iv in 4 doses Gram-negative bacteria-chloramphenicol 100 mg/kg/day iv in 4 doses No organisms visualized-nafcillin and chloramphenicol as above Penicillin 50,000-100,000 units/kg/day iv in 4 or 6 doses or nafcillin as above Penicillin 50,000-100,000 iv in 4 or 6 doses and chloramphenicol 100 rug/kg/day iv in 4 doses Penicillin or nafcillin as above See text

pathogen has been tested for beta lactamase production. Therapy is continued for seven to ten days; after the acute state, antibiotics may be administered orally. LOWER RESPIRATORY TRACT (TABLE IV) When bacterial infection of the lower respiratory tract issuspected, every effortshould be made to determine the etiologic agent prior to initiating antimicrobial therapy. Bacterial cultures from the throat and nasopharynx are worthless as diagnostic tools, and are more likely to confuse a clinical situation than to clarify it. Blood cultures should be obtained ; sputum or tracheal aspirates and pleural fluid, if present, should be cultured and examined by Gram and methylene blue stains. By combining knowledge of the patient's age, history, physical and roentgenographic findings with results of these studies, antimicrobial therapy may be properly selected. Bronchopneumonia. In older infants and children bronchopneumonia is most commonly caused by viral agents and to a lesserextent by Mycoplasma pneumoniae. In viral pneumonia, therapy is limited to supportive measures. Erythromycin (40 rug/kg/day in four doses) may be used for Mycoplasma infections of childhood although there are no data to prove efficacy in this age group. Although viruses cause most bronchopneumonias in early infancy, S. aureus and H. lnfluenzae may occasionally also produce this syndrome. Very early in the course of staphylococcal pneumonia roentgenograms may resemble those in other bronchopneumonias ; serial chest films taken over 12 to 24 hours will usually demonstrate rapid progression to the pleural surface with the development of empyema. Initial therapy is based on clinical

Volume 93 Number 3

judgment; usually an antistaphylococcal agent (nafcillin or methicillin) is given. Once culture and susceptibility results are available, appropriate changes in therapy are made. Lobar pneumonia. In consolidating lobar pneumonia, the most common bacterial pathogen is Streptococcus pneumoniae (pneumococcus). Penicillin is the drug of choice for this organism. Initial therapy should be administered parenterally in a dosage of 25,000 to 50,000 units/ kg/day; oral penicillin V (50,000 units/kg/day) may be used after this initial period, particularly in older children. Treatment is continued for seven to ten days in uncomplicated cases. If staphylococcal pneumonia is suspected, parenteral nafcilIin in a dosage of ISO rng/kg/ day is given. Methicillin (50 to 100 rug/kg/day) is preferred during the neonatal period. If the staphylococcus is found to be susceptible to penicillin G, this drug is used in a dosage of 100,000 units/kg/day (50,000 to 75,000 units/ kg/day in two or three doses during the first month of life). In patients allergic to penicillin, cephalothin is used in a dosage of 80 to 120 mg/kg/day in four to six doses. CefazoLin, a cephalosporin antibiotic, may be more acceptable because of a lower incidence of phlebitis and muscle irritation on injection. The dosage is 50 to 75 mg/kg/day in three divided doses. This drug is not recommended for use in infants because of inadequate pharmacologic and efficacy data. Hemophilus infiuenzae type b is a frequent pathogen of infants and may cause lower respiratory tract disease, including empyema, which develops in 50 to 75% of patients with pneumonia due to this organism. Because the disease may mimic pneumococcal or staphylococcal pneumonia, an early clue to the correct diagnosis may be failure of response to penicillin or one of the antistaphylococcal penicillins. In such patients, a diagnostic transthoracic lung aspiration is advisable to establish a bacteriologic diagnosis and to aid in selection of antibiotic therapy. Blood cultures are positive in 80% and concomitant meningitis is present in 20%. When H. infiuenzae infection is suspected but not proven, chloramphenicol (100 rug/kg/day) is usually combined with nafcillin (150 mg/kg/day) as initial therapy. If the H. inftuenzae is shown not to produce beta lactarnase, ampicillin (100 to 150rag/kg/day) should be used in place of the other two drugs. Chloramphenicol is the preferred agent for beta lactamase-positive organisms and for treatment of penicillin allergic patients with Hemophilus disease. Penicillin is the most effective drug for streptococcal pneumonia. For Friedlander pneumonia (Klebsiella pneumoniae) kanamycin (30 rug/kg/day in three doses) or gentamiciri (6 to 7.5 rug/kg/day in three doses) is administered for 10 to 14 days.


365

If pleural fluid is present, even in small amounts, a thoracentesis should be performed to obtain fluid for diagnostic studies. Examination of methylene blue- and gram-stained smears is essential in selecting antimicrobial therapy. In young infants the presence of gram-positive organisms in the fluid suggests pneumococcal or staphylococcal infection, whereas gram-negative organisms are most likely H. infiuenzae. Diplococcus pneumoniae is the most common cause of serous pleural effusions in children, although mycoplasma and adenoviruses (rarely) may also be involved. If purulent material is obtained on thoracentesis, closed chest tube drainage must be used. Pertussis. Although the overall incidence of pertussis has fallen sharply during the past decade, the rate of disease caused by Bordetella pertussis has doubled in newborn and young infants." Infection is usually acquired from one or both parents whose illnesses have not been correctly diagnosed. Pertussis should be suspected when an infant has paroxysmal cough (usually without a whoop) and excessive mucus. Fluorescent antibody testing for Borde/ella in mucus is faster and more sensitive than culture methods. Antimicrobial therapy is erythromycin (30 to 40 mg/ kg/day in four doses) given orally, or ampicillin (loo rug/kg/day in four ~oses) given paren terally to infan ts who are unable to retain oral medications. In most patients organisms are eradicated in less than five days. Treatment should be stopped and isolation discontinued when two successive daily fluorescent antibody examinations have been negative. Hyperimmune serum is not beneficial. Respiratory infection caused by Chlamydia trachomatis in infants may be difficult to distinguish clinically from pertussis.": Manifestations of chlamydial disease are tachypnea and a staccato cough unassociated with excessive mucus or whoop. Chest films usually show an interstitial pneumonia. Many affected infants have a history of conjunctivitis during the first days of life, and eosinophilia is found frequently. Diagnosis is established by inoculating McCoy cell cultures with mucus obtained from the nasopharynx or trachea, and/or by demonstrating a rise in antibody to Chlyamydia trachomatis. Erythromycin is effective In eradicating the organism but its clinical efficacy has yet to be established. Lung abscesses. When lung abscess occurs during infancy and childhood, a specific bacteriologic diagnosis should be made whenever possible. Cultures of blood and sputum and, whenever possible, of bronchial washings from the affected side are obtained prior to therapy. Putrid sputum usually indicates anaerobic streptococci or Bacteroides. Gram stains and aerobic and anaerobic cultures of purulent material are essential to therapy. If stained smears of sputum or washings reveal no micrcor-

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366



Table V. Treatment of urinary tract infections Clinical condition

Initial therapy

Etiology

Acute infection

E . coli, Klebsie lla-Enterobacter, Pro/ells mirabilis

Chronic, recu rrent or hosp ital acquired infection (acu te therapy)

Klebsiel la-Enterobacter. Pseudomonas, Prote us vulgar is, mixed infection

Above associated with septicemia Chronic or recurrent infection (suppressive therapy)

Same as above Same as above

*TMI'/SMX

~

Sulfisoxazole or triple sulfonamides 120-150 rug/kg/day po in 4 doses or ampicill in 30 rug/kg/day in 3 doses Gentam icin 3 rag/kg/day im in 3 doses or carbenicillin indanyl 10-30 rug/kg/day po in 4 doses or 6 mg TMP/30 mg SMX/kg / day" po in 2 doses or carbenicillin 100 to 250 mg/kg /day im, iv in 4 doses Gentamicin 6 mg/kg /day im in 3 doses Nitrofurantoin 1-2 rug/kg/day po daily or 2 mg TMPIIO mg SMX/kg/day po daily

Trimethoprim-sulfarnethoxazole,

ganisrns, initial therapy should consis t of nafcillin and chloramphenicol. In neonates a combination of methicillin and gentamicin is started, and drugs are changed according to the culture results . Clindamycin 25 to 50 mg/ kg/day in four doses is a suitable alternative to chlorarnphenicol when Bacteroides infection is suspected or proved. For nonputrid lung abscess, crystalline penicillin G 50,000 to 100,000 units/kg/day in' four or six doses is used. When lung abscesses occur secondary to other foci of infection, such as osteomyelitis, Staphylococcus aureus is commonly responsible and nafcillin 150 rug/kg/day in four doses is used. Gentamicin or kanamycin should be used fo~ lung abscess caused by coliform bacteria. The total duration of therapy is usually three to five weeks, and occasionally longer in patients with multiple lesions . Postural drainage and physical therapy to the chest should be used to encourage drainage of the abscesses. If these techniques fail, bronchoscopy or surgery may be necessary. In young infants, lung abscesses are frequently associated with congenital malformations such as bronchogenic cysts, and here surgical removal of the infected tissue is usually required for cure. URINARY TRACT INFECTION (TABLE V) There is no simple approach to the management of urinary tract infection. A specimen of bladder urine obtained by clean voided technique, catheterization, or suprapubic bladder aspiration should be examined for cells, bacteria, and protein, and the fluid cultured for quantitation (colony count) and susceptibility testing of the bacterial pathogen. Counts of 100,000 colonies per milliliter of voided urine or greater are usually indicative of infection; any organisms in urine obtained by suprapubic tap are abnormal. Most in fants and children with urinary tract infection should be evaluated for functional or structural abnormalities of the urinary tract. Differentiation of renal parenchymal infection from cystitis may

be difficult on either clinical grounds or laboratory tests. The bladder washout technique is imp ractical and the antibody-coated bacteria test on urinary sediment gives both false positive and false 'negative results in pediatric pat ien ts.I O Acute urinary tract Infection. Escherichia coli is the most common pathogen responsible for acute urinary tract infections, Less commonly encountered organisms are Proteus mirabilis and Klebslella-Enterobacter species. If therapy is indicated before identification of the etiologic agent, oral sulfisoxazole or triple sulfonamides are given in a dosage of 120to 150mg/kg/day in three or four doses. Ampicillin or amoxicillin (30 mg /kg/day in three doses) are suitable alternatives to sulfonamides. Once the organism is identified and susceptibilities known, antimicrobial therapy should be adjusted, if indicated. In most laboratories organisms are classified as susceptible or resistant on the basis of achievable serum antibiotic concentrations, Because urine levels of most antibiotics exceed serum concentrations by at least 10- to 100-fold, susceptibility studies reported from laboratories are not necessarily applicable to therapy of urinary tract infection. The best index of therapeutic activity is a repeat urine culture obtained 48 hours after start of therapy. A negative culture or a substantial reduction in the bacterial colony count is evidence of in vivo susceptibility, and therapy should be continued regardless of the in vitro susceptibility results. If the urinary bacterial count has not changed appreciably, therap y is inappropriate. Treatment is continued for 10 to 14 days. Although some physicians believe that a longer course is preferable, considerable evidence exists that 10 days is sufficient. Indeed, for uncomplicated cystitis in adults a single dose of antibiotic is effective.": Abbreviated therapy in children with cystitis is also feasible, though not recommended unless upper tract disease has been ruled OUI. Once therapy is discontinued, urine cultures should be

I.

Voilime 93 Number 3

repeated after one and three months to detect bacteriuria. If recurrence or reinfection occurs, susceptibility of the organism should again be determined and appropriate therapy reinstituted. Management of asymptomatic bacteriuria in schoolg irls is controversial. There is evidence ·to suggest that antibiotics do not affect the natural history of silent infection in females with urinary tracts shown to be normal roentgenographically.w Chronic or recurrent urinary tract lnfectlcn, When urinary tract infect ion recurs or becomes chronic or develops after instrumentation, surgical manipulation, or indwelling catheterization, Proteus vulgaris, Pseudomonas aeruginosa, or mixed infection is often the cause. These infections are frequently asymptomatic and may be associated with underlying anatomic abnormalities. Bacteriologic cure is difficult to achieve in patients with structural defects that cannot be surgically corrected, or who have indwelling catheters. Antimicrobial therapy must be selected on the basis of susceptibility studies; a specific bactericidal agent is used parenterally for a minimum of 10 to 14 days. Carbenicillin indanyl sodium, to to 30 rng/ kg/day in four doses, may be administered orally for Pseudomonas infection of the urinary tract. Because of the large size of the capsule and bitter taste of the powder, most older infants and children cannot tolerate this preparation, even when the drug is administered with food. In such cases, carbenicillin (100 to 150 trig/kg/day) or ticarcillin (50 to 75 rag/kg/day) in three or four doses is used parenterally. Prompt symptomatic improvement usually occurs during this period . After discontinuation of the bactericidal agent, prolonged therapy with bacteriostatic drugs is commonly used to prevent recurrence. Available agents include nalidixic acid (50 mg/kg/day orally in four doses) and nitrofurantoin (I to 2 mg/kg given once daily) ; the latter drug is greatly preferred. Acidification of the urine with ascorbic acid is difficult 10 achieve, but may be helpful in some patients. The patient should be encouraged to void frequently. Culture with susceptibility test ing needs to be carried out at intervals. Duration of suppressive therapy varies with the clinical situation; patients with underlying structural abnormalities may require treatment for years. Trimethoprim-sulfamethoxazole has been approved for treatment of resistant urinary tract infections in older infants (not in infants < 2 months of age) and children , but it is generally not the preferred agent in this age group. This drug has bactericidal activity against most pathogens (exceptions are Pseudomonas aeruginosa and enterococci), but shou ld be used only for treatment of urinary tract infections caused by organisms resistant to sulfonamides, cephalosporins, and ainp icillin. The dosage is 5 to 6 rng/kg TMP125 to 30 mg/kg SMX in two doses

Antimicrobal therapy. Pa rt II. Therapy

367

for acute infections and 2 mg/kg TMP/IO mg/kg SMX administered daily or every other day for long -term suppressive therapy.

GASTROINTESTINAL INFECTIONS Diarrhea is a common clinical manifestation of a wide variety of disorders, only some of which are infectious, while in others the cause remains unknown. A minority of diarrheas are of bacterial etiology. The newly recognized reovirus-like agent has been shown to cause a substantial portion of disease in infants and young children.v-> When bacterial diarrhea is strongly suspected, a Wrightstained smear of stool for presence of polymorphonuclear cells may be helpful in identifying some cases of disease caused by invasive bacteria (Shigella and Salmonella species). The immediate concern of the physician should be replacement of fluid losses and restoration of electrolyte and acid-base balance. Identification of the pathogen by culture, fluorescent antibody technique, biochemical testing, or serotyping with specific antiser.a are important techniques of identification and thus help in the selection of optimal antimicrobial therapy. Enteritis in InfaDcy. Historically, certain specific serotypes of Escherichia coli have been considered pathogens in infants with diarrheal disease. The role of these classic "enteropathogenic" strains in enteritis has been questioned recently, a development which has prompted many experts to recommend discontinuation of routine serotyping for detection. in sporadic cases ." Identification of enteropathogenic E. coli, however, remains an essential part of the evaluation of diarrheal outbreaks in closed populations of infants, in whom these organisms can cause significant morbidity and prolonged hospitalization . Because of disagreement concerning the pathogenicity of these E. coli strains, unequivocal recommendations for therapy are not possible . A majority of "enteropathogenic" E. coli strains are susceptible to neomycin, but regional differences in the proportion of susceptible bacteria exist. The drug (LOO rng/kg/day in four to six doses) has been shown to reduce significantly the number of days of diarrhea and of positive cultures when compared to placebo in infants with enteropathogenic E. coli disease." Therapy is advisable in nosocomial outbreaks of diarrhea or in specific patients with protracted watery diarrhea associated with enteropathogenic E. coli on rectal culture. Neomycin is administered for five day s; longer pe riods are unnecessary and may be associated with drug-indu ced malabsorption. Col istin sulfate (15 to 20 rug/kg/day in four doses) represents suitable alternative therapy. Necrotizing enterocolitis. Bacteria play an important

368



Table VI. Etiology and initial treatment of septic arthritis and osteomyelitis Initial therapy

Etiology

Clinical condition

Septic arthritis, neonatal

S. aureus, coliform bacilli

Septic arthritis, infancy

H. infiuenzae

Septic arthritis, childhood

S. aureus, group A streptococcus,

Septic arthritis

gonococcus Unknown etiology

Osteomyelitis Osteomyelitis associated with hemoglobinopathy (sickle cell disease) Osteomyelitis, calcaneous

S. aureus Salmonella species

Pseudomonas

Methicillin 100-150 mg/kg/day iv in 2 or 3 doses and gentamicin 5-7.5 rag/kg/day im in 2 or 3 doses" Ampicillln 150 rng/kg/day iv in 4 doses or chloramphenicol 100 mg/kg/day 4 doses Nafcillin 150 rug/kg/day iv in 4 doses Nafcillin and chloramphenicol until cultures available Nafcillin 150 rug/kg/day iv in 4 doses Ampicillin 150-200 mg/kg/day iv in 4 doses

Carbenicillin 400-600 mg/kg/day iv in 4 doses

'See text for specific dosage recommendations in neonates.

role in the pathogenesis ana complications of necrotizing enterocolitis. The specific microorganisms involved and the sequence of events leading to disease are a matter of speculation. Oral kanamycin prophylaxis to high-risk premature infants has been shown by one group of investigators to prevent development of the full syndrome." However, emergence of kanamycin-resistant coliform bacteria occurred, a predictable event because such use of antimicrobials exerts selective pressure on the intestinal microbial flora. Thus the prophylactic regimen had to be discontinued and the use of kanamycin avoided in this unit for many months. Orally administered amino, glycosides should not he used prophylactically in closed populations of hi~h-risk infants. Colistin sulfate has also been used for this purpose, but there are no data to support this prophylactic regimen in infants at risk of developing necrotizing enterocolitis. Bacteremia and peritonitis are common complications of necrotizing enterocolitis. Blood cultures are positive in approximately half of these patients, mostly with E. coli, Klebsiella, or Enterobacter species. In addition to parenteral antibiotic treatment (ampicillin or carbenicillin and an aminoglycoside), intragastric administration of kanamycin (30 rug/kg/day), gentamicin (15 rug/kg/day), or colistin sulfate (15-20 mg/kg/day) has been widely used. The efficacy of this combined parenteral-intragastric antibiotic regimen in necrotizing enterocolitis has not been established. Shigellosis. Enteritis resulting from Shigella infection may vary from a mild to a severe, often life-threatening illness. Serious disease is often due to Shigella dysenteriae (Shiga bacillus). Although patients with mild illness recover uneventfully without antimicrobial therapy, controlled studies indicate that oral or parenteral admin-

istration of ampicillin in a dosage of 100 mg/kg/day in four doses for five days significantlyreduces the period of morbidity and the duration of fecal excretion of organisms. The latter effect is an important consideration when treating patients at home, where other family members may be susceptible. In many areas of the country Shigella strains have developed resistance to ampicillin and other antibiotics." Although not officially approved for use in shigellosis (as of this writing), trimethoprim-sulfamethoxazole (8 to 12 mg TMP/40 to 60 mg/ kg/ day SMX orally in two doses)for five days is preferred for treatment of disease caused by these multiply resistant organisms." In patients allergic to penicillin, tetracycline (25 rug/kg/day in four oral doses) may be employed for susceptible strains. Sulfonamides alone are no longer useful because a high proportion of Shigella are resistant. Amoxicillin is ineffective in shigellosis. Salmonella enteritis. There is no evidence that antimicrobial therapy significantly alters the course of uncomplicated Salmonella enteritis. In a comparative, triple-blind, placebo-controlled study of Salmonella gastroenteritis in infants and young children, ampicillin or amoxicillin therapy significantly prolonged the duration of diarrhea and of positive cultures and was associated with an increased incidence of bacteriologic and clinical relapse." Thus, antimicrobial therapy should not be used in most instances of Salmonella infection unless the illness occurs in newborn infants, in patients with immunodeficiency states, or in a child with a chronic or debilitating disease. When treatment is indicated, either ampicillin or chloramphenicol may be used; each drugs is administered orally in a dosage of 75 to 100 mgJkgJday in four doses for seven to ten days. Patients with typhoid fever should be treated with

Volume 93 Number 3

either ampicillin or chloramphenicol. Chloramphenicolresistant strains of Salmonella typhi have been encountered, particularly in states bordering Mexico. Amoxicillin administered orally (40 to 50 rng/kg/day m three doses) is as effective as parenteral ampicillin in treating typhoid fever. Typhoid fever due to strains resistant to both ampicillin and chloramphenicol has responded adequately to trimethoprim-sulfamethoxazole therapy. Traveler's diarrhea. Diarrhea occurs in as many as 30 to 40% of travelers to foreign countries. This disease (known by many appellations such as tourista, Aztec two-step, Montezuma's revenge) has been found to be associated with enterotoxigenic E. coli strains in up to 60% of travelers to Mexico.." Although several recent studies have shown the effectivenessof antimicrobial prophylaxis against traveler's diarrhea, this cannot be routinely recommended. On the other hand, a simple remedy may be suggested for those travelers who have onset of watery diarrhea with associated cramps. Pepto-Bismol taken as directed on the label often will diminish symptoms if these are caused by infection with enterotoxigenic strains."

INFECTIONS OF THE SKELETAL SYSTEM (TABLE VI) Early management of suppurative arthritis and osteomyelitis is based on needle aspiration or surgical drainage, cultures of blood and specimens from the joint or bone lesions, and on proper antimicrobial thcrapy. Septic arthritis. Septic arthritis occurs more commonly in infants than in older children. Selection of antibiotics prior to availability of culture data should be based on the age of the patient and on results of examination of methylene blue- and gram-stained smears of joint fluid. When such smears from neonates reveal gram-positive cocci, staphylococcal or group B streptococcal arthritis should be suspected and methicillin (100 to 150 rng/kg/ day in two or three doses) Dr penicillin G (50,000 to 100,000 units in two or three doses) used. parenterally. Disease due to gram-negative organisms during the neonatal period aretreated initially with gentamicin 5 to 7.5 rug/kg/day in two or three doses. Once the organism is identified and susceptibilities are known, therapy may need to be changed. If the causative organism remains unknown, a combination of methicillin and gentamicin is used. Hemophilus tnfluenzae type b is the major cause of suppurative arthritis in infants two to 24 months of age, although S. aureus may also be causative. A spinal fluid examination and culture must be done in all infants with H. influenzae arthritis because meningitis occurs in as many as 20% of these patients. Initial therapy consists of nafcillin (ISO mg/kg/day in four doses) and chloram-


369

phenicol (100 rug/kg/day in four doses) unless stained smears or CIE of joint fluid reveal the specific pathogen. In disease caused by H. influenzae, beta Iactarnase-posi- : tive organisms are treated with chloramphenicol, whereas negative organisms are best treated with ampicillin (150 rug/kg/day in four doses). If the pathogen is shown to be a penicillin-susceptible staphylococcus, gonococcus, streptococcus, or meningococcus, penicillin G 100,000 units/ kg/day in four doses is used. Except for gonococcal disease, therapy in suppurative arthritis is continued for a minimum of two to three weeks, depending on the pathogen, the joints involved and the patient's clinical condition. Gonococcal arthritis requires at most a week of treatment. Osteomyelitis. When clinical or roentgenographic findings or both suggest osteomyelitis, needle aspiration ofthe SUbperiosteal space and bone should be performed to confirm the diagnosis and to guide antimicrobial therapy. Bone scans are frequently positive early in disease, but falsely positive and falsely negative tests occur. Staphylococcus aureus is the cause of osteomyelitis in 60 to 70% of infants and children. Because many staphylococci are resistant to penicillin, initial parenteral therapy consists of nafcillin or another of the antistaphylococcal drugs. If the organism proves susceptible to penicillin, this drug is used in a dosage of 100,000units/kg/day. Parenteral therapy is continued for a minimum of three to six weeks; in some cases therapy must be given for months. Antimicrobial therapy, however, is never a substitute for adequate surgical drainage. In some patients with suppurative arthritis or osteomyelitis, oral antimicrobial therapy may be instituted after five to ten days of effective parenteral therapy." Cephalexin (100 rug/kg/day), cloxacillin (100 rug/kg/day), or dicloxacillin (50 rug/kg/day) may be used for penicillinresistant staphylococci; penicillin (50,000 to 100,000 units/kg/day) is used for susceptible strains. The evidence for efficacy of cephalexin in osteomyelitis is better than for the oral beta lactarnase-resistant penicillins . Ampicillin (100 or 150 mg/kg/day), amoxicillin (50 mg/kg/day), or chloramphenicol (100 mg/kg/day) is used for Hemophilus disease. Certain prerequisites must be assured before initiating oral therapy: (1) The physician must have evidence that the patient has taken and retained all of the medication each time it is given which nearly always means continued hospitalization; (2) the pathogens must be susceptible to the oral medication; (3) serum inhibitory and bactericidal activities against the pathogen must be monitored to document adequate absorption from the gastrointestinal tract; and (4) the patient must be followed closely to assess effectiveness of therapy. Osteomyelitis caused by Salmonella species may be

370


Table VIT. Etiology and initial treatment of infections of the heart Clinical condition

Initial therapy

Bacterial endocarditis Streptococcus viridans

Enterococcus

Staphylococcus aureus

Penicillin 100,000 units/kg/day (maximum 4-6 million units/ day) iv in 4-6 doses (optional: add streptomycin 30 mg/kg/ day im in 2 doses for 2 wk) Penicillin 250,000 units/kg/day (maximum 20 million units/ day) iv in 4-6 doses and streptomycin 20 mg/kg/day im in 2 doses Nafcillin 150 rug/kg/day (maximum 8-12 gm/day) iv in 4 doses

Suppurative pericarditis Staphylococcus aureus

Nafcillin 150 mg/kg/day iv in 4

H. tnfiuenzae

Ampicillin 150 mg/kg/day iv or chloramphenicol 100 rug/kg/ day iv in 4 doses Penicillin 100,000 units/kg/day iv in 4-6 doses

doses

S. pneumoniae, N. meningitldis

encountered in patients with sickle cell disease or other hemoglobinopathies. Ampicillin 150 to 200 rug/kg/day is preferred over chloramphenicol, which suppresses the reticulocytosis necessary for maintaining hemoglobin levels. Therapy should be continued for six weeks or longer. Osteomyelitis of the calcaneus caused by Pseudomonas aeruginosa is best treated with carbenicillin 400 to 600 rug/kg/day parenterally in four doses (or ticarcillin in one-half this dosage) with or without the addition of gentamicin.

INFECTIONS OF THE HEART (TABLE VII) Endocarditis. Bacterial endocarditis is encountered in children with congenital heart defects, valvular disease resulting from rheumatic carditis, or at sites of previous cardiovascular surgery. The echocardiogram may aid in diagnosis by detecting vegetations on the valve. Bacterial endocarditis is most commonly caused by Streptococcus viridans and therapy consists of parenteral penicillin G alone or in combination with streptomycin. We prefer combined therapy because we have not encountered recurrence of disease in patients treated with this regimen. The dosage of penicillin is 100,000units/kg/ day to a maximum of 4 to 6 million units daily, administered for a total of four weeks. Streptomycin is administered intramuscularly in a dosage of30 rug/kg/day in two doses for two weeks. Enterococcal endocarditis is uncom-


mon in pediatric patients, but when encountered must be treated with larger doses of penicillin (250,000 units/kg/ day to a maximum of 20 million units daily) combined with streptomycin for four weeks. Bacterial endocarditis caused by Staphylococcus aureus is a fulminant disease in many patients, but may be indistinguishable in some children from subacute viridans endocarditis. Initial therapy consistsof nafcillin 150to 200 mg/kg/day or methicillin 200 mg/kg/day to a maximum of 8 to 12 gm daily. If the organism is susceptible to penicillin, this drug is used in a dosage of20 million units/ day. Effective antimicrobial therapy should produce serum bactericidal titers of 1:16 to 1:64 against the offending pathogen. Therapy is continued parenterally for six weeks. Blood cultures after therapy should be sterile on several occasions prior to discharge. Pericarditis. An echocardiogram should be obtained on all patients suspected of having fluid in the pericardial sac. When suppurative pericarditis seems likely, a diagnostic pericardiocentesis should be undertaken. If this reveals purulent material, cultures and stained smears are performed and drainage of the sac provided, usually through a pericardial window. Selection of antimicrobial therapy is based on examination of stained pericardial fluid or of material obtained from other infected sites (empyema , spinal fluid). If organisms are not seen, nafcillin (150 rug/kg/day) or another antistaphylococcal penicillin represents appropriate initial therapy because the staphylococcus is the most frequent cause of suppurative pericarditis in children. Because H. infiuenzae pericarditis may be encountered during infancy, chloramphenicol (100rug/kg/day) should be added to nafcillin as initial therapy in this age group, unless stained smears of pericardial fluid clearly demonstrate gram-positive cocci. Pericarditis caused by D. pneumoniae or N. meningitidis is treated with penicillin G 100,000 units/kg/day intravenously or intramuscularly in four to six doses. Therapy should be adjusted when the results of cultures and eIE are available, and continued for a minimum of two to three weeks.

INFECTIONS OF SKIN AND SUBCUTANEOUS TISSUE Infections of the skin and subcutaneous tissue range from mild impetigo to life-threatening necrotizing fasciitis. As a rule, staphylococcal infection of insect bites, chicken pox, and similar lesions need only be treated locally. Impetigo is a primary streptococcal disease, but frequently becomes superinfected with staphylococci, causing raised, weeping lesions which eventually develop crusts." Either penicillin orally or benzathine penicillin G intramuscularly will help heal existinglesions and prevent

Volume 93 Number 3

new ones. Topical antimicrobial agents, hexachlorophene, or similar antiseptics are generally ineffective in moderate or extensive disease. Cellulitis is usually due to a beta hemolytic streptococcus and is treated effectively with penicillin. Hemophilus influenzae type b is the most common cause of buccal cellulitis in infants . The lesion often has a violaceous hue and is usually associated with ipsilateral otitis media and septicemia." Meningitis occurs concurrently in some infants. Initial therapy is parenteral, ampicillin 100 to 150 mg/kg/day and chloramphenicol 100 rug/kg/day until culture results are available. Staphylococcus aureus strains belonging to phage group Il have been shown to produce a group of skin disorders collectively described as "the scalded skin syndrome," including bullous impetigo, nonstreplococcal scarlatina, Ritter disease of neonates and young infants, and toxic epidermal necrolysis of infancy and childhood (Lyell disease)." Staphylococci can consistently be recovered from cultures of skin and conjunctivae , but less often from blood of those patients with generalized disease. Because approximately 50% of phage group II S. aureus are resistant to penicillin, nafcillin 150 rug/kg/day in four doses, or another of the antistaphylococcal penicillins, is used initially. Penicillin should be substituted if the organism is susceptible. Necrotizing fasciitis is usually caused by staphylococci or streptococci, but occasionally by both organisms . Subcutaneous tissue and muscle layers are invaded and inflammation spreads along the fascial planes." Overlying skin is edematous and often violaceous; the borders of the lesion are usually indistinct. Extensive surgery involving resection of all necrotic tissue is absolutely required in addition to appropriate antimicrobial therapy. Blood and tissue cultures should be obtained and the patient started on nafcillin 150 rug/kg/day. Once the pathogen is identified, penicillin should be used if the organism is susceptible. Hypocalemia may develop during the course of the disease. If allergy precludes the use of penicillins, erythromycin 40 to 50 rng/kg/day given orally or a cephalosporin parenterally (cephalothin 80 to 160mg/kg/day or cefazolin 60 to 100 rug/kg/day) may be used. VENEREAL DISEASES (TABLE VIII) Syphilis. As in gonorrhea, penicillin continues to be the agent of choice in the treatment of infections due to Treponema pallidum. It is preferred for all forms of this disease; other drugs should be used only in those instances where a clear-cut history of penicillin allergy exists. Following sexual contact with a known or suspected

Antimicrobal therapy. Part I/. Therapy

371

Table VIll. Therapy of venereal diseases Clinical condition

Gonorrhea Gonococcal ophthalmia

Prepubertal

Postpubertal Syphilis Congenital Without eNS disease With CNS disease Primary, secondary

Therapy

Crystalline penicillin G 50.DOO75,000 units/kg/day iv, im in 2 or 3 doses for 7 days for infants or procaine penicillin G 75,000-100,000 units/kg im daily and probenecid 25 mg/ kg po 30 minutes before penicillin for 6 days for children plus topical tetracycline or chloramphenicol drops in all patients Procaine penicillin G 75,000100,000 units/kg im once and probenecid 25 mg /kg po Proca ine pen icillin G 4.8 million units im and probenecid I gm

Benzathine penicillin G 50,DOO units/kg im once Procaine penicillin G 50,000 units/kg im daily for 14 days Benzathine penicillin G 2.4 million units im (approximately 50,000 units/ leg) once

syphilitic partner, infect ion can be prevented by a single intramuscular dose of 2.4 million units of benzathine penicillin G. In children under 10 years of age, half this dose may be given. Primary or secondary syphilis in teenagers is treated with benzathine penicillin G, 2.4 million units intramuscularly. When a clear-cut history of penicillin allergy exists, tetracycline may be used in a dosage of 250 mg four times daily for 10 to 15 days in older children. and 500 mg daily for 10 to IS days in adolescents . Erythromycin is much less effective than either pen icillin or tetracycline. Congenital syphilis. Congenital syphilis is difficult to diagnose in asymptomatic or minimally affected infants. Because of transport of maternal 19O antibodies across the placenta, reactive cord serologic tests do not prove disease in the infant. Although initially believed to be the single most reliable test for congenital syphilis, the macroglobulin fluorescent treponemal antibody absorbed (FTA-ABS-IgM) test is no longer recommended because of false negative results in up to one-third of infants with proven disease." Diagnosis of silent infection must be based on history of disease and serologic conversion in the mother, associated with sustained or increasing VDRL titers in the infant during the first weeks of life. It is

372


important to identify the infant with neurosyphilis for therapeutic and prognostic reasons. A reactive cerebrospinal fluid VDRL or Kolmer test is diagnostic of central nervous system disease; however, these tests are positive in only 30%in cases. The spinal fluid FTA-ABS test is less specific and may be present in CSF of normal neonates with transplacentally acquired maternal antibody." The following recommendations for the treatment of congenital syphilis are based in part on available pharmacologic data and represent conservative therapy in the absence of adequate clinical experience. Infants with proven congenital syphilis and without evidence ofneurosyphilis, after careful clinical and laboratory evidence of neurosyphilis, should be treated either with procaine penicillin G 20,000 to 30,000 units/kg administered once daily for 10 days or with benzathine penicillin G 50,000 units/kg in one intramuscular injection. Either regimen is suitable for treatment of asymptomatic infants with reactive cord serum serologic tests when adequate treatment of the mother cannot be documented. Neither of these treatment regimens can be relied upon to produce spirochetocidal levels in the central nervous system, Infants with clinical and/or laboratory evidence of neurosyphilis and those in whom central nervous system involvement cannot be ruled out should be treated with procaine penicillin G in a dosage of 50,000 units/kg administered in one dose daily for from 10 to 14 days or longer. Aqueous penicillin Gis a suitable alternative drug, but must, of course, be given much more frequently. Benzathine penicillin does not provide adequate therapy. Gonorrhea. Gonorrhea is not commonly considered by pediatricians in differential diagnosis despite the fact that this disease is currently the most common reportable infection in the United States, affecting all age groups, social classes; and geographic areas. In the prepubertal female, gonococcal vaginitis is associated with a copious discharge of a greenish yellow material, usually unaccompanied by constitutional symptoms. If the diagnosis is suspected in males with symptoms of urethritis, a gram-stained smear of exudate represents adequate evidence if gram-negative diplococci are identified. Typically, eight to ten pairs of organisms are detected within a polymorphonuclear cell, and several of these cells should be visualized. This finding is observed less often in females, but is diagnostic when present." The diagnosis should be confirmed by culture. In females, specimens should be obtained from the vagina (prepubertal girls) or endocervix and ·anal canal, and cultured on Thayer-Martin or Transgrow media. Anal cultures are positive in as many as 75% of prepubertal girls with vaginitis. "Routine" bacteriologic media do


not permit growth of these organisms. In asymptomatic males, scrapings of material from the anterior urethral mucosa, obtained with a platinum loop or swab made from synthetic fiber (e.g., calcium alginate), should be cultured on Thayer-Martin medium. The diagnosis of extragenital forms of gonorrhea, such as arthritis, may be made by observing characteristic organisms in stained material from pus or by growing them in suitable culture media. Treatment of the various forms of gonorrhea is not difficult. Penicillin represents the drug of choice for all forms of this disease unless hypersensitivity precludes its use. Although penicillinase-producing gonococci were introduced into the United States in 1977, the percentage of resistant strains has remained low (less than 5%). Because susceptibility tests are not routinely performed, resistance should be suspected in the patient who fails to respond to appropriate penicillin or ampicillin therapy. In such patients, the organism should be cultured and tested for penicillinsusceptibility. Case contacts of these individuals must be identified. Urethritis and anal and cervical infections in the adolescent or adult male or female are treated in an identical fashion: procaine penicillin G 4.8 million units administered intramuscularly into two sites during a single visit. One gram of probenecid is administered orally, either simultaneously with or 20 to 30 minutes prior to the injection. This regimen is recommended for postpubertal males and females and for children weighing more than 50 kg. In younger or smaller children, procaine penicillin G 75,000 to 100,000 units/kg is administered in one or two sites along with probenecid (25 mg/kg) given orally." The use of benzathine penicillin G instead of procaine penicillin Gis associated with high failure rates; this product should not be employed. Although cure.rates in excess of 95% can be expected in acute genital gonorrhea treated with adequate dosages of penicillin, follow-up cultures are indicated because therapy may convert a symptomatic infection to an asymptomatic carrier state, and because of a high rate of reinfection. Relief of symptoms cannot be equated with cure. In females, the anal canal and' the endocervix should be cultured at such follow-up visits; in the male, material should be obtained from the anterior urethra, preferably with a platinum loop. Adequate cultures will also prevent confusion of postgonococcal urethritis or coexistent nonspecific urethritis with therapeutic failures or reinfections, All patients with gonorrhea should receive serologic tests for syphilis at the time of diagnosis. If the test is negative and the recommended regimen of penicillin therapy has been given, no further tests for syphilis are

Volume 93 Number 3

necessary. Individuals treated with other drugs should be re-evaluated monthly for three or four months because of the possibility that syphilis has been masked but not cured. It may be desirable to treat uncomplicated genital gonorrhea with a penicillin orally. Ampicillin in a single oral dose of 3.5 gm, preceded 30 minutes earlier by I gm of probenecid, or amoxicillin 3 gm without probenecid is highly effective in the postpubertal patient. In younger children, 50 mg/kg amoxicillin plus probenecid (25 mg/ kg) has been shown to be effective." In patients with penicillin-resistant gonococcal disease, spectinomycin 2 gm intramuscularly is preferred for postpubertal males and females, and 40 mg/kg for prepubertal patients. Follow-up cultures and case contact investigations are mandatory in these patients. The efficacy of several other antibiotics (trimethoprim-sulfamethoxazole, cefuroxime) in patients with resistant gonococcal disease is currently under investigation. In penicillin-allergic patients, other drugs may be employed. For single injection therapy, spectinomycin is recommended. Repeated injections are unnecessary and may be associated with toxicity. Tetracyclines are less effective than either penicillin or spectinomycin; there is no difference in efficacy among the various tetracycline analogues. In postpubertal children, initial tetracycline dosage is 1.5 gm orally, followed by 0.5 gm four times a day for a total dosage of 9th gm. In younger children, an initial dose of 25 rug/kg is administered, followed by 10 mg/kg every six hours for five days. Erythromycin, which in the past was recommended as an alternative drug to penicillin, does not represent adequate therapy." In the treatment of disseminated gonococcal infections, certain modifications in dosage are needed. Tenosynovitis represents the most common complication; in adults this can be effectively treated with penicillin G (10 million units/day for three to five days) or with the same dose of penicillin G until clinical improvement is noted, with amoxicillin (3 gm/day) then substituted for an additional fiveto seven days. Younger children should receive 75,000 to 100,000 units of penicillin G/kg/day. Repeated aspirations of the joint help to relieve pain and possibly prevent additional synovial damage. Intra-articular instillation of antibiotics does not significantly affect bacteriologic cure. Temporary immobilization of the joint perhaps aids in more rapid healing; once inflammation has begun to subside, physical therapy is indicated to prevent stiffness and ankylosis. In the treatment of meningitis and endocarditis, large doses of penicillin G are employed, up to 20 million units' in adolescents and 100,000 to 250,000 units/kg/day in the younger child. It is recommended that treatments be


373

continued for seven to ten days in meningitis and for a longer period (up to four weeks) in endocarditis. There is little controlled experience with tetracycline in the treatment of these conditions, but there is reason to believe that the agent would prove considerably less effective than penicillin. More localized complications such as pelvic inflammatory disease, perihepatitis, epididymitis, and prostatis are treated with penicillin G administered in a dose of from 5 to 7.5 million units/day for five to ten days, or with equivalent doses of procaine penicillin G combined with probenecid. More recently, a number of these conditions have been successfully treated with ampicillin orally plus probenecid given for an equal length of time. Data on the oral use of these drugs are still incomplete, particularly so for pediatric patients. Gonococcal ophthalmia. Ophthalmia neonatorum occurs not only among newborn infants, but also in children and adolescents. It usually begins with a watery or serosanguinous discharge and progresses very rapidly to thick pus associated with· increasing lid edema. If untreated, infection may progress to corneal ulceration, followed by penetration into the interior of the eye and a panophthalmia. Confirmation of the clinical diagnosis can only be achieved by culture, but treatment should be started at once if characteristic gram-negative diplococci are seen on a gram-stained smear of pus. Because of the potential severity of this condition, it is never treated with topical applications alone; penicillin G is given in a dosage of 50,000 to 75,000 units/kg/day in two or three doses for one week in infants. Older children or adolescents may be treated with procaine penicillin G and probenecid, as described for acute genital gonorrhea, except that the drugs should be administered daily for six days. Local therapy probably hastens control of infection, but care must be taken not to injure the cornea, which is often quite friable. As soon as the diagnosis is made or suspected, thorough but gentle saline irrigation should be carried out at quarter-hour intervals, gradually lengthened to three or four hours until resolution occurs. Each irrigation is followed by instillation of tetracycline or chloramphenicol eyedrops. If iritis occurs, ophthalmologic consultation should be promptly obtained. Inclusion blenorrhea. Inclusion blenorrhea is caused by Chlamydia trachomatis, previously known as the tric agent. The disease is often clinically indistinguishable from conjunctivitis produced by bacterial pathogens, particularly the gonococcus. Symptoms usually begin between the third and seventh day of life, not uncommonly during the second week. The lids are often swollen shut, with thick yellow discharge and edema of the palpebral

374

The Journal of Pediatrics


September 1978

conjunctivae. In some infants, clinical manifestations may be quite mild. Examination of a stained smear of pus from the eye does not represent an adequate diagnostic test since the causative agent multiplies within the epithelial cells of the conjunctivae, not in pus cells. Thus, scraping of ihe lower palpebral conjunctivae with a spatula or sterile paper clip is essential. The scrapings are then treated with Giemsa or Wright stain; in general, the characteristic inclusions are easily visible within the cells. Isolation of the agent is now possible using specially treated McCoy cells. Inclusion conjunctivitis has traditionally been treated with tetracycline ointment, or sulfacetamide solution (10 to 15%) applied every three oi four hours for 14 days. Although there usually is a rapid response to treatment, relapses have occurred and Chlamydia organisms have persisted in scrapings or cultures of the conjunctivae. Recent evidence suggests that oral treatment with erythromycin not only promptly eradicates the agent from the conjunctivae and nasopharynx but also produces rapid clinical improvement" Further experience is needed before optimal management of this. condition is known.

ANTITUBERCULOUS DRUGS Antituberculous drugs are generally administered singly or in double or triple combinations. Combination therapy is not necessarily used to increase efficacy, but to prevent the development of resistant strains of bacteria. In general, since patients with acute and severe infections harbor larger numbers of organisms than those with more established and chronic disease. the former group would be treated with three drugs whereas the latter group might be treated with one or two. Finally, there are data to indicate that in those individuals who are infectious to others, the possibility of spread can be reduced more rapidly by the use of combined therapy. Drug efficacy. A considerable number of agents with antituberculous activity are available but differ in the degree of usefulness, Only two medications may be considered to be truly outstanding: isoniazid and rifampin. All other drugs are inferior in efficacy and/or have significant toxicity, . Isoniazid (10 to 20 mg/kg/day in one or two doses, maximum, 300 to 500 mg) is rapidly absorbed and penetrates readily into all tissues and body fluids, including the central nervous system; The drug is excreted primarily through the kidney. Children tolerate and can be given substantially larger doses than adults on a weight or surface area basis. The hepatotoxicity and peripheral neuropathy occasionally observed in adults are very rarely encountered in children. In fact, toxicity in the pediatric group is so unusual that liver function need not be

monitored except iri those patients with a pre-existing hepatic disease or in those who develop symptoms suggestive of liver involvement. Furthermore, there is no need for concurrent administration of pyridoxine unless diet is inadequate. There is some suggestion that pyridoxine diminishes the efficacy of Isoniazid. Rifampin (10 to 20 mg/kg in one or two doses, maximum 600 mg) is available in the United States only in capsular form, but is so well absorbed that there is little need for a parenteral preparation. It penetrates well into tissues and spinal fluid. Because of inhibition of absorption by the concurrent administration of food, the drug should be given at least one hour before or two hours after a meal, a precaution which is not necessary with isonia-

zio. Although a warning label is required of the manufacturer in the United States, stating that little data exist on its use in patients under five years of age, Widespread experience in other parts of the world indicates that rifampin is effective and safe in small children. As with INH, the drug appears to be less toxic to children than adults; liver damage occurs far less commonly in the pediatric age group; Rifampin is never used alone for the treatment of tuberculosis, but is employed in combination with INH or other "first line" drugs which include ethambutol, streptomycin, and para-aminosalicylic acid. The combination ofrifampin and JNH may' enhance hepatotoxicity of these drugs; patients so treated should be monitored if there is clinical evidence of hepatic involvement. Ethambutol (JO io 15 mg/kg/day in une dose, maximum 1,500 mg) is a highly effective antituberculous agent which among adults had replaced PAS almost entirely. It is far cheaper than rifampin and in areas of the world where the latter drug is excessively expensive, recent studies have shown that for most p\,lrposes, excluding perhaps tuberculous meningitis, ethambutol can be safely substituted. However, its use in children remains limited because adequate toxicity data do not exist for patients less than 13 years of age. It is probably contraindicated in children less than 6 years of age (unless rifampin is not available) because in this age group its major toxic effect (optic neuritis) cannot be adequately monitored by visual acuity and color discrimination tests. Streptomycin (20 to 40 mg/kg/day in one or two doses, maximum I gm) has already been discussed in the section on aminogIycosides. In general, its use should be restricted to a four-week course because a longer period of administration increases the likelihood of cochlear and vestibular damage. Para-aminosalicylic acid (200 to 300 mg/kg/day in two or three doses, maximum 12 gm) is an orally administered

Volume 93 Number 3

Antimicrobal therapy. Part !I. Therapy

375

Table IX. Chemotherapy of tuberculosis disease syndromes Disease

Antituberculous drug therapy"

Chest Initial infection with demonstrated pulmonary disease

(I ) INH 10 mg /kg/day and RMP 10 rug/kg/day or INH plus EMB or INH

Locally progressive pulmonary disease

Duration (mo)

Other drug therapy

Comments

12-18

None

(2) INH dose of 20 mg/kg/ day may be used for 3-4 wk in more severe disease

(3) INH 20 mg /kg/day and RMP plus SM

12-18

None

Endobronchial

Same as (3)

12-18

Chronic (reactivation) pulmonary disease Pleurisy and/or pericarditis

Same as (3)

12-18

Prednisone 1-2 mg/kg/day for 4--6 wk if symptoms of compression occur None

(4) SM given for 4 wk only INH may be reduced to 10 mg/kg/day after 4-12 wk Same as (4)

Same as (I)

12-18

When effusion present, prednisone 1-2 rug/kg/day may increase rate of resorption

Miliary

Same as (3)

18-24

Predn isone 1-2 rug/kg/day for 4-6 wk if severe dyspnea

Central nervous system Meningitis

Same as (3)

18-24

None

Serous meningitis Nonpulmonary disease Skeletal

Same as (I) Same as (I) Same as .(1)

12-18

i2-18 12-18

Non e None Non e

Superficial lymph node

Same as (1)

12-18

None

Urinary tract

Same as ( I)

24

Nolie

Miscellaneous: Skin, endocrine, abdominal, upper respiratory tract, ocular, etc

Same as (I)

12-18

None

plus PAS

Same as (4) Fluid should be removed for diagnosis and/or relief of symptoms; no thoracotomy tube indicated LiJmb'ar puncture weekly for 3-4 wk

Prednisone probably decreases mortality but increases neurologic sequele, may be used in impending CSF block; monitor fluid and electrolytes Same as (2) Same as (2) Same as (2); immobilize until healing established; abscesses should be curetted and drained Surgical excision if node is caseous Repeat rvs and voiding cystourethrogram every 6 mo while on therapy and every year for IO yrs. Same as (2)

·INH-Isoniazid; RMP-rifampin ; EMB.ethambutol ; PAS-para-am inosalicylic acid; SM-strepiomycin.

drug closely related to aspirin and commonly employed with INH. It is not a very effective anti-tuberculous agent, but it does reduce the opportunity for development of resistance to other drugs, especially INH. The major side, effect of PAS is gastric and intestinal irritation ; frequent occurrence of gastritis manifested by nausea, abdominal pain, and vomiting may prevent the administration of this and other oral medications and diminish the child's food intake, which in properly nourished patients may have a

detrimental effect on the course of disease. If PAS is administered with meals in a somewhat lower dosage, which is then gradually increased, the incidence of gastritis and intestinal toxicity is significantly reduced. Unfortunately, the stablility of pAs p~wder is poor, especially in humid environments, and the liquid preparation is likely to deteriorate quickly. Thus, this drug should be prescribed in small amounts and, if liquid preparations are required in small children, the patients should be

376

Mccracken and Eichenwald

instructed to make these up from measured aliquots just prior to administration. Because of its close pharmacologic and chemical resemblance to aspirin, parents should be warned not to administer the latter drug if the child develops fever from intercurrent infection; to do so might result in acute salicylism. In addition to the first line drugs already mentioned, a number of other pharmacologic agents exist which are useful primarily when mycobacteria have been shown to be resistant to INH or rifampin, or when other drugs are not available. Unfortunately, experience with these medications in children has been relatively limited. Kanamycin, viomycin, and capreomycin all have somewhat similar toxicities and probably identical efficacy. Their major toxic effect is on the auditory portion of the eighth nerve, subsequently followed by loss of vestibular function. Viomycin possesses the additional toxic property of inducing hypersensitivity as well as a variety of electrolyte abnormalities; capreomycin is more nephrotoxic than the other two drugs. These agents are rarely useful and then only in place of streptomycin when the organism in question has been shown to be resistant to the latter agent. Cycloserine is occasionally useful in older children and in adolescents when these patients cannot tolerate PAS or ethambutol. It is given in a dose of 10 mg/kg/day, not exceeding a maximum of 500 rag/day. Generally the dose is divided into two equal portions given at about 12-hour intervals. The drug has a. variety of central nervous system toxicities; hypersensitivity to it develops quite rapidly. Ethionamide is occasionally used when the tubercle bacilli are resistant to other agents. Recommended dosage is 12 to 15 rag/kg/day divided into three equal doses with a maximum daily dose of 750 rug/kg/day. The drug is capable of causing severe gastrointestinal irritation as well as inducing hypersensitivity. Pyrazinamide is a very potent agent which possesses marked hepatotoxicity and consequently cannot usually be given for periods in excess of five to six months. No good dosage data exist for children. In general, this drug is probably too hazardous for use. Single drug therapy. Under certain circumstances, the use of a single drug regimen is indicated. The preferred drug is isoniazid, which is administered for periods of time ranging from one year in patients who are asymptomatic tuberculin converters or who have minimal evidence of disease, to one month in children previously treated but found in a situation favorable to reactivation of disease (as for example, during the administration of measles vaccine or if they become ill with measles or pertussis). Similarly, children with known positive tuberculin tests, regardless of previous therapy, should receive


INH for the entire period of immunosuppressive or corticosteroid therapy for an unrelated disease. The medication is also useful in the treatment of household contacts of known infectious cases, even if the contact's tuberculin skin test is still negative; early treatment prior to the stage of hematogenous dissemination (when hypersensitivity has not yet developed) will promptly eradicate infecting organisms and thus eliminate the focus of infection. Under these circumstances, skin tests may never become reactive. Double and triple drug therapy. For most forms of tuberculous disease, two drugs are employed (Table IX). In patients wit~ severe, potentially fatal disease such as miliary, meningeal, locally progressive and chronic cavitary tuberculosis, triple therapy is used. CORTICOSTEROIDS Glucocorticoid preparations have limited usefulness in the treatment of tuberculosis. They are known to reactivate otherwise latent disease, and in the absence of appropriate antituberculous therapy to spread infection. However, because of their antiinflammatory effect, they have use in pleural and pericardial disease because resorption of fluid is promoted. These drugs also diminish respiratory problems in miliary disease with massive pulmonary involvement. Despite their frequent use in tuberculous meningitis and endobronchial disease, there is no convincing evidence that corticosteroids contribute to a better prognosis, improve therapy, or promote more rapid healing.

REFERENCES I.

2.

3. 4.

5.

6.

7.

Monroe B, Rosenfeld CR, Weinberg AG, and Browne R: The differential leukocyte count in the assessment and outcome of early-onset neonatal group B streptococcal diseases, J PEDIATR 91:632, 1977. McCracken GH, Threlkeld N, and Thomas ML: Intravenous administration of kanamycin and gentamicin in newborn infants, Pediatrics 60:463, 1977. Burke JP, Klein JO, GlezanHM, and Finland M: Pneumococcal bacteremia, Am J Dis Child 121:353, 197t. McCarthy PL, Jekel JF, and Dolan TF: Temperature greater than or equal to 40 C in children less than 24 months of age: A prospective study, Pediatrics 59:663, 1977. Feigin RD, Wong M, Shackelford PO, Strechenberg BW, Dunkle LM, and Kaplan S: Countercurrent immunoelectrophoresis of urine as well as of CSF and blood for diagnosis of meningitis, J PSDIATR 89:773, 1976. McCracken GH, and Mize SG: A controlled study of intrathecal antibiotic therapy in gram negative enteric meningitis of infancy. Report of the Neonatal Meningitis Cooperative Study Group, J PEDlATR 89:66, 1976. Jacobson JA, McCormick JB, HayesP, Thornsberry C, and Kirvin L: Epidemiologic characteristics of infections caused by ampicillin-resistant Hemophilus influenzae, Pediatrics 58:388, 1976.


Voll/me 93 Number 3

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Long SS, and Phillips SE: Chloramphenicol-resistant Hemophilus influenzae, J PEDIATR 90:1030, 1977. Feigin RD, Stechenberg BW, Chang MJ, Dunkle LM, Wong ML, Palkes H, Dodge PR, and Davis H: Prospective evaluation of treatment of Hemophilus iniluenzae meningitis, J PEDJATR 88:542, 1976. Paredes A, Taber LM, Yow MD, Clark D, and Nathan W: Prolonged pneumococcal meningitis due to an organism with increased resistance to penicillin, Pediatrics 58:378, 1976. Appelbaum PC, Bhamjee A, Scragg IN, Hallett AF, Bowen AJ, and Cooper RC: Streptococcus pneumoniae resistant to penicillin and chloramphenicol, Lancet 2:995, 1977. Schwartz R, Rodriguez WJ, Kahn WN, and Ross S: Acute purulent otitis media in children older than 5 years. Incidence of Hemophilus as a causative organism, JAMA 238: 1032, 1977. Watters EC, Walker PH, Hiles DA, and Michaels RH: Acute orbital cellulitis, Arch OphthalmoI94:785, 1976. Nelson JD: The changing epidemiology of pertussis in young infants, Am J Dis Child 132:371, 1978. Hieber JP: Infections due to chlamydia, J PBDIATR 91:864, 1977. Beem M, and Saxon E: Respiratory tract colonization and a distinctive pneumonia syndrome in infants infected with Chlamydia trachomatis, N Engl J Med 296:306, 1977. Hellerstein S, Kennedy E, Nussbaum L, and Rice K: Localization of the site of urinary tract infections by means of antibody-coated bacteria in the urinary sediment, J PBDJATR 92: 188, 1978. Ronald AR, Boutras P, and Mourtada M: Bacteruria localization and response to single dose therapy in women, JAMA 235:1854, 1976. Fang LS, Tolkoff-Rubin NE, and Rubin RH: Efficacy of single-dose and conventional amoxicillin therapy in urinary tract infection localized by the antibody-coated bacteria technique, N Engl J Med 298:413, 1978. Lindberg D, Claesson I, Hanson LA, and Jodal D: Asymptomatic bacteriuria in schoolgirls. VIII. Clinical course during a 3-year follow-up, J PEDlATR 92:194, 1978. Kapikian AZ, Kim HW, Wyatt RG, Cline WL, Arrobio JO, Brandt CD, Rodriquez WJ, Sack DA, Chanock RM, and Parrott RH: Human reovirus-like agent as the major pathogen associated with "winter" gastroenteritis in hospitalized infants and young children, N Engl J Med 294:965, 1976. Meddleton PJ, Szymanski MT, and Petrie M: Viruses associated with acute gastroenteritis in young children, Am J Dis Child 131:733, 1977. Farmer JJ, Davis BR, Cherry WB, Brenner DJ, Dowell VR, and Balows A: "Enteropathogenic serotypes" of Escherichia coli which really are not, J Pediatr 90: 1047, 1977. Nelson JD, and Kusmiesz HT: A double-blind study of

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377

neomycin, ampicillin and placebo for enteropathogenic Escherichia coli diarrheal disease (in preparation). Egan EA, Mantilla G, Nelson RM, and Eitzman DV: A prospective controlled trial of oral kanamycin in the prevention of neonatal necrotizing enterocolitis, J PEDJATR 89:467, 1976. Ross S, Controni G, and Khan W: Resistance of shigellae to ampicillin and other antibiotics, JAMA 221:45, 1972. Nelson JD, Kusmiesz H, and Jacobson LH: Comparison of trimethoprirn-sulfamethoxazole and ampicillin therapy for shigellosis in ambulatory patients, J PEDIATR 89:491, 1976. Nelson JD: Personal communication, March 8, 1978. Gorbach SL, Kean BH, Evans DG, Evans DJ, and Bessudo D: Traveler's diarrhea and toxigenic Escherichia coli, N Engl J Med 292:934, 1975. Ericson CD, Evans DG, DuPont HL, Evans DJ, and Pickering LK: Bismuth subsalicylate inhibits activity of crude toxins of Escherichia coli and Vibrio cholera, J Infect Dis 136:693, 1977. TetzlaffTR, McCracken GH, and Nelson JD: Oral antibiotic therapy for skeletal infections of children. II. Therapy of osteomyelitis and suppurative arthritis, J PEDlATR 92:485, 1978. Derrick CW, and Dillon HC: Further studies on the treatment ofstreptococcal skin infections, J PEDJATR 77:696, 1970. Nelson JD, and Ginsburg CM: An hypothesis on the pathogenesis of Hemophilus influenzae buccal cellulitis, J PEDlATR 88:709, 1976. Melish ME, and Glasgow LA: Staphylococcal scalded skin syndrome: The expanded clinical syndrome, J PEDlATR 78:958, 1971. Wilson DH, and Haltalin KC: Acute necrotizing fasciitis in childhood, Am J Dis Child 125:591, 1973. KaufmanRE, OlanskyDC, and Wiesner PJ: The FTA-ABS (lgM) test for neonatal congenital syphilis: A critical review, J Am Vener Dis Assoc 1:79, 1974. Thorley JO, Holmes RK, Kaplan JM, McCracken GH, and Sanford JP: Passive transfer of antibodies of maternal origin from blood to cerebrospinal fluid of infants, Lancet 1:651, 1975. Wald ER: Gonorrhea. Diagnosis by gram stain in the female adolescent, Am J Dis Child 131: 1094, 1977. Nelson JO, Mohs E, Dajani AS, and Plotkin SA: Gonorrhea in preschool- and school-aged children. Report of the prepubital gonorrhea cooperative study group, JAMA 236:1359, 1976. . Brown ST, Pedeisen AHB, and Holmes KK: Comparison of erythromycin base and estolate in gonococcal urethritis, JAMA 238:1371, 1977. Beem M and Saxon E: Letter, N Engl J Med 296: 1150, 1977.

Letter: Diuretic therapy in infants and children.

Renal function and diuretic therapy in infants and children. Part III.

Therapy for acute infectious diarrhea in children.

Outpatient parenteral antimicrobial therapy (OPAT) for infectious endocarditis in Spain.

Infective endocarditis: Part II. Current therapy.

Outpatient parenteral antimicrobial therapy practices among adult infectious disease physicians.

Psychosomatic group therapy with parents of children with intractable asthma. X: The Peters family. part II.

State-of-the-art human gene therapy: part II. Gene therapy strategies and clinical applications.

Psychosomatic group therapy with parents of children with intractable asthma. VIII: The Kohl family. Part II.

Adjuvant systemic therapy in breast cancer. Part II: Adjuvant chemotherapy.

Appropriateness and safety of outpatient parenteral antimicrobial therapy in children: opportunities for pediatric antimicrobial stewardship.

Predicting response to antimicrobial therapy in children with acute sinusitis.

Orthopedic manual therapy--an overview. Part II: the spine.

Antimicrobial Blue Light Therapy for Infectious Keratitis: Ex Vivo and In Vivo Studies.

Antimicrobial therapy in pulmonary aspiration.

Antimicrobial therapy for shigellosis.

Pulmonary infectious complications of human immunodeficiency virus infection. Part II.

Outpatient parenteral antimicrobial therapy.

Editorials: Combination antimicrobial therapy.

Flucloxacillin in the treatment of infectious conditions in children.

[Therapy and prevention of infectious diseases].

[Uncertainties in the therapy of infectious diseases].

Photodynamic therapy as a new treatment modality for inflammatory and infectious conditions.

Caffeine therapy in preterm infants.