Pediatric Annals

New Applications of Old Antimicrobials

Melvin I Marks, MD

Abstract

Several antimicrobial agents have withstood the test of time in the treatment of pediatrie infectious diseases. Included among these are chloramphenicol, trimethoprim-sulfamethoxazole, and vancomycin. Selected features of these agents are reviewed herein.

CHLORAMPHENICOL

Despite its association with a serious, albeit rare, adverse effect, chloramphenicol remains a popular antimicrobial for selected infections. This is due to the fact that this agent has many favorable characteristics. These include excellent pharmacokinetic properties that enable oral administration for most indications, including the treatment of serious invasive diseases, such as meningitis. Chloramphenicol is also stable, easily synthesized and has a potent and wide spectrum of antimicrobial activity. The drug is inexpensive and is bactericidal in its action against Hoempp/uius influenzae, Neisseria species and Streptococci« pneumonias, three major pediatrie bacterial pathogens.1

Chloramphenicol remains a popular choice for the initial therapy of bacterial meningitis and the continued therapy of meningitis due to H. influenzas. Chloramphenicol is the drug of first choice in the treatment of patients less than 8 years of age with Rocky Mountain spotted fever, and is also very useful in the treatment of selected enteric and anaerobic infections.2 It is often used in the treatment of brain abscess since, in addition to excellent oral absorption, it is distributed well into tissues, including those of the central nervous system.

Three major disadvantages of chloramphenicol relate to its toxicities that are both dose-related and dose-independent.3 The former include hématologie suppression, which can be manifested as anemia, neutropenia, and, occasionally, thrombocytopenia. Neutropenia is often seen after 5 to 7 days of therapy with serum concentrations of >25 ^g/ml, but is a reversible phenomenon and rarely of clinical significance. Another dose-related toxicity is the gray baby syndrome, a cardiovascular collapse associated with serum concentrations of >40 µ§/t?!.4 This can be seen in newboms and in patients with underlying liver disease and is manifested by hypotension, peripheral vasoconstriction, and a gray ashen appearance. The doseindependent side effect, aplastic anemia, occurs in approximately 1/40,000 treatment courses and has been noted after all routes of administration, including topical application. Although a rare side effect, it is irreversible.

Since it is now feasible to monitor serum chloramphenicol concentrations by high pressure liquid chromotography assays that are rapid and relatively inexpensive (the techniques and equipment are similar to those used to measure theophylline), dose-related toxicities can generally be avoided. A dosage of 75 mg/kg/ day in normal infants and children is appropriate for both oral and intravenous administration and most commonly keeps patients within the usual therapeutic range of 10 to 20 u,g/ml. Occasionally, when sensitivities of the organism permit, these therapeutic guidelines can be made even more specific.

Table

Another indication for vancomycin is oral therapy of Clostridium difficile colitis.14

The second new feature of vancomycin is the fact that the drug is now prepared in a more refined fashion so that some of the toxicities, such as phlebitis, previously noted frequently with vancomycin, are less commonly seen. With these impurities removed, vancomycin is much better tolerated, except in a few circumstances. One of these circumstances is the "red man" or "red neck" syndrome often associated with rapid infusion of the drug, although this has been seen with slow infusions as well.15 In this syndrome (Table 4), the patient may have a rash over the face and neck and develop hypotension. For this reason, vancomycin should be administered under close observation and is probably not an appropriate drug for home IV therapy, except in special circumstances. Additive nephrotoxicity with aminoglycosides and other toxic effects may be seen.16 These are often related to the serum concentrations, which need to be monitored. Advantages and…

Several antimicrobial agents have withstood the test of time in the treatment of pediatrie infectious diseases. Included among these are chloramphenicol, trimethoprim-sulfamethoxazole, and vancomycin. Selected features of these agents are reviewed herein.

CHLORAMPHENICOL

Despite its association with a serious, albeit rare, adverse effect, chloramphenicol remains a popular antimicrobial for selected infections. This is due to the fact that this agent has many favorable characteristics. These include excellent pharmacokinetic properties that enable oral administration for most indications, including the treatment of serious invasive diseases, such as meningitis. Chloramphenicol is also stable, easily synthesized and has a potent and wide spectrum of antimicrobial activity. The drug is inexpensive and is bactericidal in its action against Hoempp/uius influenzae, Neisseria species and Streptococci« pneumonias, three major pediatrie bacterial pathogens.1

Chloramphenicol remains a popular choice for the initial therapy of bacterial meningitis and the continued therapy of meningitis due to H. influenzas. Chloramphenicol is the drug of first choice in the treatment of patients less than 8 years of age with Rocky Mountain spotted fever, and is also very useful in the treatment of selected enteric and anaerobic infections.2 It is often used in the treatment of brain abscess since, in addition to excellent oral absorption, it is distributed well into tissues, including those of the central nervous system.

Three major disadvantages of chloramphenicol relate to its toxicities that are both dose-related and dose-independent.3 The former include hématologie suppression, which can be manifested as anemia, neutropenia, and, occasionally, thrombocytopenia. Neutropenia is often seen after 5 to 7 days of therapy with serum concentrations of >25 ^g/ml, but is a reversible phenomenon and rarely of clinical significance. Another dose-related toxicity is the gray baby syndrome, a cardiovascular collapse associated with serum concentrations of >40 µ§/t?!.4 This can be seen in newboms and in patients with underlying liver disease and is manifested by hypotension, peripheral vasoconstriction, and a gray ashen appearance. The doseindependent side effect, aplastic anemia, occurs in approximately 1/40,000 treatment courses and has been noted after all routes of administration, including topical application. Although a rare side effect, it is irreversible.

Since it is now feasible to monitor serum chloramphenicol concentrations by high pressure liquid chromotography assays that are rapid and relatively inexpensive (the techniques and equipment are similar to those used to measure theophylline), dose-related toxicities can generally be avoided. A dosage of 75 mg/kg/ day in normal infants and children is appropriate for both oral and intravenous administration and most commonly keeps patients within the usual therapeutic range of 10 to 20 u,g/ml. Occasionally, when sensitivities of the organism permit, these therapeutic guidelines can be made even more specific.

Table

TABLE 1CHLORAMPHENICOL

TABLE 1

CHLORAMPHENICOL

Several other characteristics of chloramphenicol also deserve mention. The drug is bacteriostatic against many enteric pathogens and Staphylococcus aitreus. It should be used with caution, therefore, in serious invasive diseases due to these bacteria. Hence, the drug is not favored for the treatment of enteric meningitis or endocarditis. The drug is metabolized by the liver where the free-form is glucuronidated for subsequent renal excretion. Drugs that interfere with this process may elevate serum concentrations of free chloramphenicol. This might include dilantin, which may bring about this effect by competition for hepatic binding sites with chloramphenicol.5 Other drugs, such as phénobarbital, may induce liver metabolism of chloramphenicol and thereby reduce serum concentrations to subtherapeutic levels.6 Hence, drugs that may interact with chloramphenicol may increase the need for monitoring of serum concentrations, and liver function tests may often be required.7-8

Finally, another limiting factor to the use of chloramphenicol may be the development of bacterial resistance. In countries where chloramphenicol is freely available and widely used, resistance has developed among Salmonella typhi, and other enteric pathogens. This resistance, mediated by acetyltransferase, has also been seen in Spain among approximately 20% of H. influenzae strains.

Some of the advantages and disadvantages of chloramphenicol are summarized in Table 1.

Trimethoprim-Sulfamethoxazole

The fixed combination of trimethoprim-sulfamethoxazole is a very effective therapy for urinary tract infections, pneumocystosis, and selected upper respiratory and enteric infections. The antibacterial activities of this drug combination are referable to the sequential blockade of two enzymatic steps in folie acid metabolism. Since bacteria cannot use exogenous folate, this pathway is critical for their growth. Mammalian cells are less susceptible to this toxicity, since they can utilize exogenous folate. This only becomes a clinical problem when patients are severely folatedepleted and/or large doses of trimethoprim-sulfamethoxazole are used for long periods of time. Such patients may be seen among malnourished and cancer populations.

The antibacterial activity of trimethoprim-sulfamethoxazole is wide and includes upper respiratory pathogens such as pneumococcus, Haemophilus, and some strains of S. aureus. It is because of these features that the drug is used in the treatment of otitis media and sinusitis;9 however, it is not effective in the treatment of streptococcal pharyngitis or other infections due to Group A Streptococcus. The activity of the drug combination against enteric pathogens is utilized in the treatment and prevention of urinary tract infections. For this purpose, the combination can be used effectively in the vast majority of urinary infections due to Escfierichia coti and other EnteroboctaTOceae.10 A single dose given at bedtime daily or every other day can also be effective in preventing recurrent urinary tract infections in selected patients. Pneumocystis carinii is effectively prevented by this combination and is treated with it as well. The drug is not well- tolerated by patients with AIDS, however. Trimethoprim-sulfamethoxazole represents an excellent combination for the treatment of shigellosis and selected Sa/moneiia infections as well.

Trimethoprim-sulfamethoxazole is usually given orally, and, because of a long half-life, can be given once or twice a day. The dosage regimens are outlined below. It should be noted that the drug can also be given intravenously, often a requirement for the treatment of severe P. carina in patients with cancer or other immunodeficiency syndromes. By this route, the serum concentrations are approximately twice that achieved after oral administration for trimethoprim and 1.3 times that achieved with sulfamethoxazole.

Although neutropenia has been described in patients receiving trimethoprim-sulfamethoxazole, neutropenia is also frequently associated with a variety of infectious processes and may not be any more common with trimethoprim-sulramethoxazole than it is with amoxicillin.11 Toxicities conventionally noted with sulfonamides may also be seen with this combination.

The indications and dosage recommendations are outlined in Tables 2 and 3.

VANCOMYCIN

Vancomycin usage has been modified in two respects. On the one hand, it is indicated more frequently today because of the emergence of staphylococci that have developed resistance to beta-lactam drugs, including all penicillins and cephalosporins.12,13 Both Stophylococcus aureus and S. epidermidi may have this characteristic. Hence, vancomycin is a drug of first choice in the treatment of staphylococcal endocarditis, and bacteremic syndromes associated with catheter infections, unless the organism is sensitive to penicillins or cephalosporins.

Table

TABLEZTRIMETHOPRIMSULFAMETHQXAZOLE TMP/SMX

TABLEZ

TRIMETHOPRIMSULFAMETHQXAZOLE TMP/SMX

Table

TABLE 3DOSE TMP/SMZ

TABLE 3

DOSE TMP/SMZ

Table

TABLE 4VANCOMYCIN

TABLE 4

VANCOMYCIN

Table

TABLE 5VANCOMYCIN

TABLE 5

VANCOMYCIN

Another indication for vancomycin is oral therapy of Clostridium difficile colitis.14

The second new feature of vancomycin is the fact that the drug is now prepared in a more refined fashion so that some of the toxicities, such as phlebitis, previously noted frequently with vancomycin, are less commonly seen. With these impurities removed, vancomycin is much better tolerated, except in a few circumstances. One of these circumstances is the "red man" or "red neck" syndrome often associated with rapid infusion of the drug, although this has been seen with slow infusions as well.15 In this syndrome (Table 4), the patient may have a rash over the face and neck and develop hypotension. For this reason, vancomycin should be administered under close observation and is probably not an appropriate drug for home IV therapy, except in special circumstances. Additive nephrotoxicity with aminoglycosides and other toxic effects may be seen.16 These are often related to the serum concentrations, which need to be monitored. Advantages and disadvantages are outlined in Table 5.

REFERENCES

1. Laferrierc CI, Marks Ml: Criloramphemciil: Properties and clínica! use. Pediair inftit Du 1982; 1:257-264.

2. Dupont HL. Homick RB. Weiss CF, et al: Evaluation of chloramphenicol acni suce mate thetapy of induced iyphoid fever and rocky mountain spotted fever. N EnjiJ Med 1970; 282:51-57.

3. Wal !erste in ItO, Condii PK1 Kasper CK, et al Stateside study of chloramphenicol therapy and fatal anlastic anemia. JAMA 1969; 208:2045-2050.

4. Black SB, Levine P, Shinefield HR: The necessity ir monitoring thloramphenicol levels when treat ing neonatal meninRitis. I Pedían 1978; 92:235-236.

5. Koup JR. Gibaldt M, McNamara P, et al Interacnon of ctilorampfienitol with phenytoin and phénobarbital. Clin PWmocni Tfitr 1978; 24:571-575.

6. Palmer DL. Despopoulos A, Rael ED: Induction of chloramphenicol meiabolism by phenobarbital. Annrnicrob Agents Chemotber 1972; 1:112-115.

7. Riley HDJr.: Pharmacology for the pediatrician. DTIIK interactions - Part IV. Interactions among antimicrobial and minanti microbi al agents. PeJuimcs 1972; 50:954-955.

8. Prober CG: Effect of rifaropm un chloramphenicol levels. N Eng!! Med 1985, 312:788-789.

9. Klimek J], Bates TR, Nightingale C: Penetration characteristics of irimethoprimsulfamerhoxazole in middle ear fluid of patients with chronic serous otitis media. J Pediatr 1980; 96:1087-1089.

10. Edwards D, Normand ICS, Prescod N: Disappearance olvesicou reter ic reflux during long-term prophy !axis of urinary lract infection in children. BrMeJJ 1977; 2:285-288.

11. Feidma n S. Doolittle M. Loct L, et al Similar hematologie changes m children receiving trimethoprim-sutrarnethoxazole or amoxicil lin fer otitis media. } Peaia.tr 1985; 106:995*1000.

12. Kaplan EL: Vancomycin in infants and children: A review of pharmacology and indications for therapy and prophylaxis. I Antimicrob Chemother 1984, 145:59-66.

13. Cook FV, ferrar WE: Vancomycin revisited. Ann lniem MeJ 1978; 88:813-818.

14. Spinet PG, Elipoulos GM: Systemic absorption nf enterai vancomycin in a paiient with pseudomembranous colitis. Ann imem Med 1984; 100:533-534.

15. Gartelts JC, Peterie JD: Vancornycin and the "red man's syndrome". N Engl ] Med 1985; 312:245.

16. Dean RP, Wagner DJ, Tolpin MD: Vanenmycin/aminoglycoside nephrotoxicity. J Pediatr 1985; 106:861-862.

TABLE 1

CHLORAMPHENICOL

TABLEZ

TRIMETHOPRIMSULFAMETHQXAZOLE TMP/SMX

TABLE 3

DOSE TMP/SMZ

TABLE 4

VANCOMYCIN

TABLE 5

VANCOMYCIN

10.3928/0090-4481-19860601-05

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