Adverse Effects of Vancomycin in Children

Amélia Gorete Afonso da Costa Reis, Sandra Josefina Ferraz Ellero Grisi,

Adverse effects of vancomycin in children: a review of 22 cases Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo Department of Pediatrics, University of São Paulo - São Paulo, Brazil

Vancomycin has been frequently recommended for the treatment of multi-resistant infections.Twenty-two children undergoing vancomycin treatment were observed. Nine adverse effects were registered in 6 children: eosinophilia in 5 cases, skin rash in 2 cases, and an increase in plasma creatinine in 2 cases. Ali adverse effects remitted with withdrawal of the drug.

UNITERMS~ Vancomycin. Adverse effects. Children. Antibiotics.

ancomycin is a polypeptide antibiotic isolated in standards, has also contributed to a reduction in the 1956 and introduced into medicaI practice in 1958, incidence of adverse effects. V for treating infections caused by penicillin- After intravenous administration, vancomycin is resistant staphylococci.1 It has many mechanisms of action, distributed into various body fluids. Many factors the best known and probably most important being the influence the drug's pharmacodynamics, including age. inhibition of cell wall synthesis in bacteria.2 In addition Total body clearance of vancomycin increases with age. to being extremely effective against Gram-positive Due to the complex pharmacokinetics of the drug, the bacteria,3-5two features of vancomycin are of great interest monitoring of the antibiotic concentration in plasma is in medicaI practice: the low leveI of bacterial resistance recommended to assure successful therapy.6-9 to the antibiotic, and the negligible -incidence of cross The main adverse effects associated with vancomycin reactions with other antibiotics. are: 10-12 Initial preparations of vancomycin contained many • Histamine-like reaction, commonly seen as impurities frequently associated with adverse effects. flushing and a maculo-papular rash of the face, Today, with drug purification, the number of patients who neck, upper thorax, back and arms. The reaction experience toxic effects is very small. Furthermore, well- may affect the entire body surface and be controlled drug administration, according to technical accompanied by itching, paresthesia, dizziness, fever, chest pain and edema of the face, lips, and eyelids. More severe symptoms such as tachycardia or bradycardia and, more rarely, systemic arterial hypotension or shock, may be Address for correspondence: observed; 13 Amélia Gorete A. C. Reis • Nephrotoxicity has been associated with Rua Alves Guimarães 623, apto 142, Jardim Amtftriea vancomycin sinc~ the beginning of its use. São Paulo/SP - Brasil- CEP 05410-001 Analysis of these studies are difficult however,

São Paulo Medicai Journal/RPM 115(3): 1452-1455, 1997 REIS, A.G.A.C.; GRISI, S.J.F.E. - Adverse effects of vancomycin in children: a review of 22 cases . 1453

because many concomitant factors that may The drug was prepared for intravenous administration impair renal function in vancomycin treatment at a concentration of 5 mg/ml. The dosage used was 15 are also present in these studies; 14,15 mg/kg/dose over a 60-minute period, every 6 hours. • Ototoxicity has been difficult to evaluate, as most Measurements of plasma concentration of vancomycin patients are not submitted to audiometric tests were taken at maximal and minimal concentration leveIs of during treatment. Impairment of the auditory the phase of equilibrium, that is, after the second day of nerve, considered the most severe adverse effect, therapy. Plasma concentration was determined by poIarized may lead to permanent hearing IOSS;16,17 immunofluorescence on TDx equipment. As plasma • Thrombophlebitis was frequent with initial concentrations presented great individual variation, leveIs preparations of vancomycin, occurring in up to of 30 to 40 mcg/ml at maximal, and below 10 mcg/mI at 9 50 percent of cases. The incidence fell to minimal were considered adequate. Optimum plasma leveIs between 6-13 percent after the purification were observed in only eight children. process; 18 Hemogram, urea and creatinine concentration, serum transaminase leveIs and urinanalysis were performed at • Today, fever and chills are rare adverse effects; the beginning of therapy and weekly during treatment in they were more commonly observed with initial order to monitor adverse effects. Ototoxicity was not preparations of the antibiotic; 10,19 evaluated. Concomitant therapy with a cephalosporin or Hemotoxicity, mainly represented by • aminoglycoside was necessary in 14 cases. neu tropenia and eosinophilia, has been Nine adverse effects observed in six children are described more frequently, and does not seem described in the Table. Changes in plasma urea and to be related to dosage or plasma concentration creatinine leveIs upon introduction of vancomycin therapy of the drug. Blood count returns to normal did not occur. values upon withdrawal of the drug;20 The following adverse effects were observed: two • Although increase in serum bilirubin has been cases of skin rash (9.1 percent), five episodes of associated to the use of vancomycin, there is eosinophilia (22.7 percent), and two cases of increase in no clear proof of hepatoxicity; 10 serum creatinine concentration (9.1 percent). Arterial hypertension has been described recently, Skin rashes were observed during drug infusion, aIthough hypotension is the cardiovascular effect most and after the second week of treatment. Eosinophilia frequently observed. was defined as the number of eosinophils above 500 cells/ The Children ~s Institute of the Hospital das Clinicas ml, and was observed after the second week of treatment of the University of São Paulo, a major tertiary hospital, in five cases. Remission occurred after the end of treats children with chronic anel/or severe diseases in which treatment. Changes in plasma creatinine were observed immunodepression, the use of invasive procedures, and during the second and third weeks of treatment. Twofold frequent hospital admissions often lead to the development or greater increases were considered significant. Both of multi-resistant Gram-positive bacterial infections. cases with an increase in plasma creatinine concentration Vancomycin plays an important role in the treatment of Table these infections. Adverse effects and serum concentrations of vancomycin Therefore, we followed 22 children in whom van- Serum Serum Adverse comycin was clinically concentrations concentrations Effects indicated for treating severe Peak (mcg/ml) Low (mcg/ml) infections caused by suspected Case 1 50.4 25.6 eosinophilia or confirmed multi-resistant Case 2 37.7 16.7 eosinophilia, skin rash staphyIococci. We observed possibIe adverse effects of the Case 3 23.1 04.0 skin rash drug through clinicaI and increase in serum creatinine laboratory follow-up, and Case 4 30.9 08.1 eosinophilia attempted to relate these Case 5 54.6 15.0 eosinophilia effects to treatment length and plasma concentrations of the Case 6 29.9 05.6 eosinophilia drug. increase in serum creatinine

REIS, A.G.A.C.; GRISI, S.J.F.E. - Adverse effects of vancomycin in children: São Paulo Medicai JournallRPM 115(3): 1452-1455,1997 a review of 22 cases 1454

occurred with simultaneous use of other drug's, in one • Plasma concentrations presented great case amycacin, and in another, ceftriaxone. Creatinine individual variation, confirming that the plasma leveIs returned to normal after the drugs were recommended dosage of vancomyci~ is suitable withdrawn. for initial therapy, but serum concentrations Serum concentrations above 40mcg/ml occurred in should be monitored to adjust dosage; two of the six children who suffered adverse effects, and • Significant adverse effects were not observed in four children the serum concentrations were below 40 during infusion, suggesting that administration mcg/ml. standards have a protective role; From the analysis of the data above we can conclude Adverse effects were transient and remitted that: after vancomycin was withdrawn.

REFERENCES 4. McGowan JE Jr, Metchock BG. Penicil1in-resistant pneumococci: An emerging threat to successful therapy. J Hosp Infect 1995;30 Suppl:472-82. 5. Lee HJ, Park JY,Jang SH, Kim JH, Kim EC, Choi KW. High 1. Geraci JE, Heilman FR, Nichols DR, Wellman WE, Ross incidence of resistance to multiple antimicrobials in clinicaI GT. Some laboratory and clinicaI experiences with a new isolates of Streptococcus pneumoniae from a university antibiotic, vancomycin. Proceedings of the Staff Meetings .hospital in Korea. Clin Infect Ois 1995;20:826-35 of the Mayo Clinic 1956;31:564-82. 2. Anderson JS, Matsuhashi M, Haskin MA, Strominger JL. 6. Banner W Jr. Why read a pharmacokinetic article? AJDC Lipid-phosphoacetylmuramyl-pentapeptide and lipid- 1986;140:104-6 phosphodisaccharide-pentapeptide: Presumed membrane 7. Matzke GR, Zhanel GG, Guay ORP.Clinicai pharmacokinetics transport intermediates in cell wall synthesis. Proe NAS of vancomycin. Clin. Pharmacokinet 1986;11:257-82. 1965;53:881-9. 8. Chang D. Influence of malignancy on the pharmacokinetics 3. Wang WC, Wong WY, Rogers ZR, Wilimas JA, Buchanan of vancomycin in infants and children. Pediatr Infect Ois J GR, Powars DR. Antibiotic-resistant pneumococcal infection 1995;14:667-73. in children with sickle cell disease in the United States. J 9. Logsdon BA, Lee KR, Barret FF. Correct dosing of Pediatr Hematol Oncol 1996;18: 140-4. vancomycin in infants and children. Pediatrics 1995;96:1177.

São Paulo Medicai JournaVRPM 115(3): 1452-1455, 1997 REIS, A.G.A.C.; GRISI, S.J.F.E. - Adverse effects of vancomycin in children: a review of 22 cases 1455

10. Sorrell TC, Collignon PJ. A prospective study of adverse the elderly hospitalized patient. J Antimicrob Chemother reactions associated with vancomycin therapy. J Antimicrob 1994;33:811-21. Chemother 1985;16:235-41. 16. Geraci JE, Heilman FR, Nichols OR, Wellman WE. 11. Mellor JA, Kingdom J, Cafferkey M, Keane CT. Vancomycin Antibiotic therapy ofbacterial endocarditis: VII vancomycin toxicity: A prospective study. J Antimicrob Chemother for acute micrococcal endocarditis. Proceedings of the Staff 1985; 15:773-80. Meetings of the Mayo Clinic Nutr 1958;33: 172-81. 12. Woodley OW, Hall WH. The treatment of severe 17. Geraci JE, Hermans PE. Vancomycin. Mayo Clin Proc staphylococcal infections with vancomycin. Ann InternaI 1983;58:88-91. Med 1961;55:235-49. 13. Odio "C,Mohs, E, Sklar FH, Nelson JO, McCracken GH Jr. 18. Farber BF, Moellering RC Jr. Retrospective study of the Adverse reactions to vancomycin used as prophylaxis for toxicity of preparations of vancomycin from 1974 to 1981. CSF shunt procedures. AJDC 1984;138:17-9. Antimicrob Agents Chemother 1983;23:138-41. 14. Nahata MC, King OR, Powell OA, Marx SM, Ginn-Pease 19.5chaad UB, McCracken GH Jr, Nelson JO. ClinicaI ME. Management of catheter-related infections in pediatric pharmacology and efficacy of vancomycin in pediatric patients. JPEN J Parenter Enteral Nutr 1988;12:58-9. patients. J Pediatr 1980;96: 119-26. 15. Vance-Bryan K, Rotschafer JC, Gilliland SS, Rodvold KA, 20. Shinohara YT, Colbert 1. Vancomycin-induced neutropenia Fitzgerald CM, Guay OR. A comparative assessment of during treatment of endocarditis in a pediatric patient. Ann vancomycin-associated nephrotoxicity in the young versus Pharmacother 1994;28:723-6.

REIS, A.G.A.C.; GRISI, S.J.F.E. - Adverse effects of vancomycin in children: São Paulo Medicai JournallRPM 115(3): 1452-1455,1997 a review of 22 cases