Necrotizing
Enterocolitis
Although the pathogenesis of necrotizing enterocolitis (NEC) has
yet to be delineated, there is ample evidence to support a role of intestinal
bacteria in the genesis and complications of this disease in neonates. The importance of coliform bacilli has been demonstrated in experimental NEC in newborn rats, and sporadic outbreaks of NEC in neonatal intensive care units have frequently been associated with intestinal colonization or septicemia caused by various members of the Enterobacteriaceae family.1,2 Stanley and Null3 reported that temporal alterations in the intestinal microflora of infants were correlated with changes in the incidence of NEC and that neonates initially colonized with Klebsiella pneumoniae had an almost threefold greater likelihood of developing disease than those colonized with other enterobacterial species. Surveillance studies from one intensive care unit have shown that K pneumoniae and Escherichia coli strains are recovered significantly (P < .01) more often from rectal cultures of infants with NEC than from their cohorts without NEC.4 These data support the contention that the fecal microflora contribute in some way to the pathogenesis of necrotizing enterocolitis. That orally administered aminoglycosides might be efficacious in man¬ agement of patients with NEC was suggested by Bell and co-workers,5 who reported a reduced incidence of intestinal perforation in affected in-
fants treated orally with kanamycin sulfate or gentamicin sulfate. Egan and associates6 and Boyle et al7 demonstrated a reduced number of NEC cases in high-risk infants treated with kanamycin. However, a significant (P .038) difference in incidence rates of NEC was only demonstrated in the Egan study. In addition, Rowley and Dahlenburg8 have recently reported the results of a placebo-controlled trial in which gen¬ tamicin given orally did not provide protection from development of NEC. If an antimicrobial regimen is to be protective, it would presumably be on the basis of the substantial reduction in the number of Gram-negative enteric bacteria colonizing the bowel of orally treated infants.7 " The report of a randomized doubleblind controlled trial of oral gentami¬ cin prophylaxis in infants considered at high-risk of developing NEC appears in this issue of the Journal (p 1192). This regimen was successful in preventing NEC and NEC-like enteropathies. Grylack and Scanlon's enthu¬ siasm for prophylaxis is reflected by their recommendation that gentami¬ cin be given orally to all infants possi¬ bly at risk of developing NEC. Is this recommendation justified? We believe that the aminoglycosides should not be used routinely for prevention of neonatal necrotizing enterocolitis, or, if used, prophylaxis should be restricted to a small number of high-risk infants and given only for a limited period of time. Our caution=
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Iowa User on 05/30/2015
ary are
position is not because unconvincing; rather,
the data we
are
concerned that emergence of resistant strains will develop among previously susceptible enteric Gram-negative bacilli. This has certainly been the case with parenterally administered aminoglycosides in nurseries,1" " and one would predict that oral therapy will exert a more rapid selective pres¬ sure on the intestinal microflora. For example, in the study by Boyle and co-workers,7 development of kanamy¬ cin resistance occurred in almost half of the infants receiving kanamycin orally, and the rate of colonization by resistant coliforms on days 17 through 30 of therapy was significantly (P < .05) greater in kanamycintreated than in placebo-treated in¬ fants. In Gainesville, Fla, kanamycin was used routinely in all low-birthweight infants after completion of the controlled prophylaxis trial in 1975.6 Surveillance studies disclosed that a substantial percentage of Staphylococ¬ cus epidermidis and S aureus strains were resistant to kanamycin, gentam¬ icin, and tobramycin. Additionally, approximately 10% of coliforms were resistant to these aminoglycosides. Possible, untested, alternative can¬ didates for oral prophylaxis are the polymyxins. These agents have bacte¬ ricidal activity sharply limited to Gram-negative bacteria and have been used safely by the oral route for therapy of gastroenteritis caused by enteropathogenic E coli. Development of bacterial resistance to the polymyx-
ins is infrequent and, if encountered, would not jeopardize newborn care, since these drugs are rarely used for therapy of systemic bacterial dis¬ eases.
It should be pointed out that the oral administration of antimicrobials that selectively suppress the coliform flora of the gut will promote growth of other bacteria, some of which may be deleterious. It has recently been antibiotic-associated shown that pseudomembranous colitis is most likely caused by proliferation of toxin-producing clostridial strains that are resistant to the ingested drugs.1213 This entity has not been demonstrated in newborn infants, but Clostridia have been implicated in the etiology of NEC14 or NEC-like ill¬ nesses,15 and these organisms are resistant to the aminoglycosides and
would be small, it is likely that they would constitute a substantial portion of the high-risk, low-birth-weight pop¬ ulation in the unit, and this could have an important impact on the develop¬ ment of resistant organisms through¬ out the entire unit. GEORGE H. MCCRACKEN, JR, MD Department of Pediatrics University of Texas Health Science Center at Dallas Southwestern Medical School 5323 Harry Hines Blvd Dallas, TX 75235 DONALD V. EITZMAN, MD Department of Pediatrics University of Florida College of Medicine Gainesville, FL 32601
References
polymyxins.16
Because of the anticipated rapid emergence of resistant enteric bacte¬ ria and of the possible selective growth of potentially harmful mem¬ bers of the bowel microflora, we do not believe that either kanamycin or gentamicin should be used orally routinely for prevention of NEC. Although the number of infants receiving prophylaxis at any one time
1. Barlow B, Santalli
TV, Heird WG, et al:
An
experimental study of acute necrotizing enterocolitis. J Pediatr Surg 9:587-595, 1974. 2. Speer ME, Taker LH, Yow MD, et al: Fulminant neonatal sepsis and necrotizing enterocolitis associated with a "nonenteropathogenic" strain
of Escherichia coli. J Pediatr 89:91-95, 1976. 3. Stanley MD, Null DM: Relationship between intestinal colonization with specific bacteria and the development of necrotizing enterocolitis. Pediatr Res 11:542, 1977. 4. Bell MJ, Feigin RD, Ternberg JL, et al: Evaluation of gastrointestinal microflora in
necrotizing
enterocolitis. J Pediatr 92:589-592,
1978. 5. Bell Neonatal
MJ, Kosloske AM, Benton C, et al: necrotizing enterocolitis: Prevention of perforation. J Pediatr Surg 8:601-605, 1973. 6. Egan EA, Mantilla G, Nelson RM, et al: A prospective controlled trial of oral kanamycin in the prevention of neonatal necrotizing enteroco-
litis. J Pediatr 89:467-470, 1976. 7. Boyle R, Nelson JS, Ross B, et al: Alterations in stool flora resulting from oral kanamycin prophylaxis of necrotizing enterocolitis. J Pediatr, to be published. 8. Rowley MP, Dahlenburg GW: Gentamicin in prophylaxis of neonatal necrotising enterocolitis. Lancet 2:532, 1978. 9. Bell MJ, Ternberg JL, Feigin RD, et al: Neonatal necrotizing enterocolitis: Therapeutic decisions based upon clinical staging. Ann Surg 187:1-7, 1978. 10. Franco JA, Eitzman DV, Baer H: Antibiotic usage and microbial resistance in an intensive care nursery. Am J Dis Child 126:318-321, 1973. 11. Howard JB, McCracken GH: Reappraisal of kanamycin usage in neonates. J Pediatr 86:949-956, 1975. 12. Bartlett JG, Chang TW, Gurwith M, et al: Antibiotic-associated pseudomembranous colitis due to toxin-producing Clostridia. N Engl J Med 298:531-534, 1978. 13. Larson HE, Price AB, Honour P, et al: Clostridium difficile and the aetiology of pseudomembranous colitis. Lancet 1:1063-1066, 1978. 14. Pederson PV, Hansen FH, Halveg AB, et al: Necrotising enterocolitis of the newborn\p=m-\isit gas-gangrene of the bowel? Lancet 2:715-716, 1976. 15. Howard FM, Flynn DM, Bradley JM, et al: Outbreak of necrotising enterocolitis caused by Clostridium butyricum. Lancet 2:1099-1102, 1977. 16. Weinstein L: Antibiotics, in Goodman LS, Gilman A (eds): The Pharmacological Basis of Therapeutics. London, Macmillan Co, 1970, pp 1269-1299.
Circumcision routine circumcision of the male infant will greet the appearance of the with and Goldblum Annunziato article by the one and by Sussman et al (p 1187) (p 1189) on unusual complications of the operation. Those who favor routine circumcision will be quick to point out that Fournier's syndrome and the scalded skin syndrome are very rare complications that should not deter parents from requesting circumcision
Opponents pleasure
for the newborn boy. Circumcision of the newborn continues for the following reasons: it may be routine because of religious beliefs, and parents and physicians have for years accepted the procedure on the basis of arguments that the circumcised male is at less risk of having cancer of the penis develop, and that a malignant neoplasm in the genital tract of women married to circumcised men is less frequent than
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Iowa User on 05/30/2015
in
married to uncircumcised It is an incontestable fact at this point that there are more deaths each year from complications of circumcision than from cancer of the penis. In addition, there are no solid data to prove that the end of man's arrogance is related to the risk of malignancy in the female. Perhaps the only sound argument for routine circumcision of the male came from World War II, during which soldiers in the South women
men.
Enterocolitis
Although the pathogenesis of necrotizing enterocolitis (NEC) has
yet to be delineated, there is ample evidence to support a role of intestinal
bacteria in the genesis and complications of this disease in neonates. The importance of coliform bacilli has been demonstrated in experimental NEC in newborn rats, and sporadic outbreaks of NEC in neonatal intensive care units have frequently been associated with intestinal colonization or septicemia caused by various members of the Enterobacteriaceae family.1,2 Stanley and Null3 reported that temporal alterations in the intestinal microflora of infants were correlated with changes in the incidence of NEC and that neonates initially colonized with Klebsiella pneumoniae had an almost threefold greater likelihood of developing disease than those colonized with other enterobacterial species. Surveillance studies from one intensive care unit have shown that K pneumoniae and Escherichia coli strains are recovered significantly (P < .01) more often from rectal cultures of infants with NEC than from their cohorts without NEC.4 These data support the contention that the fecal microflora contribute in some way to the pathogenesis of necrotizing enterocolitis. That orally administered aminoglycosides might be efficacious in man¬ agement of patients with NEC was suggested by Bell and co-workers,5 who reported a reduced incidence of intestinal perforation in affected in-
fants treated orally with kanamycin sulfate or gentamicin sulfate. Egan and associates6 and Boyle et al7 demonstrated a reduced number of NEC cases in high-risk infants treated with kanamycin. However, a significant (P .038) difference in incidence rates of NEC was only demonstrated in the Egan study. In addition, Rowley and Dahlenburg8 have recently reported the results of a placebo-controlled trial in which gen¬ tamicin given orally did not provide protection from development of NEC. If an antimicrobial regimen is to be protective, it would presumably be on the basis of the substantial reduction in the number of Gram-negative enteric bacteria colonizing the bowel of orally treated infants.7 " The report of a randomized doubleblind controlled trial of oral gentami¬ cin prophylaxis in infants considered at high-risk of developing NEC appears in this issue of the Journal (p 1192). This regimen was successful in preventing NEC and NEC-like enteropathies. Grylack and Scanlon's enthu¬ siasm for prophylaxis is reflected by their recommendation that gentami¬ cin be given orally to all infants possi¬ bly at risk of developing NEC. Is this recommendation justified? We believe that the aminoglycosides should not be used routinely for prevention of neonatal necrotizing enterocolitis, or, if used, prophylaxis should be restricted to a small number of high-risk infants and given only for a limited period of time. Our caution=
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Iowa User on 05/30/2015
ary are
position is not because unconvincing; rather,
the data we
are
concerned that emergence of resistant strains will develop among previously susceptible enteric Gram-negative bacilli. This has certainly been the case with parenterally administered aminoglycosides in nurseries,1" " and one would predict that oral therapy will exert a more rapid selective pres¬ sure on the intestinal microflora. For example, in the study by Boyle and co-workers,7 development of kanamy¬ cin resistance occurred in almost half of the infants receiving kanamycin orally, and the rate of colonization by resistant coliforms on days 17 through 30 of therapy was significantly (P < .05) greater in kanamycintreated than in placebo-treated in¬ fants. In Gainesville, Fla, kanamycin was used routinely in all low-birthweight infants after completion of the controlled prophylaxis trial in 1975.6 Surveillance studies disclosed that a substantial percentage of Staphylococ¬ cus epidermidis and S aureus strains were resistant to kanamycin, gentam¬ icin, and tobramycin. Additionally, approximately 10% of coliforms were resistant to these aminoglycosides. Possible, untested, alternative can¬ didates for oral prophylaxis are the polymyxins. These agents have bacte¬ ricidal activity sharply limited to Gram-negative bacteria and have been used safely by the oral route for therapy of gastroenteritis caused by enteropathogenic E coli. Development of bacterial resistance to the polymyx-
ins is infrequent and, if encountered, would not jeopardize newborn care, since these drugs are rarely used for therapy of systemic bacterial dis¬ eases.
It should be pointed out that the oral administration of antimicrobials that selectively suppress the coliform flora of the gut will promote growth of other bacteria, some of which may be deleterious. It has recently been antibiotic-associated shown that pseudomembranous colitis is most likely caused by proliferation of toxin-producing clostridial strains that are resistant to the ingested drugs.1213 This entity has not been demonstrated in newborn infants, but Clostridia have been implicated in the etiology of NEC14 or NEC-like ill¬ nesses,15 and these organisms are resistant to the aminoglycosides and
would be small, it is likely that they would constitute a substantial portion of the high-risk, low-birth-weight pop¬ ulation in the unit, and this could have an important impact on the develop¬ ment of resistant organisms through¬ out the entire unit. GEORGE H. MCCRACKEN, JR, MD Department of Pediatrics University of Texas Health Science Center at Dallas Southwestern Medical School 5323 Harry Hines Blvd Dallas, TX 75235 DONALD V. EITZMAN, MD Department of Pediatrics University of Florida College of Medicine Gainesville, FL 32601
References
polymyxins.16
Because of the anticipated rapid emergence of resistant enteric bacte¬ ria and of the possible selective growth of potentially harmful mem¬ bers of the bowel microflora, we do not believe that either kanamycin or gentamicin should be used orally routinely for prevention of NEC. Although the number of infants receiving prophylaxis at any one time
1. Barlow B, Santalli
TV, Heird WG, et al:
An
experimental study of acute necrotizing enterocolitis. J Pediatr Surg 9:587-595, 1974. 2. Speer ME, Taker LH, Yow MD, et al: Fulminant neonatal sepsis and necrotizing enterocolitis associated with a "nonenteropathogenic" strain
of Escherichia coli. J Pediatr 89:91-95, 1976. 3. Stanley MD, Null DM: Relationship between intestinal colonization with specific bacteria and the development of necrotizing enterocolitis. Pediatr Res 11:542, 1977. 4. Bell MJ, Feigin RD, Ternberg JL, et al: Evaluation of gastrointestinal microflora in
necrotizing
enterocolitis. J Pediatr 92:589-592,
1978. 5. Bell Neonatal
MJ, Kosloske AM, Benton C, et al: necrotizing enterocolitis: Prevention of perforation. J Pediatr Surg 8:601-605, 1973. 6. Egan EA, Mantilla G, Nelson RM, et al: A prospective controlled trial of oral kanamycin in the prevention of neonatal necrotizing enteroco-
litis. J Pediatr 89:467-470, 1976. 7. Boyle R, Nelson JS, Ross B, et al: Alterations in stool flora resulting from oral kanamycin prophylaxis of necrotizing enterocolitis. J Pediatr, to be published. 8. Rowley MP, Dahlenburg GW: Gentamicin in prophylaxis of neonatal necrotising enterocolitis. Lancet 2:532, 1978. 9. Bell MJ, Ternberg JL, Feigin RD, et al: Neonatal necrotizing enterocolitis: Therapeutic decisions based upon clinical staging. Ann Surg 187:1-7, 1978. 10. Franco JA, Eitzman DV, Baer H: Antibiotic usage and microbial resistance in an intensive care nursery. Am J Dis Child 126:318-321, 1973. 11. Howard JB, McCracken GH: Reappraisal of kanamycin usage in neonates. J Pediatr 86:949-956, 1975. 12. Bartlett JG, Chang TW, Gurwith M, et al: Antibiotic-associated pseudomembranous colitis due to toxin-producing Clostridia. N Engl J Med 298:531-534, 1978. 13. Larson HE, Price AB, Honour P, et al: Clostridium difficile and the aetiology of pseudomembranous colitis. Lancet 1:1063-1066, 1978. 14. Pederson PV, Hansen FH, Halveg AB, et al: Necrotising enterocolitis of the newborn\p=m-\isit gas-gangrene of the bowel? Lancet 2:715-716, 1976. 15. Howard FM, Flynn DM, Bradley JM, et al: Outbreak of necrotising enterocolitis caused by Clostridium butyricum. Lancet 2:1099-1102, 1977. 16. Weinstein L: Antibiotics, in Goodman LS, Gilman A (eds): The Pharmacological Basis of Therapeutics. London, Macmillan Co, 1970, pp 1269-1299.
Circumcision routine circumcision of the male infant will greet the appearance of the with and Goldblum Annunziato article by the one and by Sussman et al (p 1187) (p 1189) on unusual complications of the operation. Those who favor routine circumcision will be quick to point out that Fournier's syndrome and the scalded skin syndrome are very rare complications that should not deter parents from requesting circumcision
Opponents pleasure
for the newborn boy. Circumcision of the newborn continues for the following reasons: it may be routine because of religious beliefs, and parents and physicians have for years accepted the procedure on the basis of arguments that the circumcised male is at less risk of having cancer of the penis develop, and that a malignant neoplasm in the genital tract of women married to circumcised men is less frequent than
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Iowa User on 05/30/2015
in
married to uncircumcised It is an incontestable fact at this point that there are more deaths each year from complications of circumcision than from cancer of the penis. In addition, there are no solid data to prove that the end of man's arrogance is related to the risk of malignancy in the female. Perhaps the only sound argument for routine circumcision of the male came from World War II, during which soldiers in the South women
men.
