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Update: Clostridium difficile
91
Infectious Diseases Newsletter
college-aged populations. In order for a community to deal effectively with such outbreaks, we must: (i) know what to expect; (2) recognize it in occurring;and (3) organize our efforts at control. In this article, I've dealt with what we can expect. In a future article, I plan to discuss recognition and management strategies. Vincent A. Fulginiti, M.D. Professor and Head Department of Pediatrics Arizona Health Sciences Center References i.
Hadler, SE, et al., N Engl J Med 302:1222, 1980. --2; Picketing, LK, et al., J Pediatr 99:51, 1981. 3. Vernon, AA, et al., Am J Epidemiol 115:325, 1982. 4. Storch, G, et al., J A ~ 242:1514, 1979. 5. Black, RE, et al., Pediatr 60:486, 1977. 6. Doyle, A, Pediatr 58:687, 1976. 7. Granoff, DM, et al., Pediatr 63:397, 1979. 8. Black, RE, et al., Am J Epidemiol 113:445, 1982. 9. Strangert, K, Pediatr 57:191, 1976. i0. Glezen, WP, et al., J Pediatr 78:397, 1971. ii. Shaw, PK, et al., J Infect Dis 134:414, 1976. 12. Orkin, M,'JAMA 236:1136, 1976. UPDATE:
CLOSTRIDIUM
DIFFICILE
The discovery of new etiologic agents accounting for diarrheal and enterocolitis syndromes has been one of the most active fields in infectious diseases over the past ten years. As discussed in an earlier issue of the Newsletter (Vol. i, No. 10, p. 2, Nov. 1981), the association between Clostridium difficile and antibiotic-associated diarrheas has been one such area in which reasonable diagnostic methods have reached the clinical laboratory. With the application of cultural and cytotoxin detection methods to ever larger numbers of patients it is not surprising that some notes of caution are now being raised as to their interpretation. While the association between the presence of C. difficile itself and/or its cy~otoxin and antibiotic-associated pseudomembranous colitis (PMC) is very strong, it does not necessarily follow that the presence of
the organism or toxin in stool should be equated with disease. The puzzling frequency of C. difficle and its toxin in healthy infants is an obvious example. Clostridium difficile has been isolated from infant stools in rates ranging between 30% and 60%, and 27% to 63% of healthy neonates may have toxin positive stools. Large bowel colonization levels as high as 107 organisms per gram of feces have been seen without disease. Colonization occurs in both breastand formula-fed infants although it generally starts earlier and reaches higher numbers in the latter group. This colonization may be stable during the first year of life but carriage rates begin to fall in the second year. 5 Even in adults with antibiotic-associated diarrhea, interpretation can be a problem. In a recent study reported by George, Rolf, and Finegold at UCLA, 223 patients from the Wadsworth VA Medical Center and other western United States hospitals were evaluated by culture and cytotoxin detection techniques. 1 In patients with documented PMC, C. difficile was detected in 89% and its cytotoxin in 83% of cases. In patients in which PMC was not documented, however, the organism or toxin were present in less than 40% of cases. In addition, C. difficile was isolated in 5 of 28 patTents with various conditions associated with diarrhea (Crohn's disease, ulcerative colitis). Two of these patients had not been treated with an antimicrobic. These investigators suggest diagnosis of C. difficile induced diarrhea be limited ~o cases where diarrhea develops in association with an antimicrobial agent and there are: (I) positive laboratory studies (positive culture or cytotoxin); (2) endoscopy or barium enema evidence of PMC; and (3) a response to oral vancomycin where such therapy is indicated. A significant proportion of patients who have antibiotic-associated diarrhea (but not PMC) probably also have C. difficile disease. Whether culture or cytotoxin positivity are sufficient to define these cases is the question now being raised. Further studies of p a t h o genesis (see below) will probably be necessary to resolve these issues. Studies on the mechanisms involved in C. difficile, PMC and diarrhea are beginning to shed light on some of these questions. It is clear now that C. .difficile produces at least two toxin~, now called toxin A and toxin B. These toxins have been purified 2 and have different biologic activities. 3, 4 The
9 1982 by Elsevier Science Publishing Co., Inc.
92 Infectious Diseases N e w s l e t t e r
A toxin has potent enterotoxic properties. It illicits a hemorrhagic fluid response in rabbit intestinal loops and a positive fluid accumulation response in infant mice. The B toxin lacks these enterotoxic properties but is a potent cytotoxin (tissue culture). Although the A toxin has weak cytotoxic properties, it appears likely that the tissue culture assay used for diagnosis is detecting only the B toxin. It seems possible that antibiotic-associated diar"rhea and PMC are overlapping syndromes depending on the quantity and type of toxin produced. Further understanding of the biologic effects of.these toxins in humans would surely improve our ability to interpret these diagnostic tests. Until then, the:~solation of C. difficile and detection of its cytotoxin in stool specimens remain useful when interpreted together with clinical and epidemiologic findings. Kenneth J. Ryan, M.D. Professor of Pathology Chief of Clinical Microbiology Arizona Health Sciences Center References i. 2. 3.
4. 5.
George, LW, Rolfe, RD, Findgold, SM, J Clin Microbiol 15:1049, 1982. Sullivan, NM, Pellett, S, Wilkins, TD, Infect Immun 35:1032, 1982. Lyerly, DM, Lockwood, DE, Richardson, SH, Wilkins, TD, Infect Immun 35:1147," 1982. Libby, JM, Jortner, BS, Wilkins, TD, Infect Immun 36:822, 1982. Stark, PL, Lee, A, Parsonage, BD Infect Immun 35:895, 1982.
OTITIS MEDIA:
IS ANYTHING
NEW?
Otitis media (OM) is a disease recognized since antiquity but until recent times, poorly understood and inadequately studied. A few dedicated workers (Klein, Howie, Coffey, Bass, Nelson, Lepow, Mortimer, Paridise, Bluestone and others) and their colleagues have labored in the past two decades to bring OM into the 20th century. Advances have been made in our knowledge of pathogenesis, etiology, diagnosis, epidemiology and prognosis. Despite these considerable gains, we still have unanswered questions such as: ~i. 2. 3.
Does every child with OM need to receive antibiotics? Does myringotomy have any place in initial therapy? How long do we treat; if we do, with what and what do we do if there's no response?
4. 5.
6.
Which child has his blood cultured? Which his CSF examined? When is OM chronic or persistent or recurrent? When it is, what do we do? Are tympanostomy tubes effective? Does medical "decongestion" work? Can we inflate the middle ear effectively? (Do the Valsalva and Politzer methods really work?) How do we treat chronic draining OM?
The way in which I've proposed these questions suggests that we have no answers. That is not entirely true but the skeptic in me suggests that the answers we have are far from clear. For example, a recent study of OM in 84 children 2 to I0 years old (note omission of infants in which most of the q u e s t ~ above are pertinent) demonstrated no clinical differences, no change in failure rate and no difference in frequency of recurrence between three and ten days of amoxicillin. 1 The British investigators estimate more than one million pounds in health care costs could be saved by deleting seven days from the usual course. But, we must remember they selected a thin slice of the OM-prone population. The Boston group showed that OM occurred in 15-20% of more than 2500 children but was minimal after 6 years. 2 They and others point out the peak prevalence is between 6 and 36 months. 3 Hence, one cannot generalize too readily from the London study. Even more iconoclastic was the study reported from Holland in which 171 children (again aged 2 to 12 years) were treated in double-blind fashion with nothing, o_~r myringotomy alone, o_~r antibiotics alone, or antibiotics and myringotomy. 4 Va~-- Buchem and colleagues found no significant differences in clinical course, audiography, or recurrence rate among their groups. They do note a nonstatistically significant longer time of drainage or healing of the tympanic membrane in the groups not receiving antibiotics. They advocate use of nose drops and analgesia initially for OM, reserving myringotomy and antibiotics for those children with "irregular courses." Looking closely at their data: (i) 31 patients were excluded for a variety of reasons, not all well specified but including failures~ (e.g., OM on the other side within 14 days of otitis); (2) further earache was rated severe in 131 initially but dropped to 20 within 24 hours; (3) after 14 days there were 4 children with draining ears, all had not received antibiotics. One is hard-pressed to place these reports in the perspective of the total
9 1982 by Elsevier Science Publishing Co., Inc.
Infectious Diseases Newsletter
college-aged populations. In order for a community to deal effectively with such outbreaks, we must: (i) know what to expect; (2) recognize it in occurring;and (3) organize our efforts at control. In this article, I've dealt with what we can expect. In a future article, I plan to discuss recognition and management strategies. Vincent A. Fulginiti, M.D. Professor and Head Department of Pediatrics Arizona Health Sciences Center References i.
Hadler, SE, et al., N Engl J Med 302:1222, 1980. --2; Picketing, LK, et al., J Pediatr 99:51, 1981. 3. Vernon, AA, et al., Am J Epidemiol 115:325, 1982. 4. Storch, G, et al., J A ~ 242:1514, 1979. 5. Black, RE, et al., Pediatr 60:486, 1977. 6. Doyle, A, Pediatr 58:687, 1976. 7. Granoff, DM, et al., Pediatr 63:397, 1979. 8. Black, RE, et al., Am J Epidemiol 113:445, 1982. 9. Strangert, K, Pediatr 57:191, 1976. i0. Glezen, WP, et al., J Pediatr 78:397, 1971. ii. Shaw, PK, et al., J Infect Dis 134:414, 1976. 12. Orkin, M,'JAMA 236:1136, 1976. UPDATE:
CLOSTRIDIUM
DIFFICILE
The discovery of new etiologic agents accounting for diarrheal and enterocolitis syndromes has been one of the most active fields in infectious diseases over the past ten years. As discussed in an earlier issue of the Newsletter (Vol. i, No. 10, p. 2, Nov. 1981), the association between Clostridium difficile and antibiotic-associated diarrheas has been one such area in which reasonable diagnostic methods have reached the clinical laboratory. With the application of cultural and cytotoxin detection methods to ever larger numbers of patients it is not surprising that some notes of caution are now being raised as to their interpretation. While the association between the presence of C. difficile itself and/or its cy~otoxin and antibiotic-associated pseudomembranous colitis (PMC) is very strong, it does not necessarily follow that the presence of
the organism or toxin in stool should be equated with disease. The puzzling frequency of C. difficle and its toxin in healthy infants is an obvious example. Clostridium difficile has been isolated from infant stools in rates ranging between 30% and 60%, and 27% to 63% of healthy neonates may have toxin positive stools. Large bowel colonization levels as high as 107 organisms per gram of feces have been seen without disease. Colonization occurs in both breastand formula-fed infants although it generally starts earlier and reaches higher numbers in the latter group. This colonization may be stable during the first year of life but carriage rates begin to fall in the second year. 5 Even in adults with antibiotic-associated diarrhea, interpretation can be a problem. In a recent study reported by George, Rolf, and Finegold at UCLA, 223 patients from the Wadsworth VA Medical Center and other western United States hospitals were evaluated by culture and cytotoxin detection techniques. 1 In patients with documented PMC, C. difficile was detected in 89% and its cytotoxin in 83% of cases. In patients in which PMC was not documented, however, the organism or toxin were present in less than 40% of cases. In addition, C. difficile was isolated in 5 of 28 patTents with various conditions associated with diarrhea (Crohn's disease, ulcerative colitis). Two of these patients had not been treated with an antimicrobic. These investigators suggest diagnosis of C. difficile induced diarrhea be limited ~o cases where diarrhea develops in association with an antimicrobial agent and there are: (I) positive laboratory studies (positive culture or cytotoxin); (2) endoscopy or barium enema evidence of PMC; and (3) a response to oral vancomycin where such therapy is indicated. A significant proportion of patients who have antibiotic-associated diarrhea (but not PMC) probably also have C. difficile disease. Whether culture or cytotoxin positivity are sufficient to define these cases is the question now being raised. Further studies of p a t h o genesis (see below) will probably be necessary to resolve these issues. Studies on the mechanisms involved in C. difficile, PMC and diarrhea are beginning to shed light on some of these questions. It is clear now that C. .difficile produces at least two toxin~, now called toxin A and toxin B. These toxins have been purified 2 and have different biologic activities. 3, 4 The
9 1982 by Elsevier Science Publishing Co., Inc.
92 Infectious Diseases N e w s l e t t e r
A toxin has potent enterotoxic properties. It illicits a hemorrhagic fluid response in rabbit intestinal loops and a positive fluid accumulation response in infant mice. The B toxin lacks these enterotoxic properties but is a potent cytotoxin (tissue culture). Although the A toxin has weak cytotoxic properties, it appears likely that the tissue culture assay used for diagnosis is detecting only the B toxin. It seems possible that antibiotic-associated diar"rhea and PMC are overlapping syndromes depending on the quantity and type of toxin produced. Further understanding of the biologic effects of.these toxins in humans would surely improve our ability to interpret these diagnostic tests. Until then, the:~solation of C. difficile and detection of its cytotoxin in stool specimens remain useful when interpreted together with clinical and epidemiologic findings. Kenneth J. Ryan, M.D. Professor of Pathology Chief of Clinical Microbiology Arizona Health Sciences Center References i. 2. 3.
4. 5.
George, LW, Rolfe, RD, Findgold, SM, J Clin Microbiol 15:1049, 1982. Sullivan, NM, Pellett, S, Wilkins, TD, Infect Immun 35:1032, 1982. Lyerly, DM, Lockwood, DE, Richardson, SH, Wilkins, TD, Infect Immun 35:1147," 1982. Libby, JM, Jortner, BS, Wilkins, TD, Infect Immun 36:822, 1982. Stark, PL, Lee, A, Parsonage, BD Infect Immun 35:895, 1982.
OTITIS MEDIA:
IS ANYTHING
NEW?
Otitis media (OM) is a disease recognized since antiquity but until recent times, poorly understood and inadequately studied. A few dedicated workers (Klein, Howie, Coffey, Bass, Nelson, Lepow, Mortimer, Paridise, Bluestone and others) and their colleagues have labored in the past two decades to bring OM into the 20th century. Advances have been made in our knowledge of pathogenesis, etiology, diagnosis, epidemiology and prognosis. Despite these considerable gains, we still have unanswered questions such as: ~i. 2. 3.
Does every child with OM need to receive antibiotics? Does myringotomy have any place in initial therapy? How long do we treat; if we do, with what and what do we do if there's no response?
4. 5.
6.
Which child has his blood cultured? Which his CSF examined? When is OM chronic or persistent or recurrent? When it is, what do we do? Are tympanostomy tubes effective? Does medical "decongestion" work? Can we inflate the middle ear effectively? (Do the Valsalva and Politzer methods really work?) How do we treat chronic draining OM?
The way in which I've proposed these questions suggests that we have no answers. That is not entirely true but the skeptic in me suggests that the answers we have are far from clear. For example, a recent study of OM in 84 children 2 to I0 years old (note omission of infants in which most of the q u e s t ~ above are pertinent) demonstrated no clinical differences, no change in failure rate and no difference in frequency of recurrence between three and ten days of amoxicillin. 1 The British investigators estimate more than one million pounds in health care costs could be saved by deleting seven days from the usual course. But, we must remember they selected a thin slice of the OM-prone population. The Boston group showed that OM occurred in 15-20% of more than 2500 children but was minimal after 6 years. 2 They and others point out the peak prevalence is between 6 and 36 months. 3 Hence, one cannot generalize too readily from the London study. Even more iconoclastic was the study reported from Holland in which 171 children (again aged 2 to 12 years) were treated in double-blind fashion with nothing, o_~r myringotomy alone, o_~r antibiotics alone, or antibiotics and myringotomy. 4 Va~-- Buchem and colleagues found no significant differences in clinical course, audiography, or recurrence rate among their groups. They do note a nonstatistically significant longer time of drainage or healing of the tympanic membrane in the groups not receiving antibiotics. They advocate use of nose drops and analgesia initially for OM, reserving myringotomy and antibiotics for those children with "irregular courses." Looking closely at their data: (i) 31 patients were excluded for a variety of reasons, not all well specified but including failures~ (e.g., OM on the other side within 14 days of otitis); (2) further earache was rated severe in 131 initially but dropped to 20 within 24 hours; (3) after 14 days there were 4 children with draining ears, all had not received antibiotics. One is hard-pressed to place these reports in the perspective of the total
9 1982 by Elsevier Science Publishing Co., Inc.