Natural History of Impetigo II. ETIOLOGIC AGENTS AND BACTERIAL INTERACTIONS ADNAN S. DAJANI, PATRICIA FERRIERI, and LEWIS W. WANNAMAKER From the Departments of Pediatrics and Microbiology, University of Minnesota Medical School, Minneapolis, Minnesota 55455 A B S T R A C T Intensive observations on 37 children in a population with endemic skin infections provided an opportunity to study the interrelationships between and the significance of the bacterial genera commonly associ- ated with impetigo. Cultures of the respiratory tract, three normal skin sites, and lesions, when present, were taken three times weekly from July to October 1969. Impetigo developed in all 37 children. Group A strepto- cocci alone were recovered from 21% of 361 lesions, Staphylococcus aureus alone from 8%, Staphylococcus epidermidis alone from 5% and mixtures of streptococci and staphylococci from 61%. Vesicular or pustular lesions were more often pure streptococcal than pure staphylococcal. Streptococci alone were more often recovered from early stage lesions rather than from later ones. The pure staphylococcal lesions characteristically occurred early in the season whereas streptococcal or mixed lesions had later peaks. Serial observations on 74 lesions revealed longer per- sistence of streptococci than staphylococci in mixed le- sions. In 85% of the instances the same streptococcal serotype was recovered repeatedly from an individual lesion, whereas staphylococcal types changed in 57% of instances. Phage type 75 accounted for the majority of staphylo- coccal isolates from all sites, whereas phage type 54 was recovered only from skin lesions. In contrast to streptococci, the site sequence of staphy- lococcal spread was from the nose to normal skin to skin lesions. This work was presented in part at the American Pedi- atric Society meetings in Atlantic City, N. J., 28 April- 1 May, 1971. Dr. Dajani is a recipient of a Research Career Develop- ment Award from the National Institute of Allergy and Infectious Diseases. Dr. Ferrieri was a Career Investigator Fellow of the American Heart Association. Dr. Wanna- maker is a Career Investigator of the American Heart Association. Received for publication 11 April 1972 and in revised form 6 July 1972. These studies reveal important differences in the nli- gration of staphylococci (as compared with streptococci) to various body sites and suggest a subsidiary role for staphylococci in nonbullous impetiginous lesions yielding both organisms. INTRODUCTION In the past two decades, several studies from various parts of the world have amply confirmed that Group A beta hemolytic streptococci and Staphylococcus aureus are the two bacterial genera most commonly recovered in human impetigo (1-7). Two separate clinical entities are believed to exist: (a) a bullous impetigo, the lesions of which, after rupture, form a thin varnish-like crust and are associated with staphylococci in phage group II, notably type 71; (b) a thick crusted variety which may be ephemerally vesicular in the early stages and yields either streptococci alone or a mixture of strepto- cocci and staphylococci. The clinical, bacteriological, and epidemiological contrasts between these two forms of im- petigo have been discussed in a recent review (8). Most previous reports indicate that in the majority of instances, cultures of impetiginous lesions yield mixtures of streptococci and staphylococci (4-8). Some observers propose that such lesions represent a third variety of im- petigo, caused by the combined action of the two genera. Conversely, it may be quite possible that this group may merely represent one or the other type of impetigo sec- ondarily infected with the other genus. The interrelationships between and the significance of these two bacterial genera in impetigo remain poorly understood. This may be due, in large part, to the paucity of information based on serial observations of the early development and the natural history of human impetigo. The present reports describe a prospective study of im- petigo designed to investigate the bacteriology and epi- demiology of the disease in a group of children before, during, and after the development of skin lesions. In an The Journal of Clinical Investigation Volume 51 November 1972 2863
Transcript
Natural History of Impetigo
II. ETIOLOGIC AGENTSANDBACTERIAL INTERACTIONS
ADNANS. DAJANI, PATRICIA FERRIERI, and LEWIS W. WANNAMAKER
From the Departments of Pediatrics and Microbiology, University of MinnesotaMedical School, Minneapolis, Minnesota 55455
A B S T R A C T Intensive observations on 37 children ina population with endemic skin infections provided anopportunity to study the interrelationships between andthe significance of the bacterial genera commonly associ-ated with impetigo. Cultures of the respiratory tract,three normal skin sites, and lesions, when present, weretaken three times weekly from July to October 1969.Impetigo developed in all 37 children. Group A strepto-cocci alone were recovered from 21% of 361 lesions,Staphylococcus aureus alone from 8%, Staphylococcusepidermidis alone from 5% and mixtures of streptococciand staphylococci from 61%.
Vesicular or pustular lesions were more often purestreptococcal than pure staphylococcal. Streptococci alonewere more often recovered from early stage lesions ratherthan from later ones. The pure staphylococcal lesionscharacteristically occurred early in the season whereasstreptococcal or mixed lesions had later peaks.
Serial observations on 74 lesions revealed longer per-sistence of streptococci than staphylococci in mixed le-sions. In 85% of the instances the same streptococcalserotype was recovered repeatedly from an individuallesion, whereas staphylococcal types changed in 57% ofinstances.
Phage type 75 accounted for the majority of staphylo-coccal isolates from all sites, whereas phage type 54 wasrecovered only from skin lesions.
In contrast to streptococci, the site sequence of staphy-lococcal spread was from the nose to normal skin to skinlesions.
This work was presented in part at the American Pedi-atric Society meetings in Atlantic City, N. J., 28 April-1 May, 1971.
Dr. Dajani is a recipient of a Research Career Develop-ment Award from the National Institute of Allergy andInfectious Diseases. Dr. Ferrieri was a Career InvestigatorFellow of the American Heart Association. Dr. Wanna-maker is a Career Investigator of the American HeartAssociation.
Received for publication 11 April 1972 and in revisedform 6 July 1972.
These studies reveal important differences in the nli-gration of staphylococci (as compared with streptococci)to various body sites and suggest a subsidiary role forstaphylococci in nonbullous impetiginous lesions yieldingboth organisms.
INTRODUCTIONIn the past two decades, several studies from variousparts of the world have amply confirmed that Group Abeta hemolytic streptococci and Staphylococcus aureusare the two bacterial genera most commonly recovered inhuman impetigo (1-7). Two separate clinical entitiesare believed to exist: (a) a bullous impetigo, the lesionsof which, after rupture, form a thin varnish-like crustand are associated with staphylococci in phage groupII, notably type 71; (b) a thick crusted variety whichmay be ephemerally vesicular in the early stages andyields either streptococci alone or a mixture of strepto-cocci and staphylococci. The clinical, bacteriological, andepidemiological contrasts between these two forms of im-petigo have been discussed in a recent review (8).
Most previous reports indicate that in the majority ofinstances, cultures of impetiginous lesions yield mixturesof streptococci and staphylococci (4-8). Some observerspropose that such lesions represent a third variety of im-petigo, caused by the combined action of the two genera.Conversely, it may be quite possible that this group maymerely represent one or the other type of impetigo sec-ondarily infected with the other genus.
The interrelationships between and the significance ofthese two bacterial genera in impetigo remain poorlyunderstood. This may be due, in large part, to the paucityof information based on serial observations of the earlydevelopment and the natural history of human impetigo.The present reports describe a prospective study of im-petigo designed to investigate the bacteriology and epi-demiology of the disease in a group of children before,during, and after the development of skin lesions. In an
The Journal of Clinical Investigation Volume 51 November 1972 2863
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FIGURE 1 Patterns of prevalence of impetigo in six families. (No observations were madeduring the 13th week. Family 3 was incorporated in the study at the beginning of the 5th wk.)
accompanying communication (9), detailed analysis ofthe site sequence and familial spread of streptococci ispresented. The present communication focuses primarilyon the etiology of impetigo and the interaction of thebacterial genera associated with this infection.
METHODS
Clinical material. The subjects of these studies were 37children belonging to six families at the Red Lake IndianReservation in northern Minnesota. Details of the durationand frequency of observations, sites of cultures, and strep-tococcal methods and studies were presented in the previousreport (9). The six extra children included in this com-
munication belong to one family that was not included inthe companion report (9) because of the infrequent re-
covery of streptococci from members of that family.Staphylococcal studies. One bacterial colony morpho-
logically identified as staphylococcal was picked from eachoriginal plate. In instances when morphologically differentcolony forms were detected, several colonies were picked.Pure cultures were propagated in vials containing 3 ml ofTryptic Soy Broth (Difco, Detroit, Mich.) and after incu-bation at 370C for 18-24 hr were frozen at - 20'C forfurther testing. All isolates were tested for mannitol fer-mentation and for coagulase production, the tube test beingutilized for the latter. All mannitol negative and coagulasenegative strains were considered Staphylococcus epidermidis.Coagulase positive, mannitol positive strains were classifiedas S. aureus, and were phage typed by standard techniques(10). If no reaction was demonstrable at routine test dilu-tion (RTD), the concentrated phage was used at 100 XRTD. A disc of methicillin (5 ,ug) was placed on the agarplate at the time of phage typing to test for any resistantstrains (11).
RESULTS
Prevalence and bacteriology of lesions. At the com-
mencement of the studies on July 1, 1969, 11 of 30children seen at the time had skin lesions. Impetigodeveloped in all 37 children at one time or anotherduring the study period. A sharp increase in skin lesionswas observed in the middle of July, the peak persisteduntil the end of August, and then a rapid declineoccurred. Inter-family differences were observed rela-tive to the prevalence, peak, and persistence of thedisease. Fig. 1 graphically illustrates the various pat-
terns in the six families. Comparison of family 1 withfamily 6 shows that while in the former most memberswere afflicted for the major part of the study period,little disease occurred in family 6 with only one sharppeak in the 4th wk of July. All 37 children were ob-served once in November and none had any evidenceof impetigo.
A total of 361 skin lesions was cultured, and theselesions represented various stages of impetigo. Lesionswere considered in a relatively early stage if they were
vesicular or pustular without any evidence of crusting.Crusted lesions were considered of longer duration andrepresentative of a later stage. The 361 lesions were
cultured on 755 occasions. Table I shows the distribu-tion of the various bacterial genera recovered from thelesions. In the over-all picture (total cultures at allstages), streptococci and staphylococci coexisted in themajority of instances (61%). S. aureus was more com-
2864 A. S. Dajani, P. Ferrieri, and L. W. Wannamaker
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TABLE I
Bacterial Genera Isolated from 361 Skin Lesions
Distribution of culture results
fl-hemolytic S-hemolyticCultures strep. strep.
0-hemolytic S. aureus S. epidermidis + + NoDescription of lesions Category No. strep. only only only S. aureus S. epidermidis organisms
monly associated than S. epidermidis with streptococci.In 619 instances (82%) beta hemolytic streptococci,either alone or along with staphylococci, were isolatedfrom the total cultures from lesions. Group A ac-counted for 611 (98.6%) of the beta hemolytic strep-tococcal isolates, with Group G accounting for the re-maining 8 (1.4%). In 562 instances (74%) staphylo-cocci, either alone or along with streptococci, were iso-lated from the cultures.
Comparison of lesions in an early stage with ones ina later stage (Table I) indicates that while cultures ofboth types of lesions were more often pure streptococcalthan pure staphylococcal, the streptococcal predomi-nance is more pronounced in the early stage lesions.Furthermore, recovery of streptococci alone from cul-tures of early lesions occurred more frequently thanfrom cultures of later lesions. Both of these observa-tions suggest the possibility of a primary role forstreptococci in the initiation of the process.
Comparison of the initial cultures from the 361 lesionswith subsequent cultures from the same lesions (TableI) shows some interesting differences. All subsequentcultures of early stage lesions were mixed (streptococcaland staphylococcal). In later stage lesions recovery ofstaphylococci alone (S. aureus as well as S. epider-midis) was half as frequent for subsequent cultures asfor initial cultures. However, recovery of streptococcialone from these lesions was somewhat more frequentin subsequent cultures as compared with initial ones.
Among the early stage lesions, approximately equalnumbers of vesicular and pustular lesions were noted.No difference as to the distribution of bacterial isolateswas observed between the two types of lesions.
The temporal recovery of the various organisms fromskin lesions during the study period was analyzedfurther, and the results are shown in Fig. 2. This figureillustrates the frequency of skin lesion cultures con-
taining beta hemolytic streptococci alone, S. aureusalone, S. epidermidis alone and mixtures of streptococciwith staphylococci for each week of the study period.Recovery of beta hemolytic streptococci, alone or alongwith staphylococci, gradually increased and reachedhigh levels during the 5th to the 9th wk of the study.This corresponded to the last few days in July and allof August. In sharp contrast, recovery of S. aureusalone from skin lesions had an earlier and shorter peak.During the last 2 wk in July (weeks 3 and 4) 43 ofthe 64 pure S. aureus lesions can be accounted for.Little recovery of S. aureus alone occurred before or
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FIGURE 2 Distribution of the 755 lesion cultures as to theorganisms recovered by week of study.
Etiologic Agents and Their Interaction in Impetigo 2865
TABLE I IRelation of Initial to Final Flora in 74 Lesions
Serially Cultured
Initial flora Final flora
Pure streptococcal (17)* Pure streptococcal (7)Mixedt (10)
Pure staphylococcal (3) Pure staphylococcal (1)Mixed (2)
Mixed (54) Pure streptococcal (13)Pure staphylococcal (4)Mixed (37)
* Figures in parentheses refer to number of lesions containingthese flora.I Mixed: streptococcal and staphylococcal.
after that period. Additional analyses of the S. aureusrecoveries will be presented later on in this paper.
Flora of lesions cultured repeatedly. Further con-firmation of the primary role played by streptococci inthe impetigo seen in this particular population resultedfrom sequential culturing and close observation of 74impetiginous lesions. Each such lesion was serially cul-tured at least three times (range 3-13 times, mean 4.9times) over a period of 6 days or longer (range 6-31days, mean 12.6 days) until spontaneous healing oc-curred. The cultural data, expressed as initial and finalflora from these 74 lesions, are shown in Table II. Of17 lesions yielding only beta hemolytic streptococci oninitial culturing, the streptococci persisted in all in-stances. Among the 54 lesions yielding both organismson initial cultures, streptococci persisted longer in 13lesions (24%) whereas staphylococci outlasted strepto-cocci in only four lesions (7%).
More conclusive evidence of a subsidiary role forstaphylococci was obtained when the bacterial isolatesfrom these 74 lesions were examined for changes instrains. A change in serological identity of a strepto-
LesionI
T12I Strep. IT2 Ti2S. oureus I|-
TABLE II I
Changes in Strains fromi 74 Sequentially Cultured Lesions*
Distribution of isolates fromsubsequent cultures
Bacterial isolates frominitial culture Same strain Different strain
Group A streptococci 61 (85%) 1 1 (15%)(72 lesions)
S. aureus 28 (43%) 37 (57%)(65 lesions)
* In two lesions streptococci were never recovered, and innine lesions staphylococci were never isolated.
coccal strain was considered present if a definite altera-tion in T-protein agglutination pattern or M-proteinprecipitation reaction occurred. A change in staphylo-coccal 'phage type (60 of 65 instances) or an alterationof antibiotic sensitivity pattern for a nontypable strain(5 of 65 instances) was considered evidence for achanges in staphylococcal strain. Table III shows ananalysis of changes in bacterial strains recovered fromsequentially cultured lesions. In 72 lesions where strep-tococci were repeatedly isolated, the same streptococcalstrain persisted in an individual lesion in 61 instances(85%); a change occurred in only 11 instances (15%).In marked contrast, a change in staphylococcal typeoccurred in 37 of 65 (57%) lesions from which thisgenus was isolated repeatedly.
Fig. 3 presents three examples of sequentially cul-tured lesions. In the first lesion a streptococcus identi-fied as T-12 by T-agglutination was the sole organismrecovered repeatedly over a period of 27 days. In thesecond lesion streptococci and staphylococci coexistedfor the 1st wk, during which time a change in thestaphylococcal phage type occurred. The same strep-tococcal type was recovered throughout the 3 wkperiod and no staphylococci were present in repeatedcultures taken during the last week. The third lesion
T12 T12
2 |3-Strep 1M57 M57Soureus NT NT
M57 M57NT 75
M57 M57 M57M57M57
s3-Strep. T12 T12 T123 Soureus - 54 54
l I/ 5
T12 T12T12T1254 54 54 75
Ti2
I/0 /5
Day of Culture
T12 T1275 81/42E/54
20 25 30
FIGURE 3 Examples of longitudinal bacteriologic findings in sequentially cultured lesions.
2866 A. S. Dajani, P. Ferrieri, and L. W. Wannamaker
again illustrates the persistence of the same strepto-coccal strain over a period of I month with threechanges occurring in the staphvlococcal p)hage pattern s.
Distributtion of stopl/ vlococcol pl/i ofc types. A totalof 1252 S. (110itiS isolates wvas recovere(l (luring thestut(lvy perio(l: 276 isolates from the resl)pitory tract(predominantlv fromn the nose ), 471 isolates fromll n0or-mal skin sites, and 505; isolates from skill lesionls. Noneof the isolates Was resistant to methicillin. IPhage tvp-ing at RTI) or 100 X RTD was successful oIn 978 iso-lates (78 ). The majority of tile staphylococcal iso-lates wvere tVl)alle only -with concentrated l)hage.
The distrihution of staplIhVlococcal phage typ_)es atvarious hodv- sites for the total population of 37 chil -dren (luring the study l)erio(l is shown in 4io . Plhaety-lie 75 accounted for thle maLjoritV of stall dVlococcalisolates from the resl)iratOrV tract (6 101-nal skill(68(W ), and( skin lesions (58c ). It was encountere(dthroughout thle suimmer -with no particular peak at anysingle tinme. I'lhage type 81 stal)hvlococci. like pliagetvl)e 75, Nvere recovere(l from tile reslpiratorv tract, nor-mld skill, and skill lesion-s hut in much less frequency(approximatelyv 3%; for all sites). However, phage txpe79 stapIh-lococci were encountere(l unv1 in the respilra-tory tract ( and phage typ)e 54 were recovered oil \yfrom skin lesions (12- ) The aIlllmost total ahsenceof pliage group TI stalphylococci types 3A, 3C. 55, aml71 ) should he eml)hasize(l.
\When the (listril)ution of the stalilhylococcal tpl)es inlifferent families was analxzed, marked varliatiolls were
note(d, as shown in Fig. 5. Inl this figure, family uinit Ais a composite of families 1 and 4 since these twofamilies geographically- and sociallxv represent an ex-
Resp/r-aloiyTract
Family Unit
Family UnitBr
fespira/or-yTract
/lorma!Skin
Ski/t-Lesibns
PHAGE - 75 F l 8/ ED 79TYPES 808//42E/54 54 EDNontypoble
Others
Il( iRE 4 Distributiiin of staph-lococcal phage types atdifferent bodv sites for the total studv population.
panded fanily unit. For similar i-eas( ins, families 2 and3 are rel)resentedl as family unit B. As can he noted, illfamily uinit A. phage tx-pe 75 stalihxlococcus accountsfor vil-ttally aLl tIme staphxlococcal isolates at all three>ites. Ill Conltrast, other pliage tx-pes were more com-monlx encounteied in faniilx- unit B al thoughIihlgetl ie 75 remained the singcle most coiiimmon staiphylo-coccus at all sites. Agaill the occurrence of plhagetxple 54 in skimn lesions onl\ in hoth family units isevi(leilt. Ill families 5 and 6 almlost all the staphx-l-Oc(ccal, isolates froiii varioiius odv sites wx-ere non-
tylpahle.Family 6 exhiibited certain othei elii(lellologic (lis-
tinctiolns hlen coml)ared with the rest of the studygIroup. It has lieen pointe(l out alreadv (Fig. 1) thatlittle disease occurred in memhers of this family. Therewas a, total of 26 lesions ill the six children of thisfanmilx- and these lesions were ctultured on 33 occasions.
N/orma!Skin/
SkinLesilns
I
PHAGE - 75 EJ 8/ E Vonrtypab/eTYPES M 8//42E/54 = 54 3 Others
Fmi( I<} 5 I)istrihution of staplyx-loci(cal pihage tx-lies in two family Units.
Etiologic Agents IWd I heiir JnteriyiCfion in Imo petiao
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TABLE IVDistribution of Various Staphylococcal Phage Types in Mixed
* Streptococcal and staphylococcal.t Pure staphylococcal.
17 of these lesions occurred in the two youngest chil-dren (ages 4 and 6 yr). Of the 33 cultures of lesions,22 (67%) were pure staphylococcal (14 S. aureus and8 S. epidermidis), four were mixed streptococcal andstaphylococcal, and only two had pure beta hemolyticstreptococci. In five instances no organisms were re-covered. All the pure staphylococcal lesions occurredin July. Because of the very infrequent recovery ofstreptococci from this family it was not included inthe previous report (9).
Pure staphylococcal lesions. Detailed analysis oflesions yielding only S. aureus from all 37 children wasmade in an attempt to differentiate such lesions fromones yielding streptococci or mixtures of streptococciand staphylococci. Of the 64 lesions in which only S.aureus was recovered there were 43 single lesions fromwhich the organism was isolated repeatedly in pure cul-ture. Of these 43 lesions, 39 (91%) occurred in Julyand only 4 (9%) in August or later. The 43 lesionswere equally distributed among the various families.The increased frequency of staphylococcal lesions infamily 6 mentioned above is perhaps more apparent asa result of the paucity of streptococcal disease in thisfamily.
TABLE VSite Sequence of Spread of Phage Type 75 S. aureus
in 25 Children
Duration
Sequence of appearance Frequency Range Mean
daysNose prior to skin 12/20* (60%) 1-27 10.7Nose prior to lesion 13/20* (65%) 2-32 13.2Skin prior to lesion 17/25 (68%) 2-20 11.1
* In five children the organism never was isolated from thenose.
None of the 43 pure staphylococcal lesions was bull-ous in appearance. There were four vesicular and threepustular lesions and the others were crusted. The crustsof these lesions were distinct from others in that thestaphylococcal crusts were thin, varnish-like, and lightbrown in color. Crusts of lesions yielding streptococcieither alone or along with staphylococci were similarto each other. They- were thick, yellowish, and friable.The 43 pure staphylococcal lesions were equally dis-tributed among younger and older children. It was ourclinical impression that these lesions spontaneouslyhealed much faster than ones containing streptococci.
The phage type distribution of the S. aureus isolatesfrom cultures of lesions yielding only this organismwas compared with the general distribution of thestaphylococcal types from cultures of mixed lesions.As shown in Table IV, some differences were foundin the distribution of phage types in pure or mixed cul-tures of lesions. Phage type 75 staphylococci werepresent less frequently in pure staphylococcal culturesthan in mixed ones (P = 0.05). Phage type 54 staphyl-ococci were never isolated from normal skin or therespiratory tract, and there was a tendency for lessfrequent recovery of this phage type 54 in pure formin cultures of skin lesions (P < 0.1, > 0.05). Amongthe staphylococci recovered more frequently in pureform, 18 isolates were nontypable. No particular phagetypes predominated among the 10 isolates in the mis-cellaneous group.
Site sequence of staphylococcal spread. The previouscommunication (9) about the site sequence of strepto-coccal spread in the same population of children hasindicated the appearance of streptococci on normal skinbefore the occurrence of skin lesions, with delayed ap-pearance in the respiratory tract. When the appearanceof staphylococci on various body sites of an individualwas examined, a distinctly different sequence of spreadwas noted. Detailed analysis of the sequence of staphyl-ococcal spread was possible for phage type 75 staphyl-ococcus only, since other phage types were either en-countered infrequently or were restricted in distributionto a particular body site. Table V shows the sequenceof spread of phage type 75 staphylococci from one siteto another in 25 children who developed lesions fromwhich this organism was recovered. In most instancesthe organism appeared in the respiratory tract beforeits recovery from normal skin sites or from lesions.Recovery of this staphylococcus from normal skin be-fore the nose occurred in six instances, and in twoinstances simultaneous appearance of the organismoccurred in the nose and on the skin. Similarly, in mostinstances the organism appeared in the nose beforedevelopment of lesions with this type. The staphylococ-cus was recovered from lesions before nose in only six
2868 A. S. Dajani, P. Ferrieri, and L. W. Wannamaker
instances, and was simultaneously recovered from thesesites in one instance. In 17 of 25 instances the organismwas recovered from normal skin sites before its appear-ance in skin lesions, and in the remaining eight in-stances the recovery of the organism from normal skinsites followed its recovery from lesions.
DISCUSSIONThe results of this study, in agreement with many othersfrom various parts of the world, indicate that Group Abeta hemolytic streptococci and staphylococci are thepredominant bacterial genera recovered from impetigi-nous lesions. The interrelationships between and the sig-nificance of these two bacterial genera in impetigo arestill poorly understood and have been the subject ofconsiderable controversy among pediatricians, bacteriolo-gists, and dermatologists. Simpson (12) reviewed theliterature dealing with the relative importance of strepto-cocci and staphylococci in this disease. The author pro-posed the "impetigococcus" as the single organism re-sponsible for skin lesions, basing conclusions primarilyon epidemiologic observations that contacts of an indexcase usually develop impetigo but no other clinicalmanifestations of streptococcal or staphylococcal infec-tion. While subsequent studies have failed to confirm aunitarian etiology of impetigo, they did delineate cer-tain distinctive features of the staphylococcal and strep-tococcal isolates from impetiginous lesions (8).
Detailed analysis of the streptococcal isolates from thepresent studies have been presented in a previous com-munication (9). The data presented now strongly sug-gest a primary role for streptococci in the pathogenesisof the nonbullous impetigo characteristically seen in thispopulation. Three major observations support this con-clusion. Firstly, when pure cultures were obtained frominitial cultures of early lesions, streptococci were morecommonly isolated (36%) than staphylococci (9%),and streptococci alone were more often recovered frominitial cultures of lesions in early stages (36%) ratherthan from those in a later stage (17%). This suggeststhat streptococci may be the initiators of the process andthat staphylococci are more likely to be secondary in-vaders. In the case of S. epidermidis this seems par-ticularly true since these organisms were never recoveredalone from early stage lesions. Secondly, observation onthe 74 serially cultured lesions indicate that streptococcioutlasted staphylococci in mixed lesions. Of the 54 initiallymixed lesions, 13 (24%) ultimately became pure strepto-coccal, as opposed to only 4 (7%) that became purestaphylococcal. The third and perhaps the most con-clusive evidence for the subsidiary role of staphylococci,however, stems fromn analysis of the changes in typepatterns in sequentially cultured lesions. Significantchanges occurred in the staphylococcal strains in indi-
vidual lesions serially cultured, whereas the same strep-tococcal strain persisted in 85% of the instances. Thiswould suggest repeated contamination of a streptococcallesion with staphylococci that are part of the residentflora of the skin or the respiratory tract.
Additional evidence for the secondary role of staphylo-cocci in impetigo yielding both staphylococci and strep-tococci on culture can be found in analyses of treatmentstudies. In experimental impetigo, healing of pure strep-tococcal lesions is comparable to healing of mixed lesionscontaining penicillin-resistant staphylococci in animalstreated with penicillin G (13). Similar results have alsobeen reported by other investigators with regard to theefficacy of penicillin G alone in the treatment of non-bullous, human impetigo (14, 15). Such studies do notnegate the possibility of staphylococci as initiators ofimpetigo, but would certainly strongly suggest that inmixed lesions these organisms probably do not play aprimary role in perpetuating the process.
In the present study 43 lesions yielded pure culturesof S. aureus on repeated culture. These lesions exhibitedcertain unique features. The great majority of thesestaphylococcal lesions appeared in July and were virtu-ally absent thereafter, a finding similar to that previouslyreported by Epstein (16). Their clinical appearance wasdistinct and they healed faster than streptococcal lesionsor mixed streptococcal and staphylococcal lesions. Ofinterest is that 36 (84%) of these purely staphylococcallesions were crusted and thus probably represented le-sions in a later stage. Since the staphylococcal phagetypes in the 43 lesions were not unusual and since thesame phage types continued to be present throughout thestudy period, it is difficult to ascribe any special dermato-tropic potential to these staphylococci.
That certain staphylococci are primary skin pathogensis a well-documented observation. Phage group IIS. aureus (3A, 3C, 55, and 71) have been repeatedly in-criminated as the etiologic agents of bullous impetigo(5, 8, 17, 18). Phage type 71 S. aureus possesses manyunique features including production of a bacteriocin(19, 20) which is markedly bactericidal to Group Abeta hemolytic streptococci in vitro and in vivo (20, 21).An implication of these experimental studies is that phagetype 71 staphylococci may secondarily invade a pre-existing streptococcal skin lesion and eradicate the strep-tococci from it. Since many strains of phage type 71produce this bacteriocin, these studies also imply thatstaphylococcal lesions of the bullous type which comn-monly contain these organisms may resist secondary in-fection with streptococci. The data presented hereneither refute nor support these hypotheses since phagetype 71 S. aureus was virtually absent from this groupof children at all sites throughout the study period.
Etiologic Agents and Their Interaction in Impetigo 2869
'Respiratory Tract
FIGURE 6 Contrasting patterns of streptococcal and staph-ylococcal sequences of spread. (The pattern for Group Astreptococci is shown on the left hand side of the figure;that for S. aureus on the right hand side.)
The recovery of phage type 54 staphylococcus fromskin lesions only suggests that it, like phage group II,may be a primary skin pathogen. This seems unlikely,however, for several reasons. There were no distinguish-ing features of the clinical appearance of skin lesionsfrom which phage type 54 staphylococci were isolated,and the distribution of these staphylococci in lesions wassimilar to that of other staphylococci.
Most studies dealing with the etiology of skin infec-tions indicate the occasional presence of coagulase nega-tive staphylococci in lesions, usually in association withGroup A streptococci. While the data presented heredoes not define a definite role for these organisms, cer-tain considerations deserve some discussion. S. epidermi-dis alone was never recovered in the present studies inearly lesions, but was present as the sole organism in8% of initial cultures of later lesions. The presence ofS. epidermidis alone in later lesions raises the possibilityof production of antibiotic-like substances by these or-ganisms that are bactericidal to streptococci. Such sub-stances have indeed been isolated from coagulase nega-tive staphylococci and much more commonly than fromS. aureus (22). Studies to define a possible role of thisorganism in human skin infection are therefore war-ranted.
Frequent monitoring of this group of children has en-abled clarification of several epidemiologic distinctionsbetween streptococci and staphylococci in a populationat high risk of developing impetigo. Staphylococci alonewere recovered from skin lesions much more commonlyin July than in later months. In contrast, streptococcalrecovery rates from skin lesions were constant through-out the observation period and paralleled the over-allprevalence of skin infections in the population of children.
Definite differences are also evident in the sequenceof spread of the two genera to various body sites. InFig. 6 is a diagrammatic presentation of this sequence.The reservoir(s) from which both of these organisms
originate remains unknown and definitely requires fur-ther epidemiologic exploration. For both organisms, ap-pearance of a particular strain oin normal skin occursbefore recovery from skin lesions in the majority ofinstances. Once the organisms appear on normal skin,lesions develop if local environmental conditions are ap-propriate. The role of trauma in initiating the processis probably quite significant. The peak incidence of im-petigo in this and other populations occurs in the summermonths, at which time skin is more exposed, is moreeasily traumatized mechanically and the likelihood ofinsect bites and poison ivy are present. The distributionof lesions as compared with the distribution of strepto-cocci on normal skin (9) and attempts to produce imn-petigo experimentally in man (8, 23) are also consistentwith the view that trauma may play an important role inthe initiation of infection.
The initial site of deposition of a streptococcal strainis the normal skin (Fig. 6). A streptococcal strain wasnever found in the respiratory tract before its appearanceon normal skin or in a skin lesion (9). In marked con-trast, a staphylococcal strain colonizes the respiratorytract first then appears on normal skin before appear-ance in lesions. The predominance of staphylococcal re-covery early in the season and the differences in sequenceof spread of staphylococci and streptococci may havesignificant epidemiologic implications with regard to thereservoirs of these impetiginous organisms in nature andto their transmission from one individual to another.
ACKNOWLEDGMENTSThe authors acknowledge Dr. Jonathan B. Jensen for hisassistance in the epidemiologic studies. Judith Jaqua andJerry Stanke rendered valuable technical assistance in thestaphylococcal identification.
This work was supported by U. S. Public Health Servicegrant AI-09527 and was conducted under the sponsorship ofthe Commission on Streptococcal and Staphylococcal Dis-eases, Armed Forces Epidemiological Board, and supportedby the U. S. Army Medical Research and DevelopmentCommand under contracts Nos. DADA-17-70-C-0081 andDADA-17-70-C-0082.
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