For debate

~
(
For debate
Br. J. Surg. 1990. Vol. 77. March.
260-264
D. Kingston
D. V. Seal
and
Microbial Pathogenicity Research
Group, Clinical Research Centre,
Watford Road, Harrow, Middlesex
HA 1 3UJ, UK
Correspondence
Mr D. Kingston
lo:
We have reVieli'ed spreading ÜifeClions of lhe dermis, li'ilh special
reference lo lhe imporlance of synergy in lheir causalion. Evidence for
lhis is accumulaling fi'om bOlh clülical sludies and frol11 sludies Ül
laboralory animals. Necrolizing fasciilis (rapid spread over 2411)cal1
be caused by fJ-haemolylic slreplococci, somelülles li'ilh Staphylococcus
aureus, or by mixed üifeclions of aerobes al1d anaerobes, often of gUl
origino Al1imal sludies provide good evidel1ce lhal S. aureus can
polentiale tlle fJ-llaemolylic streptococcal üifeclion in necrolizing
fasciitis. There is also evidence thal mixlures of aerobes and anaerobes
can act synergistical/y, bul animal modelsfor necrotizing fasciilis llave
nol been developed. Anaerobic cel/ulitis (variable rate of spread from
110urs,to days) can be caused by mi.\"ed aerobes and anaerobes or by
mixed closlridia. Animal studies provide good evidence for S}'llergy in
lhe former. Meleney's S}lnergistic postoperative gangrene (SIOI\1spread
over Ii'eeks) may be cutaneous al110ebiasis:tlle animal model of Brelt"er
and Meleney relates to the more rapid üifections of anaerobic cel/ulitis.
Keywords: Bacterial synergy, anaerobic cellulitis, cutaneousamoebiasis,Meleney's synergistic
gangrene,necrotizing fasciitis, streptococcalgangrene
This paperdiscussesthe microbiology of spreadinginfections of
the dermis. This compartment consists of a loose network of
libres containing blood vessels,lymphatics and fat, bounded
on one side by the epidermal basementmembraneand on the
other by the tight connective tissue fascia of the muscle. We
wish to draw attention to the evidence that many of these
infections seemto be caused by synergy betweentwo or more
organisms. By synergywe mean that the mixtures of organisms
causemore severeinfections than eachofthe organismssingly.
By the term mixed infection we imply that the pathogenic effect
is no greater than the sum of the damage caused by infection
with each organism alone. Clinical isolates often consist of
mixtures of organismsand it is common practice to report only
the organism that is regarded as the (single)pathogen.We are
therefore accustomed to think only of single pathogens.
Although there is muchevidencethat synergycanbe important,
it is in practice often disregarded.
What evidenceis required to establishthe role of synergy
in these infections? Firstly competent bacteriology needsto be
carried out and all the organisms recorded. Many synergistic
infectionsinvolve anaerobicbacteriaand satisfactorytechniques
for culturing fastidious anaerobes are of fairly recent
introduction and are still far from universal. Our experience
has been that homogenization of tissue specimens is algo
important for culture. Valuable additional evidence can be
found from serologyl..2,and electron microscopycan showthat
the tissue contains a mixture of microcolonies of different
organisms3. Even if it is established,however, that a genuine
mixed culture is generally present in these infections, it can
always be argued that th~r~ is still only a single pathogenand
that the other organisms are irrelevant colonizers of necrotic
tissue. Thus it becomes essential to establish a convincing
animal model to demonstrate synergy. Satisfactory animal
models are not easyto establish and need careful analysis. It
is very unfortunate that, in our view, the famous animal model
of Brewer and Meleney4 (anaerobic streptococcus and
Staph}lococcus aureus)is unrelated to the disease(Meleney's
postoperative 'synergistic' gangrene)which it was developedto
explain. Because the crucial difference between the animal
model and the diseaseis the speedof progressionof the lesion,~
we intend to discuss the different clinical syndromes divided
into three different rates of progression. Rapidly progressive
infections, the first category (e.g. necrotizing fasciitiss-8),have
atime coursemeasuredin hours,the second,moderatelyrapidly
progressiveinfections (e.g.anaerobic cellulitiss.6),are measured
in days and the third, very slowly progressiveinfections (e.g.
Meleney'spostoperativesynergisticgangrene4.9),
are measured
in weeks.A simplified summaryis given in Table1. It is probable
that this grouping of spreading infections of the dermis is an
arbitrary division of a continuum. The question also arisesas
to whether very similar syndromes should be differentiated
becausetheyarecausedby differentorganisms(c.f.pneumonia).
Rapidly progressive infection (hours)
Human sludies
Swartz6lists eight syndromesfalling under this head of rapidly
progressiveinfections, of which for the presentwe excludetwo
asbeing primarily diseasesofthe muscle (streptococcalmyositis
and gas gangrene -clostridial myonecrosis)oThe remaining
syndromes are streptococcal gangrene, necrotizing fasciitis,
synergistic cellulitis, non-clostridial anaerobic celluJitis, bacteraemic Pseudomonasgangrenous cellulitis and necrotizing
cutaneous mucorrnycosiso These infections are still very
serious; Ahrenholz8pro videsa table showing that the mortality
rate for necrotizing fasciitis remains unchanged at about
40 per centoFurther, theserapidly progressiveinfections usually
need early surgical intervention. We intend to discussthe first
two in this section,and the remaining four under the head of
moderately rapid progressiono
Necrotizing fasciitis begins with a patchy erythema of the
skin that is swollen and painfulo The edge is not raised and
demarcated,as in erysipelas,and lymphangitis is absent. The
patient is febrile, later becoming toxaemic, with confusion and
disorientationo After 24 h, dusky purple afeas develop with
blistering and bullae, while the erythema and tissue oedema
spread further oRapid necrosis of subcutaneoustissue occurs
with deepundermining of ulcerated afeas but superficialto the
fasciallayer. Examination of necrotic tissueshowsfocal abscess
formation with widespreadthrombosis of small arterioles and
Synergistic
microbial
gangrene: D. Kingston and D. V. Seal
1"able1 Spreadings.vnergisticilifections of the derlllis and h)podermis
Clinical entity
Anaerobic cellu)itis
Spreadingulcers
decubitus
Rate of spread
Hours or days
Principal microbial cause
Animal model
Clinical sub.types
BHS:!:S. aureus
24
Streptococcal gangrene 7.10
Mixed aerobesjanaerobes
Non-streptococcal
fasciitis 1S-20
Mixed aerobesjanaerobes
Fournier's gangrene (male
genitalia )13
necrotizing
Mouth anaerobes
68,69
Noma, cancrum orisl4 (mouth)
Mixed clostridia
-
Clostridial
Mixed aerobesjanaerobes
4, 54 (59-67)
Non-clostridial anaerobic
cellulitisl4.28
anaerobic cellulitis26.27
¡
I
i
ti
Days or weeks
t¡
,. !
Mixed aerobes/anaerobes36-38
tropical
BHS:t: S. aureus39.42
Mixed aerobes/anaerobes40.41
diabetic root
Mixed aerobes/anaerobes43.44.46
ti"
, 1
-
t" ¡
,
~
Meleney's 'synergistic'
gangrene(u)cer)4.9.'3
Weeks
Cutaneousamoebiasis74.7' (Weeks)t
\;
?Entamoebahisioó.tica9
-*
EntamoebahistolJ'tica
(73)
Numbers refer to selectedreferentes,those in brackets refer to Iessclose!yrelated work. (73) is a review of Entamoebafhacterialinteractions, not
a description of an animal model; BHS, f¡'-haemolyticstreptococci; * we do not consider that Meleney's animal model adequately reproduces the
disease;t rapid progression sometimesoccurs (reference74)
venules7; adjoining muscleand skin shows comparativelylittle
inflammation. Streptococcal gangrene is the form caused by
p-haemolytic streptococcus.The substantial early description
by Meleneyl0 was of a p-haemolytic streptococcal infection,
but in nine of his 20 casesa Staphy/ococcuswas also isolated.
We cultured S. aureus and p-haemolytic streptococcusas a
mixed infection from six of 36 patients7, and Hammar and
Wagner11 from four of eight patients. Other causative
organisms in most instances are mixed cultures of intestinal
originS.6.B, and it is therefore not surprising that this
form of necrotizing fasciitis is most commonly (though far from
exclusively) associated with abdominal wounds or surgeryS
(including dental drainageI2). We do not considerthis sufficient
grounds for making it into a separateclinical entity. The same
comment applies to Fournier's gangrene13 (streptococcal
gangreneor necrotizing fasciitis ofthe male genitalia)and noma
(gangrenous stomatitis). Noma is predominantly (but not
exclusively)caused by anaerobic bacteria found in the mouth,
namely fusiform bacteria and spirochaetesl4. It is difficult to
find good clinical descriptions of the development of this
disease,but it probably develops in the submucosalconnective
tissueofthe mouth. Howeverthe similarity ofthis to the dermis
and the similarity of the microbiology leads us to classify it
with necrotizing fasciitis. Further studies on the bacteriology
ofnon-streptococcal necrotizing fasciitis can be foundI3.1S-23;
others are cited by Feingolds.J4, Swartz6, AhrenholzB and
ourselves24. Development of reliable anaerobic techniques
has shown that the isolation of mixed flora is common in many
infectionsl4. Direct examination by electron microscopy of
necrotic tissue from three patients with necrotizing fasciitis
showed that small microcolonies of many different bacteria
were scattered throughout the tissue3.Thus a genuine mixed
infection was present in the tissue and it was not an artefact
of sampling. Recent studies with oral bacteria have suggested
that co-aggregationmay be important in bringing this about2S.
Animalstudies
In our animal model for streptococcal gangrene24 we found
that intradermal injection of {J-haemolytic streptococcus into
the flank of New Zealand white rabbits gave rise to a spreading
lesion (cellulitis or necrotizing fascijtis) on only 12per cent of
occasions, but on 50 per cent of occasions when co-injected ~'ith
an abscessproducing strain of S. aureusand on 75per cent of
occasions when co-injected with crude staphylococcal cx-lysin
at a titre which would give infIammation without necrosis.
Whether or not a given infection produced necrotizing fasciitis
or spreading cellulitis dependedto some extent on the site of
injection. Thus in one group, at th"einjeétion site nearest the
head, ten spreading lesions developed from 13 injections of
which six were diagnosedas necrotizing fasciitis. At other sites
there were 13spreadinglesions from 18injections ofwhich one
was so diagnosed.We concluded that synergy with S. aureus
facilitates the developmentofthis rapidly spreading lesionoWe
did not investigate whether other bacteria or their toxins could
substitute for S. aureus,or ifincreasedamounts o( streptococcal
lysinswould substitute for staphylococcal:x-lysin.There is much
animal work suggesting that synergy between aerobic and
anaerobic bacteria can have great pathogenic significance,but
this falls short of a model for necrotizing fasciitis and will be
discussedin the next section.
Progressive
infection
of modera te rapidity
(days)
Human studies
In this section we discuss infections with a variable rate of
progression from the moderately rapid to the very rapid. We
also include a discussion of spreading ulcers (decubitus, tropical
and diabetic foot) becaue ofthe similarity oftheir bacteriology.
Cellulitis also begins with erythema ofthe skin that is swollen
and painful. Deep blistering and ulceration with necrosis does
not occur; superficial blistering, however, can be presento The
patient may be febrile but is not toxaemic. The spreading
erythematous edge is difTusely demarcated, but is not
raised, while Iymphangitis can be present together with
Iymphadenopathy. In severe cellulitis due to {J-haemolytic
streptococcus group A or S. aureus, patients respond to
benzylpenicillin or cloxacillin therapy within 7 days. Failure to
respond together with incipient necrosis suggests that
thrombosis of subcutaneous vessels has occurred.
Clostridial26.27 and non-clostridial14 anaerobic cellulitis
difTer froin necrotizing fasciitis in that there is much less pain
and systemic toxicity and minimal discoloration of the skin.
The two types of cellulitis present very similarly28. Clinically
it is important to distinguish the condition from incipient gas
ffl
f ¡
1. !
Synergistic
microbial gangrene: D. Kingston and D. V. Seal
gangreneand surgical exploration may be required to exclude
muscle involvement, followed by debridements.The causative
organisms of clostridial anaerobic cellulitis are a mixture of
clostridia with Clostrídíum sporogenes being that. most
commonly isolated26. Non-clostridi~l anaerobic cellulitis is
usually associatedwith a mixed flora consisting of two or more
ofthe following: Escheríchíacolí, Klebsíellaspecies,streptococci,
anaerobic streptococciand BacteroídesspeciesI4.26.28.
Synergisticnecrotizing cellulitis29can be non-crepitant (due
to p-haemolytic streptococcus and S. aureus), or crepitant,
when a variety of gut organismsare isolated, often anaerobic.
It is associatedwith diabetes and there is frequently muscle
involvement,thus putting it outside our remitoSwartz6regards
the crepitant type asa variant of (non-streptococcal)necrotizing
fasciitis but it seemsto us to be a more severe manifestation
of non-clostridial anaerobic cellulitis in which the infection has
spread to the muscle. Another syndrome listed by Swartz6 in
this category is infected vascular gangrene which we exclude
as being an infection of ischaemicmuscle. However, we note
that it is commonly a mixed infection (Proteus species,
Bacteroídesspecies,anaerobic streptococci), as is anaerobic
streptococcal myonecrosis (anaerobic streptococci and phaemolytic streptococcusor S. aureusI4.26).
Bacteraemic Pseudomonas
gangrenouscellulitis and necrotizing cutaneous mucormycosis may be synergistic infections.
The latter, algo called phycomycotic gangrenousceIlulitis, is a
rafe, rapidly progressive and serious diseaseS.30.31.
Correct
diagnosis (involving histological demonstration of hyphae)is
essential;treatment includes debridementand amphotericin B.
Apart from patients with severebums there is a substantial
associationwith diabetes,or with other diseaseswith impaired
host response30-32.
In the two casesreported by Wilson el a1.32
a variety of bacteria was algo presentin the infected tissue,but
we cannot be certain of the significance of this observation. It
is, however, clearly possible that the bacteria may contribute
to the pathogenesis. The Pseudomonasinfections occur in
various forms6.33.34of which gangrenous cellulitis seemsthe
most relevant. There has also been an account of 48 casesof
noma neonatorumassociatedwith Pseudomonas
septicaemia3S.
We are perturbed by the absenceof anaerobic bacteriology
carried out in studying these severe spreading infections
ascribedto Pseudomonas
speciesand considerthat there is some
possibility that they may be the mixed infections of necrotizing
fasciitis or non-clostridial anaerobic celIulitis, or that these
diseasesare subsequentlyinfected by pseudomonads.This is
particularly true of noma, which is usualIy associatedwith the
anaerobic mouth flora 14.
A serious and common ulcer whose possible bacterial
causation is rarely discussedis the decubitus ulcer. While the
initial stepis most probably ischaemicnecrosisdue to pressure,
the bacterial flora is very similar to that of non-streptococcal
necrotizing fasciitis or non-clostridial anaerobic celIulitis36-38.
Its relation to thesetwo syndromesand the animal studiescited
later lead us to the opinion that the mixed aerobic and anaerobic
bacteria presentcontribute to the spread of this lesion and are
not just irre!evant co!onizers of necrotic tissue. Tropical ulcers
are interesting in that two types of bacterial flora are reported
corresponding to streptococcal and non-streptococcal necrotizing fasciitis, namely p-haemolytic streptococcus and S.
aureus39,or mixtures of aerobic and anaerobic organisms
(though the anaerobes seemto be predominant!y of mouth
origin)14.40.41.In an earlier paper42we suggestedthat a tropical
phagedaeniculcer might representlocalized necrotizing fasciitis
caused by p-haemolytic streptococcus. A similar situation
occurs in diabetic foot infections though the isolation
of p-haemolytic streptococcus seems to be relatively
uncommon43-46.
There are, of course,severa! spreading bacterial infections
of the dermis where only one organism is involved: we are not
saying that bacterial synergyis always responsiblefor spreading
infections of the dermis, merely that it often may be. Such
infections include erysipelas, lupus vulgaris, cutaneous
amoebiasisand cutaneousLeishmaniasis.A caseof necrotizing
fasciitis was reported causedby Haemophilusi'!t7uen=aetype b
(Reference 22) and various cases of cellulitis have been
attributed to it47.48. Similar attributions have been made to
Vibrio rulnificus21 and to Aeromonas species49.50,both
associated with injuries contaminated by polluted water.
Erysipelas2.11is of interest here in that it is not streptococcal
necrotizing fasciitis. It is possible that the haemolytic
streptococciinvolved are deficient in some virulence factor or
factors, or that theseare neutralized by the immune response
of the patient. The Mycobacterium ulcerans infection (Buruli
ulcer)is of interest in that it is a spreadingnecrotic lesion51,52;
we feel that synergy with other bacteria should be excluded.
Animal studies
Brewer and Meleney4.53described an animal model, further
investigated by Mergenhagenel al. 54, in which cultures of an
anaerobic streptococcusand S. aureuswere injected into the
skin of various animals. This resulted in a synergistic infection
causing an afea of acute gangrene within 48h. Within 5 days
the tissue had separatedat the margin and sloughedoff. Both
organisms were recovered from the lesiono (The original
description ~'as of a non-haemolytic microaerophilic Streptococcus, but it would only grow properly under anaerobic
conditions and its cultural characteristics would now classify
it as an anaerobic Streptococcus.)
This is an important animal
model for infections of moderate rapidity. Other experimental
studies of mixed infections are of ovine foot rot and the more
seriousdiseaseinfective bulbar necrosis55-57.
The studiesofthe
latter55 suggest that a leukocidin produced by Fusiformis
(Fusobaclerium)/lecrophorusand a growth factor produced
by CorY/lebacterium
pyogeneswere the agents in the synergy.
Studies of necrobacillosis in mice showed that a wide variety
of organismscould act synergisticallywith F. necrophorum~8.
A
study of synergy between Bacleroides asaccharol.vlicusand
Klebsiellapneumo/liaesuggestedthat the agentwas a succinate
elaborated by the Klebsiella59.An earlier study60,61had sho\\'n
ihat a combination of E. coli and Bacteroidesjragilis or
Fusobacteriumrarium would give rise to intra-abdominal
abscesses
in rats whenthe organismsindividually would not, It
was also shown that caecalcontents would give rise to wound
abscessescontaining mixed cultures, and pure culture of B.
jragilis and B. melaninogenicuswould not, but that the pure
cultures mixed with sterile caecalcontents also causedabscess
formation61. Another study showed that E. coli and B.jragilis
could causewound infections wheninoculated at levelsat which
individually they could not do S062. Studies of pelvic
infIammatory diseaseimplicate a wide variety of bacteria63.
Animal studies suggest a synergistic Tole for mixtures of
Neisseriagonorrhoeaeand Bacteroidesspecies,possibly by the
promotion of encapsulationof both organisms64.There was a
generaltendencyfor mixtures of anaerobicand aerobic bacteria
to act synergistically64-67,
including StreplococCUs
milleri (Slr.
intermedius) combined with Bacteroides species. Other
workers68,69studied the combination of fusobacteria and
spirochaetesfound in ulcerative and necrotizing infections of
the oropharynx. They found that the two organisms gro\\'n
together gave many more severe lesions on intracutaneous
injection into rabbits than either injected separately. To
summarize,thereis a considerablebody of evidencefrom animal
studies that synergy can be of great importance in these
infections, though only some of it4.24,53.59
refers specificallyto
spreading infections,
Very slow progressive infection (\\eeks)
Human studies
In this category we only wish to discussone syndrome,namely
'Meleney'ssynergisticgangrene'.Meleney..S3describedboth a
diseaseand an animal model, but we do not consider the two
to be related. The human diseasedescribed by Meleneyis of a
severe but very slowly progressing infection, 'extending only
one or two centimetres in the course of a week or ten davs'.
According to FeingoldS: 'postoperative progressivegangr~ne
Synergistic microbial gangrene: D. Kingston and D. V. Seal
might be a better term, sincethe infection almost always begins
at an abdominal or thoracic operative wound site and
frequently where wire retention sutures are employed. The
appearance(and bacteriology)are characteristic.A fewdays to
a fewweeksafter operation a tender, red, swollen,and indurated
afeadevelopsnearthe wound. This slowlyevolvesinto a shaggy
ulcer with gangrenous purple margins fading into an
oedematous,erythematous periphery. Without treatment the
courseis one of relentlessspread to enormous size with severe
pain but little accompanyingtoxicity. Multiple fistulous tracts
and extensive undermining may occur; this lesiono also
describedby Meleney,has beencalled chronic burrowing ulcer
or Meleney's ulcer.'
However, according to Davson et al.9: 'Postoperative
cutaneousamoebiasiscan exhibit preciselysimilar features.The'
topography is essentiallytruncal and the onset often delayed;
severepain and inexorable progressionare characteristic.The
triple zonation of colour and the serpiginous outline exactly
mimic those present in Meleney's synergisticgangrene.
It must be accepted that, clinically, the two entities are
indistinguishable and it follows that a certain diagnosis of
Meleney's synergistic gangrene is not feasible on clinical
grounds'.
Referenceto case reports is confusing as this very slowly
progressinginfection was sometimesconfusedwith the rapidly
progressive necrotizing fasciitis or anaerobic cellulitis, and
adequate bacteriology was not always carried out. Meleney70
statesthat amoebaewere not found on histological examination
of material from all five of bis cases 'by three different well
trained parasitologists', but Davson et a1.9draw attention to
the need for suitable staining techniques(periodic acid Schiff).
80th of these authors draw attention to studies other than
Meleney's where amoebae were found. Meleney isolated a
'microaerophilic' Streptococcusand S. aureusfrom two of bis
patients, However, while Davies, Wallace and Irving71 found
the lesion in their patient to be bacteriologically sterile other
investigators found various bacteria to be present (e.g.
Willard72 found p-haemolytic streptococcuswith S. aureusand
E. coli). Thus we cannot acceptFeingold's assertionthat there
is a characteristic bacteriologys. Thesepossibilities need to be
borne in mind in treatment. Entamoebahistolytica requires low
oxygen levels for growth, and claims have been made of
successfultreatment with hypebaric oxygen.
We are impressedby the arguments of Davson et a1.9that
cutaneous amoebiasis is probably the correct diagnosis of
Meleney's synergistic gangrene. There are however some
reservations. Cutaneous amoebiasis is rafe, even following
amoebic abscesses.If E. histolJ-.ticais the cause of Meleney's
postoperative gangrene, then the gangrene should be more
common in countries where amoebic infection (or carriage of
invasive strains)ismore common. We also believethat bacterial
cqcktails can produce serious diseaseand could contribute to
the pathogenesisof cutaneousamoebiasis;there is also the effect
of bacteria on the growth rate and possible pathogenicity of E.
histolytica73. It is much to be hoped that all casesdiagnosed
as Meleney's synergistic gangrene will be studied for both
bacterial and amoebic infection using the appropriate methods
(cultural, serologicaland histological). Further information on
amoebic diseasecan be found73-76.
Animal sludies
The animal model4, which has already been discussed, would
seem to relate to non-clostridial anaerobic cellulitis in that it
runs a moderately rapid course (gangrene in 48 h, sloughing
within 5 days). We do not consider that its rapid progression
is relevant to the slowly spreading infection of the human
disease. Mirelman 73 cites evidence that bacteria can affect the
acting synergistically. The afea has been a difficult one. The
relatively infrequent occurrence of cases has the result that
consensusas to what is a significant syndrome is only slowly
reached. Further the grouping joto syndromesis probably an
arbitrary division of a continuum and eachsyndrome may have
a variety of microbial causes.The bacteriological aspect has
been handicapped by two facts. One is the fairly recent
introduction of satisfactory techniques for handling the
fastidious strict anaerobes which are still not available in all
microbiology laboratories. The other is the strong inbuilt
assumption that microbial diseaseshave a single microbial
cause,and that other organisms isolated are irrelevant. This
last assumption is an aspect of the important principIe of
Occam's razor77 ('entia non sunt multiplicanda praeter
necessitatem'-no more things should be presumed to exist
than are necessary),but we think we have demonstrated that
it is necessaryto considerbacterial synergy.Thus we hope there
will be further studies on a substantial number of well
-=haracterizedpatients using good anaerobic techniques and
with necessaryback up from serology, histology and electron
microscopy. AlI isolates should be considered potentially
synergistic,but this can only be demonstratedin animal models
which properly reproduce the infection within an appropriate
time periodoWe summarize our views in Table1 but recognize
that it will need revision. However we hope it pro vides a
continuing basis for debate.
Acknowledgements
We are very grateful to numerous friends and colleagues for
commenting on this review.
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Paper accepled5 Seplember 1989