REVIEW ARTICLE

Streptobacillus moniliformis-a zoonotic

pathogen. Taxonomic considerations, host
species, diagnosis, therapy, geographical
distribution

Michael Wullenweber
Central Institute for Laboratory Animal Breeding, Dept. Bacteriology & Hygiene, PO Box 910345,0-30423
Hannover, Germany*

Summary
Streptobacillus moniliformis (Sm), the causative agent of rat-bite fever and Haverhill
fever in man, is also a pathogen in certain laboratory and domestic animals. With the
introduction of modern maintenance systems, this microorganism seemed to be
eradicated from laboratory animal units, but recent reports of Streptobacillus
moniliformis (Sm) in colonies of laboratory rodents give evidence that this 'forgotten'
bacterium can still be found even behind hygienic barrier systems.
Although various national and international recommendations on microbiological
screening include Sm, attempts to screen might fail because of insufficient knowledge
about this remarkable bacterium. This article highlights these problems. As there is no
recent review of Streptobacillus moniliformis, present knowledge of this zoonotic agent is
summarized to include: description of the bacterium, its taxonomic position, host
spectrum and clinical importance for animals and man, cultivation, diagnosis, antibiotic
therapy, risk to laboratory personnel (occupational hazard) and geographical distribution.

Keywords Rat-bite feverj Haverhill feverj Streptobacillus moniliformis; laboratory animals;

occupational hazard

Characterization of Streptobacillus microorganism requires media containing

moniliformis blood, serum or ascites fluid; optimum
temperature is 35-37°C. Sm grows
Streptobacillus moniliformis (Sm j is a
optimally under microaerophilic conditions,
Gram-negative, non-motile rod which tends
but also anaerobically and aerobically. It
to be highly pleomorphic. Depending on
exists in 2 variant types, the 'normal'
the mode of cultivation and the age of the
bacillary form and the inducible or
culture, single rods occasionally with
spontaneously occurring L-form which
lateral bulbar swellings, filaments and
exhibits the typical 'fried-egg' colony
chains of variable morphology may be
morphology. The latter is regarded as an
observed (Fig 1). In serum-supplemented
apathogenic Sm variant (Freundt 1956bj.
liquid media, bacterial growth shows a
Key reactions which separate Sm from
typical 'cotton-ball like' appearance.
other biochemically related bacteria are
Cultivation of the fermentative
catalase, oxidase, indole production and
'Present address: Dynamis Zentmm, Steinweg 1, D-30989
reduction of nitrate to nitrite (Savage 1984).
Gehrden, Gennany In all four tests Sm gives negative reactions.
Accepted 5 May 1994 laboratory Animals (1995) 29. 1-15
2 Wullenweber
Fig 1 Gram stain of S. moniliform is AlCC 49567
(Hannover epizootic strain). Microaerophilic
cultivation on sheep blood agar (24 h; 37°C)
Phenotypic characterization of 13 Sm
isolates derived from man, turkey, rat and
mouse performed with classical biochemical
tests (24 carbohydrates, 19 enzymic
reactions) and a commercial enzyme test
system (apiZYMTM,Niirtingen, FRG)
reveals a high degree of conformity. The
only variable characters are acid production
from salicin, aesculin hydrolysis and
activity of trypsin, chymotrypsin and
B-glucoronidase (Hofmann & Wullenweber
unpublished datal. Recently, the first
haemolytic Sm strain isolated from a rat with
otitis media was described (Wullenweber
et a1. 1992). This is now available from the
American Type Culture Collection as
ATCC 49940. Gas-liquid chromatography
analysis of the fatty acid pattern of 7
Streptobacillus moniliformis isolates
including the type strain demonstrated
palmitic, stearic, oleic and linoleic acid as
major components (Edwards & Finch 1986).
Thus, they confirmed previous findings of
Rowbotham (1983) based on 9 Sm strains
including the four isolates from the
Chelmsford epidemic (Shanson et a1. 1983).
Another approach was adopted by Costas
and Owen (1987). On the basis of
numerical analysis of SDS-PAGEprotein
profiles they identified 7 subgroups among
31 Sm cultures representing 22 different
strains of human, murine and avian origin
isolated in Europe, USA and Australia. As
these groups showed a close similarity,
they concluded that Sm is a very homologous
species.
This assessment is supported by the
serological findings of Boot et a1. (in press I
who tested 11 different Sm strains of human
and murine origin for cross-reactivity in an
ELISA.They stated that all Sm strains
studied were clearly serologically related.
In contrast to Costas and Owen (1987),
they neither described differences between
human and murine isolates nor between
Haverhill fever and rat-bite fever strains.
Taxonomy of Streptobacillus
moniliformis
In Bergey's Manual of Systematic Bacteriology
(1984),Sm is placed in section 5: 'Facultatively
anaerobic Gram-negative rods'. Savage
(1984) commented on its taxonomic
position: 'It seems desirable not to ally it
with any particular family until more
definitive taxonomic studies, such as
nucleic acid hybridizations, are done.'
Although these data are still missing
there is some information on the
relationship to other procaryotes.
The mol% G + C of the DNA for the L-
phase variant of Sm is 24-26, and of the
bacillary form 24-25 (Savage 1984, Williams
et al. 1969). Such low GC values are known
only for members of the order Mycoplasmato1es
(Razin & Freundt 19841.
Pachas et a1. (1986) could show that
DNA-DNA hybridization of H3-labelled
Acholeplasma laidlawii DNA with the Sm
type strain (ATCC 14647, human isolate)
gave 21% homology but only 4% with Sm
ATCC 27747 (turkey isolate). Later,
contradictory results were given by the
same group. Thereafter, DNA-DNA
hybridization with various A.laidlawii
strains gave homology values of only 1.1 to
3.3% (Aulakh et 01. 1987). Unfortunately,
the strains used were not further specified.
The same authors use the immuno-
fluorescence technique to investigate the
serological relationship between Sm L-
variants and A. laidlawii. They could not
find cross-reactions between antibodies to
A. laidlawii and Sm (Pachas et 01. 1986).
Our own results, obtained using the same
S. moniliformis-a zoonotic pathogen
technique and of Boot et a1. (in press) using
an ELISA, demonstrated a serological
relationship between A. laidlawii and the
bacillary form of Sm ATCC 49567 and
ATCC 14647 (type strain, own unpublished
data) respectively strain Sm KUN 3 (Koopman
et a1. 1991). Furthermore, we observed cross-
reactivity between Sm ATCC 49567 and rabbit
antisera against A. axanthum, A. oculi and
A. equifeto1e, and no cross-reactivity with
antisera to A. granularum, A. modicum,
A. hippikon, and A. florum lemon (IIF, own
unpublished data. All rabbit antisera against
Mycoplasma spp. and Acholeplasma spp. were
donated by Prof. Kirchhoff, Veterinary School,
Hannover). Moreover, there was no cross-
reaction between antisera against Mycoplasma
arthritidis and M. pulmonis and Sm ATCC
49567 (TIF,own unpublished data).
Thin layer chromatography of acetone-
extracted cells showed the lack of quinones
in Sm ATCC 14647, ATCC 49567 and
ATCC 49940 [Hofmann, unpublished data)
which is in agreement with members of
the genus Mycoplasma (Razin &. Freundt
1984). The polyamine patterns of some
representative Sm strains are specific and
different from those of the alpha-, beta- and
gamma-subclass of the proteobacteria
(Hofmann unpublished data).
Although Streptobacillus shows more
links to some members of the Myco-
plasmatales than to other bacteria (Savage
1984) it is still too early to comment
further on its phylogenetic origin.
Therefore, the question posed by Pachas et
01. (1986) Streptobacillus
I moniliformis: A
new parent for Acholeplasma laidlawii?' is
still not answered, but it seems worth
while to follow this up. Sequencing of the
Sm 16S rRNA genes is in progress in the
Dept. of Bacteriology (Central Institute,
Hannover) with the objective of obtaining
reliable information on its genetic
relatedness to other bacterial groups.
(See Addendum.)
Infectivity spectrum
Humans
Sm is a pathogen for humans. Clinical
pictures of the disease are similar despite
3
two different modes of transmission. Oral
uptake of Sm via contaminated food leads
to a disease known as Haverhill fever,
named after the place where the first well-
documented epidemic was observed in 1926
(Place &. Sutton 1934). Affected individuals
had consumed unpasteurised milk or milk
products to which rats had access. In
another well-documented epidemic
(Chelmsford, UK 1981) boarding school
pupils became affected after using water
from a spring in the vicinity of which rats
were observed (McEvoy et a1. 1987). As in
Haverhill, Sm was not isolated from
captured rats. However, in both cases,
epidemiological data suggested it was most
probable that foodstuffs or water
contaminated by rats were responsible for
the epidemics.
Rats are also the source of the second
type of human streptobacillosis, the so-
called rat-bite fever (RBF). (Another form of
rat-bite fever called sodoku is caused by
Spirillum minus which is not the subject
of this review). Sm can be transmitted by
rat-bite, but, recent reports suggest that
not only the rat-bite but also simple
contact with (pet) rats (Clausen 1987,
Rygg &. Bruun 1992) may result in RBF.
The disease is characterized by an acute
onset with chills, vomiting, malaise,
headache, irregularly relapsing fever,
erythematous rash especially of the
extremities, and arthralgia. Untreated it
often leads to a severe septic polyarthritis
and lymphadenopathy. If untreated,
mortality is estimated to be about 13%
(Roughgarden 1965, Simon &. Wilson 1986).
Complications of streptobacillary rat-bite
fever are endocarditis (Rey et a1. 1987,
Rupp 1992), pericarditis (Carbeck et a1.
1967) brain abcess (Oeding &. Pedersen
1950), amnionitis (Faro et a1. 1980),
septicaemia (Brown &. Nunemaker 1942,
Dellamonica et a1. 1979, Renaut et a1.
1982, Rygg &. Bruun 1992), interstitial
pneumonia, prostatitis and pancreatitis
(Delannoy et a1. 1991).
Raffin and Freemark (1979) suggest that
streptobacillary RBF is a paediatric
problem. Roughgarden (1965) found that
55% of reported cases in the United States
4 Wullenweber
were children under the age of 12. Infants
have died because of an undiagnosed
streptobacillosis (McHugh et a1. 1985, Sens
et a1. 1989), although human streptobacillosis
usually has a good prognosis after appropriate
antibiotic therapy, e.g. with penicillin.
Recent reports describe streptobacillary RBF
in a Greek (Konstantopoulos et a1. 1992) and
a Norwegian child (Rygg & Bruun 1992).
Laboratory animals
Information concerning occurrence,
pathogenicity, epidemiology etc. of Sm for
various laboratory animal species is
summarized in Table 1.
Rat So far as is known, the rat is the
natural reservoir of Sm and therefore plays
the dominant role in harbouring and
transmitting the infectious agent. Most
probably the microorganism is a member of
the commensal flora of the upper
respiratory tract. Hence, main isolation
sites in healthy rats are the nasopharynx
(Strangeways 1933), larynx, upper trachea
(peagle et a1. 1976) and the middle ear
(Koopman et a1. 1991). Although of only
low pathogenicity for the rat, Sm may act
as a secondary invader (Weisbroth 1979) in
conjunction with presumptive pathogens,
such as Pasteurella pneumotropica, Myco-
plasma pu1monis or other PPLO causing
otitis media (Olson & McCune 1968,
Wullenweber et a1. 1992, Boot et ai. in
pressl, conjunctivitis (Young & Hill 1974),
bronchopneumonia (Bell & Elmes 1969)
and chronic pneumonia (Gay et a1. 1972).
Mouse It is well-documented that laboratory
mice may suffer from streptobacillosis. A typical
sign of disease is a septic lymphadenitis
predominantly of the ventral cervical
lymph nodes. Subcutaneous lymph nodes
(inguinal and axillary) can also be involved
in the final phase of disease whereas septic
processes in the mesenteric lymph nodes
are rarely observed (Fig 2). If the mouse
survives the acute stage of infection
without dying of septicaemia, septic
arthritis or polyarthritis (Fig 3) may
develop. In addition to the extremities, the
tail joints and the spinal cord may be
affected. The spleen is usually enlarged and
can be patterned by multiple micro-abscesses
(Kaspareit-Rittinghausen et a1. 1990;
Wullenweber et a1. 1990). Abscesses of the
liver and ovary, pericarditis and purulent
keratoconjunctivitis are limited to
individual cases (Nagel 1991). Septicaemia
is often accompanied by cachexia and is
usually fatal. Sawicki et a1. (1962) found
that Sm caused abortion in pregnant mice.
We studied the course of infection after
oral administration of Sm ATCC 49567
which was isolated during a devastating
epizootic among C57BL/6 mice in our
institute in 1988 (Wullenweber et a1.
1990). At 3 days post infection (dpi) lentil-
sized abscessation in the submaxillary
lymph nodes were observed at necropsy.
About 7 dpi abscessation of the ventral
neck became macroscopically visible as
swellings in the intact mice. Abscesses
were already bean-sized (about 1 cml. If
untreated, the mice died from septicaemia
usually within further 3 to 5 days. Sm
could then be isolated from the affected
lymph nodes, blood and spleen.
Injection of Sm into the tail vein leads
to a septic polyarthritis of the hind legs
without involvement of the lymph nodes
and may lead to a spontaneous amputation
of the affected extremity (Freundt 1956a).
Sm may cause epizootic infections in
stocks of micej 4 are documented (Mackie
et a1. 1933, Freundt 1956a, Sawicki 1962,
Wullenweber et a1. 1990).
In one (Freundt 1956a) the epizootic could
be traced back to contaminated rats as the
source of infection whereas in the other cases
(Mackie et a1. 1933, Wullenweber et a1.
1990) the origin of Sm remained obscure or
was not given (Sawicki et a1. 1962).
Besides animal welfare considerations
and the health risk to personnel, such an
epizootic results in severe economic and
scientific loss, as entry of Sm into a
laboratory animal unit always requires the
subsequent close-down of the entire unit.
On the occasion of the Hannover
epizootic, we observed that only C57BL! 6
mice showed clinical signs of streptobacillosisj
other inbred and athymic strains of mice
remained healthy, and therefore, we assume
S. moniliformis-a zoonotic pathogen 5

Table 1 Occurrence of Streptobacillus moniliformis in laboratory animals (1932-1992)

laboratory animal Status/disease Remarks References

Rat Healthy Caused human infection levaditi et al. 1932

Rat Healthy Caused epizootic in mice Strangeways 1933
Rat Healthy Caused human infection Dawson & Hobby 1939
Rat Healthy Caused human infection Borgen & Gaustad 1948
Rat Healthy Caused human infection Hamburger & Knowles 1953
Rat Healthy Caused epizootic in mice Freundt 1956a
Rat Healthy Caused epizootic in mice Sawicki et al. 1962
Rat Healthy Caused human infection Roughgarden 1965
Rat Healthy Caused human infection Gledhill 1967
Rat Chronic respiratory disease Secondary invader? Bell & Elmes 1969
Rat Healthy Caused human infection Cole et al. 1969
Rat Chronic pneumonia Mixed infection Gay et al. 1972
Rat Conjunctivitis Mixed infection Young & Hill 1974
Rat Healthy Peagle et al. 1976
Rat Meningoencephalitis Katkiewicz 1977
Rat Healthy Caused human infection Anderson et al. 1983
Rat Healthy Koopman et al. 1991
Rat Otitis media Mixed infection Wullenweber et al. 1992
Mouse Streptobacillosis levaditi et al. 1932
Mouse Streptobacillosis Epizootic, origin unknown Mackie et al. 1933
Mouse Streptobacillosis Origin rat Strangeways 1933
Mouse Streptobacillosis Epizootic, origin rat Freundt 1956a
Mouse Streptobacillosis Epizootic, origin rat Sawicki et al 1962
Mouse Not known Caused human infection Gilbert et al. 1971
(No cultivation of Sm)
Mouse Streptobacillosis Epizootic, origin unknown Wullenweber et al. 1991
Guineapig Cervical adenitis Sm sensu stricto? Smith 1941
Guineapig Cervical adenitis Epizootic. Sm sensu stricto? Aldred et al. 1974
Guineapig Cervical adenitis Epizootic. Sm sensu stricto? Fleming 1976
Guineapig Granulomatous pneumonia TypicalSm Kirchner et al. 1992

Gerbilb Healthy Caused human infection Wilkens et al. 1988

'only the report's title is available

bnot from a laboratory animal breeder

that the genetic background of the host

must influence the outcome of infection.
Mackie et al. (1933) and Van Rooyen (1936)
referring to the same epizootic, observed
differences in susceptibility to disease in
two different strains of mice. Levaditi et al.
(1932) observed differences in susceptibility
to streptobacillosis between their
laboratory strain of white mice and wild
mice after experimental infection.
Therefore a study was undertaken to
elucidate the influence of the genetic
background on the course of disease
Fig 2 Natural streptobacillosis in a C57Bl/6Han
IWullenweber et al. 1991). This is now mouse. lymphadenitis of ventral cervical (typical).
complete (Wullenweber et al. in axillary (rare) and inguinal (rare) lymph nodes.
preparation). Briefly, one can state that out (Reproduction with permission of the Paul Parey
of a broad panel of inbred strains of mice, Verlag, Berlin & Hamburg)
6 Wullenweber
Fig 3 Natural streptobacillosis in a C57BL/6Han
mouse. Septic polyarthritis of the extremities. Seealso
swelling of the ventral neck region (lymphadenitis)
only C57BL/6 mice develop the typical
signs of streptobacillosis. AKR/N mice
show a short period of mild illness post
infection, but recover completely. In
contrast to other strains, C57BL/6 and
AKR/N mice exhibit a strong antibody
response. MHC-genes and the ability to
produce functional T- and/or B-cells do not
influence the development of disease.
As genetic host factors are involved in
the disease process, it is most probable that
within a population of outbred mice, one
will find susceptible and resistant animals.
This might explain why experimental
infection of outbred mice, especially if only
small numbers are used, may fail, as was
observed in recent reports (Rygg &. Bruun
1992, Boot et al. in press). To circumvent
these problems, the use of C57BL/6 or
C57BL/10 mice as sentinel animals for
streptobacillosis is recommended.
With respect to the health risk for
laboratory personnel and animal caretakers,
it is important to know whether laboratory
mice can function as clinically silent
carriers of Sm. Savage et al. (1981)
observed that Sm persisted for about 6
months.in infected animals. In contrast to
Levaditi et al. (1932), neither Freundt
(1956a) nor Wullenweber et al. (1990)
could ever isolate Sm from urine and
caecal contents. However, orally infected,
diseased C57BL/6 mice harboured Sm up
to 24 dpi in their nasopharynx, but BALB/c
(which are resistant to streptobacillosis)
were negative from 3 dpi until the end of
the study at 60 dpi (Nagel 1991). During
the Hannover epizootic, we screened about
200 nasopharyngeal swabs from mouse
strains, other than C57BL/6, from the
same unit for Sm. All attempts to isolate
Sm failed. From these observations, it
seems that there is a low risk of the bite of
an inbred mouse, other than a Sm-infected
C57BL/6, transmitting RBF. However, the
situation may be different if outbred strains
of mice or wild mice are used (see also
below, occupational risk).
Guineapig There are 4 reports of disease
caused by Sm in guineapigs (Smith 1941,
Aldred et al. 1974, Fleming 1976, Kirchner
et al. 1992). Kirchner et al. (1992)
described a case of granulomatous
pneumonia. The isolate showed the typical
morphological and biochemical characters
of Sm, and its facultative anaerobiosis. The
other reports on Sm isolated from
guineapigs described an obligate anaerobiont
unable to ferment carbohydrates which is
unusual for Sm sensu stricto. However, the
clinical picture looked very much like
lymphadenitis in acute diseased mice.
Evaluating various aspects of their Sm
isolates, Aldred et ai. (1974) concluded that
they are not identical to those derived from
mice and rats.
Smith's (1941) primary culture grew
anaerobically but became facultatively
anaerobic after a few passages. Two types
of colonies developed, both of bacilli and,
one of them showed extreme pleomorphism.
There was no indication of spontaneous
development of L-forms as described by
Klieneberger (1942). Lack of further
phenotypical characters impede a
comparison with Sm sensu stricto.
Gerbil There is one report giving some
evidence that gerbils might function as
carriers of Sm and thus may transmit rat-
bite fever to humans (Wilkens et al. 1988).
Nothing is noted about its pathogenicity to
gerbils.
Cat Although cat scratches and bites are
repeatedly described (mainly in textbooks)
as possible vectors of transmission of Sm to
man, there is no confirmatory evidence
S. moniliformis-a zoonotic pathogen
that cats act as carriers and transmitters
of Sm.
Gascard et a1. (1967) described a patient
with septicaemia showing typical
accompanying rat-bite fever symptoms after
a cat bite. Although Sm could neither be
isolated from blood culture nor confirmed
by serology, the authors finally diagnosed a
septicaemia due to Sm.
Dog Das (1986) isolated Sm from the
aspirate of an abscess in the left scapula of
a dog. Its growth characteristics, growth on
non-supplemented brain heart infusion
agar, and resistance to an undefined
'majority of antibiotics' is not in
accordance with the Sm sensu stricto. Our
observations and a survey of the literature
[see below) concerning susceptibility to
antibiotics showed a broad spectrum of
antibiotics to be effective under in vitro
conditions. The dog recovered under
'strepto-penicillin' therapy.
Old reports concerning rat-bite fever
acquired after dog-bites should be regarded
as sceptically as those concerning cat bites
and scratches. Study of the original
literature shows that the aetiology of rat-
bite fever is often unclear or can be traced
back to Spirillum (minus?), the causative
agent of sodoku, the other form of rat-bite
fever (Ripley & van Sant 1934).
Other laboratory animals Nothing is
known on the occurrence of 8m sensu
stricto in hamsters, rabbits, ferrets and
primates. Experimental infections of
chickens (Boyer et a1. 1958, Yamamoto &
Clark 1966, Ghinder et a1. 1982), rabbits
and hamsters (Boyer et al. 1958) with
turkey isolates failed. Rabbits inoculated
subcutaneously with Smith's (Smith 1941)
guineapig isolate developed slowly-growing
abscesses at the site of injection. Intra-
testicular inoculation led to a purulent
orchitis. As already mentioned, this isolate
should not be regarded as typical Sm.
Domestic animals
There are 4 reports of turkeys becoming
diseased after natural infection with Sm
IBoyer et a1. 1958, Yamamoto & Clark
7
1966, Mohamed et a1. 1969, Ghlnder et ai.
1982). The authors described purulent
alterations of different joints, tendon
sheaths and the bursa sternalis. In some
cases the infection could be traced back to
feral rats caught in the enclosure environs
(Yamamoto & Clark 1966, Mohamed et a1.
1969). Attempts to infect lambs and pigs via
different routes failed (Mohamed et ai. 1969).
Other animals
Hopkinson & Lloyd (1981) described
several cases of septicaemia in spinifex
hopping mice (Notomys alexis) kept at the
Perth Zoological Garden (Australia). Rats
which broke into the animal cages, were
considered the most likely source of
infection. From the same continent, there is
a report of a koala (Phascolarctos cinereus)
that died in the course of pleuritis caused
by Sm (Russell & Straube 1979l. Cases of
rat-bite fever caused by wild mice (Jenkinson
& Jordan 1932, Reitzel et a1. 1936) and a
weasel (Dick & Tunnicliff 1918) were most
likely not due to Sm.
Inanimate environment
Nothing is known of the occurrence of Sm
in the inanimate environment. Under in
vitro conditions viability of Sm is poor, so
the microorganism has to be stored deep-
frozen, lyophilized or be passaged at 3 to
5 day intervals.
Diagnosis of streptobacillary
infection
Problems in diagnosing streptobacillosis in
humans have been mentioned briefly
already. Rumley et a1. (1987) speak of a
'diagnostic dilemma' and summarize the
problem as follows: 'Although rat-bite fever
is an uncommon disease, we believe that
the non-specific clinical manifestations,
difficulties with organism identification,
and problems with identifying rodent
exposure make an accurate diagnosis quite
difficult.' Moreover, it has to be pointed
out that the recovery of Sm from routinely
taken blood culture is impeded by the use
of sodium polyanethol sulphonate (liquoid)
in blood culture bottles ILambe et al. 1973
8 Wullenweber

However, improvements may be on the agglutinating antibodies in experimentally

way if one takes the increasing number of
reports on Sm as indicative of an increasing Van Rooyen (1936) described the agglutina-
sensitivity for this pathogen.
Once grown, its typj.cal morphological
appearance and growth characteristics on
culture make it relatively simple to establish experimentally infected mice, and RaHin
a preliminary diagnosis of Sm followed by
biochemical identification in test tubes on
serum-supplemented media [commercial
test kits fail to identify Sm).
Fatty acid profiles obtained by gas-liquid
chromatography (GC) together with
characteristic growth in serum broth and the (1972) on mice suffering from experimental
Gram stain reaction can also be used for rapid streptobacillary arthritis.
identification of Sm (Rowbotham 1983).
The classical test to confirm the
diagnosis of streptobacillus is the foot pad
injection of Sm performed in mice. Within
days a localized septic arthritis develops
from which Sm can be isolated in pure
culture. Ethical considerations should
forbid this painful test, especially as
sensitive in vitro identification can be
achieved.
There is still a need for an appropriate
selective medium for the cultivation of Sm
from silent carriers whereas the isolation
from purulent or septicaemic processes
usually does not cause any problem. The
problem of isolating Sm from a mixed flora raises the question of specificity. In
in carriers, especially from the
nasopharynx, is impeded by its slow
growth and the risk of being overgrown by
Gram-negative bacteria, e.g. Proteus
mirabilis (coprophagia) and the
nasopharyngeal Gram-positive flora.
Elimination of Enterobacteriaceae can
easily be achieved by addition of nalidixic
acid [1mg/l) to the medium (Wullenweber
et a1. 1991), but methods of suppressing
the Gram-positive flora still need to be
developed.
Serological methods were used early on
the indirect detection of Sm infections.
Historically, the first method applied was
the demonstration of agglutinating
antibodies against Sm. During the
Haverhill epidemic, Parker and Hudson
(1926) demonstrated anti-Sm-agglutinins in
the blood of RBF patients. Brown and
Nunemaker (1942) showed the presence of
infected mice and in human cases of RBF.
tion test as a tool for taxonomic studies on
Sm strains. Even recent investigations used
the agglutination test, Savage (1972) on
and Freemark (1979) on a case of RBF.
The complement fixation test (CFT) to
detect Sm infections was used by Bell and
Elmes (1969) and Gay et a1. (1972) for
routine monitoring of SPF and
conventional laboratory rats and by Savage
By introducing modern methods into
serologic diagnosis of streptobacillary
infection, routine testing became more
convenient. The indirect immuno-
fluorescence test (IIF) was and is in use in
this laboratory for routine testing of
breeding and experimental mouse colonies
(Wullenweber et a1. 1990, Wullenweber et
a1. 1992) and in rats (Wullenweber &.
Nicklas unpublished, see also below).
Furthermore, the ELISAtechnique (Koopman
et 01. 1991, Boot et a1. in press) has been
shown to be applicable to the detection of
anti-Sm-antibodies in rat sera.
The use of serological techniques always
adsorption experiments with Sm
hyperimmune sera, cells of Bordetella
bronchiseptica, Campylobacter fetus,
Campylobacter sputorum, Eikenella
corrodens, Escherichia coli, Haemophilus
sp., Mycoplasma pulmonis and Pasteurella
pneumotropica were not able to reduce
ELISAactivity. There was only a partial
reduction with Acholeplasma laidlawii
(Boot et a1. in press). Using the I1F, we
observed cross-reactivity between Sm
ATCC 49567 and rabbit antisera to A.
laidlawii ATCC 23206, A. axanthum
H86N, A. oculi ATCC 27350 and A.
equifeto1e ATCC 29724, but not to other
Acholeplasma species, Mycoplasma
pulmonis and M. arthritidis. These are the
only available investigations concerning
information on cross-reactivity between Sm
and other bacterial groups. With respect to
routine monitoring by means of the ELISA,
S. moniliformis-a zoonotic pathogen
it should be pointed out that sera to be
tested should derive from rats not older
than 16 weeks, otherwise an age-dependent
increase of false positive findings can be
observed (Boot personal communication).
Etscorn and Blodgett (1987) stated that
10 to 100% of otherwise healthy rats
harbour Sm as part of their normal
nasopharyngeal flora, and further, that
approx. 10% of about 14,000 annual bites
in US laboratories and in urban areas with
poor sanitation result in rat-bite fever.
Recent reports clearly give evidence that
laboratory animals can still be
contaminated with Sm: pneumonia in a
guineapig (Kirchner et 01. 1992), epizootic
in C57BL/6 mice (Wullenweber et 01.
1990), healthy rats (Koopman et 01. 1991)
and rats suffering from otitis media
(Wullenweber et 01. 1992). In the latter
case, diseased animals came from a
German university animal facility, and 19
of 25 rat sera derived from 6 different
inbred strains of rats showed high titres
of IgG IIF [unpublished), indicating a
high degree of contamination of the unit
with Sm.
Being startled by these findings, R. Boot
(RIVM, Bilthoven, NL), W. Nicklas [DKFZ,
Heidelberg, FRG) and I started a serological
investigation of European rat colonies. The
goal of this interlaboratory co-operation is
to evaluate better the incidence of
contamination with Sm. Identities of the
sera were coded before distribution, and
results were exchanged at the end of the
testing. Using the ELISA (RB)and the IIF
[WN and MW), we found a considerable
number of positive rat sera. Results
obtained were in good agreement. A
limited number of healthy rats were
investigated culturally and serologically.
Although some of the investigated rats
were seropositive in all 3 labs, we failed to
isolate Sm, but known difficulties in
isolating Sm from healthy animals from a
mixed flora, in spite of using a semi-
selective medium, have to be taken into
consideration. This poses some difficulties
in interpretation of the findings. Axe the
colonies really infected with Sm or did we
have false positive results due to some
9
unknown factors like cross-reactions, for
example with anaerobionts? Moreover, our
information on the epidemiology of
streptobacillosis is still rather poor. Boot
et 01. (in press) described the failure to
detect seroconversion in rats after Ln.
infection with the Sm type strain [ATCC
14674) and its reisolation. Wullenweber
et 01. (1990 unpublished) observed the
same phenomenon after oral infection of
non-susceptible inbred strains of mice. So,
how can this particular problem be solved?
An infective agent such as Sm, which is
difficult to isolate, and serological results
which cannot be interpreted properly because
of failure to isolate the corresponding agent
is, in my opinion, a typical application for
the PCR (polymerase chain reaction)
technique. In my laboratory, Nicola
Hofmann is about to amplify and sequence
the 16 SrRNA genes of Sm. One objective
is to find Sm specific primer sequences for
the PCR which, after solving further
technical problems, would enable us to
establish an alternative confirmatory test
to decide whether a rodent colony is
contaminated with Sm.
Rat-bite fever as an occupational risk
The reported incidence of RBF caused by
Sm in laboratory personnel is low.
Anderson et 01. (1983) documented 13 cases
of RBF in the USA between 1958 and 1983.
Of these, 5 cases could be traced back to
Sm transferred by bites of laboratory rats.
Holden and McKay (1964) recorded the first
culturally proven Canadian case of RBF due
to Sm in a laboratory worker who was
bitten by a rat derived from a contaminated
colony.
In Norway [Borgen &. Gaustad 1948l, the
first documented case of RBF in laboratory
personnel occurred in 1946.
In England} a worker at the National
Institute of Medical Research at Mill Hill
(Gledhill 1967) suffered from RBF, and in
Australia} an agricultural scientist
developed RBF after being bitten by a
laboratory mouse (Gilbert et 01. 1971).
The latter diagnosis was only presumptive
as no causative agent could be isolated
 10 Wullenweber

Table 2 Antibiotic susceptibility of 13 Streptobacillus moniliformis isolates of different origin

Antibiotic Reaction Remarks

Ampicillin, azlocillin, aztreonam, cefalozin, cefixime, cefotaxime,

Cefoxitin, cefpirome, ceftazidime, c1indamycin, erythromycina,
Fosfomycin, imipenem, meropenem, mezlocillin, mezlocillin/sulbactam, All sensitive aNo clear reaction
Nitrofurantoin, novobiocina, ofloxacin, oxacillin, penicillin, Piperacillin, with 2 strains
Rifampicin, teicoplanin, tetracycline, vancomycin

Amikacin, chloramphenicol, ciprofloxacin, gentamicinb, tobramycin Intermediate bOne strain

sensitive
Nalidixic acid, norfloxacin, polymyxin B, trimethoprim/sulfamethoxazol Resistant

Fusidic acid Sensitive to

intermediate

either from the patient or from the mouse
which was not available for examination.
The fact that only a few occupational
cases are reported does not necessarily
represent the real incidence of RBF in
laboratory personnel. As Wilkens et 01. (1988)
stated '.... Despite this, S. momliformis
may be a commoner cause of the triad
fever, arthralgia and rash, than is realized,
the diagnosis being missed because of the
organism's strict growth requirements and
the generally low index of suspicion among
clinicians'. RaHin and Freemark (1979)
evaluated the problem ' .... Although rarely
considered as a diagnosis, streptobacillary
rat-bite fever continues to merit our
consideration, particularly in areas of rural
poverty and urban crowding where
sanitation is poor and children may come
in contact with rats. The true incidence of
the disease at present is unknown. One can
only wonder if the incidence of a recognizable
form of the disease and its potentially
severe complications would be appreciably
higher were it not for frequent use of
penicillins in ambulatory paediatric settings.'
Special attention to streptobacillary RBF
should be taken in those facilities where
wild rodents are used.
Antibiotic susceptibility and
antimicrobial therapy
Penicillin is still regarded as the antibiotic
of first choice for the treatment of human
RBF. Roughgarden (1965) who reviewed the
antimicrobial therapy of RBF, recommended
a daily dosage of not less than 400,000 to
600,000 units continued for not less than 7
daysj if no response occurs within 2 days,
the dosage should be raised to 1,200.000
units daily. In the case of endocarditis, 12
to 15 million units daily should be given
either intravenously or intramuscularly for
3 to 4 weeks. Further information on
treatment of S. moniliformis endocarditis
can be obtained from 2 recent review
articles (Rey et al. 1987, Rupp 1992).
Other antibiotics used for the treatment
of streptobacillary RBF in humans are
ampicillin (Mandel 1985, Kunnert et al.
1985), streptomycin (McGill et al. 1966),
tetracycline (Holden & McKay 1964),
chloramphenicol (Hamburger & Knowles
1953), gentamicin (Rumley et al. 1987j,
cefuroxime (Clausen 1987), vancomycin
(Fordham et 01. 1992) and erythromycin
(Konstantopoulos et al. 1992). Usually
antibiotics were given in combinations.
In vitro testing of antibiotic susceptibility
with different techniques e.g. agar incorporation
method of MIC determination [Edwards &
Finch 1986) and disk diffusion technique
(Wullenweber et al. 1990, Rygg &. Bruun
1992) revealed similar results, all showing
a broad spectrum of antibiotic sensitivity of
the Sm isolates tested.
A comparison of the antibiotic susceptibility
of 13 different Sm isolates of human,
murine and avian origin using break
point microtitre plates (Radiometer,
Copenhagen) is given in Table 2 (Hofman
&. Wullenweber unpublished) where
recently developed antibiotic substances
S. moniliformis-a zoonotic pathogen 11

Table 3 Geographical origin of reports on Streptobacillus moniliformis (US cases not considered)

Country Origin DiseaselComplication Remarks Reference

America (ex USA):

Brazil H Meningitis Atala et al. 1973
Canada H RBF Anderson & Marrie 1987
Canada H RBF Holden & MacKay 1964
Mexico H RBF Osimani et al. 1972
Paraguay H RBF Canese & de DaSilva 1974

Europe:
Denmark H Brain abscess Oeding & Pedersen 1950
Denmark M Streptobacillosis Freundt 1956a
Finland H Inflammation Puolijoki et a/. 1988
France H Polyarthritis 8an et al. 1991
France H Septicaemia Dellamonica et a/. 1979
France H Pneumonia, prostatis, Delannoy et a/. 1991
pancreatitis
France H Septicaemia Gascard et al. 1967
France H RBF Kunnert et al. 1985
France M Streptobacillosis levaditi et al. 1932
France H Septicaemia Renaut et al. 1982
France H Endocarditis Rey et al. 1987
Germany T Polyarthritis GIOnder et al. 1982
Germany M Streptobacillosis Wullenweber et a/. 1990
Germany R Otitis media Mixed infection Wullenweber et al. 1992
Greece H RBF Konstantopoulos et al. 1992
Italy H Otomastoiditis Pirodda 1965
Netherlands H Brain abscess Doubtful diagnosis' Dijkmans et al. 1984
Netherlands R Healthy Koopman et al. 1991
Norway H RBF Borgen & Gaustad 1948
Norway H Septicaemia Rygg & 8ruun 1992
Poland R Meningoencephalitis Katkiewicz 1977
Spain H Arthritis Anglada et a/. 1990
UK GP Cervical abscesses Sm sensu stricto? Aldred et al. 1974
UK R CRD Secondary invader? Bell & Elmes 1969
UK GP Cervical abscesses Sm sensu stricto? Fleming 1976
UK H RBF Without rat bite Fordham et al. 1992
UK R Chronic pneumonia Mixed infection Gay et al. 1972
UK M Streptobacillosis Mackie et al. 1933
UK H RBF McGill et al. 1966
UK M Arrested pregnancy, Sawicki et 131. 1962
abortion
UK H Haverhill fever Shanson et al. 1983, McEvoy
etal.1987
UK GP Cervica I abscess Smith 1941
UK R Healthy carrier Strangeways 1933
UK G Healthy carrier Wilkens et 131. 1988
UK R Conjunctivitis Mixed infection Young & Hill 1974

Asia
India D Abscess Sm sensu stricto? Das 1986

Australia:
H RBF Gilbert et 131. 1971
SHM Septicaemia Hopkinson & Lloyd 1981
K Pleuritis Russell & Straube

CRD=chronic respiratory disease, RBF=rat bite fever, H=human, M=mouse, R=rat, T=turkey, GP=guineapig, G=gerbil,
D=dog, SHM=spinifex hopping mouse, K=koala
"Retrospectively, the recultivated isolate could not be confirmed as Sm (Boot, personal communication)
12
like e.g. quinolone derivates are also taken
into consideration.
There appears to be a lack of information
on antibiotic treatment of diseased
laboratory animals. On the occasion of a
Sm epizootic amongst mice which occurred
in our institute in 1988, we tried to treat
the breeding nuclei with ampicillin in
drinking water. Ampicillin was chosen
because of its good penetration into the
joint cavities. To prevent survival of
penicillin-resistant L-forms, tetracycline
was given in succession. The efficiency of
the antibiotic treatment was controlled in
naturally infected C57BL/6 mice kept in
an isolator (Wullenweber et al. 1990).
Clinical signs decreased dramatically under
therapy within 24 h. Most of the animals
recovered completely. However, after
finishing therapy, some of the mice
relapsed, became emaciated and died
with septicaemia. So the field trial was
stopped, and the breeding unit abandoned
(Wullenweber et al. 1990).
Geographical aspects
Quantitatively, most of the references concern-
ing Sm in humans and animals originate
from the US literature, and are already
summarized in a couple of papers (see e.g.
Brown & Nunemaker 1942, Roughgarden
1965, Anderson et al. 1983). Table 3,
therefore refers exclusively to non-US cases.
Concerning the American continent,
occurrence of Sm has been described in
Brazil, Canada, Mexico and Paraguay. With
respect to Europe, most reports come from
the United Kingdom (13) and France (81,
but its occurrence is also documented for
Norway, Finland, Germany, Spain, Italy,
Greece, Poland, Denmark and The
Netherlands. Australian authors have
contributed three reports. The only paper
from Asia (India) describes the isolation of
Sm from an abscess of a dog (Das 1986). As
mentioned before, the nutritional requirements
and antibiotic sensitivity of this isolate is
not typical for Sm sensu stricto. There is
no report from Africa. Lack of reports from
third world countries probably understates
the real incidence of Sm because it is known
that the distribution of streptobacillosis is
correlated with poor sanitation, rural areas
Wullenweber
and agricultural occupations (Clausen 1987,
Gilbert et al. 1971).
Final remarks
My principal intention in writing this
article was to promote interest in the
scientific community in our field of
research on this, in many respects,
remarkable bacterium. Although I must
not overestimate problems in which
Streptobacillus moniliformis might be
involved, I fear that, after studying programmes
of recent congresses on laboratory animals
and many discussions with colleagues,
microbiological study of the animals we are
working with risk being pushed aside by
other topics, e.g. animal welfare aspects,
ethics etc. However, animal welfare
includes a duty to keep laboratory animals
free from pathogenic microorganisms. By
this, avoidable stress and pain during
maintenance and experimentation can be
reduced. Keeping laboratory animals free
from zoonotic pathogens also reduces
occupational hazard. Moreover, for
bacteriologists, Sm is a fascinating
microorganism which poses a lot of
questions to be answered in the future.
Addendum
In the meantime, 16 S rRNA analysis could
be finished. There are 2 Sm subspecies
which show relationship to Sebaldella
termitidis and some Fusobacterium spp.
(Hofmann & Wullenweber, in preparation).
Acknowledgments I thank DipI. BioI. Nicola
Hofmann from my group for providing me with
data conccrning the taxonomy and antibiotic
susceptibility of the 13 Sm strains. Dr R. Boot
(RIVM, Bilthoven, NL) and Dr D. Taylor (AFRC &.
MRC Neuropathogcncsis Unit, Edinburgh, UK) arc
thanked for their frank and helpful comments and
discussions. My collcaguc from the ZFV, Prof. Dr
K. Larcher is thanked for his thorough literature
scarch on a broad panel of data bascs and supplying
me with even the most 'exotic' papers.
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