Journal of Infection (I99o) zx, I95-2o3
CASE REPORT Salmonella septic arthritis: a case report and review M. G. Morgan,* K. J. F o r b e s t and S. G. Gillespie* * Microbiology Departments, The Royal Free Hospital, London and t Aberdeen University Medical School, Aberdeen, U.K. Accepted for publication 29 March I99O
Summary We describe a case of septic arthritis in a child with no apparent predisposing conditions. Salmonella virchow was isolated from her knee and faeces, both isolates being identical except for the latter's resistance to ampicillin. Evidence is presented for the acquisition of ampicillin resistance in vivo, including the demonstration of the R plasmid and its ready transferability to Escherichia coli. The recent literature on the subject is reviewed and the role of group CI salmonellae in invasive disease is examined.
Introduction Salmonella infections r e p o r t e d to the Public H e a l t h L a b o r a t o r y Service ( P H L S ) C o m m u n i c a b l e Disease Surveillance Centre (unpublished) are on the increase, 25 83I infections having been reported in I989 as o p p o s e d to IO76I in I98O. T h i s increase has accompanied enhanced awareness of the public and the news media a b o u t salmonella and the associated food hygiene controversies. Enteritis is the most c o m m o n manifestation of salmonellosis, occurring in 70 % cases. Localised extraintestinal infections are less c o m m o n and usually follow salmonella bacteraemia. Bone and joint involvement in salmonellosis is unusual, reactive arthritis being the most frequent manifestation (I.6-3.9 %),1-4 osteomyelitis being less c o m m o n at o'76 % and septic arthritis rare (o'24 ~/o).~ Salmonella septic arthritis (SSA) was first described in I896 b y Achard and Bensaude 6 w h o isolated p a r a t y p h o i d bacilli from the right sternoclavicular joint of a girl aged 7 months. D a v i d and Black 7 in a review of the world literature, f o u n d 84 cases, most of which (49/84) were in the preantibiotic era. C o h e n et al., 8 in a recent review of extraintestinal salmonellosis f o u n d 44 cases of S S A in the antibiotic era (up to I983) and presented two further cases. T h e first of these was a 36-year-old w o m a n with S L E w h o was also a renal transplant recipient and had had a total hip replacement. Salmonella typhimurium was isolated from her left knee, b l o o d and faeces. T h e second was a 5 I - y e a r - o l d w o m a n with no apparent predisposing conditions. Salmonella choleraesuis was isolated from her left knee and blood. O r t i z - N e u et al., 9 r e p o r t e d nine cases (included in the above review 8) of septic arthritis due to Address correspondence to : Dr M. G. Morgan, Microbiology Department, University Medical Building, ForesterhiU, Aberdeen, AB9 2ZD, U.K. oi63-4453/9o/o5oi95 +o9 $02.22/0
© z99o The British Society for the Study of Infection
4
Not specified I 2
9
Samra et al., 198612
Ebong et al., 198718
Martin-Santos et al., i98714 Sankaran-Kutty et al., I988 t5
Medina et al., 198916
* SLE = Systemic lupus erythematosus. t Four multiple joints affected.
I 3
Petty et al., 19831° Quismorio et al., I98311
Reference
Number of cases
SLE*
Heart transplant Sickle-ceU disease
Sickle-cell disease
None (laboratory worker) SLE* (I), Rental transplant (I), Waldenstrom macroglobulinemia (r) Total hip replacement
Predisposing conditions
ankle (2)
Knee (8)t, elbow (4),
Salmonella serotype not specified (to)
Not specified Knee (I) Hip (z)
Salmonella, serotype not specified (2) Group A Salmonella (2), group B salmonella (7), exact serotypes not specified
S. enteritidis
S. typhi(3), S. muenchen (I)
S. heidelberg S. arizonae (formerly Arizona hinshawii) (3)
Organism isolated (no.)
Hip (4)
Knee (i) Knee (3)
Joint(s) affected (no.)
Table I Reports of salmonella septic arthritis 1983-1989
Z ~n
0
o~
Salmonella septic arthritis
I97
salmonella between I964 and I978. Six of them were due to the CI serotype and included S. choleraesuis (z) and S. virchow (I). T h e latter patient was a 25year-old man with villonodular synovitis who had had a knee operation 2 years earlier. Salmonella virchow was isolated from his knee and blood. He also had osteomyelitis. We reviewed the world English language literature on SSA in the period I983-I989 and found seven further reports, details of which are summarised in Table I. We now present a further case of salmonella septic arthritis in a child with no apparent predisposing condition. Salmonella virchow was isolated from her knee and faeces, the latter isolate becoming resistant to ampicillin. We also describe how we demonstrated the ampicillin resistance plasmid and discuss the management of this case in the light of current knowledge. Finally we attempt to quantitate the role of group CI salmonellae in invasive disease. Case report
A z-year-old-girl presented to her general practitioner in the first week of July I989 reportedly having abdominal pain but no diarrhoea. She was diagnosed as having tonsillitis and was prescribed a course of amoxycillin for i week. A week later, she developed pain in her left leg, refusing to bear weight on it. She was seen again by her general practitioner who noted free painless movements in both legs and prescribed a course of penicillin V Iz5 mg q.d.s, for a further 7 days. Over the following week she developed clear signs of synovitis in her left knee which was swollen and slightly warm. She was otherwise well and afebrile. Her ESR was 42 m m / h and routine haematological investigations, including WBC count, were normal. Towards the end of that week she presented at the paediatric clinic at the Royal Free Hospital, London where an X-ray demonstrated effusion in her left knee. She was noted to be generally improving. T h e dosage of penicillin was increased to 5oo mg t.d.s, and she was given an appointment to be seen I week later. After a few days, however, she was admitted to the paediatric ward crying inconsolably and still not bearing weight on the left leg. Her knee was swollen but there was no redness and a range of movement of about 5o ° was achievable but painful. She was intermittently febrile during the first few days after admission, her axillary temperature ranging from 37.6-39 °C. Investigations revealed a haemoglobin concentration of ~o'8 g/dl, WBC count 9"2 x io9/1, A S O T zoo I U / m l and C-reactive protein r64 mg/1. A throat swab did not reveal any bacterial pathogens and a blood culture was sterile after 7 days' incubation. Aspiration of the left knee yielded 5 ml yellow turbid fluid with 2oox Io9/1 WBC, 90% of which were polymorphonuclear leucocytes. Organisms were not seen on Gram-staining but a group C salmonella was isolated and subsequently identified as S. virchow phage type 26. Disc sensitivity testing by a modified Stokes method showed full sensitivity to ampicillin, cefotaxime, gentamicin, trimethoprim and chloramphenicol. This was confirmed by plate dilution and Sensititre (Seward Laboratories, London, U.K.) M I C determinations. Treatment with ampicillin 250 mg q.d.s. zv began and the left leg was splinted. Bone scintigraphs revealed increased
I98
M. G. M O R G A N
ET AL.
uptake of the tracer in the left lower femoral area, extending either side of the epiphyses, thereby indicating possible osteomyelitis. A few days later (first week in August), a faecal culture yielded a group C salmonella subsequently identified as S. virchow. T h i s isolate had a biochemical profile, (API 47o4752, A P I Laboratories, Hants, U.K.), serotype and phage type identical to that of the one derived from the knee. Its antibiotic sensitivity pattern was also the same except for resistance to ampicillin ( M I C > 32 mg/1 as opposed to I mg/1). T r i m e t h o p r i m 5o m g orally b.d. was therefore added to the antibiotic regimen. T h e range of leg movements continued to improve and faecal cultures became negative. T h e patient was discharged h o m e on oral antibiotics after 2 weeks in hospital. A full blood count on her discharge from hospital revealed a haemoglobin concentration of I2.O g / d l and a W B C count of 6.6 x IO"/1. W h e n seen at hospital 2 weeks later the patient was still unable to walk but was increasingly bearing weight on her left leg. After a further 2 weeks, she had a full range of m o v e m e n t and was able to walk, albeit with an unsteady gait. Eight weeks after treatment with ampicillin began, the appearance of the left knee and her gait were completely normal.
Molecular biology T h e recovery of both ampicillin sensitive and resistant isolates of S. virchow from the patient suggested that the resistant isolate may have been derived from the sensitive strain by the transfer of a plasmid carrying ampicillin resistance. T h e transmissibility of ampicillin resistance from the resistant strain to Escherichia coli H B I o I (recA hsdRM strA, plasmid free) was demonstrated in vitro by mixing the strains together in nutrient broth, incubating it at 37 °C for 7 h and then selecting for HB ~oI transconjugants on nutrient agar containing ampicillin and streptomycin; the large n u m b e r of transconjugant colonies that were recovered suggests that the ampicillin resistance is transmissible. T h e plasmid profiles of the sensitive and resistant isolates of S. virchow were determined by the methods of Eckhardt 17 and of Kado and Liu. Is These m e t h o d s allow the rapid detection of plasmids up to > 300 Md. T h e two isolates carried two identical plasmids of < 5 M d (Plate I). T h e resistant isolate additionally carried a plasmid of 36 M d . T h e Escherichia eoli H B I o I ampicillin resistant transconjugant m e n t i o n e d above was also found to carry a plasmid of 36 M d . In a similar series of matings with E. coli recipients (KF29: strA F') and the resistant Salmonella sp. as donor, ampicillin resistant E. coli transconjugants were again isolated at high frequency. In this instance, the plasmid profile of the E. coli transconjugants showed both the 36 M d Salmonella sp. plasmid and the resident F' E. coli plasmid, indicating that the 36 M d plasmid does not belong to plasmid Incompatibility G r o u p I n c F I . Matings were also used to construct H B I o I carrying the 36 M d plasmid and the RP4 (amp ® karl ® tet®); these transconjugants carried both plasmids, indicating that the 36 M d plasmid is not in IncP.
Journal of Infection
Plate I
o
b
c
Plate I. Electrophoretic gel of plasmids isolated by the method of Kado and Liu is and separated by o.7 % agarose gel electrophoresis. Lane a: Escheriehia coli showing 36 Md plasmid carrying ampicillin resistance derived from Salmonella virchow faecal isolate, Lane b: S. virchow faecal isolate. Lane c: S. virchow isolate from knee.
M. G. MORGAN ET AL.
(Facing p. 198)
Salmonella septic arthritis
I99
Discussion
Table II outlines some comparative features of salmonella septic arthritis, reactive arthritis and osteomyelitis. In most cases of SSA there is no preexisting joint disease. Some cases, however, have followed trauma and surgery especially for prosthetic joints. T M Other predisposing conditions include SLE, T M administration of a corticosteroid or other imrnunosuppressant treatment, neoplasia and sickle cell disease. 8' 15 Our patient did not have any specific predisposing condition although frequent minor injuries are commonplace in children and a definite history of trauma is often hard to obtain. Most cases of SSA are monoarticular and, as in our patient, the knee is the most common joint affected (57 %) followed by the hip (23 %) and shoulder (9%). 8 Joint swelling and pain, together with fever, are the commonest presenting symptoms. Diarrhoea is often present but was absent in our patient as well as her seven siblings who shared the same meals. Diagnosis is established by the clinical features and isolation of a salmonella from the joint fluid. T h e latter is necessary since patients with reactive arthritis may present with joint swelling and pain as well as positive faecal or blood cultures but, by definition, have joint aspirates negative for Salmonella sp. Gram-staining of synovial fluid is positive in about half the cases~ faecal culture is positive in 43 % and blood culture in 65 %.8 Our patient had negative Gram staining but positive cultures of synovial fluid and faeces although blood cultures were negative. Salmonella virchow belongs to the serological group Cr which also encompasses such serotypes as S. choleraesuis, S. oranienburg, S. montevideo, S. thompson and S. hartford, all of which have been implicated in SSA. Isolations of S. virchow reported to the P H L S have been rising steadily since I975. It was the second commonest serotype in I9842° and the third commonest in I989 (PHLS, Communicable Disease Surveillance Centre) after S. enderitidis and S. typhimurium. T h e reservoir and usual vehicle of transmission is considered to be poultry. Some authors in the U.S.A. have noted a preponderance of group C salmonella isolates in certain extra-intestinal salmonella infections such as bacteraemia ~'21 osteomyelitis 22 and septic arthritis, 7,9 Salmonella choleraesuis being the most commonly isolated serotype. In the period i962-i97 r, salmonella of group CI accounted for 5-r% cases of salmonella bacteraemia, 21 24% cases of salmonella osteomyelitis and 67 % cases of SSAfl while accounting for only around 5"5 % salmonella isolates. T h u s it was postulated that salmonellae of group CI have a special predilection for bones and joints as well as a generally enhanced virulence over other non-typhoid salmonellae. In another series of 44 cases of SSA 8 the most common serotype isolated with S. typhimurium (39 %) followed by S. choleraesuis (II %). This series, however, contained a disproportionately large number of immunosuppressed patients who are especially susceptible to S. typhimurium infections. British workers have also remarked on the invasiveness of S. virchow. Mani et al., 23 described an outbreak of S. virchow food poisoning in the Manchester area in which one third (7/zr) of cases had a typhoidal or septicaemic illness. T o d d and McC M u r d o c h 24 reported septicaemia in 6o % (9/I5) sporadic cases of infection due to this organism. In a I5 year retrospective study, Mandal and
I'6--3"9 % 1-4
Reactive arthritis
2580
2578
Year I988
I989
Communicable Diseases Scotland Unit (unpublished data)
Total salmonella isolates
28
38
315 (I2"2)
6 (t5"8)
5 (I7"9)
Total Group C I salmonella salmonella bacteraemia bacteraemia (%)
I48 (5.7)
Group CI salmonella isolates (%)
Table III Reported salmonella isolates I988, I989 Salmonella septic arthritis
Good prognosis with antibiotic therapy alone. Poorer prognosis in chronic osteomyelitis which may require surgery
Excellent prognosis with non-steroidal anti-inflammatory agents
S. typhimurium S. enteritidis
Positive culture from bone, abscess cavity, joint or blood As in septic arthritis
Usually affects one bone; most commonly femur, tibia or humerus
o'76% s Sickle-cell disease~9
Osteomyelitis
Positive faecal culture negative joint fluid culture
Possession of H L A B27 antigen 2 (69 %) Usually polyarticular and migratory; knee, ankle and wrist most commonly affected
Source
* See text for references.
Outcome
Organisms most commonly isolated 5, 7.,
S. choleraesuis or other of the CI group S. typhimurium Good prognosis with antibiotic therapy and aspiration
Usually monoarticular Knee 57 % Hip 23 ~/o Shoulder 9 % Positive joint aspirate
Site 8
Microbiological diagnosis
0"24 ~/o~ See text
Incidence Association
Septic arthritis
Table II Some comparative features of salmonella bone and joint infections*
0
o o
Salmonella septic arthritis
20I
Brennand 25 reported bacteraemia in I6"5 % (I9/II5) S. virchow infections. Only S. infantis and S. dublin were more invasive. In order to address the question whether the entire CI group of salmonellae causes disproportionately more cases of invasive disease compared to other serogroups we examined figures for salmonella isolations reported in Scotland in I988 and i989 [Communicable Diseases (Scotland) U n i t - unpublished data] - Table III. Compared to other Salmonella sp., those of group CI caused disproportionately more cases of bacteraemia (i 7"9 % and 15"8 °//o respectively) in relation to their rates of isolation from faeces (5"7 and i r a ~/o respectively). This observation tends to support the enhanced role of group CI organisms over other salmonellae in the aetiology of bacteraemia. T h e figures for septic arthritis, however, were too small as to allow for meaningful interpretation. Most of the group C I organisms (9/I I) causing bacteraemia were S. virchow while, of the two isolates causing septic arthritis, one was a rough strain Of salmonella that could not be speciated, the other S. enteritidis phage type 4. In a recent review, s 29 ~/o patients with SSA, including three with sickle-cell disease, had co-existing osteomyelitis. Our patient had scintographic changes indicative of osteomyelitis but no X-ray evidence of bone destruction. Recommended treatment for SSA includes appropriate IV antibiotics for 2-4 weeks and repeated arthrocentesis up to twice a day. Intra-articular antibiotics are contra-indicated since they may induce chemical synovitis. Surgical drainage is required only if antibiotic treatment fails or the joint cannot be adequately aspirated. Our patient responded well to medical treatment alone in spite of the delay in instituting appropriate antibiotic therapy and the fact that the joint was aspirated only once. In a previous review of SSA, patients treated more promptly required shorter courses of antibiotic therapy. 8 Delay in treatment can be avoided if children with joint-swelling and pain are immediately referred to hospital for appropriate investigations. T h e good outcome with medical treatment alone in SSA contrasts with the poor outcome in patients with non-salmonella arthritis caused by other Gram-negative bacteria. Poor outcome in SSA is often associated with pre-existent neoplasia or immunosuppression and is not related to age of the patient or the salmonella serotype involved. T h e two isolates of S. virchow recovered from our patient's knee and faeces were identical in biotype, serotype, phage type and small-plasmid profile, so almost certainly indicating that they were the same organism. We postulate that the patient had acquired an ampicillin-sensitive strain of S. virchow in her intestinal tract, probably from food. During transient bacteraemia, the organism was deposited in her knee thereby initiating the arthritic changes. Subsequent treatment with amoxycillin for tonsillitis for I week, followed by repeated courses of penicillin V, selected S. virchow organisms in the intestinal tract that had acquired a plasmid carrying resistance to ampicillin, this plasmid presumably being already present in the resident bacterial gut flora. T h e rapid and excellent response of the patient's knee to ampicillin therapy indicates that the organisms in the knee had never acquired the resistance plasmid and so remained sensitive to ampicillin. Other authors ~2'26 have also noted the isolation of ampicillin-resistant
202
M.G. MORGAN E T AL.
salmonellae following surgery with pre-operative beta-lactam antibiotic p r o p h y l a x i s . W e r e p o r t h e r e t h e first r e c o r d e d case o f p l a s m i d - b o r n e a m p i c i l l i n r e s i s t a n c e in S. virchow, a n d o n e o f o n l y a f e w cases in w h i c h a c q u i s i t i o n o f a m p i c i l l i n r e s i s t a n c e in a s a l m o n e l l a has b e e n d e m o n s t r a t e d in vivo. ~7'2s I n b o t h o f t h e o t h e r cases, t h e i s o l a t i o n o f n o v e l a m p i c i l l i n - r e s i s t a n t o r g a n i s m s , d u e to t h e a c q u i s i t i o n o f p l a s m i d - b o r n e r e s i s t a n c e , f o l l o w e d t r e a t m e n t w i t h ampicillin. (We thank Professor B. Taylor for allowing us to report on his patient and Professor T. H. Pennington for reading the manuscript. We are also grateful to staff of the Division of Enteric Pathogens, Central Public Health Laboratory, Colindale, L o n d o n , for typing this organism, and to D r J. C. M. Sharp, Communicable Diseases (Scotland) Unit, for supplying epidemiological data.)
References
I. Friis J, Svejgaard A. Salmonella arthritis and HLA 27. Lancet 1974; i: I350. 2. Hakansson U, Eitrem R, Low B, Winblad S. HLA-antigen B27 in cases with joint affections in an outbreak of salmonellosis. Scand J Infect Dis I976 ; 8 : 245-248. 3. Vartiainen J, Hurri L. Arthritis due to Salmonella typhimurium. Report of 12 cases of migratory arthritis in association with Salmonella typhimurium infection. Acta Med Scand 1964; 175:771-776 • 4. Warren CPW. Arthritis associated with salmonella infection. Ann Rheum Dis 197o; 29: 483-487. 5. Saphra I, Winter JW. Clinical manifestations of salmonellosis in man. An evaluation of 7779 human infections identified at the New York Salmonella Center. N Englff Med 1957; 256: 1128-1134. 6. Achard C, Bensaude R. Infections paratyphoidiques. Societe Medicale des Hospitaux de Paris Bulletins et Memoires 1896; 13: 82o-853. 7- David JR, Black RL. Salmonella arthritis. Medicine 196o; 39: 385-4o3. 8. Cohen JI, Bartlett JA, Corey GR. Extraintestinal manifestations of salmonella infections. Medicine 1987; 66: 349-388. 9. Ortiz-Neu C, Marr SJ, Cherubin EC, Neu HC. Bone and joint infection due to salmonella. ff Infect Dis 1978; 138: 82o--828. IO. Petty BG, Sowa DT, Charache P. Polymicrobial polyarticular septic arthritis. J A M A 1983; 249: 2o69-2o72. II. Quismorio FP Jr., Jakes JT, Zarnow AJ, Barber D, Kitridou RC. Septic arthritis due to Arizona hinshawii. J Rheumatol 1983 ; IO : 147-15o. 12. Samra Y, Shaked Y, Maier MK. Non-typhoid salmonellosis in patients with total hip replacement. Report of four cases and review of the literature. Rev Infect Dis 1986; 8: 978--983. 13. Ebong WW. Septic arthritis in patients with sickle cell disease. Br J Rheumatol 1987; 26: 99-1o2. 14. Martin-Santos JM, Alonso-Pulpor L, Pradas G e t al. Septic arthritis by salmonella enteritidis after heart transplantation, ff Heart Transplant 1987; 6: 177-179. 15. Sankaran-Kutty M, Sadat-Ali M, Kutty MK. Septic arthritis in sickle cell disease. Int Orthop 1988; I2: 255-257. 16. Medina F, Fraga A, Lavalle C. Salmonella septic arthritis in systematic lupus erythematosus. The importance of the chronic carrier state, ff Rheumatol 1989; 16: 2o3-2o8. 17. Eckhardt T. A rapid method for the identification of plasmid deoxyribonucleic acid in bacteria. Plasmid 1978; I: 584-588. 18. Kado CI, Liu S-T. Rapid procedure for detection and isolation of large and small plasmids. ff Bacteriol 1981 ; 145 : 1365-1373.
S a l m o n e l l a septic arthritis
203
19. Hodges, FJ, Holt JF, Jacox H W , Collins VP. Editorial comments. In: Yearbook of radiology. Chicago: Yearbook Medical Publishers, r957: 89. 2o. P H L S Microbiology Digest. Salmonella special I986; 3: 3. 22. Cherubin CE, Neu H C , Imperato PJ, Harvey RP, Bellen N. Septicemia with non-typhoid salmonella. Medicine (Baltimore) I974; 53:365-376. 22. White G, Meynell MJ. Paratyphoid osteomyelitis of tibia. Lancet 2956; i: 362. 23. Mani V, Brennand J, Mandal BK. Invasive illness with Salmonella virchow infection. Br Medff I974; z: I43-I44. 24. T o d d W T A , M c C Murdoch J. Salmonella virchow: a cause of significant bloodstream invasion. Scott Med J 2983; 28: i76--278. 25. Mandal BK, Brennand J. Bacteraemia in salmonellosis : a I5 year retrospective study from a regional infectious diseases unit. Br Med J I988 ; 297: I242-I243. 26. Cheung N, Muller JC. Salmonella osteomyelitis in patients with total hip replacement. A case report of hematogenous infection from the gastrointestinal tract. Arch Orthop Trauma Surg i982; 99: 281-283. 27. Cohen SL, Wylie BA, Sooka A, Koornhof HJ. Bacteremia caused by a lactose-fermenting, multiply resistant Salmonella typhi strain in a patient recovery from typhoid fever, ff Clin Microbiol I987; 25: I516-I528. 28. Platt DJ, Sommerville JS, Gribben J. Sequential acquisition of R plasmids in vivo by Salmonella typhimurium, ff ,4ntimicrob Chemother I984; 13 : 65-69.
CASE REPORT Salmonella septic arthritis: a case report and review M. G. Morgan,* K. J. F o r b e s t and S. G. Gillespie* * Microbiology Departments, The Royal Free Hospital, London and t Aberdeen University Medical School, Aberdeen, U.K. Accepted for publication 29 March I99O
Summary We describe a case of septic arthritis in a child with no apparent predisposing conditions. Salmonella virchow was isolated from her knee and faeces, both isolates being identical except for the latter's resistance to ampicillin. Evidence is presented for the acquisition of ampicillin resistance in vivo, including the demonstration of the R plasmid and its ready transferability to Escherichia coli. The recent literature on the subject is reviewed and the role of group CI salmonellae in invasive disease is examined.
Introduction Salmonella infections r e p o r t e d to the Public H e a l t h L a b o r a t o r y Service ( P H L S ) C o m m u n i c a b l e Disease Surveillance Centre (unpublished) are on the increase, 25 83I infections having been reported in I989 as o p p o s e d to IO76I in I98O. T h i s increase has accompanied enhanced awareness of the public and the news media a b o u t salmonella and the associated food hygiene controversies. Enteritis is the most c o m m o n manifestation of salmonellosis, occurring in 70 % cases. Localised extraintestinal infections are less c o m m o n and usually follow salmonella bacteraemia. Bone and joint involvement in salmonellosis is unusual, reactive arthritis being the most frequent manifestation (I.6-3.9 %),1-4 osteomyelitis being less c o m m o n at o'76 % and septic arthritis rare (o'24 ~/o).~ Salmonella septic arthritis (SSA) was first described in I896 b y Achard and Bensaude 6 w h o isolated p a r a t y p h o i d bacilli from the right sternoclavicular joint of a girl aged 7 months. D a v i d and Black 7 in a review of the world literature, f o u n d 84 cases, most of which (49/84) were in the preantibiotic era. C o h e n et al., 8 in a recent review of extraintestinal salmonellosis f o u n d 44 cases of S S A in the antibiotic era (up to I983) and presented two further cases. T h e first of these was a 36-year-old w o m a n with S L E w h o was also a renal transplant recipient and had had a total hip replacement. Salmonella typhimurium was isolated from her left knee, b l o o d and faeces. T h e second was a 5 I - y e a r - o l d w o m a n with no apparent predisposing conditions. Salmonella choleraesuis was isolated from her left knee and blood. O r t i z - N e u et al., 9 r e p o r t e d nine cases (included in the above review 8) of septic arthritis due to Address correspondence to : Dr M. G. Morgan, Microbiology Department, University Medical Building, ForesterhiU, Aberdeen, AB9 2ZD, U.K. oi63-4453/9o/o5oi95 +o9 $02.22/0
© z99o The British Society for the Study of Infection
4
Not specified I 2
9
Samra et al., 198612
Ebong et al., 198718
Martin-Santos et al., i98714 Sankaran-Kutty et al., I988 t5
Medina et al., 198916
* SLE = Systemic lupus erythematosus. t Four multiple joints affected.
I 3
Petty et al., 19831° Quismorio et al., I98311
Reference
Number of cases
SLE*
Heart transplant Sickle-ceU disease
Sickle-cell disease
None (laboratory worker) SLE* (I), Rental transplant (I), Waldenstrom macroglobulinemia (r) Total hip replacement
Predisposing conditions
ankle (2)
Knee (8)t, elbow (4),
Salmonella serotype not specified (to)
Not specified Knee (I) Hip (z)
Salmonella, serotype not specified (2) Group A Salmonella (2), group B salmonella (7), exact serotypes not specified
S. enteritidis
S. typhi(3), S. muenchen (I)
S. heidelberg S. arizonae (formerly Arizona hinshawii) (3)
Organism isolated (no.)
Hip (4)
Knee (i) Knee (3)
Joint(s) affected (no.)
Table I Reports of salmonella septic arthritis 1983-1989
Z ~n
0
o~
Salmonella septic arthritis
I97
salmonella between I964 and I978. Six of them were due to the CI serotype and included S. choleraesuis (z) and S. virchow (I). T h e latter patient was a 25year-old man with villonodular synovitis who had had a knee operation 2 years earlier. Salmonella virchow was isolated from his knee and blood. He also had osteomyelitis. We reviewed the world English language literature on SSA in the period I983-I989 and found seven further reports, details of which are summarised in Table I. We now present a further case of salmonella septic arthritis in a child with no apparent predisposing condition. Salmonella virchow was isolated from her knee and faeces, the latter isolate becoming resistant to ampicillin. We also describe how we demonstrated the ampicillin resistance plasmid and discuss the management of this case in the light of current knowledge. Finally we attempt to quantitate the role of group CI salmonellae in invasive disease. Case report
A z-year-old-girl presented to her general practitioner in the first week of July I989 reportedly having abdominal pain but no diarrhoea. She was diagnosed as having tonsillitis and was prescribed a course of amoxycillin for i week. A week later, she developed pain in her left leg, refusing to bear weight on it. She was seen again by her general practitioner who noted free painless movements in both legs and prescribed a course of penicillin V Iz5 mg q.d.s, for a further 7 days. Over the following week she developed clear signs of synovitis in her left knee which was swollen and slightly warm. She was otherwise well and afebrile. Her ESR was 42 m m / h and routine haematological investigations, including WBC count, were normal. Towards the end of that week she presented at the paediatric clinic at the Royal Free Hospital, London where an X-ray demonstrated effusion in her left knee. She was noted to be generally improving. T h e dosage of penicillin was increased to 5oo mg t.d.s, and she was given an appointment to be seen I week later. After a few days, however, she was admitted to the paediatric ward crying inconsolably and still not bearing weight on the left leg. Her knee was swollen but there was no redness and a range of movement of about 5o ° was achievable but painful. She was intermittently febrile during the first few days after admission, her axillary temperature ranging from 37.6-39 °C. Investigations revealed a haemoglobin concentration of ~o'8 g/dl, WBC count 9"2 x io9/1, A S O T zoo I U / m l and C-reactive protein r64 mg/1. A throat swab did not reveal any bacterial pathogens and a blood culture was sterile after 7 days' incubation. Aspiration of the left knee yielded 5 ml yellow turbid fluid with 2oox Io9/1 WBC, 90% of which were polymorphonuclear leucocytes. Organisms were not seen on Gram-staining but a group C salmonella was isolated and subsequently identified as S. virchow phage type 26. Disc sensitivity testing by a modified Stokes method showed full sensitivity to ampicillin, cefotaxime, gentamicin, trimethoprim and chloramphenicol. This was confirmed by plate dilution and Sensititre (Seward Laboratories, London, U.K.) M I C determinations. Treatment with ampicillin 250 mg q.d.s. zv began and the left leg was splinted. Bone scintigraphs revealed increased
I98
M. G. M O R G A N
ET AL.
uptake of the tracer in the left lower femoral area, extending either side of the epiphyses, thereby indicating possible osteomyelitis. A few days later (first week in August), a faecal culture yielded a group C salmonella subsequently identified as S. virchow. T h i s isolate had a biochemical profile, (API 47o4752, A P I Laboratories, Hants, U.K.), serotype and phage type identical to that of the one derived from the knee. Its antibiotic sensitivity pattern was also the same except for resistance to ampicillin ( M I C > 32 mg/1 as opposed to I mg/1). T r i m e t h o p r i m 5o m g orally b.d. was therefore added to the antibiotic regimen. T h e range of leg movements continued to improve and faecal cultures became negative. T h e patient was discharged h o m e on oral antibiotics after 2 weeks in hospital. A full blood count on her discharge from hospital revealed a haemoglobin concentration of I2.O g / d l and a W B C count of 6.6 x IO"/1. W h e n seen at hospital 2 weeks later the patient was still unable to walk but was increasingly bearing weight on her left leg. After a further 2 weeks, she had a full range of m o v e m e n t and was able to walk, albeit with an unsteady gait. Eight weeks after treatment with ampicillin began, the appearance of the left knee and her gait were completely normal.
Molecular biology T h e recovery of both ampicillin sensitive and resistant isolates of S. virchow from the patient suggested that the resistant isolate may have been derived from the sensitive strain by the transfer of a plasmid carrying ampicillin resistance. T h e transmissibility of ampicillin resistance from the resistant strain to Escherichia coli H B I o I (recA hsdRM strA, plasmid free) was demonstrated in vitro by mixing the strains together in nutrient broth, incubating it at 37 °C for 7 h and then selecting for HB ~oI transconjugants on nutrient agar containing ampicillin and streptomycin; the large n u m b e r of transconjugant colonies that were recovered suggests that the ampicillin resistance is transmissible. T h e plasmid profiles of the sensitive and resistant isolates of S. virchow were determined by the methods of Eckhardt 17 and of Kado and Liu. Is These m e t h o d s allow the rapid detection of plasmids up to > 300 Md. T h e two isolates carried two identical plasmids of < 5 M d (Plate I). T h e resistant isolate additionally carried a plasmid of 36 M d . T h e Escherichia eoli H B I o I ampicillin resistant transconjugant m e n t i o n e d above was also found to carry a plasmid of 36 M d . In a similar series of matings with E. coli recipients (KF29: strA F') and the resistant Salmonella sp. as donor, ampicillin resistant E. coli transconjugants were again isolated at high frequency. In this instance, the plasmid profile of the E. coli transconjugants showed both the 36 M d Salmonella sp. plasmid and the resident F' E. coli plasmid, indicating that the 36 M d plasmid does not belong to plasmid Incompatibility G r o u p I n c F I . Matings were also used to construct H B I o I carrying the 36 M d plasmid and the RP4 (amp ® karl ® tet®); these transconjugants carried both plasmids, indicating that the 36 M d plasmid is not in IncP.
Journal of Infection
Plate I
o
b
c
Plate I. Electrophoretic gel of plasmids isolated by the method of Kado and Liu is and separated by o.7 % agarose gel electrophoresis. Lane a: Escheriehia coli showing 36 Md plasmid carrying ampicillin resistance derived from Salmonella virchow faecal isolate, Lane b: S. virchow faecal isolate. Lane c: S. virchow isolate from knee.
M. G. MORGAN ET AL.
(Facing p. 198)
Salmonella septic arthritis
I99
Discussion
Table II outlines some comparative features of salmonella septic arthritis, reactive arthritis and osteomyelitis. In most cases of SSA there is no preexisting joint disease. Some cases, however, have followed trauma and surgery especially for prosthetic joints. T M Other predisposing conditions include SLE, T M administration of a corticosteroid or other imrnunosuppressant treatment, neoplasia and sickle cell disease. 8' 15 Our patient did not have any specific predisposing condition although frequent minor injuries are commonplace in children and a definite history of trauma is often hard to obtain. Most cases of SSA are monoarticular and, as in our patient, the knee is the most common joint affected (57 %) followed by the hip (23 %) and shoulder (9%). 8 Joint swelling and pain, together with fever, are the commonest presenting symptoms. Diarrhoea is often present but was absent in our patient as well as her seven siblings who shared the same meals. Diagnosis is established by the clinical features and isolation of a salmonella from the joint fluid. T h e latter is necessary since patients with reactive arthritis may present with joint swelling and pain as well as positive faecal or blood cultures but, by definition, have joint aspirates negative for Salmonella sp. Gram-staining of synovial fluid is positive in about half the cases~ faecal culture is positive in 43 % and blood culture in 65 %.8 Our patient had negative Gram staining but positive cultures of synovial fluid and faeces although blood cultures were negative. Salmonella virchow belongs to the serological group Cr which also encompasses such serotypes as S. choleraesuis, S. oranienburg, S. montevideo, S. thompson and S. hartford, all of which have been implicated in SSA. Isolations of S. virchow reported to the P H L S have been rising steadily since I975. It was the second commonest serotype in I9842° and the third commonest in I989 (PHLS, Communicable Disease Surveillance Centre) after S. enderitidis and S. typhimurium. T h e reservoir and usual vehicle of transmission is considered to be poultry. Some authors in the U.S.A. have noted a preponderance of group C salmonella isolates in certain extra-intestinal salmonella infections such as bacteraemia ~'21 osteomyelitis 22 and septic arthritis, 7,9 Salmonella choleraesuis being the most commonly isolated serotype. In the period i962-i97 r, salmonella of group CI accounted for 5-r% cases of salmonella bacteraemia, 21 24% cases of salmonella osteomyelitis and 67 % cases of SSAfl while accounting for only around 5"5 % salmonella isolates. T h u s it was postulated that salmonellae of group CI have a special predilection for bones and joints as well as a generally enhanced virulence over other non-typhoid salmonellae. In another series of 44 cases of SSA 8 the most common serotype isolated with S. typhimurium (39 %) followed by S. choleraesuis (II %). This series, however, contained a disproportionately large number of immunosuppressed patients who are especially susceptible to S. typhimurium infections. British workers have also remarked on the invasiveness of S. virchow. Mani et al., 23 described an outbreak of S. virchow food poisoning in the Manchester area in which one third (7/zr) of cases had a typhoidal or septicaemic illness. T o d d and McC M u r d o c h 24 reported septicaemia in 6o % (9/I5) sporadic cases of infection due to this organism. In a I5 year retrospective study, Mandal and
I'6--3"9 % 1-4
Reactive arthritis
2580
2578
Year I988
I989
Communicable Diseases Scotland Unit (unpublished data)
Total salmonella isolates
28
38
315 (I2"2)
6 (t5"8)
5 (I7"9)
Total Group C I salmonella salmonella bacteraemia bacteraemia (%)
I48 (5.7)
Group CI salmonella isolates (%)
Table III Reported salmonella isolates I988, I989 Salmonella septic arthritis
Good prognosis with antibiotic therapy alone. Poorer prognosis in chronic osteomyelitis which may require surgery
Excellent prognosis with non-steroidal anti-inflammatory agents
S. typhimurium S. enteritidis
Positive culture from bone, abscess cavity, joint or blood As in septic arthritis
Usually affects one bone; most commonly femur, tibia or humerus
o'76% s Sickle-cell disease~9
Osteomyelitis
Positive faecal culture negative joint fluid culture
Possession of H L A B27 antigen 2 (69 %) Usually polyarticular and migratory; knee, ankle and wrist most commonly affected
Source
* See text for references.
Outcome
Organisms most commonly isolated 5, 7.,
S. choleraesuis or other of the CI group S. typhimurium Good prognosis with antibiotic therapy and aspiration
Usually monoarticular Knee 57 % Hip 23 ~/o Shoulder 9 % Positive joint aspirate
Site 8
Microbiological diagnosis
0"24 ~/o~ See text
Incidence Association
Septic arthritis
Table II Some comparative features of salmonella bone and joint infections*
0
o o
Salmonella septic arthritis
20I
Brennand 25 reported bacteraemia in I6"5 % (I9/II5) S. virchow infections. Only S. infantis and S. dublin were more invasive. In order to address the question whether the entire CI group of salmonellae causes disproportionately more cases of invasive disease compared to other serogroups we examined figures for salmonella isolations reported in Scotland in I988 and i989 [Communicable Diseases (Scotland) U n i t - unpublished data] - Table III. Compared to other Salmonella sp., those of group CI caused disproportionately more cases of bacteraemia (i 7"9 % and 15"8 °//o respectively) in relation to their rates of isolation from faeces (5"7 and i r a ~/o respectively). This observation tends to support the enhanced role of group CI organisms over other salmonellae in the aetiology of bacteraemia. T h e figures for septic arthritis, however, were too small as to allow for meaningful interpretation. Most of the group C I organisms (9/I I) causing bacteraemia were S. virchow while, of the two isolates causing septic arthritis, one was a rough strain Of salmonella that could not be speciated, the other S. enteritidis phage type 4. In a recent review, s 29 ~/o patients with SSA, including three with sickle-cell disease, had co-existing osteomyelitis. Our patient had scintographic changes indicative of osteomyelitis but no X-ray evidence of bone destruction. Recommended treatment for SSA includes appropriate IV antibiotics for 2-4 weeks and repeated arthrocentesis up to twice a day. Intra-articular antibiotics are contra-indicated since they may induce chemical synovitis. Surgical drainage is required only if antibiotic treatment fails or the joint cannot be adequately aspirated. Our patient responded well to medical treatment alone in spite of the delay in instituting appropriate antibiotic therapy and the fact that the joint was aspirated only once. In a previous review of SSA, patients treated more promptly required shorter courses of antibiotic therapy. 8 Delay in treatment can be avoided if children with joint-swelling and pain are immediately referred to hospital for appropriate investigations. T h e good outcome with medical treatment alone in SSA contrasts with the poor outcome in patients with non-salmonella arthritis caused by other Gram-negative bacteria. Poor outcome in SSA is often associated with pre-existent neoplasia or immunosuppression and is not related to age of the patient or the salmonella serotype involved. T h e two isolates of S. virchow recovered from our patient's knee and faeces were identical in biotype, serotype, phage type and small-plasmid profile, so almost certainly indicating that they were the same organism. We postulate that the patient had acquired an ampicillin-sensitive strain of S. virchow in her intestinal tract, probably from food. During transient bacteraemia, the organism was deposited in her knee thereby initiating the arthritic changes. Subsequent treatment with amoxycillin for tonsillitis for I week, followed by repeated courses of penicillin V, selected S. virchow organisms in the intestinal tract that had acquired a plasmid carrying resistance to ampicillin, this plasmid presumably being already present in the resident bacterial gut flora. T h e rapid and excellent response of the patient's knee to ampicillin therapy indicates that the organisms in the knee had never acquired the resistance plasmid and so remained sensitive to ampicillin. Other authors ~2'26 have also noted the isolation of ampicillin-resistant
202
M.G. MORGAN E T AL.
salmonellae following surgery with pre-operative beta-lactam antibiotic p r o p h y l a x i s . W e r e p o r t h e r e t h e first r e c o r d e d case o f p l a s m i d - b o r n e a m p i c i l l i n r e s i s t a n c e in S. virchow, a n d o n e o f o n l y a f e w cases in w h i c h a c q u i s i t i o n o f a m p i c i l l i n r e s i s t a n c e in a s a l m o n e l l a has b e e n d e m o n s t r a t e d in vivo. ~7'2s I n b o t h o f t h e o t h e r cases, t h e i s o l a t i o n o f n o v e l a m p i c i l l i n - r e s i s t a n t o r g a n i s m s , d u e to t h e a c q u i s i t i o n o f p l a s m i d - b o r n e r e s i s t a n c e , f o l l o w e d t r e a t m e n t w i t h ampicillin. (We thank Professor B. Taylor for allowing us to report on his patient and Professor T. H. Pennington for reading the manuscript. We are also grateful to staff of the Division of Enteric Pathogens, Central Public Health Laboratory, Colindale, L o n d o n , for typing this organism, and to D r J. C. M. Sharp, Communicable Diseases (Scotland) Unit, for supplying epidemiological data.)
References
I. Friis J, Svejgaard A. Salmonella arthritis and HLA 27. Lancet 1974; i: I350. 2. Hakansson U, Eitrem R, Low B, Winblad S. HLA-antigen B27 in cases with joint affections in an outbreak of salmonellosis. Scand J Infect Dis I976 ; 8 : 245-248. 3. Vartiainen J, Hurri L. Arthritis due to Salmonella typhimurium. Report of 12 cases of migratory arthritis in association with Salmonella typhimurium infection. Acta Med Scand 1964; 175:771-776 • 4. Warren CPW. Arthritis associated with salmonella infection. Ann Rheum Dis 197o; 29: 483-487. 5. Saphra I, Winter JW. Clinical manifestations of salmonellosis in man. An evaluation of 7779 human infections identified at the New York Salmonella Center. N Englff Med 1957; 256: 1128-1134. 6. Achard C, Bensaude R. Infections paratyphoidiques. Societe Medicale des Hospitaux de Paris Bulletins et Memoires 1896; 13: 82o-853. 7- David JR, Black RL. Salmonella arthritis. Medicine 196o; 39: 385-4o3. 8. Cohen JI, Bartlett JA, Corey GR. Extraintestinal manifestations of salmonella infections. Medicine 1987; 66: 349-388. 9. Ortiz-Neu C, Marr SJ, Cherubin EC, Neu HC. Bone and joint infection due to salmonella. ff Infect Dis 1978; 138: 82o--828. IO. Petty BG, Sowa DT, Charache P. Polymicrobial polyarticular septic arthritis. J A M A 1983; 249: 2o69-2o72. II. Quismorio FP Jr., Jakes JT, Zarnow AJ, Barber D, Kitridou RC. Septic arthritis due to Arizona hinshawii. J Rheumatol 1983 ; IO : 147-15o. 12. Samra Y, Shaked Y, Maier MK. Non-typhoid salmonellosis in patients with total hip replacement. Report of four cases and review of the literature. Rev Infect Dis 1986; 8: 978--983. 13. Ebong WW. Septic arthritis in patients with sickle cell disease. Br J Rheumatol 1987; 26: 99-1o2. 14. Martin-Santos JM, Alonso-Pulpor L, Pradas G e t al. Septic arthritis by salmonella enteritidis after heart transplantation, ff Heart Transplant 1987; 6: 177-179. 15. Sankaran-Kutty M, Sadat-Ali M, Kutty MK. Septic arthritis in sickle cell disease. Int Orthop 1988; I2: 255-257. 16. Medina F, Fraga A, Lavalle C. Salmonella septic arthritis in systematic lupus erythematosus. The importance of the chronic carrier state, ff Rheumatol 1989; 16: 2o3-2o8. 17. Eckhardt T. A rapid method for the identification of plasmid deoxyribonucleic acid in bacteria. Plasmid 1978; I: 584-588. 18. Kado CI, Liu S-T. Rapid procedure for detection and isolation of large and small plasmids. ff Bacteriol 1981 ; 145 : 1365-1373.
S a l m o n e l l a septic arthritis
203
19. Hodges, FJ, Holt JF, Jacox H W , Collins VP. Editorial comments. In: Yearbook of radiology. Chicago: Yearbook Medical Publishers, r957: 89. 2o. P H L S Microbiology Digest. Salmonella special I986; 3: 3. 22. Cherubin CE, Neu H C , Imperato PJ, Harvey RP, Bellen N. Septicemia with non-typhoid salmonella. Medicine (Baltimore) I974; 53:365-376. 22. White G, Meynell MJ. Paratyphoid osteomyelitis of tibia. Lancet 2956; i: 362. 23. Mani V, Brennand J, Mandal BK. Invasive illness with Salmonella virchow infection. Br Medff I974; z: I43-I44. 24. T o d d W T A , M c C Murdoch J. Salmonella virchow: a cause of significant bloodstream invasion. Scott Med J 2983; 28: i76--278. 25. Mandal BK, Brennand J. Bacteraemia in salmonellosis : a I5 year retrospective study from a regional infectious diseases unit. Br Med J I988 ; 297: I242-I243. 26. Cheung N, Muller JC. Salmonella osteomyelitis in patients with total hip replacement. A case report of hematogenous infection from the gastrointestinal tract. Arch Orthop Trauma Surg i982; 99: 281-283. 27. Cohen SL, Wylie BA, Sooka A, Koornhof HJ. Bacteremia caused by a lactose-fermenting, multiply resistant Salmonella typhi strain in a patient recovery from typhoid fever, ff Clin Microbiol I987; 25: I516-I528. 28. Platt DJ, Sommerville JS, Gribben J. Sequential acquisition of R plasmids in vivo by Salmonella typhimurium, ff ,4ntimicrob Chemother I984; 13 : 65-69.
