ORIGINAL ARTICLE
Rhodococcus equi infection in non-HIV-infected patients. Two case reports and review Claudio Farina', Silvia Ferruxxi2, Filippo Mamprin3 and Francesca I/aiEati3 lServizio di Microbiologia, 2Divisione di Medicina I, 3Divisione di Cardiochirurgia, Ospedali Riuniti,
Bergamo, Italy
Objective: To review two recent cases in HIV-negative subjects in the light of literature reports (52 patients without HIV infection till 1994).
Methods: Epidemiology (animal contacts, risk factors, year, country), clinical presentation, diagnostic methods (X-ray, tomography, microbiological techniques), therapeutic approach (antibiotics, surgery) and outcome were evaluated on the basis of clinical literature reports. Results: Tumors constituted an important predisposing factor and less frequently hepatobiliary pathology, rheumatologic diseases, iatrogenic causes, psychiatric pathology and trauma. Exposure to animals was reported by 55% of the patients. Pneumonia and pleurisy, without preferential localization, were detected in 50% of the patients. Etiologic diagnosis was usually obtained after an invasive collection. Combined medical therapy and surgery were required by 27.8% of the patients, and 16.7% of the patients died. Conclusions: In recent years the number of Rhodococcus egoicases has been rising also in HIV-negative patients. The infection is ubiquitous. Accurate diagnosis and the prompt selection of the most appropriate therapy depend on close cooperation between clinicians and microbiologists. Key words: Epidemiology, review, Rhodococcus equi
fellow, in the fifih edition of Bergey's Manual of Systematic Bacteriology, rendered official the term nocardioform actinomycetes, covering many bacterial genera, including Rkodocoms [3]. The first description of R. equi as an animal pathogen, causing pyogranulomatous pulmonitis in foals, dates back to 1923 [4]. The first human case, however, was reported much later, by Golub et al., in 1967, who described it in an immunodepressed patient [5]. By 1986 [61 there had been numerous reports of R. equi infection in patients with pathologies related to human immunodeficiency virus (HIV). Ffty-two cases have been described in patients who were negative for HIV [7-441. Our observation of two cases of R. equi infection in patients without HIV infection suggested a review of the epidemiologic, chical and diagnostic data on this increasingly fiequent infection.
INTRODUCTION Bacteria of the genus Rkodocoaus are Gram-positive microorganisms, obligate aerobes, mesophilic, chemoorganotrophic, immobile, partially alcohol/acid fast (in certain stages of their growth cycle), with a mycelium which can break up into bacillary or coccoid elements. They were first reported in 1889 when Zopf described a microorganism initially referred to as rkodockrous, meaning pink-tinged; this term is no longer used [l]. Rkodococcus has been assigned to various genera: Corynebacterium, Gordona, Mycobucterium, Nocardia, etc. However, in 1974 Tsukamura suggested the current denomination used for the genus, comprising the telluric species rkodockrous (subsequently considered a type species) [2]. GoodCorresponding author and reprint requests:
CASE REPORT No. 1
Claudio Farina, Servizio di Microbiologia, Ospedali Riuniti, Largo Barozzi, 1-24128 Bergamo, Italy
A 68-year-old woman, resident in a country area, reported contact with farmyard a n i m a l s and horses. The patient had been diagnosed as having non-
Tel: +39.35.269505 Fax: +39.35.269666 Accepted 14 August 1996 12
F a r i n a e t a l : R e v i e w o f R. e q u i i n f e c t i o n
Hodgkin's lymphoma 17 years earlier, and had received repeated cycles of chemo- and radiotherapy. In June 1992 she presented an erythematous intiltrative lesion near the umbilicus, close to an area of recent radiotherapy; it had partially regressed in response to amoxycfin and clavulanic acid, but had then rapidly progressed, causing an abscess. Although the patient was given diaminocihn, 1,200,000 U every 2 weeks, as an outpatient, and erythomycin 1 g twice-dady for 10 days, with daily topical application of polyvinylpyrrolidone iodme, the abscess spontaneously discharged after 1 month, leaving a sinus. She was admitted to hospital with fever (40.2"C), and empirical antibiotic therapy was started with sulbactam/ampicillin 2 g twice-daily. Her erythrocyte sedimentation rate (ESR) was 80rnm/h and she had peripheral neutrophilia (WBC 2740/mm3, neutrophds 81%). Serologic tests found no HIV antibodies. Blood cultures of samples taken on the first and fifth day in hospital and of purulent material fiom the periumbilical fistula were positive for R. equi. O n the basis of in vitro antibiotic sensitivity testing results, the patient was treated with pefloxacin 400 mg twice-daily, until she was discharged on day 15. Three months later the patient presented an unexpected fever again, and despite treatment with teicoplanin 400 mg, she died at home. No autopsy was done.
CASE REPORT No. 2 A 50-year-old man with chronic active hepatitis (HCVAb positive) received an orthotopic heart transplant with continuous normothermal potassium retroperfusion for New York Heart Association (NYHA) class IV dilatatory myocardiopathy. During surgery, five epicardial pacemaker wires were positioned, three ventricular and two atrial. The patient subsequently received cyclosporin A. In the immediate postoperative phase he suffered vascular shock &om peripheral vasoplegia, and hyperthermia (39.5 "C). Blood cultures were all negative. O n day 15 he presented fever (38°C) and complained of spontaneous pain and pain on palpation in the left parasternal area, localmed to the mid-zone, but radiating to the left shoulder. Inspection of the surgical wound showed nothing noteworthy and there was no appreciable sternal displacement. There was neutrophil leukocytosis (WBC 9980/mrn3, neutrophils 76.4%), and his ESR was 112 mm/h. The atrial pacemaker wires and one ventricular wire were removed, and culture grew R . equi. Blood cultures were negative. Symptoms regressed spontaneously and by day 20 the patient no longer had fever. However, on day 30 he
13
still had some slight redness and swelling at the lower third of the surgical wound, causing pain at the left sternal margin. A scan with labeled leukocytes showed an accumulation at this site. The patient was therefore treated with ciprofloxacin, 500 mg twice-dady. Computer scan (tomodensitometry) of the mediastinum showed an oval low-density area, about 15 mm in diameter, within the anterolateral wall of the right ventricle; this was not easy to interpret, and culture of seropurulent matter sampled &om the medioproximal region of the sternal wound gave no bacterial growth. The patient later suffered herpes zoster infection in the left cexvicobrachial region and Legionella pneumophila infection. Serologic tests before surgery and during followup gave negative results for HIV antibodies.
MICROBIOLOGICAL METHODS Blood samples were inoculated into BACTEC Plus 26 and 27 flasks (Becton Dickinson, Diagnostic Instrument Systems, Sparks, MD, USA); signs ofgrowth were evident after 72 h of incubation at 35 "C. Subculture of these samples, like the first culture of pus, incubated in a COz-enriched atmosphere for 24 h, yielded small colonies (diameter 1 to 2 m),smooth, glossy and moderately mucous, convex with regular edges, and tending to confluence &er 48 to 72 h. Microscopic examination showed pleiomorphic Gram-positive coccobaciUi, and no spores. API Coryne kits (Bio-Mirieux s.a., Marcy l'Etoile, France) detected the following enzymatic activities: nitratoreductase, alkahne phosphatase, alpha-glucosidase, urease, and catalase; there was no carbohydrate fermentation capacity. The strains had myristate lipase (C14) activity, tested by the Bio-Mirieux API ZYM system. O n the basis of these biochemical features, and the gross and microscopic appearance of the colonies, the microorganism was identified as R. equi. The isolates were tested for antibiotic sensitivity by the agar diffusion method according to NCCLS procedures. Both strains were resistant to penicillin, first-generation cephalosporins and clindamycin, but sensitive to macrolides, quinolones, vancomycin, thirdgeneration cephalosporins, piperacillin and imipenem.
DISCUSSION Bacteria of the genus Rhodococcus are saprophytes found in earth and vegetation, where they break down organic plant substances, in fiesh and salt water, and in the intestinal contents of mammals, mainly herbivores, and hematophage arthropods [45]. Some species of Rhodococcus are phytopathogens; others cause infection
14
C l i n i c a l M i c r o b i o l o g y a n d I n f e c t i o n , V o l u m e 3 N u m b e r 1 , F e b r u a r y 1997
in herbivores (horses, sheep and cattle), pigs and fish; others have been isolated h m human respiratory material [3]. Infection with R. equi is of interest in veterinary medicine, occurring almost exclusively in foals, where it frequently causes rapidly progressive suppurative bronchopneumonia, with multiple abscesses, and sometimes colitis and granulomatous mesenteric lymphadenitis. There are occasional reports of ‘tubercular-like’ episodes in pigs and cattle, and in other locations in dogs, cats, reptiles and koala bears [45]. In human pathology Rhodococcus spp. infection is very idequent. However, in recent years the numbers of cases have been rising, possibly because of increased attention being given to this pathogen, but also because of the rising numbers of patients, especially immunodepressed ones, exposed to the infection. About fifty cases of HIV patients infected with R. equi were found in the international literature up to the end of 1994, many of them in Medterranean countries. R. equi is often the cause of the first opportunistic infection [46-491, especially when the patient’s absolute CD4 lymphocyte count is less than 100 mm3. It has thus been suggested that isolation of R. equi is a diagnostic indication of AIDS, and R. equi might be included in CDC classification group 4c1. R. equi infection in non-HIV patients presents particular epidemiologic and clinical features, and generally the prognosis is better than in seropositive cases [46]. We found 52 cases reported in the literature, covering three decades up to the end of 1994, all HIV negative [5,7-441. Eight of 54 were observed from 1965 to 1974,15 in the next decade, and 31 in the years 1985-94. The dection was diagnosed in 33 males and 21 females (female-to-male ratio 1 : 1.5), aged from 7 months to 76 years (mean 40, median 40.5 years). The infection was ubiquitous, and the Merent geographc distribution of the isolates appears to reflect local microbiological practice more than the existence of specific reservoirs: 32 cases were described in North America; 11 were from Europe; five were &om Oceania; and the remaining three were from Asia or South America (one from Brazil). Table 1 shows the epidemiologic and clinical features of these cases. Malignant blood disorders (Hodgkin’s and nonHodgkm’s lymphomas, leukemia and sarcoma) accounted for 17 of 54 of the underlying diseases; solid tumorsadenocarcinoma and ependymoblastomaaccounted for only two cases. Less frequently, there was hepatobiliary pathology resulting h m alcoholism, cirrhosis or gallbladder diseases (five cases); rheumatologic diseases-rheumatoid arthritis, polyarthritis and sarcoidosis-accounted for four cases. Iatrogenic causes
are becoming more frequent: organ transplant (nine cases), valve replacements and continuous ambulatory peritoneal dialysis (CAPD) (one each). One patient presented two risk factors-renal transplant and Hodgkm’s lymphoma. Two cases had concomitant psychiatric illness, one of them involving self-injury, which suggested a traumatic pathogenic mechanism. Post-traumatic infections thus amounted to six cases, and in these the clinical course was particularly serious, with endophthalmitis and sepsis, or subcutaneous lesions like mycetomas. Two patients had chronic respiratory dseases and six had no identifiable risk factor. Exposure to animals,possible reservoirs of R. equi, was reported by 22 of the 40 patients who were asked about this. One case of R. equi infection was described in a laboratory technician who, however, had had no contact with experimental animals or microorganisms. It would appear that in most cases-as confirmed by the two we report here-contamination is due to direct contact with R. equi through burns, surgery, or dnect trauma, or to the inhalation of bacterial cells with dust or environmental debris, even if no animal reservoir is actually present. In 27 of the 54 cases, presentation involved the respiratory tract, with pneumonia or, more rarely, pleurisy. Radiologic examination found cavitary progression in 13 of 27 cases, stabihed infiltrates in 12, and atelectasis in one. There seemed to be no preferential localization in the lungs. Etiologic diagnosis was usually based on specimens obtained invasively (16 of 54 pus or vitreous; 15 out of 54 biopsy). Respiratory specimens were also usually collected invasively: seven by bronchial or pulmonary biopsy, five fiom pus h m cavitation, two horn bronchal lavage, four fiom pleural fluid, and two from transtracheal puncture. In three cases R. equi was isolated from sputum culture, but only in one case was the positive material the basis for diagnosis. Blood and bone marrow cultures were positive in 20 of 53 cases, in 10 of them without contirmation &om other positive specimens. One case was diagnosed at autopsy. Two patients relapsed, one of them four times. One patient, with psychiatric pathology, presented eight successive episodes of sepsis. Fifteen cases (27.8%) required combined medical therapy and surgery; in the remainder, antibiotics, with a variety of long-term regimens, resolved the clinical picture. There were nine deaths (16.7%), usually patients in very poor general condition. Etiologic hagnosis was often difficult, since R. equi is often dismissed as a contaminant in the sample, and rhodococcosis is rarely considered in differential diagnosis, especially in HIV-negative patients. How-
Dogs
Not detected
Horses
None
Not evaluated
Not evaluated
Dog; horses
Not detected
Not detected
Horses
Horse, pig
Not evaluated
Not evaluated
None
None
None
Kidney transplant
Kidney transplant
Kidney transplant
Heart transplant
Heart transplant
Prosthetic valve replacement HD
HD
HD
HD
3/F
38/M
40/F
39/F
45/F
38/M
30/M
52/M
8
9
10
11
15 50/M
16 51/M
18 26/M
18/M
7
14 42/M
34/M
6
13 62/M
52/M
5
12 64/M
53/F
4
19
20
21
22
17
47/F
Horses
Kidney transplant
ALL
HD
None
Not evaluated
Kidney transplant/HD Cattle
Pig
Kidney transplant
Not evaluated
Laboratory researcher
None
28/M
3
Kidney transplant
Cat
None
2
2/F
9/M
1
Pigs?
Animal contact
None
Patient Age/sex Risk factor
Fever Pneumonia, pleuritic Fever, cough Pneumonia Fever, sternal wound infection So) tissue infection Fever Endocarditis Fever, dyspnea, cough Pneumonia Fever, dyspnea, cough Pustular lesions Pneumonia, soft tissue infction Fever Sepsis Fever; cough Pneumonia Fever Sepsis Fever Pneumonia
Lung biopsy
Cavitation (LUL) Multiple nodules Not done
Infiltrate (LLL)
Bronchial washing
Blood/sputum
Bronchial biopsy
Infiltrate (RML) Infiltrate (RML)
Bone marrow
Lung biopsy; blood; skin Surgical tissue; PC pus
Aortic valve vegetations
Wires
Negative
Cavitation (RML)
Infiltrate (RUL)
Not reported
Negative
Lung biopsy, blood
Lung autopsy
Infiltrate (RML) Cavitation (RUL)
Urine. muscle necrosis
Paraspinal abscess pus
Lung nodule pus Brain pus
Skin biopsy
Bronchial biopsy; P C PUS
PC pus
Pus
Sputum
Lysis metaphysis
Not reported
Cavitation (RLL) Brain abscesses
Not done
Infiltrate (LUL)
Cavitation (LUL)
Not done
Cavitation (LLL)
Synovial/bone biopsy
Osteal reaction
Blood
Lymph node biopsy
Not done
Fever, neck swehng Cervical lymphadenitis Painless swelling hand Osteomyelitis Cough, dyspnea, chest pain Pneumonia Fever, cough, neck swelling Sepsis, cervical lymphadenitis Fever, chills, cough Pneumonia Arm kactudislocation &ft fissue infection Fever, chest pain, cough Pneumonia Fever, dyspnea, chest pain, lethargy, cough Pneumonia Burn Burn infection Asymptomatic relapse: headache Pneumonia; CNS infect. Myalgia, fever, UAP Soj tissue infrtion Thigh enlargement Osteomyelitis @mu!)
Culture
X-ray
Clinical presentation/ Clinicd diagnosis
Table 1 Epidemiological and clinical features of rhodococcosis
Oxa, then C C + C
Not specified
Not specified
SXT
then E+Tet P, then E
E,
P+GN
Va+Cip then Cip+Anc Cip
Fu+Toh then E+RF P, then E+Va then E+ TMP-SXT IMP+Tob
E+TMP-SXT, then C+Va+GN
AMX
then E+GN
AMX,
No
Va+RF
E
Ofl+Cef+Lat, then Ofl+Tic E, then CTX
E+AMX
INH, then
Doxy
Antibiotics
None
None
None
None
Lobectomy
Valve replacement Lobectomy
None
None
None
Sequestr.
Drainage
Lobectomy Drainage
None
None
Lobectomy
Drainage
None
None
None
None
None
Surgery
Died
Died
Cured
Died
Cured
Cured
Cured
Cured
Cured
Died
Cured
Cured
Relapse Cured
Relapsed (4)
Died
Cured
Cured
Cured
Cured
Cured
Cured
Cured
Outcome
1974/USA
1979/France
1979/USA
1977/USA
1975/USA
11
17
16
15
12
13
21
NK/uK 1974/USA
C
43
39
29
32
22
20
14
8
42
44
44
33
18
7
Ref,
1992/Italy
199l/Spain
1991/Spain
1986/USA
1985/N. Zealand
1980/USA
1975/N. Zealand
197WAustralia
197l/USA
NK/Italy
NK/USA
NK/USA
1987/Japan
1976/USA
1965/Denmark
Year/Country
a
Ln
2:
W 3
-I
-.
W
n
Table 1 continued ~~
23
6/F
24
9/F
25 26
ALL. myringotomy ALL?
Not evaluated
68/F
NHL
Horses
6/M
CML
Not evaluated
Not evaluated
27
73/F
CLL
None
28
64/M
LL
Farmer
29
36/M
APL
Hones
30
58/M
AML
None
Fever, cough Pneumonia Fever Sepsis Fever, skin abscess Sofr tissue infeaion Fever, tachypnea. cough Pneumonia Fever, cough Pneumonia Cachexia, ascites Pleuritis Myalgia, fever Sepsis Fever
Cavitation (RUL) Nodule (LLL) Not reported
Lung biopsy, blood
E+RF
None
Cured
1988/Canada
30
Blood
Not reported
None
Cured
1990/NK
34
Negative
Pus; blood
S A M , then Pef
None
Died
1992/Italy
C
Infiltrate (LLL)
Pleural fluid
CAZ+Net
Drainage
Cured
NK /USA
37
+On,then P Iditrate (RLL)
Transtracheal fluid
TMP-SXT
None
Cured
1977/USA
15
Infiltrate (RLL)
Blood/pleural fluid
T MP-SXT
None
Died
19791USA
22
Negative
Blood
E+RF
None
cured
1990/USA
41
Negative
Blood, catheter tip
Pef+Tob+Va
None
Cured
1990/France
36
Iditrate (LLL)
Blood; pleural fluid
CF+GN
None
Died
1974/USA
13
Cavitation (LUL)
PC pus; blood
A+GN
None
Died
1971/USA
9
LPE
Pleural pus
A+Clo then A+Tob
Drainage
Cured
1980/N. Zealand
32
Negative
Blood
AZT+SAM
None
Cured
NWUSA
44
1ntent.accent.
Blood
Va
None
Cured
NK/USA
37
Not reported
Foot pus and biopsy
TMP+SXT
None
Cured
1985/Brazil
26
Not reported
Vitreous fluid
GN
Vitrectomy
Cured
1985/USA
27
Not reported
Vitreous fluid
CFZ+GN
Viwctomy
Cured
NK/USA
31
Not done
Knee joint fluid
CFZ
Arthrotomy
Cured
NK/USA
44
Not done Infiltrate (RUL)
Wound pus Transtracheal fluid
CF INH+ETH
None None
Cured Unchanged
NK/USA 1977/USA
44 15
Not reported
Blood
None
Cured
1988lSweden
35
Cavitation (Rh4L)
Blood
TMP-SXT +IMP E+GN+RF
None
Cured
NK/USA
40
Infiltrate (LLL)
Lingular mass
Doxy+Va
None
Cured
1985/USA
25
Cavitation (RUL)
Sputum
None
Died
NK/USA
38
Cavitation (LUL)
Blood and rib biopsy
CFZ, then INH+ RF+ETH E+RF
None
Cured
1982/Sweden
28
Not reported
Pus
None
None
Cured
1981/Germany
19
sepsis
31
53/F
R C sarcoma
None
32
39/M
LS
Horses
33 53/M
LS
Foals
34
52/F
Adenocarcinoma
Not detected
35
3/F
Ependymoblastoma
Not evaluated
36
62/M
Trauma
Farmer
37
9/M
Trauma
None
38
29/M
Trauma
Not mluated
39
4/M
Trauma
Not detected
40 41
9/M 70/M
Trauma COPD
Not detected Not detected
42
33/F
Factitious illness
Not evaluated
43
76/F
Schizophrenia
Not detected
44
69/M
RA
Farmer
45
51lF
RA
None
46
54/F
Sarcoidosis
Cattle. swine
47
69/F
Poliarthritis
Not evaluated
Fever, vomiting, cough Pneumonia Fever, dyspnea. cough Pneumonia Empyema, then tentorial herniation Pneumonia; CNS infect. Fever, vomiting Sepsis Fever, cough Sepsis Left foot tumor Mycetoma Eye pain Endophthalmitis Corneal laceration Endophthalmitis Knee pain, fever Articular infrrfion Lymphangitis Fever, dyspnea, cough Pneumonia Fever Sepsis (8 times) Respiratory distress Pneumonia Cough, hemoptysis Pneumonia Dyspnea. chest pain Pneumonia Hemoptysis, fever Pneumonia Gluteal abscess So$ tissue infiction
+ CAZ
F a r i n a e t al: R e v i e w o f
R. e q u i
infection
17
II
ever, clinical microbiologists and attending physicians should always bear in mind that R. equi is no longer a rare opportunistic microorganism, particularly after transplants or in leukemia. Accurate diagnosis and the prompt selection of the most appropriate therapy depend on close cooperation between clinicians and microbiologists.
I1
References 1. Zopf W. Ueber Ausscheidung von fettfarbstoffen. Lipo-
z
z
d c
B
.-U n
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Clinical M i c r o b i o l o g y a n d I n f e c t i o n , Volume 3 N u m b e r 1, F e b r u a r y 1997
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