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DIAGN MICROBIOLINFECTDIS 1991;14:347-352

CASE REPORT

Infections with Rhodococcus equi in Children Karin L. McGowan and Mark F. Mangano

Three cases of serious infection in children, including the first two reports of bacteremia, due to Rhodococcus equi are described. Only seven pediatric cases have been reported to date. In the laboratory, R. equi can easily be misidentified as a nonpathogenic Corynebacterium spp. (diphtheroid) or a Mycobacterium spp. Despite an overall mortality rate of 25% in adults, no pediatric deaths have occurred due to R. equi. The

INTRODUCTION Rhodococcus (Corynebacterium) equi has been reported as a frequent animal pathogen and as an unusual cause of serious infection in humans (Van Etta et al., 1982; Barton and Hughes, 1984). In adults, infections have been restricted to those with the acquired immunodeficiency syndrome (AIDS), those receiving immunosuppressive therapy, and those with an underlying malignancy (Berg et al., 1977; Van Etta et al., 1982; Barton and Hughes, 1984; LeBar and Pensler, 1986; MacGregor et al., 1986; Samies et al., 1986; Sane and Durack, 1986; Fierer et al., 1987). In such patients, the organism has been reported as a cause of pneumonia, pleural effusion, bacteremia, osteomyelitis, and abscesses of the lung, brain, and subcutaneous tissues. To date, only four pediatric cases have been reported and only two are in immunocompromised hosts (Thomsen et al., 1968; Gardner et al., 1976; Ebersole and Paturzo, 1988; Muller et al., 1988). We report here three additional cases including, to the best of our knowledge, the

From the Departments of Pediatrics (K.L.M.,M.F.M.)and Pathology, Divisionof InfectiousDiseases, Universityof Pennsylvania School of Medicine, Philadelphia, Pennsylvania,USA. Address reprint requests to Dr. K.L. McGowan,Children's Hospital of Philadelphia, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA. Received 21 August 1990; revised and accepted 9 November 1990. © 1991 ElsevierScience PublishingCo., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/91/$3.50

organism is generally susceptible to vancomycin, aminoglycosides, chloramphenicol, and erythromycin, but, optimal duration of antibiotic therapy is unknown. Treatment with multiple antibiotics was successful in all three cases reported here. Although only a small number of cases have been reported in children, R. equi appears to be an important pediatric pathogen.

first two reports of bacteremia in children due to Rhodococcus equi. In addition, we review the previ-

ously reported pediatric cases.

PATIENT REPORTS Case 1 A 3-year-old girl who carries the diagnosis of congenital hepatic fibrosis with polycystic kidneys was admitted for possible sepsis. On admission, her temperature was 39.3°C, pulse 148, and respiratory rate 32. Physical examination was notable only for shotty anterior cervical lymph nodes and a grade I/IV systolic murmur heard best at the left, upper sternal border. The central venous catheter skin-entry site showed no signs of inflammation. A complete blood count (CBC) showed a hemoglobin of 11 g/dl, hematocrit of 33.9%, platelet count of 125,000/bL1, and a total white blood cell (WBC) count of 3200/pA with 72% polymorphonuclear cells, 22% lymphocytes, 4% mononuclear cells, and 2% immature cells. Blood cultures were drawn through the broviac catheter and from a peripheral vein, and the child was started on oxacillin and gentamicin. One day after admission, she continued to be febrile, thus her therapy was changed to vancomycin and gentamicin, she defervesced the following day. After 72 h of incubation, both the central venous [>100 colonyforming units (CFU)/ml] and peripheral (18 CFU/ml) blood cultures grew Gram-positive rods identified

K.L. McGowan and M.F. Mangano

348

as Rhodococcus equi. Repeat blood cultures were performed, and therapy was changed to a 10-day course of intravenous penicillin. Disc diffusion and broth dilution susceptibility testing was attempted but the isolate failed to grow in the basal media. Blood cultures taken after 24 h of vancomycin and gentamicin were sterile as were all subsequent cultures. Her broviac catheter was removed after therapy, and she was discharged without further problems. Case 2

This 3-year-old girl was diagnosed 1 year prior to this admission with a right, parietal occipital ependymoblastoma that was partially resected. For the past year, she had been receiving both chemotherapy and radiation therapy. The patient was reasonably well until the day of admission when she developed a fever and cough. On admission, she was noted to be febrile (40.2°C) and neutropenic (ANC = 700), and on physical examination had a respiratory rate of 36 and an occasional cough with an otherwise normal respiratory exam. The central venous catheter site showed no signs of inflammation. Blood cultures were drawn through the broviac catheter and from a peripheral vein, urine was obtained for culture, and she was started on antibiotic therapy with oxacillin, netilmicin, and ceftazidime. The admission CBC showed a hemoglobin of 7.6 g/dl, hematocrit of 23.4%, and a total WBC count of 1400 with 39% neutrophils, 34% monocytes, 22% lymphocytes, 4% bands, and 1% eosinophils. After 2 days, the broviac catheter and peripheral blood cultures both grew :>100 CFU/ml of a Gram-positive rod later identified as Rhodococcus equi. Antibiotic susceptibility testing was performed using Microscan Gram-positive panels (Baxter Scientific), and the isolate was sensitive to ampicillin, cefamandole, cefazolin, cefotaxime, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, ciprofloxacin, clindamycin, erythromycin, gentamicin, oxacillin, penicillin, r i f a m p i n , t e t r a c y c l i n e , t r i m e t h o p r i m sulfamethoxazole, and vancomycin. Therapy was changed to ceftazidime and vancomycin. She defervesced by the third hospital day, and repeat central venous catheter and peripheral blood cultures taken at that time were sterile. She was discharged on day 6 after admission to continue on home intravenous ceftazidime therapy for an additional 7 days, and has done well since that time. Case 3

A 6½-year-old boy presented with cough, wheezing, fever, and severe lower-extremity pain - 1 month after being diagnosed as having chronic myelogenous leukemia (CML). Physical exam showed a tem-

perature of 38°C, a respiratory rate of 40, shotty lymphadenopathy, hepatosplenomegaly, supraclavicular and subcostal retractions, coarse end-expiratory rales at the left lung base, and occasional wheezes. A chest x-ray taken at the time of the initial CML diagnosis was normal, but one taken on this admission showed a patchy left, lower-lobe infiltrate with a small left-sided effusion. A CBC showed anemia, thrombocytopenia, and a total WBC count of 56,800/p3 with 66% polymorphonuclear cells, 13~7~, bands, 8°/c lymphocytes, 5% mononuclear cells and 4% blast forms. Blood and urine specimens were obtained for culture, and intravenous oxacillin, ceftazidime, and netilmicin was begun. Although the patient was intermittently febrile over the next several days, multiple blood cultures taken during this time were sterile. He remained tachypneic and chest x-rays showed development of a small right-sided infiltrate with persistence of the left-sided effusion and infiltrate. On the ninth hospital day, his total WBC count dropped to 1900 cells/~l, and he was started on amphotericin B. Over the next 3 weeks, he remained febrile, neutropenic, and thrombocytopenic. Five weeks after admission, a splenectomy was performed for persistent thrombocytopenia. He was started on penicillin postoperatively. Three days after surgery, he became increasingly tachypneic with respiratory rates to 60. Chest x-rays showed an increase in the right-sided effusion. A pleurocentesis was performed, and 350 ml of bloody fluid was removed. The fluid contained 400,000 RBC/p,I, 3000 WBC/p,1, with 47~7~ polymorphonuclear cells, 10'F, lymphocytes, and 39% histiocytes. A glucose level on the fluid was 71 mg/dl, protein 4.4 g/dl. A Gram stain of the fluid showed no organisms, but culture revealed both an c~-hemolytic streptococcus (not group D) and Rhodococcus equi. Antibiotic susceptibility testing was performed using Microscan Gram-positive panels (Baxter Scientific), and the isolate was sensitive to all antibiotics tested (see case 2). The patient was continued on penicillin and defervesced 1 day after the pleural tap. His tachypnea resolved and his exudates gradually improved. He was discharged 10 days later to continue oral penicillin at home.

RESULTS

Both blood specimens (Isolator tubes) and the pleural fluid were inoculated onto a 5% sheep blood agar plate, a chocolate agar plate, and a eugonic enrichment broth. In addition, the pleural fluid was inoculated onto a MacConkey agar plate and an anaerobic 5% sheep blood agar plate. All media except the anaerobic plate were incubated with 5%-8% CO2 at 35°C. Within 72 hr, all three cultures (two at 48 hr) yielded pink, mucoid colonies on sheep blood

Infections with Rhodococcus equi in Children

and chocolate agar. No growth appeared on either MacConkey agar or on the anaerobic sheep blood agar. An initial Gram stain of the pleural fluid revealed 4 + neutrophils, but no bacteria. After 48 hr of incubation, acridine orange smears examined on the eugonic broth of all three specimens were positive for rods that were confirmed as Gram-positive rods by Gram stain. All three isolates were acid fast (modified Kinyouns) and positive for catalase, nitrate, and urease, but were negative for bile esculin, lactose, xylose, indole, and DNase. Two isolates were glucose positive, one glucose negative. Based on the catalase reaction, lack of 13-hemolysis on the sheep blood agar, and acid-fast reaction, the isolates were tentatively identified as Rhodococcusspp. Because these represented unusual isolates in our laboratory, they were sent to reference laboratories for confirmation. The identification and speciation of the isolates were subsequently confirmed as R. equi by the Pennsylvania State Laboratory (Lionville, PA) and ApiLab (Analytab Products, Plainview, NY).

DISCUSSION

Rhodococcus equi, formerly Corynebacterium equi, is a ubiquitous aerobic Gram-positive rod whose taxonomic position has been extremely controversial. Rhodococcus is a genus that shares a number of characteristics with Nocardia, Mycobacterium, and Corynebacterium. In a number of reported cases, the clinical diagnosis was delayed because of failure to recognize R. equi as a pathogen or because it was originally misidentified as a nonpathogenic Cownebacterium spp. (diphtheroid) (Noval et al., 1988; Weingarten et al., 1988). Because it resembles nonpathogens, its isolation can easily be overlooked. Infections with this organism have only been recognized since 1967, with 25 cases being reported since that time (Golub et al., 1967). Although the taxonomy for this organism has been confusing, guidelines for the laboratory identification of R. equi have been clearly established (Van Etta et al., 1982; Mueller et al., 1988). The microbiologic features of this organism are summarized in Table 1. Historically, R. equi has been recognized as a cause of equine pneumonia and is a frequent pathogen of horses, cattle, and swine (Lipsky et al., 1982). Its principle pathology in animals has been as a cause of pneumonia and lung abscesses with frequent spread to regional lymph nodes. Although animal exposure was originally thought to be an important factor for disease in man, the natural reservoir for this organism appears to be soil. This has been supported by isolation of the organism directly from soil and by the increasing number of patients who have serious infection with R. equi, but no history of animal contact (Lipsky et al., 1982; Van Etta et al., 1982;

349

TABLE 1

Microbiologic Features of Rhodocuccus

equi Test, Substrate, or Morphology Catalase Oxidase Kligler iron agar Hydrogen sulfide (lead acetate paper) Lipase Christensen's urea Indole Ornithine, lysine, and arginine decarboxylase Nitrate reduction Bile esculin hydrolysis Simmons' citrate Phenylalanine deaminase Gelatin hydrolysis Growth in 6.5% NaC1 ONPG Carbohydrate fermentation Motility Partially acid fast (modified Kinyouns) ]3-Hemolysis on sheep blood agar Pigment

Result Positive Negative Alk-Alk Positive Positive Variable Negative Negative Variable Negative Negative Negative Negative Negative Negative Variable, usually negative Negative Variable Negative Pink to coral

Alk-Alk, alkaline-alkaline; and ONPG, O-nitrophenylq3-ogalacto-pyranoside. Barton and Hughes, 1984). In adults, the organism has been the etiologic agent in pneumonia, pleural effusion, bacteremia, osteomyelitis, and abscesses (Berg et al., 1977; Van Etta et al., 1982; LeBar and Pensler, 1986; MacGregor et al., 1986; Samies et al., 1986; Sane and Durack, 1986; Fierer et al., 1987). From reviewing pediatric and adult cases, there appear to be two methods of acquiring this organism. The first is by inhalation (Lipsky et al., 1982). Typically, patients present with fever, fatigue, nonproductive cough, and pleuritic chest pain, and development of symptoms can take from days to weeks. Chest x-rays typically show a lobar infiltrate that cavitates in 2--4 weeks, and the diagnosis can initially be confused with a Mycobacteria infection (Van Etta et al., 1982; Sane and Durack, 1986). The histologic appearance of R. equi shares a number of features with the Mycobacteria in that the organism is an acidfast bacillus and presents as an indolent pulmonary infiltrate that in adults frequently cavitates (Thornsen et al., 1968; Samies et al., 1986; Weingarten et al., 1988). In AIDS patients, the initial presentation may also be confused with Pneumocystis carinii (MacGregor et al., 1986). The second method of acquiring R. equi appears to be through trauma by direct inoculation of the organism (Ebersol and Pa-

350

K.L. M c G o w a n a n d M . F . M a n g a n o

turzo, 1988; M u e l l e r et al., 188). Both cases of t r a u m a i n d u c e d i n f e c t i o n w e r e in n o n i m m u n o c o m p r o m i s e d c h i l d r e n , o n e of w h o m p r e s e n t e d w i t h e n d o p h t h a l m i t i s f o l l o w i n g c o r n e a l l a c e r a t i o n w i t h t h e p o i n t of a n u m b r e l l a , a n d t h e s e c o n d as a n o p e n k n e e w o u n d f o l l o w i n g a fall. E x t r a p u l m o n a r y sites of i n f e c t i o n , such as subcutaneous nodules and brain abscesses w i t h R. equi, h a v e b e e n r e p o r t e d in a d u l t s a n d t h e s e a r e t h o u g h t to r e p r e s e n t s e c o n d a r y foci f r o m h e m atogenous spread following a primary respiratory i n f e c t i o n ( G o l u b et al., 1967; Berg et al., 1977; V a n Etta et al., 1982). To d a t e , a d u l t p a t i e n t s h a v e all b e e n i m m u n o c o m p r o m i s e d d u e to A I D S , u n d e r l y ing malignancies, or immunosuppressive therapy; h o w e v e r , t h i s d o e s n o t a p p e a r to b e t h e c a s e in child r e n . P r i o r to this r e p o r t , o n l y f o u r p e d i a t r i c c a s e s of R. equi h a d b e e n c i t e d in t h e l i t e r a t u r e ( T h o m s e n et al., 1968; G a r d n e r et al., 1976; E b e r s o l e a n d Pat u r z o , 1988; M u e l l e r et al., 1988). T a b l e 2 s u m m a r i z e s t h e clinical c h a r a c t e r i s t i c s of t h e p e d i a t r i c c a s e s of R. equi i n f e c t i o n . P a t i e n t s r a n g e d in a g e f r o m 9 m o n t h s to 18 y e a r s w i t h a m e a n a g e of 7.6 y e a r s . A h i s t o r y

TABLE 2

Characteristics of Pediatric Cases of

of t r a u m a o r d i r e c t i n o c u l a t i o n c o u l d b e e l i c i t e d in t w o p a t i e n t s , t w o p r e s e n t e d w i t h f e v e r a n d clinical s i g n s of b a c t e r e m i a , t w o w i t h f e v e r a n d s e v e r e res p i r a t o r y s y m p t o m s , a n d o n e w i t h f e v e r a n d cervical a d e n i t i s . In c o n t r a s t to a d u l t c a s e s w h e r e i n f e c t i o n h a s b e e n l i m i t e d to p a t i e n t s r e c e i v i n g i m m u n o s u p p r e s s i v e t h e r a p y o r t h o s e w i t h A I D S , o n l y f o u r of the seven pediatric cases were immunocompromised. Three were receiving immunosuppressive t h e r a p y for l e u k e m i a o r c a n c e r a n d o n e h a d c o n g e n i t a l h e p a t i c f i b r o s i s a n d p o l y c y s t i c k i d n e y s as a n u n d e r l y i n g d i s e a s e . In t w o of t h e c a s e s , R. equi w a s c u l t u r e d f r o m b l o o d . T h e o t h e r five i s o l a t e s w e r e o b t a i n e d f r o m p l e u r o c e n t e s i s fluid, v i t r e o u s fluid, pus from a knee wound, sputum and bronchial w a s h i n g s , a n d a l y m p h - n o d e b i o p s y . O f t h e 21 a d u l t c a s e s in t h e l i t e r a t u r e , 19 (90.5%) h a d p r o m i n e n t pulmonary involvement with effusions, infiltrates, a n d c a v i t a r y p n e u m o n i a . O n l y 2 (28.6%) of t h e p e diatric cases presented with significant pulmonary. f i n d i n g s that i n c l u d e d infiltrates in o n e or b o t h lungs. Clinical c u r e f o l l o w i n g a n t i b i o t i c t h e r a p y o c c u r r e d

Rhodococcusequi

ImmunoClinical Underlying suppressive Presentation D i s e a s e T h e r a p y

Chest X-ray Findings

Isolate Source

Case Age

Sex

1

3 yr

F

Fever, bacteremia

Congenital hepatic fibrosis, polycystic kidneys

None

Not done

2

3 vr

F

Fever, cough, neutropenia

Brain tumor

Yes

Slight Blood interstitial (peripheral accentuation and line)

3

6.5 yr M

Fever, tachypnea, wheezing, leukemia

Juvenile Yes chronic myelogenous leukemia

4

9 mo

M

Cervical adenitis, fever

None

5

13 yr

M

Chills, fever, pneumonitis

Acute Yes lymphocytic leukemia

6

13 yr

M

Superficial None wound infection

7

9 yr

M

Endophthalmitis None following corneal tear

LLL, left lower lung.

l'herapy

Outcome

Reference

Vancomycin and Cure penicillin(10 days)

"l'hs report

Ceftazidime, netilmicin, and oxacillin(48 hr); then vancomycin, and ceftazidime (10 days)

Cure

This report

Atelectasis, effusions, infiltrates

Cure Pleurocentesis Ceftazidime. netilmicin, and fluid oxacillin(10 days); then penicillin(10 days)

This report

Not done

Cervical node, soil

Blood (peripheral and line)

Excision, sulfonamide (unknown duration)

Cure

Thomsen et al., 1968

Pneumonia, Sputum, I.LL bronchial infiltrates wash

Clindamycin and chloramphenicol (I0 days)

Cure

Gardner et al , 1976

None

Not done

Pus from knee

Iodophore rinses, Cure fusidic acid (unknown duration)

None

Not done

Vitreousfluid gentamicin (eye drops and systemic) (unknown duration)

None

Cure

Muller et al., 1988

Ebersole and Paturzo, 1988

Infections with Rhodococcus equi in Children

in all seven pediatric cases. In contrast, seven (33%) of 21 adults with R. equi died as a result of their infection (Savdie et al., 1977; Van Etta et al., 1982; MacGregor et al., 1986; Sane and Durack, 1986; Fierer et al., 1987; Weingarten et al., 1988). Information regarding the treatment of patients with R. equi is still limited. In vitro antimicrobial sensitivity testing has shown penicillin, doxycycline, erythromycin, lincomycin, and aminoglycosides to be the most active agents against R. equi; however, development of resistance to ~-lactam antibiotics and the production of a 13-1actamase has also been reported (Woolcock and Mutimer, 1980; Samies et al., 1986; Fierer et al., 1987). With the seven pediatric isolates, four were sensitive to all antibiotics tested, whereas one (case 3) was resistant to oxacillin. The majority of pediatric isolates (four of seven) have only been tested using disc-diffusion methods, presumably due to poor growth of the isolates. This is problematic as reference standards for interpretation of disk-diffusion testing with this specific organism are not available. The wide variation in in vitro susceptibility results seen between adult and pediatric isolates reflects this problem and shows that a distinctive pattern of susceptibility has not yet been established. In adults, recurrent disease appears to be common, and successful therapy involves the use of multiple antibiotics, surgical drainage, or resection when needed, and a prolonged (2-6 months) course of therapy (Marsh and Von Graevenitz, 1973; Woolcock

351

and Mutimer, 1980; Van Etta et al., 1982; Noval et al., 1988). This does not seem to be the case with children as recurrence of infection has yet to be reported and none of the pediatric cases required a prolonged course of therapy. In both cases of catheter-associated bacteremia reported here, the children were treated successfully without requiring removal of the central venous catheter. With one exception (case 3, where the child required surgical drainage), all pediatric patients responded rapidly to antibiotic treatment. Despite the limited number of cases available, R. equi clearly appears to be an important pediatric pathogen. In contrast to the infections seen in adults, R. equi seems to cause a spectrum of disease in children ranging from severe bacteremia and pneumonia in the immunocompromised, to fever and tachypnea, or superficial wound infections in immunocompetent children. The reason for emergence of R. equi infections in humans is unclear and may merely reflect increased awareness on the part of clinicians and laboratorians, but it cannot be dismissed as a nonpathogen.

The authors thank the Pennsylvania State Laboratory and ApiLab (Analytab Products) reference laboratory for confirming the identification of Rhodococcus equi isolates, and the medical technologists in the clinical microbiology laborato~, at the Children's Hospital of Philadelphia for their invaluable technical support.

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K.L. M c G o w a n a n d M.F. M a n g a n o

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