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CID 1996;23 (November)
Brief Reports
vicular tender mass with a diameter of 5-8 cm was noted, and there
was a papulomacular erythematous skin lesion (1 cm in diameter) on
top of the mass; tender small axillary lymph nodes were also found.
The liver was palpable 5 cm subcostally.
The results of laboratory investigations were as follows: erythrocyte sedimentation rate, 80 mm/h; C reactive protein, 60 mg/L;
hemoglobin, 13.3 g/dL, WBC count, 15,900/mm 3 ; platelets,
664,000/mm 3 ; and alanine aminotransferase, 37 U/L. Serological
investigations for HIV, cytomegalovirus, and hepatitis viruses A,
B, and C as well as for Toxoplasma gondii were negative. IgM to
EBV viral capsid antigen was detected. A CT scan revealed the
supraclavicular lymph node, generalized abdominal lymphadenopathy with tumors of up to 3.6 cm in diameter, and slight enlargement of liver and spleen. Examination of biopsy specimens from
the cervical tumor revealed pus, but cultures of these specimens
were negative for bacteria and mycobacteria. Histological examination of the biopsy specimens showed necrotic granulomatous
inflammation with giant cells; stains for acid-fast bacteria and
argyrophilic bacilli were negative.
Upon specific questioning, the patient remembered having
played with a young cat some weeks before the onset of his present
illness. CSD was considered in the patient's differential diagnosis.
Serology performed as described in previous reports [3, 4] showed
an IgG titer of antibodies to B. henselae of 1:2,048. B. henselaespecific DNA was detected in the tumor biopsy specimen by PCR
with use of primers that allow the simultaneous amplification of
B. henselae and Bartonella quintana followed by species-specific
hybridization [2].
The patient was treated with clarithromycin (500 mg twice daily
for 4 weeks), and he felt well afterwards. Six months later, an
abdominal ultrasonogram still showed slight hepatosplenomegaly.
IgM to EBV viral capsid antigen was no longer detected, and the
titer of IgG to B. henselae was 1:512. IgG seroconversion to
B. henselae and to nuclear antigen of EBV was documented. The
first serum specimen (obtained 20 August 1994) revealed an already positive titer of IgG to EBV viral capsid antigen (table 1).
This case emphasizes that CSD may be a severe systemic disease
and demonstrates that generalized lymphadenopathy should be
carefully investigated. EBV infection may have been reactivated
by B. henselae or EBV may have promoted dissemination of
B. henselae, which led to our patient's severe illness. Because of
the lack of controlled therapeutic trials, it is not known whether
antibiotic treatment of immunocompetent patients with CSD is
Isolation of Candida norvegensis from Clinical Specimens:
Four Case Reports
In recent years, we have seen a greater number of previously
unusual yeasts isolated from patient specimens; this circumstance
corresponds to the increasing population of immunocompro-
Reprints or correspondence: Dr. S. V. Hood, Monsall Unit, North Manchester General Hospital, Delaunay's Road, Crumpsall, Manchester M8 6RL,
United Kingdom.
Clinical Infectious Diseases 1996; 23:1185-7
© 1996 by The University of Chicago. All rights reserved.
1058-4838/96/2305-0046$02.00
1185
Table 1. Reciprocal titers to Bartonella henselae and Epstein-Barr
virus in a patient who presented with general lymphadenopathy.
Date of serum
specimen
08/20/94
10/21/94
11/09/94
05/04/95
IgG to
EBV VCA
IgG to
EBNA
B. henselae
640
1,280
1,280
2,560
<10
<10
10
>10
<64
1,024
2,048
512
IgG to
NOTE. EBNA = Epstein-Barr virus nuclear antigen; EBV VCA =
Epstein-Barr virus viral capsid antigen.
beneficial. Spontaneous resolution of CSD in immunocompetent
persons is common, but treatment is indicated for immunocompromised persons and may be indicated for immunocompetent
persons with systemic CSD.
Acknowledgment
The authors thank Dr. W. Strupler for data collection and Dr.
R. Geertsen and D. Goldenberger for technical help.
References
1. Dolan MJ, Wong MT, Regnery RL, et al. Syndrome of Rochalimaea
henselae adenitis suggesting cat scratch disease. Ann Intern Med 1993;
118:331-6.
2. Anderson B, Sims K, Regnery R, et al. Detection of Rochalimaea henselae
DNA in specimens from cat scratch disease patients by PCR. J Clin
Microbiol 1994; 32:942 —8.
3. Nadal D, Zbinden R. Serology to Bartonella (Rochalimaea) henselae may
replace traditional diagnostic criteria for cat-scratch disease. Eur J Pediatr
1995;154:906-8.
4. Zbinden R, HOchli M, Nadal D. Intracellular location of Bartonella henselae
cocultivated with Vero cells and used for an indirect fluorescent-antibody
test. Clinical and Diagnostic Laboratory Immunology 1995; 2:693-5.
Reinhard Zbinden, Sylvia Baumann Kurer, Martin Altwegg,
and Rainer Weber
Department of Medical Microbiology and Division of Infectious
Diseases, University of Zurich, Zurich; and Department of Internal
Medicine, Kantonsspital, Winterthur, Switzerland
mised patients [1-3]. Candida norvegensis was originally isolated
in 1954 by Dietrichson [3a] and was later described by other
investigators [4]. We searched the world literature and found a
single case report of invasive diseak due to C. norvegensis [5].
We describe four seriously ill patients from whom C. norvegensis
was isolated; two of these patients had AIDS. To our knowledge,
C. norvegensis infection has not previously been reported among
patients with AIDS.
Patient 1. A 31-year-old HIV-infected man with a history of
Pneumocystis carinii pneumonia (PCP) and Kaposi's sarcoma had
oropharyngeal candidiasis (OPC), which was treated with fluconazole. He developed cytomegalovirus esophagitis and probable
PCP when his CD4 cell count was 12 x 10 6/L. He had another
episode of OPC that responded to fluconazole therapy, but his
respiratory symptoms persisted, and C. norvegensis was isolated
1186
CID 1996; 23 (November)
Brief Reports
Table 1. Characteristics of and susceptibility test results for four patients from whom C. norvegensis was isolated.
MIC (pg/mL)
Patient
no.
Underlying condition
Flucytosine*
Susceptible (by disk
diffusion method)
Susceptible
1
AIDS
Sputum
2
AIDS
Mouth washings (two isolates)
3
Obstruction of small bowel,
CSU, sputum, wound
Susceptible
Throat
Susceptible
Klebsiella oxytoca
4
septicemia, ARDS
Gastric ulcer, metastatic
bronchogenic carcinoma
Site of isolation
Fluconazole*
Amphotericin Bt
25
ItraconazoleI
0.125
0.06
25
25t
50
25
0.25
0.03
0.06
NOTE. ARDS = adult respiratory distress syndrome; CSU = catheter specimen of urine.
* Method described in [6].
t Method described in [7].
Method modified from that for fluconazole, as described in [6]: medium = yeast nitrogen broth with glucose containing 0.57% trisodium citrate; itraconazole
concentration, range, 0.03125-8 itg/mL; Candida krusei FA/063 used as the control.
Two isolates were obtained from these patients.
from his sputum on 12 December 1994 (table 1). His respiratory
status deteriorated, and he died on 20 January 1995.
Patient 2. An HIV-infected man with a history of severe cryptosporidial diarrhea, recurrent OPC, and cerebral toxoplasmosis
developed worsening OPC that was unresponsive to treatment with
oral fluconazole (150 mg daily). Culture of mouth washings
yielded only C. norvegensis (table 1). The OPC did not respond
to further oral treatment with fluconazole, itraconazole (200 mg
daily), miconazole gel, or amphotericin (200 mg q.i.d.). The patient's condition deteriorated, and he died shortly thereafter.
Patient 3. A 63-year-old female ex-smoker underwent laparoscopic cholecystectomy in 1993. She presented on 29 May 1994
with small-bowel obstruction, marked hypotension, and hypoxia
while breathing room air. She was resuscitated with intravenous
fluids and underwent laparotomy, at which time an adhesive mass
and some dilated small bowel was resected. There was no evidence
at this time that the bowel was perforated. A fever (temperature,
38.5°C) was noted. The patient was ventilated postoperatively, and
treatment with intravenous broad-spectrum antibiotics was begun.
She developed hypoxemia, and a chest radiograph showed diffuse
bilateral shadowing, consistent with adult respiratory distress syndrome (ARDS). Therapy with high-dose iv hydrocortisone was
started. Fast atrial fibrillation and recurrent pyrexia developed.
C. norvegensis was isolated from catheter urine and sputum specimens (table 1).
Ventilation of the patient remained difficult. No fungal blood
cultures were done, and she received no systemic antifungal treatment. C. norvegensis was isolated again from the abdominal
wound. Her respiratory function worsened, and she developed
pneumothoraces and died on 17 June 1994. Postmortem examination revealed scattered foci of bronchopneumonic consolidation
with areas of edematous tissue, consistent with ARDS. The tissue
was not examined microscopically.
Patient 4. A 65-year-old man had undergone right nephrectomy
for renal cell carcinoma and had had a myocardial infarction in
1993. He was admitted to the hospital for evaluation of melena
on 19 January 1995. He continued to bleed, and Polya's operation
was performed, followed by a second laparotomy for postoperative
bleeding. An abdominal CT scan showed probable metastases from
a bronchogenic primary lesion. Culture of a throat swab yielded
C. norvegensis. Despite further treatment, the patient's condition
deteriorated, and he died 9 days after surgery.
C. norvegensis isolates were identified for production of pseudohyphae with use of the ID 32C strip (bioMerieux, Marcy l'Etoile,
France) and rice-agar-tween medium (bioMerieux). C. norvegensis
appears as long oval-to-cylindrical cells that are 2-8 p,m by
5-13 tim after 3 days of growth at 25°C in glucose-yeast extractpeptone water [4].
The cases of the patients described herein do not provide unequivocal evidence of the inherent pathogenicity of C. norvegensis,
although this pathogenicity is likely in cases 2 and 3. The common
factors (i.e., that all four patients had severe, ultimately fatal underlying conditions and that all were receiving antibiotics) characterize the clinical setting in which this unusual Candida species may
be isolated from patients. There are few previous reports of the
isolation of C. norvegensis from human specimens. Nielsen et al.
[5] reported a similar clinical scenario in which C. norvegensis
was cultured in peritoneal fluid from a patient receiving immunosuppresive therapy who was undergoing continuous ambulatory
peritoneal dialysis. The patient developed a large gastrointestinal
hemorrhage secondary to a perforated duodenal ulcer and subsequently died.
The only other published report of C. norvegensis infection cites
this case [5] and one other case in which fungemia occurred and
two isolates were recovered from urine specimens, with no further
clinical details given [8]. The susceptibility test results for our
isolates support other evidence that C. norvegensis is a species
with a degree of inherent antifungal resistance [9]. All of these
isolates were resistant to fluconazole, and two were recovered from
patients who had had no previous exposure to any azole. Our
method of testing fluconazole susceptibility yields results that correlate with clinical outcome in the context of OPC in patients with
AIDS [6, 10] as is demonstrated by case 2. Yeast identification
and susceptibility testing are likely to be increasingly helpful in
Brief Reports
CID 1996;23 (November)
patient care given the increasing number of unusual fungi now
being recovered.
Stephen V. Hood, Caroline B. Moore,
and David W. Denning
Department of Infectious Diseases and Tropical Medicine, North
Manchester General Hospital, Manchester; and Department of
Microbiology and Section of Infectious Diseases, Department of
Medicine, The University of Manchester, Hope Hospital, Salford,
United Kingdom
References
1. Hazen KC. New and emerging yeast pathogens. Clin Microbiol Rev 1995;
4:462-78.
2. Cunliffe NA, Denning DW. Uncommon invasive mycoses in AIDS. AIDS
1995;9:411-20.
3. Gradon JD, Timpone JG, Schnittman SM. Emergence of unusual opportunistic pathogens in AIDS: a review. Clin Infect Dis 1992; 15:
134-57.
Hypothermia Following the Intravenous Administration
of Amphotericin B
We describe a case of severe hypothermia following the intravenous administration of amphotericin B; we believe this is a previously unreported adverse drug reaction.
A 41-year-old, HIV-infected male (CD4 cell count, 6/mm 3 )
was admitted to the hospital with a 2-4-day history of fevers,
diarrhea, nausea, vomiting, and chills. Physical examination
revealed a temperature of 39.2°C, blood pressure of 100/62
mm Hg, and heart rate of 91. No infiltrates were seen on a
chest radiograph, and all other laboratory values were within
normal limits. Sputum, urine, blood, and stool were cultured.
Empirical treatment with intravenous antibiotics was started
and consisted of vancomycin, ceftizoxime, and fluconazole.
Medications on admission included chlorhexidine gluconate,
fluconazole, ethinyl estradiol, conjugated estrogens, medroxyprogesterone, beclomethasone metered dose inhaler, meclizine, omeprazole, and acetaminophen.
From hospital day 1 through 5, the patient remained febrile,
and cultures were negative. Repeated blood cultures on hospital day 6 were positive for Histoplasma capsulatum. Empirical
antibiotic therapy was discontinued, and treatment with peripherally administered intravenous amphotericin B (0.8 mg/
[kg • d]; 50 mg of amphotericin B in 500 mL of 5% dextrose
in water with 25 mg of hydrocortisone to be infused over 4
hours) was started. The patient was premedicated with hydrocortisone and acetaminophen 2 hours before infusion. Vital
Reprints or correspondence: Dr. Theodore G. Barlows III, Nova Southeastern
University, College of Pharmacy, 3200 South University Drive, Health Professions Division 1366, Fort Lauderdale, Florida 33328.
Clinical Infectious Diseases 1996; 23:1187-8
© 1996 by The University of Chicago. All rights reserved.
1058 4838/96/2305 0047$02.00
-
-
1187
3a. Dietrichson E. Etude d'une collection norvegienne de levuref. Ann Parisitol Hum Comp 1954;29:460-98.
4. Van Uden N, Buckley H. A taxonomic study. In: The yeasts. Lodder J,
ed. 2nd ed. Amsterdam: North Holland Publishing Company, 1970:
1015-8.
5. Nielsen H, Stenderup J, Bruun B, Ladefoged J. Candida norvegensis peritonitis and invasive disease in a patient on continuous ambulatory peritoneal dialysis. J Clin Microbiol 1990;7:1664-5.
6. Law D, Moore CB, Wardle HM, Ganguli LA, Keaney MGL, Denning
DW. High prevalence of antifungal resistance in Candida spp. from
patients with AIDS. J Antimicrob Chemother 1994; 34:659-68.
7. Wardle HM, Law D, Denning DW. In vitro activity of BMS-181184
compared with those of fluconazole and amphotericin B against various
Candida spp. Antimicrob Agents Chemother 1996;40 (in press).
8. Nielsen H, Stenderup J, Bruun B. Fungaemia in a university hospital,
1984-1988. Clinical and mycological characteristics. Scand J Infect
Dis 1991;23:275-82.
9. Ahearn DG, McGlohn MS. In vitro susceptibilities of sucrose-negative
Candida tropicalis, Candida lusitaniae, and Candida norvegensis to
amphotericin, fluorocytosine, miconazole, and ketoconazole. J Clin Microbiol 1984;19:412-6.
10. Baily GG, Perry FM, Denning DW, and Mandal BK. Fluconazole resistance in an HIV cohort. AIDS 1994; 8:787-92.
signs were temperature, 37°C; blood pressure, 135/95 mm Hg;
and heart rate, 80.
Within 30 minutes, the patient's temperature declined to
35.5°C, and the infusion was discontinued 1 hour later. A total
of 20 mg of amphotericin B had been administered when the
patient's temperature was noted to be 34.5°C (figure 1). Six
hours after the infusion was initiated, the patient's temperature
had continued to decline to 32°C, his blood pressure was
140/90 mm Hg, and his pulse rate was 48. A heating blanket
was applied. A cortisol stimulation test demonstrated normal
adrenal function. An electrocardiogram was remarkable for
inverted T waves, consistent with hypothermia. The patient's
temperature gradually increased over the next 30 hours to
36.6°C. Treatment with amphotericin B was discontinued, and
oral itraconazole therapy (200 mg t.i.d.) was initiated.
Over the next several days, the patient's condition continued
to deteriorate. Treatment with itraconazole was subsequently
discontinued, and amphotericin B was readministered, as described earlier, on hospital day 9. Hydrocortisone, acetaminophen, and diphenhydramine were administered 1 hour before
the infusion. The patient's rectal temperature was initially
noted to be 40.6°C (figure 1). Six hours and 11 hours after
the infusion was initiated, the patient's oral temperature had
decreased to 36.7°C and 35.1°C, respectively. Despite aggressive treatment, the patient died on hospital day 11.
During more than 40 years of experience with amphotericin
B therapy, this is the first time that hypothermia has been
associated with use of this drug. Following the first infusion
of amphotericin B, the patient's temperature decreased a total
of 5°C within 6 hours and did not increase until a heating
blanket was applied. On readministration of amphotericin B,
the patient's temperature again decreased, this time by 5.5°C.
The rechallenge with amphotericin B and the subsequent reoccurrence of the adverse event strongly suggest that amphotericin B was responsible for the hypothermia.
Although not well understood, adverse drug reactions and
hypersensitivity reactions are more common in HIV-infected