Dealing with immunocompromised cancer patients with infectious disease complications

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1 Viewpoint Vol. 29 No. 1 Dealing with immunocompromised cancer patients with infectious disease complications:- Chitasombat M. 1 Dealing with immunocompromised cancer patients with infectious disease complications Maria Chitasombat, M.D. During my clinical rotation as infectious disease consultant, specialized in infection among immunocompromised patients, I encountered various challenging situations in this subspecialty. First of all, the patients had underlying cancer and were predisposed to various treatments such as surgery, chemotherapy and radiation. This resulted in cellular damage, loss of mucosal integrity and eventually a secondary infection due to either commensal pathogens or opportunistic pathogens. 1 Commensal organisms in gastrointestinal flora can invade damaged tissue and can cause secondary bacteremia related to mucositis especially in the setting of neutropenia. In such patients, low virulence pathogens can become invasive. Other pathogens such as fungal infection including yeast and mould are also a concern especially in neutropenic patients as well. Newer chemotherapy regimens and immunomodulating agents have been reported with reactivation of latency of viruses and tuberculosis. 2 As mentioned with broad range of different diagnosis of the list of possible pathogens, in order to stratify the likelihood of pathogens in the clinical setting, individualized patient would require thorough history and physical examination. 3 For example, in neutropenic patients, oral mucosa, dental, paranasal air sinus, skin and perirectal examination must be evaluated with special attention apart from general physical examination. Complications may have occurred from this minor mucosal damage as I recalled several cases of perianal fissures that progressed into cellulitis and abscesses later on. These were rather difficult to manage due to the frequency of recurrence and polymicrobial infection in nature or dental root infection that progressed into deep neck infection. Source of infection can be multiple sites concomitantly, such as phlebitis, mucositis, diarrhea or pneumonia. Multiple pathogens including bacteria, fungi, virus and parasites could play a role. Imaging study remains a helpful tool in the diagnosis. More importantly microbiological and tissue diagnosis remain the gold standard. However, diagnosis rarely yielded results in a timely fashion and isolating an organism was rather difficult in the setting of prior antibiotics exposure. Hospital-acquired pathogens with multidrug resistant phenotypes had become more problematic in these populations; gram-negative pathogens such as extended-spectrum beta-lactamase (ESBL) producing bacteria or carbapenem-resistant Acinetobactor, and Stenotrophomonas, and gram-positive pathogen such as methicillin-resistant Staphylococcus aureus (MRSA). Initial empiric antibiotics would be mostly relied on hospital epidemiology and local antibiogram Division of Infectious Diseases, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand. Reprint request: Maria Chitasombat, M.D., Division of Infectious Diseases, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand. mchitasombat@gmail.com 1

2 2 J INFECT DIS ANTIMICROB AGENTS Jan-April 2012 correlated with site of infection and possible pathogens. Frequently, I used a combination of antibimicrobial agents in neutropenic patients in setting of sepsis. Antimicrobial management in this population is rather difficult due to comorbidity and toxicities of chemotherapeutic agents or other medication that predispose patients to hepatic and renal dysfunction. Appropriate antimicrobial treatment has to be individualized on the basis of indication, safety profile, pharmacokinetics/pharmacodynamics and drug-drug interaction. Often, I had encountered problems with drug-drug interaction such as concomitant therapy of rifampicin which is a strong enzyme inducer with azole as enzyme inhibitor in settings of treatment for tuberculosis and invasive fungal infection. Drug allergy is also a challenging issue to differentiate whether results from chemotherapy, antibiotics commonly seen with beta-lactams or contrast agent. Various types of allergic reactions occurred, immediate or delayed types; all of those preclude the patients from such antimicrobial agents, although desensitization process can be attempted later on. Detail documentation of reaction to antibiotics must be clarified at onset including type of reaction and severity. Most of the time in clinical practice, history of penicillin allergy was mostly unreliable since history was from childhood memory. Another dilemma lies with the diagnosis of fungal infection in these neutropenic patients, mostly dependant on biomarker and imaging study. Delay in diagnosis often occurs. Bronchoscopy and tissue diagnosis sometimes are delayed due to various conditions such as availability of personnel and blood component, and patient condition. Isolating fungal pathogens remain challenging and most of the time the diagnosis of cases were not definite; only probable and possible invasive fungal infection. Cost of treatment for invasive fungal infection remains a heavy burden especially with lengthy therapy. As response to antifungal agents depends greatly on host status and recovery of neutrophils, the duration of treatment is rather on an individual basis, and largely depends on imaging study. 4 Monitoring outcome of infection in these patients is also challenging since lack of effective immune system. Concurrent illness and advanced malignancy status make evaluation of outcome of success in treatment rather difficult. Delay in response and recovery from infection from immune defect would lead to prolonged antimicrobial therapy until the recovery of the immune system which also predisposes the patients to various toxicities of antimicrobial therapy such as antibiotic-associated diarrhea. Overall infections usually get under control in patients who respond to chemotherapy and recover immune status. On the other hand in patients with relapsed refractory disease often have one type infection which lead to another and curing infection is an endless task and causes suffering for the patients. In summary, service for immunocompromised cancer patients require multidisciplinary care and collaboration of hematologist-oncologist and infectious disease specialist. Infectious disease complications from anti-cancer treatment should be something that can be avoided or minimized from screening and preventative measures. In our institution, screening chest X-ray, dental exam, stool exam was usually done and high risk neutropenic patients would be placed in HEPA filtered unit in controlled environment in order to attempt to decrease incidence of invasive fungal infection. Close follow-up and early diagnosis and treatment could lead to prevention of morbidity and mortality. References 1. Johnson R, Sober A. Mucocutaneous infection in

3 Vol. 29 No. 1 Dealing with immunocompromised cancer patients with infectious disease complications:- Chitasombat M. 3 the immunocompromised host. In: Rubin RH, Young LS, eds. Clinical Approach to Infection in the Compromised Host. 4 th ed. New York: Kluwer Academic, 2002: Koo S, Baden LR. Infectious complications associated with immunomodulating monoclonal antibodies used in the treatment of hematologic malignancy. J Natl Compr Canc Netw 2008;6: Sipsas NV, Bodey GP, Kontoyiannis DP. Perspectives for the management of febrile neutropenic patients with cancer in the 21 st century. Cancer 2005;103: Donowitz GR, Maki DG, Crnich CJ, Pappas PG, Rolston KV. Infections in the neutropenic patient-- new views of an old problem. Hematology Am Soc Hematol Educ Program 2001;(1):

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5 Original Article Vol. 29 No. 1 Primary prophylaxis for cryptococcosis with fluconazole:- Oniem N & Sungkanuparph S. 5 Primary prophylaxis for cryptococcosis with fluconazole among HIV-infected patients with CD4 cell count < 100 cells/mm 3 in the era of highly active antiretroviral therapy Noparat Oniem, M.D., Somnuek Sungkanuparph, M.D. ABSTRACT Objective: To evaluate the clinical benefit of primary prophylaxis for cryptococcosis with fluconazole among HIV-infected patients with CD4 cell count <100 cells/mm 3 and receiving antiretroviral therapy (ART). Methods: A retrospective cohort study was conducted among HIV-infected patients who had CD4 <100 cells/mm 3 in a university hospital. Patients were categorized into fluconazole group (receiving fluconazole) and control group (not receiving fluconazole). Results: Of 189 patients, 136 were in fluconazole group and 53 in control group. Mean age was 36.3 years and 64.6% were males. Mean CD4 was 35 cells/mm 3. All patients had received ART. Demographics, history of opportunistic infections, time from CD4 <100 cells/mm 3 to ART initiation and ART regimens were similar between two groups (p>0.05). During a median follow-up of 5.9 years, no patient died. One patient (0.7%) in fluconazole group and 2 patients (3.8%) in control group developed cryptococcosis (p=0.190). Kaplan-Meier analysis showed that there was no difference of new cryptococcosis between two groups (log-rank test, p=0.138). Conclusion: In the era that ART is widely available and can be commenced shortly after finding of low CD4, primary prophylaxis for cryptococcosis with fluconazole among HIV-infected patients with CD4 <100 cells/mm 3 may not be necessary and the recommendation should be reconsidered. (J Infect Dis Antimicrob Agents 2012;29:5-10.) Note: Abstract of this study is presented in the 6 th IAS Conference on the HIV Pathogenesis, Treatment, and Prevention, Rome, July Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand. Reprint request: Somnuek Sungkanuparph, M.D., Professor of Medicine, Division of Infectious diseases, Department of Medicine, Ramathibodi Hospital, 270 Rama 6 Road, Bangkok 10400, Thailand. somnuek.sun@mahidol.ac.th Keywords: primary prophylaxis, cryptococcosis, fluconazole, HIV, AIDS 5

6 6 J INFECT DIS ANTIMICROB AGENTS Jan-April 2012 INTRODUCTION Cryptococcosis is a serious opportunistic infection in HIV-infected patients. Prior to the era of highly active antiretroviral therapy (HAART), a million new cases of cryptococcosis per year world wide and at least 500,000 deaths are estimated. 1 Cryptococcosis is also a frequent cause of death in resource-limited countries. 2,3 In Thailand, cryptococcal meningitis is the third most common opportunistic infection in HIVinfected patients. 4 Several randomized clinical trials have demonstrated that primary prophylaxis with fluconazole reduces the incidence of cryptococcosis in advanced HIV-infected patients, particularly those with CD4 cell counts <100 cells/mm However, only a randomized controlled trial in Thailand could demonstrate a survival benefit. 6 This could be explained with the higher incidence of disease and limited capacity of diagnosis and antifungal treatment in countries with limited resources. Although primary prophylaxis with fluconazole is not generally recommended in developed countries, it is recommended in the Thai National HIV Treatment Guidelines 8,9 and is widely used in Thailand. World Health Organization (WHO) has advised that antifungal prophylaxis with fluconazole should be considered for HIV-infected patients with WHO clinical stage 4 or CD4 <100 cells/mm 3 in areas where cryptococcal disease is common (C-I) with the note of the limited evidence of survival benefit from prophylaxis and the uncertain benefit of prophylaxis in persons receiving HAART. 10 Of note, all the studies of primary prophylaxis for cryptococcosis, including the randomized controlled study in Thailand that showed the survival benefit, were conducted in the period that HAART was not available. A recent study by Parkes-Ratanshi R et al had enrolled patients who were waiting to receive ART and those who had recently started ART but not yet had a significant improvement in their immune status. 7 Currently, HAART are widely accessible in Thailand. The clinical benefit of primary prophylaxis for cryptococcosis in the real-life setting and in the HAART period has never been evaluated. This study was aimed to evaluate the survival benefit of primary prophylaxis for cryptococcosis with fluconazole among HIV-infected patients with CD4 cell count < 100 cells/ mm 3 in the current real-life setting and to compare rate of new cryptococcosis between patients who received and did not receive primary prophylaxis. METHODS A retrospective cohort study was conducted in HIV-infected patients in an outpatient clinic of a tertiarycare (800-bed) hospital in Bangkok, Thailand. The study included HIV-infected patients who visited HIV clinic between 1998 and Inclusion criteria were 1) aged greater than 15 years old, 2) had CD4 cell count < 100 cells/mm 3, 3) had no previous diagnosis of cryptococcosis, 4) had negative serum cryptococcal antigen, and 5) had followed up for at least 6 months. Patients whose medical records or result of the baseline CD4 was not available were excluded. The medical records were retrieved and reviewed. Baseline data included age, gender, underlying diseases, date of first diagnosis of HIV infection, previous opportunistic infections, hepatitis B virus and hepatitis C virus coinfections, antiretroviral regimen and CD4 cell count. Study patients were categorized into two groups: patients who received fluconazole for primary prophylaxis were classified as fluconazole group ; those who did not receive fluconazole were as control group. In fluconazole group, the cohort started at the date of the start of fluconazole for prophylaxis when CD4 cell count < 100 cells/mm 3. In control group, the cohort started at the date of first CD4 cell count < 100 cells/mm 3. The new diagnosis of cryptococcosis and

7 Vol. 29 No. 1 Primary prophylaxis for cryptococcosis with fluconazole:- Oniem N & Sungkanuparph S. 7 death from any cause were determined and compared between the two groups. The diagnosis of cryptococcosis was based on one or more of the following: positive culture for Cryptococcus neoformans, positive cryptococcal antigen, positive India ink preparation and histopathology compatible with cryptococcosis. The primary end point was the mortality and the secondary end point was new event of cryptococcosis. Categorical data is presented as frequency and percentage. Continuous data is presented as mean and standard deviation or median and interquartile rage (IQR) for data with and without normal distribution, respectively. Categorical variables between the two groups were compared using Chi square or Fisher s exact test as appropriate. Continuous variables between the two groups were compared using Student s t test and Mann-Whitney U test as appropriate. Kaplan-Meier analysis with the log-rank test was used to determine and compare the probability to develop cryptococcosis between the two groups. All analysis was performed using SPSS program version 16.0 (Chicago, IL, U.S.A.). A p value of < 0.05 was considered statistical significance. The study was approved by the institutional review board. RESULTS There were 189 patients included in the study: 136 in fluconazole group and 53 in control group. The characteristics of the patients are shown in Table 1. Of all, mean (SD) age was 36.3 (10.9) years and 64.6% of patients were males. Mean (SD) CD4 cell count was 35 (25) cells/mm 3 and 56.6% of patients had previous diagnosis of opportunistic infections other than cryptococcosis, such as tuberculosis (36 patients, 19.0%), Pneumocystis pneumonia (PCP, 46 patients, 24.3%), CMV disease (14 patients, 7.4%) and others. All patients had subsequently received HAART at a 7 median (IQR) time of 2 (0-7) weeks after the finding of CD4 < 100 cells/mm 3. Non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens were commonly used (92.6% of patients). There were no differences of baseline characteristics between fluconazole group and control group (Table 1). No patient in either group died from any causes. During a median (IQR) follow-up time of 5.9 ( ) years, 1 patient (0.7%) in fluconazole group and 2 patients (3.8%) in control group developed cryptococcosis (p = 0.190). Median (range) time to develop cryptococcosis was 5.4 ( ) months after the finding of CD4 < 100 cells/mm 3. Kaplan-Meier analysis showed that there was no difference of the probability to develop cryptococcosis between the two groups (log-rank test, p = 0.138). There was no event of cryptococcosis development in either group after one-year follow up. DISCUSSION The results from the present study have shown that fluconazole for primary prophylaxis of cryptococcosis in HIV-infected patient with CD4 cell count < 100 cells/mm 3 in the era of HAART did not provide any survival benefit. As previously noted in WHO recommendation for primary prophylaxis for cryptococcosis with fluconazole, there was limited evidence of survival benefit from prophylaxis and uncertain benefit of prophylaxis in persons receiving HAART. 10 The results from the present study provide information for consideration regarding this concern. The new events of cryptococcosis in both fluconazole group and control group were similar. Although the rate of new diagnosis of cryptococcosis was slightly higher in control group (3.8% vs. 0.7%), there was no statistical significance. The median followup time of 5.9 years in the present study ensured the

8 8 J INFECT DIS ANTIMICROB AGENTS Jan-April 2012 Table 1. Baseline characteristics between HIV-infected patients in fluconazole group and control group. Characteristics Fluconazole group (n=136) Control group (n=53) P value Gender, number (%) Male 85 (62.5) 37 (69.8) Female 51 (37.5) 16 (30.2) Age, years, mean + SD Previous OIs, number (%) 81 (59.6) 26 (49.1) Tuberculosis 25 (18.4) 11 (20.8) PCP 36 (26.5) 10 (18.9) CMV disease 11 (8.1) 3 (5.7) Toxoplasmosis 5 (3.7) 0 (0) Penicillosis 2 (1.5) 0 (0) MAC infection 2 (1.5) 0 (0) Others 3 (2.2) 1 (1.9) HBV co-infection, number (%) 12/112 (10.7) 2/41 (4.9) HCV co-infection, number (%) 4/104 (3.8) 2/35 (5.7) Baseline CD4, mean, + SD Received HAART, number (%) 136 (100) 53 (100) - ART regimen, number (%) NNRTI-based 132 (97.1) 45 (84.6) PI-based 4 (2.9) 8 (15.4) Time from CD4 <100 cell/mm 3 to receive 1.2 (0-7.2) 2.2 ( ) HAART, weeks, median (IQR) Duration of follow-up, years, median (IQR) 5.6 ( ) 6.8 ( ) OIs = opportunistic infections, HBV = hepatitis B virus, HCV = hepatitis C virus long-term effect of fluconazole prophylaxis and it did not show any benefit of fluconazole prophylaxis in terms of prevention of new events of cryptococcosis. This finding is different from the results from previous studies that fluconazole prophylaxis can decrease the occurrence of cryptococcosis. 5,6 Of note, these previous studies were conducted in the period that HAART was not available. HAART may play an important role in immune reconstitution and decrease the risk of acquiring opportunistic infections. A previous study in Thailand had demonstrated that HAART significantly decreased the relapse rate of

9 Vol. 29 No. 1 Primary prophylaxis for cryptococcosis with fluconazole:- Oniem N & Sungkanuparph S. 9 cryptococcosis. 11 Thus, the results from the present study may suggest that fluconazole for primary prophylaxis of cryptococcosis in HIV-infected patients receiving HAART is not necessary. This warrants the need of further study in a prospective randomized control trial to confirm our findings. Of note, all patients in the present study had negative serum cryptococcal antigen. The role of screening for serum cryptococcal antigen among HIVinfected patients with CD4 < 100 cells/mm 3 has been established. 12 This warrants the importance of the screening for serum cryptococcal antigen prior to omitting primary prophylaxis for cryptococcosis with fluconazole. There are limitations in the present study, such as the retrospective design, relatively small sample size and small number of patients in control group. However, this retrospective cohort study allowed us to study the long-term effect of primary prophylaxis. Regarding the sample size, we had included the cases in the 12-year period that HAART had been available to enlarge the size of study sample as much as possible. In conclusion, in the era that HAART is widely available and can be commenced shortly after the finding of low CD4 cell count, primary prophylaxis for cryptococcosis with fluconazole among HIV-infected patients with CD4 < 100 cells/mm 3 may not be necessary and the recommendation should be reconsidered. However, a large randomized control trial designed to confirm our findings should be conducted. References 1. Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 2009;23: McCarthy KM, Morgan J, Wannemuehler KA, et al. Population-based surveillance for cryptococcosis in 9 an antiretroviral-naive South African province with a high HIV seroprevalence. AIDS 2006;20: French N, Gray K, Watera C, et al. Cryptococcal infection in a cohort of HIV-1-infected Ugandan adults. AIDS 2002;16: Chariyalertsak S, Sirisanthana T, Saengwonloey O, Nelson KE. Clinical presentation and risk behaviors of patients with acquired immunodeficiency syndrome in Thailand, : regional variation and temporal trends. Clin Infect Dis 2001;32: Chang LW, Phipps WT, Kennedy GE, Rutherford GW. Antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV. Cochrane Database Syst Rev 2005;(3):CD Chetchotisakd P, Sungkanuparph S, Thinkhamrop B, Mootsikapun P, Boonyaprawit P. A multicentre, randomized, double-blind, placebo-controlled trial of primary cryptococcal meningitis prophylaxis in HIVinfected patients with severe immune deficiency. HIV Med 2004;5: Parkes-Ratanshi R, Kamali A, Wakeham K, et al. Successful primary prevention of cryptococcal disease using fluconazole prophylaxis in HIVinfected Ugandan adults [Abstract 32]. Program and abstracts of the 16 th Conference on Retrovirus and Opportunistic Infections. Montreal, Canada; February 8-11, Chitwarakorn A, Woratanarat T, Lo Y. Thailand National Guidelines for the Clinical Management of HIV Infection in Children and Adults. 6 th ed. Nonthaburi, Thailand: Ministry of Public Health, Ministry of Public Health. Thailand National Antiretroviral Treatment Guideline 2006/2007. Bangkok: The Agricultural Co-operative Federation of Thailand, World Health Organization. Essential Prevention and Care Interventions for Adults and Adolescents Living with HIV in Resource-Limited Setting.

10 10 J INFECT DIS ANTIMICROB AGENTS Jan-April 2012 Geneva: WHO, Jongwutiwes U, Kiertiburanakul S, Sungkanuparph S. Impact of antiretroviral therapy on the relapse of cryptococcosis and survival of HIV-infected patients with cryptococcal infection. Curr HIV Res 2007;5: Pongsai P, Atamasirikul K, Sungkanuparph S. The role of serum cryptococcal antigen screening for the early diagnosis of cryptococcosis in HIVinfected patients with different ranges of CD4 cell counts. J Infect 2010;60:474-7.

11 Case Report Vol. 29 No. 1 Fatal disseminated histoplasmosis:- Panthuwong S, et al. 11 Fatal disseminated histoplasmosis in a previously healthy person Siripen Panthuwong, M.D., Pisud Siripaitoon, M.D., Khachornsakdi Silpapojakul, M.D. ABSTRACT Histoplasma capsulatum, a dimorphic fungus that causes human disease (histoplasmosis), is endemic in eastern USA, the Caribbean, Central and South America, and in South East Asia. Patients with HIV infection, solid organ transplantation, and those who are receiving immunosuppressive agents are predisposed to disseminated histoplasmosis. Disseminated infection in immunocompetent persons is quite uncommon. We reported here, a case of fatal disseminated histoplasmosis in a presumed immunocompetent patient. (J Infect Dis Antimicrob Agents 2011;29:11-5.) Note: This case had been presented and discussed in the Interhospital Case Conference on Infectious Disease (ICCID), 13 October 2011, Chonburi, Thailand. CASE REPORT A 40-year-old female, fertilizer vendor from Nakornsrithammarat Province, was admitted to Songklanagarind Hospital on the 23 August 2011 with a history of having prolonged fever and small neck nodes enlargement treated with herbal medicines for a year. Her clinical condition did not improve. Fever persisted with progressive jaundice for the last 2 months. Sixteen kilograms weight loss was also reported. Initial physical examination revealed a thin pale woman with a body temperature of 38.8 C and marked icteric sclera. Enlarged, diameter range cm., bilateral submandibular and cervical lymph nodes were palpated. Liver was enlarged to 4 cm below right costal margin. Splenomegaly, 2 cm below left costal margin, with moderate tenderness also detected. Initial laboratory studies disclosed the followings: WBC 5,830 cells/mm 3 (N 90%, band 4%, L 2%, M 2%, E 2%), hematocrit 20%, platelet 15,000/mm 3. Liver function test showed total bilirubin 20.9 mg%, direct bilirubin 19.8 mg%, aspartate aminotransferase (AST) 148 U/L, aminotransferase (ALT) 148, alkaline phosphatase 193 U/L. Renal function test, urine examination, and Division of Infectious Diseases, Department of Medicine, Prince of Songkla University, Songkhla 90110, Thailand. Reprint request: Siripen Panthuwong, M.D., Division of Infectious Diseases, Department of Medicine, Prince of Songkla University, Songkhla 90110, Thailand. Keywords: Histoplasma capsulatum, histoplasmosis 11

12 12 J INFECT DIS ANTIMICROB AGENTS Jan.-April 2012 chest radiograph were unremarkable. Anti-HIV antibody test was negative. Computer tomography abdomen showed few mildly enlarged retroperitoneal and pelvic nodes and diffuse hepatosplenomegaly without focal lesion. Gall bladder, bile ducts, pancreas, and adrenal gland were unremarkable. Bone marrow studies revealed multiple intracellular pear-shapes, small yeast liked organisms with budding morphologically compatible with H. capsulatum by Gomori s Methinamine Silver (GMS) stain (Figure 1). On the third day of admission, she developed scattered erythematous maculopapular rash predominately at lower extremities without neither pain nor itching. Few small budding yeast (GMS stain) morphologically compatible with H.capsulatum was demonstrated from skin biopsy. Finally bone marrow and skin tissue culture confirmed growth of H. capsulatum. Conventional 1 mg/kg/day of amphotericin B was started. Three days later, it was switched to liposomal amphotericin B due to rising of serum creatinine. However, multiorgan failure, and refractory shock developed. She died on the seventh day of treatment. Postmortem liver and spleen pathology demonstrated extensive involvement by H. capsulatum (Figure 2). DISCUSSION Histoplasmosis is endemic in eastern USA, the Caribbean, Central and South America, and South East Asia. 1 The etiologic agent, H. capsulatum, was typically found in humid areas where soil is enriched with organic material such as bird and bat droppings. It is a dimorphic fungus, existing as mold in the environment and as yeast in human body. The common signs and symptoms of disseminated histoplasmosis are fever (100%), lung involvement (70%), weight loss (60%), hepatomegaly (60%), splenomegaly (40%), and peripheral lymphadenopathy (30%). 2 Involvement of gastrointestinal system (eg. bleeding due to mucosal ulceration), and the central nervous system (chronic lymphocytic meningitis), have been reported. 3 Despite frequent gastrointestinal and hepatic involvement in disseminated histoplasmosis (70-90%) 4, histoplasmosis may uncommonly present as cholestatic jaundice as in our case. 5 The clinical manifestations of histoplasmosis are quite different in the immunocompetent and immunocompromised patient. Most of the immunocompetent patients are asymptomatic or have clinically insignificant infection 4,6, whereas more severe or disseminated diseases occur in immunocompromised patients. 7-9 In a retrospective review of patients with disseminated histoplasmosis diagnosed at Mayo Clinic over a 15- year period between 1991 to 2005, 59% of cases occurred in immunocompromised patients. This study also indicated that immunocompromised patients with histoplasmosis were more likely to have bone marrow suppression and elevated liver enzymes than immunocompetent patients (64% vs. 43%). 9 This patient was a non-hiv-middle-aged woman without a history of malignancy diseases, chronic organ failure, or immunosuppressive medication usage. Thus, we presumed as an immunocompetent patient that presented with disseminated histoplasmosis. Since 20% of disseminated histoplasmosis is known to occur in otherwise healthy persons especially in those who had a heavy inoculums exposure to the fungi 10, we postulated that she might have contracted this deadly form of the disease from exposure to large quantities of contaminated soil during her career as a fertilizer vendor. A large urban histoplasmosis outbreak in India demonstrated that the only risk factor for fatal disseminated infection was immunosuppression. Fatal disseminated infections occurred in 73.8% of immunosuppressed patients compared to 6.5% of

13 Vol. 29 No. 1 Fatal disseminated histoplasmosis:- Panthuwong S, et al. 13 Figure 1. (A) Bone marrow aspiration showed multiple small intracellular, pear-shaped, yeast-like organisms (arrows), (B) Bone marrow biopsy (H&E, original magnifications X40), demonstrated chronic granulomatous inflammation with (C) numerous intracellular small yeast-like organisms (arrows), (D) exhibited many budding in Gomori s Methenamine Silver stain. patients without underlying immunosuppression (p<0.05). For the non-immunosuppressed patients, fatal or disseminated infections were significantly more frequently found in patients over 54 years of age. 2 Center for Disease Control Cooperative Mycoses Study data, showed that adrenal gland involvement with insufficiency was found in half of patients with severe histoplasmosis and probably contributed to the mortality. 11 However, our patient did not have this endocrine dysfunction because her serum cortisol level during shock was 38.4 μg/dl. Amphotericin B is the drug of choice for 13 treatment of severe disseminated histoplasmosis Without treatment, the mortality rate is 80% 17 compared to 23% amphotericin B treated patients. 11,18-19 Even with amphotericin B treatment, this patient showed no improvement and died due to extensive involvement with histoplasma. References 1. Williams J. Treatment and prevention of invasive fungal diseases in patients with HIV. London: BMJ Publishing, Wheat LJ, Slama TG, Norton JA, et al. Risk factors for

14 14 J INFECT DIS ANTIMICROB AGENTS Jan.-April 2012 Figure 2. Postmortem pathology of the liver (A) and the spleen (B) (H&E, original magnificantions X40), showed extensive involvement by numerous small intracellular yeast-like organisms. disseminated or fatal histoplasmosis. Analysis of a large urban outbreak. Ann Intern Med 1982;96: Wheat J, Sarosi G, McKinsey D, et al. Practice guidelines for the management of patients with histoplasmosis. Infectious Diseases Society of America. Clin Infect Dis 2000;30: Wheat J. Histoplasmosis. Experience during outbreaks in Indianapolis and review of the literature. Medicine (Baltimore) 1997;76: Wee EW, Lim SG, Wee A, Chai LY. Disseminated histoplasmosis presenting as fever and jaundice. Ann Acad Med Singapore 2009;38: Wheat J, Sarosi G, McKinsey D, et al. Practice guidelines for the management of patients with histoplasmosis. Infectious Diseases Society of America. Clin Infect Dis 2000;30: Goodwin RA Jr, Shapiro JL, Thurman GH, Thurman SS, Des Prez RM. Disseminated histoplasmosis: clinical and pathologic correlations. Medicine (Baltimore) 1980;59: Wheat LJ, Connolly-Stringfield PA, Baker RL, et al. Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature. Medicine (Baltimore) 1990;69: Assi MA, Sandid MS, Baddour LM, Roberts GD, Walker RC. Systemic histoplasmosis: a 15-year retrospective institutional review of 111 patients. Medicine (Baltimore) 2007;86: Coiffier T, Roger G, Beust L, et al. Pharyngo-laryngeal histoplasmosis: one case in an immunocompetent child. Int J Pediatr Otorhinolaryngol 1998;45: Sarosi GA, Voth DW, Dahl BA, Doto IL, Tosh FE. Disseminated histoplasmosis: results of long-term follow-up. A center for disease control cooperative mycoses study. Ann Intern Med 1971;75: Wang TL, Cheah JS, Holmberg K. Case report and review of disseminated histoplasmosis in South-East Asia: clinical and epidemiological implications. Trop Med Int Health 1996;1: Walsh TJ, Gonzalez C, Lyman CA, Chanock SJ, Pizzo PA. Invasive fungal infections in children: recent advances in diagnosis and treatment. Adv Pediatr Infect Dis 1996;11:

15 Vol. 29 No. 1 Fatal disseminated histoplasmosis:- Panthuwong S, et al Tobon AM, Franco L, Espinal D, et al. Disseminated histoplasmosis in children: the role of itraconazole therapy. Pediatr Infect Dis J 1996;15: McKinsey DS, Kauffman CA, Pappas PG, et al. Fluconazole therapy for histoplasmosis. The National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis 1996;23: Johnston AW, Brown PA, Ewen SW. Histoplasmosis-- a ten year follow-up. J Infect 1996;33: Rubin H, Furcolow ML, Yates JL, Brasher CA. The course and prognosis of histoplasmosis. Am J Med 1959;27: Sathapatayavongs B, Batteiger BE, Wheat J, Slama TG, Wass JL. Clinical and laboratory features of disseminated histoplasmosis during two large urban outbreaks. Medicine (Baltimore) 1983;62: Wilson DA, Muchmore HG, Tisdal RG, Fahmy A, Pitha JV. Histoplasmosis of the adrenal glands studied by CT. Radiology 1984;150:

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17 Case Report Vol. 29 No. 1 Brain abscesses caused by A. fumigatus:- Wannasirikul V & Chayakulkeeree M. 17 Multiple brain abscesses caused by Aspergillus fumigatus in a patient with systemic lupus erythematosus Varan Wannasirikul, M.D.*, Methee Chayakulkeeree, M.D., Ph.D.** ABSTRACT We report a case of multiple brain abscesses caused by Aspergillus fumigatus in a young woman with systemic lupus erythematosus (SLE). The clinical features included progressive headache, visual deterioration and paraparesis. Computed tomography (CT) scan of the brain demonstrated multiple ring-enhancing lesions with surrounding edema at frontal, occipital and parietal lobes. Laboratory tests showed anemia, hypoalbuminemia and marked proteinuria with renal impairment. Brain abscesses with active lupus nephritis were initially diagnosed. Stereotactic guided aspiration of an abscess was achieved and Gram s stain of pus revealed numerous septate hyphae with dichotomous branching, subsequently grew A. fumigatus. Voriconazole was commenced with significant clinical improvement. Brain CT scan performed six weeks and four months after voriconazole treatment revealed less number and smaller in size of the abscesses. Aspergillus spp. should be included in differential diagnosis as a potential causative organism of brain abscess in SLE patients. (J Infect Dis Antimicrob Agents 2011;29:17-20.) INTRODUCTION Aspergillus fumigatus is a ubiquitous fungus and an opportunistic fungal pathogen of human and animal. It causes infections with a wide spectrum of clinical manifestations, ranging from benign colonization of the lung resulting in allergic disease, such as allergic bronchopulmonary aspergillosis (ABPA), to lifethreatening diseases, such as invasive pulmonary aspergillosis (IPA). 1 In a rare occasion, it may hematogenously disseminate and cause endocarditis, endophthalmitis, cutaneous aspergillosis, abscesses in internal organs such as liver, spleen, bone, kidney, myocardium and brain. 2 Cerebral aspergillosis is responsible for 10% - 20% of all cases of invasive * Division of Hematology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand. ** Division of Infectious Diseases and Tropical Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand. Reprint request: Methee Chayakulkeeree, M.D., Ph.D., Division of Infectious Diseases and Tropical Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Prannok Road, Bangkoknoi, Bangkok 10700, Thailand. simcy@mahidol.ac.th Keywords: Aspergillus fumigatus, aspergillosis, brain abscess, cerebral aspergillosis, invasive aspergillosis, voriconazole, systemic lupus erythematosus 17

18 18 J INFECT DIS ANTIMICROB AGENTS Jan.-April 2012 aspergillosis and the mortality rate in such patients is extremely high. The major recognized risk factors for acquiring invasive aspergillosis include defects in phagocyte respiratory burst, such as those with chronic granulomatous disease 3,4, corticosteroid-induced suppression of macrophage conidiocidal activity 5,6, and neutropenia. Systemic lupus erythematosus (SLE) was found to be an underlying disease in about 1% of patients of invasive aspergillosis. In immunocompromised individuals with cerebral aspergillosis, meningism is not common and clinical manifestation may be non-specific which includes alteration of mental status, headache or seizures. CASE REPORT A 39-year-old Thai woman with history of SLE, treated with prednisolone for 2 years, presented with progressive headache and visual deterioration for 2 months. She had neither fever nor neurological deficit. Physical examination revealed a young woman with cushingoid appearance. Her temperature was 36.7 C, pulse rate of 120/min, respiratory rate of 20/min and blood pressure of 177/112 mmhg. Her skin showed discoid rash at right pinna. Neurological examination revealed bilateral papilloedema and paraparesis (motor power grade 4/5 at both lower extremities). Complete blood count showed hemoglobin 8.9 g/dl, hematocrit 28.2%, platelet 465,000 /mm 3, white blood cell counts 5,430 cells/mm 3 with 30.2% neutrophil, 52.7% lymphocyte, 7.2% monocyte and 9% eosinophil. Renal function test showed blood urea nitrogen (BUN) 20.5 mg/dl and creatinine 1.4 mg/dl. Liver function test showed total bilirubin 0.1 mg/dl, aspartate transaminase 24 IU/L, alanine transaminase 15 IU/L, alkaline phosphatase 68 IU/L, albumin 2.8 g/dl and globulin 3.2 g/dl. Urinalysis showed ph 8, specific gravity 1.010, protein 4+, sugar-negative, ketone-negative, white blood cell 1-2 cells/hpf, red blood cell 5-10 cells/ HPF, and no cast. Serum complement level was decreased. A computed tomography (CT) scan of the brain was performed and demonstrated multiple ringenhancing lesions with surrounding edema at frontal, occipital and parietal lobes (Figure 1). Brain abscesses with active lupus nephritis were diagnosed and she was treated empirically with intravenous ceftriaxone, metronidazole and TMP-SMX for coverage of common causative bacteria including streptococci, enterobacteriaceae, anaerobes and Nocardia spp. Although her symptoms of headache, visual deterioration and paraparesis were slightly improved, brain CT scan after 1 week of treatment demonstrated no decrease in size of the lesions. Therefore, stereotactic guided aspiration of abscess was achieved and three milliliters of yellow-green colored pus was collected intraoperatively. Gram s stain of the aspirated pus revealed numerous septate hyphae with dichotomous branching. Antimicrobial agents were therefore discontinued and Amphotericin B (1 mg/kg/ day) was commenced. Pus culture was subsequently reported as A. fumigatus and the antifungal agent was changed to voriconazole. Brain CT performed 6 weeks and 4 months after voriconazole treatment showed disappearance of some lesions and smaller in size of the remaining abscesses (Figure 2). The patient continued voriconazole for 1 year with marked improvement. DISCUSSION This is a case of cerebral aspergillosis in SLE patient. Aspergillosis is relatively less common than the other infections in patients with SLE. Differential diagnosis of brain abscess in SLE patient normally includes cerebral nocardiosis, listeriosis, mixed bacterial brain abscess, tuberculosis and cryptococcosis. Although cerebral aspergillosis in SLE is relatively rare, the mortality rate is high. Therefore, high index of

19 Vol. 29 No. 1 Brain abscesses caused by A. fumigatus:- Wannasirikul V & Chayakulkeeree M. 19 Figure 1. Computed tomography of brain showed multiple ring enhancing lesions with perilesional edema. Figure 2. Computed tomography of brain showed disappearance and smaller in size of cerebral abscesses after treatment with voriconazole for 4 months. suspicion to achieve prompt diagnosis and treatment is crucial and an attempt to get tissue histopathology for definite diagnosis by invasive interventions is the key milestone. A systematic review by Lin et al. reported an overall case fatality rate of 58% in 1,941 patients with invasive aspergillosis. The mortality was highest in patients with bone marrow transplant recipients and those with disseminated or cerebral aspergillosis (approximately 88%). 7 A. fumigatus is the most common reported species that causes invasive aspergillosis which was also isolated from our patient. Other pathogenic species include A. flavus, A. niger, and A. nidulans. 8,9 Although it has been shown in a randomized controlled trial that voriconazole was superior to amphotericin B deoxycholate for treatment of invasive aspergillosis 10, and voriconazole became the primary antifungal treatment for invasive aspergillosis 11, 19 most of the cases were invasive pulmonary infection. Randomized controlled trial to compare treatment outcomes in patients with cerebral form of aspergillosis is lacking and therefore warranted. Furthermore, the Infectious Diseases Society of America (IDSA) Practice Guidelines for Diseases Caused by Aspergillus suggested that intracranial Aspergillus abscess is not well-penetrated by systemic antifungal agents. 11 Stereotactic procedures for abscess drainage should be considered. In addition, an open-label study showed that voriconazole in combination with surgical intervention gave favorable outcomes in 35% and a long-term survival of 31%. 12 Voriconazole is therefore the treatment of choice for cerebral aspergillosis. Our case successfully underwent cerebral abscess drainage and received antifungal treatment with voriconazole and the outcome was favorable.

20 20 J INFECT DIS ANTIMICROB AGENTS Jan.-April 2012 We report here a case of cerebral aspergillosis presented with multiple abscesses in the brain successfully treated with voriconazole and stereotactic guided abscess aspiration. Aspergillus spp. should be considered as a potential pathogen of brain abscesses in patients with SLE receiving corticosteroid therapy. References 1. Rhodes JC. Aspergillosis. In: Murphy JW, Friedman H, Bendinelli M, eds. Fungal Infections and Immune Responses. New York: Plenum Press, 1993: Barnes PD, Marr KA. Aspergillosis: spectrum of disease, diagnosis, and treatment. Infect Dis Clin North Am 2006;20:545-61, vi. 3. Cohen MS, Isturiz RE, Malech HL, et al. Fungal infection in chronic granulomatous disease. The importance of the phagocyte in defense against fungi. Am J Med 1981;71: Morgenstern DE, Gifford MA, Li LL, Doerschuk CM, Dinauer MC. Absence of respiratory burst in X-linked chronic granulomatous disease mice leads to abnormalities in both host defense and inflammatory response to Aspergillus fumigatus. J Exp Med 1997;185: Palmer LB, Greenberg HE, Schiff MJ. Corticosteroid treatment as a risk factor for invasive aspergillosis in patients with lung disease. Thorax 1991;46: Schaffner A. Therapeutic concentrations of glucocorticoids suppress the antimicrobial activity of human macrophages without impairing their responsiveness to gamma interferon. J Clin Invest 1985;76: Lin SJ, Schranz J, Teutsch SM. Aspergillosis casefatality rate: systematic review of the literature. Clin Infect Dis 2001;32: Cuccia V, Galarza M, Monges J. Cerebral aspergillosis in children. Report of three cases. Pediatr Neurosurg 2000;33: Walsh TJ, Lutsar I, Driscoll T, et al. Voriconazole in the treatment of aspergillosis, scedosporiosis and other invasive fungal infections in children. Pediatr Infect Dis J 2002;21: Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347: Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008;46: Schwartz S, Ruhnke M, Ribaud P, et al. Improved outcome in central nervous system aspergillosis using voriconazole treatment. Blood 2005;106:

21 Case Report Vol. 29 No. 1 Infectious endocarditis cause by A. defective:- Malaisri C & Sungkanuparph S. 21 Infectious endocarditis cause by Abiotrophia defectiva Chitprasong Malaisri, M.D., Somnuek Sungkanuparph, M.D. ABSTRACT We report a case of 61-year-old man presented with progressive dyspnea for 5 month followed by respiratory failure. Transthoracic echocardiogram revealed bacterial vegetation, rheumatic change mitral valve and destruction of the aortic valve. Initial hemoculture reported gram-positive cocci in chain for two specimens and its resistance to penicillin and vancomycin. Daptomycin was administered as a primary drug, but the latter hemoculture was identified as Abiotrophia defectiva. Infectious endocarditis caused by A. defectiva was diagnosed, he was treated with diuretic and penicillin G. Aortic valve replacement and valvulopathy of mitral valve was done due to congestive heart failure and large vegetation. After operation and total penicillin G 4 weeks, he improved and was discharged from the hospital. Infectious diseases caused by A. defectiva are extremely rare, and identification of this pathogen is important, as its bacterial characteristics require proper attention. (J Infect Dis Antimicrob Agents 2012;29:21-5.) Note: This case was presented in the Interhospital Case Conference on Infectious Diseases (ICCID), 18 August 2011, Bangkok, Thailand. INTRODUCTION Abiotrophia species, first described as nutritionally variant (deficient) streptococci in , were originally discovered as small satellite colonies around coagulasenegative bacteria or with supplementation of complex media with cysteine or pyridoxal. 2 Taxonomic studies of the Abiotrophia spp. concluded that this group of organisms should be reclassified separately into Abiotrophia defectiva and Granulicatella adiacens, G. balaenopterae, and G. elegans. 3 Although Abiotrophia/Granulicatella are parts of the normal flora of the oral cavity, the genitourinary tract, and the intestinal tract, the pathogenic potential of these organisms has been well established. They have been estimated to cause approximately 5-6% of microbiologically proven cases of endocarditis 4, Division of Infectious Diseases, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand. Reprint request: Somnuek Sungkanuparph, M.D., Professor of Medicine, Division of Infectious Diseases, Department of Medicine, Ramathibodi Hospital, 270 Rama 6 Road, Bangkok 10400, Thailand. somnuek.sun@mahidol.ac.th Keywords: Abiotrophia defectiva, Nutritionally variant Streptococci, Infectious endocarditis 21

22 22 J INFECT DIS ANTIMICROB AGENTS Jan.-April 2012 and have likewise been implicated in the pathogenesis of culture-negative endocarditis. 5 However, with current laboratory media and techniques, recovery of strains is no longer as significant a problem. Among NVS, A. defectiva seems especially suited to cause endovascular infection because of its ability to adhere to fibronectin in the extracellular matrix. Abiotrophia defectiva, a nutritionally variant streptococcus (NVS), represents a rare but clinically important cause of infective endocarditis. Endocarditis caused by NVS carries greater morbidity and mortality than endocarditis caused by other streptococci and it has been reported to result in heart failure by destroying heart valves. Therefore, immediate treatment based on a correct diagnosis and identification of the pathogen have a bearing on the prognosis of patient with endocarditis caused by Abiotrophia defective. CASE REPORT A 61-year-old Thai man, from Songkhla province, presented with progressive dyspnea for 5 months. The patient denied underlying disease and alcoholic drinking but he smoked approximately 30 pack-years. Five months prior to admission, he developed progressive dyspnea and follow by respiratory failure. He was admitted at a provincial hospital due to congestive heart failure caused by NSTEMI. He received intubation and was on a respirator for six days. After discharge from provincial hospital, despite good compliance of medication, he was still dyspnea so he came to our hospital for further investigation and treatment. On examination, the patient was afebrile with a temperature of 37.5 C, regular heart rate of 100 beats/ min, blood pressure of 120/60 mmhg, respiratory rate of 30 breaths/min, and room air oxygen saturation of 94%. Physical exam was significant for cardiac auscultation that was regular rate and rhythm with a 3/6 diastolic murmur heard at the right upper sternal border, 2/6 pansystolic murmur heard at apex, engorged neck veins, fine crepitation both lungs and nontender hepatomegaly (liver span 10 cm.). No Janeway s lesions and Osler s nodes. The eye examination revealed no Roth s spots. His initial laboratory studies were remarkable for a creatinine of 1.82 mg/dl, a normocytic anemia (hemoglobin 7.5 g/dl), white blood cells of 16,000/ mm 3 (neutrophil 83%, lymphocyte 10%, monocyte 7%), and platelet of 154,000/mm 3. No microscopic hematuria. Liver function test was total bilirubin 2.0 mg/dl, direct bilirubin 0.6 mg/dl, aspartate aminotransferase 285 IU/ L, alanine aminotransferase 541 IU/L and serum albumin 2.9 g/dl. His chest radiograph showed increased cardiothoracic ratio and bilateral interstitial infiltration. His electrocardiograms showed sinus tachycardia 120/min, incomplete RBBB, left ventricular hypertrophy by voltage, ST depression and T inversion in V5,V6. Transthoracic echocardiograms revealed mobile vegetation at aortic valve 2.41 cm. with severe aortic regurgitation and moderate to severe mitral valve. Initial hemoculture reported gram-positive cocci in chain two specimen and its resistance to penicillin and vancomycin. Daptomycin was administered as a primary drug. During admission, he developed respiratory failure from congestive heart failure. His clinical features suggested need for surgical intervention due to large vegetation and valvular dysfunction. Aortic valve replacement and valvuloplasty of mitral valve was done. The valve culture was negative. During the early postoperative period, his hemoculture was identified as Abiotrophia defectiva. The organism was susceptible to penicillin with the minimum inhibitory concentration (MIC) for penicillin of μg/ml. It showed technical error about initial procedure for drug susceptibility. Diagnosis of infective endocarditis was made using modified Dukes criteria

23 Vol. 29 No. 1 Infectious endocarditis cause by A. defective:- Malaisri C & Sungkanuparph S. 23 and antimicrobial was changed from daptomycin to penicillin G sodium (PGS) 24 million units per 24 hr iv, divided q 4 hr total 4 weeks. No plus gentamicin due to acute kidney injury. Two month after surgical and antimicrobial therapy, he had no fever with marked improvement of clinical signs and symptoms without relapse or complication. DISCUSSION Infectious endocarditis caused by Abiotrophia defectiva has been rarely reported. Abiotrophia species were first described as nutritionally variant streptococci (NVS) in 1961, having been found to grow as satellite colonies around those of helper bacteria (staphylococci) (Figure 1) and later, in media supplemented by sulhydryl compounds, pyridoxine, or cysteine. 1,6,7 More than 100 cases of NVS endocarditis have been reported in the literature NVS strains are part of the normal oral, intestinal and genitourinary flora. The portal of entry in most cases of endocarditis is via the mouth, teeth or throat. NVS cause approximately 3% to 5% of cases of streptococcal infective endocarditis. Despite a considerable number of published cases worldwide, this is the first case report from Thailand. Because Abiotrophia spp. are fastidious organisms, it is likely that most cases are misdiagnosed as culture-negative endocarditis; therefore, their role in endocarditis may be underestimated. The present case highlights the importance of the correct microbiological diagnosis. Abiotrophia defectiva has many bacterial characteristics, including (1) vitamin B6 and L-cysteine are required for growth 2, thus this bacteria cannot grow in culture plates without these nutrients, but can grow in chocolate agar. (2) Abiotrophia defectiva was originally considered coccobacillus, but its appearance differs depending on various culture conditions. 17 (3) Abiotrophia defectiva grows more slowly than other streptococci 18 and this may be one of the reasons for the difficulty in identification. (4) Higher affinity with the endocardium 19,20 because of its ability to adhere to fibronectin in the extracellular matrix. Our patient did not have any underlying cardiac or immunosuppressive illness and did not undergo dental manipulations. The portal of entry Figure 1. Abiotrophia spp. (formerly known as nutritionally deficient streptococci) showing satellite growth with Staphylococcus aureus. 23