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Journal of Clinical Microbiology, August 2008, p. 2809-2813, Vol. 46, No. 8
0095-1137/08/$08.00+0     doi:10.1128/JCM.00494-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

CASE REPORT

Invasive Infections with Community-Associated Methicillin-Resistant Staphylococcus aureus after Kidney Transplantation

Oluwadamilola A. Adeyemi,¹ Chao Qi,^2,6 Teresa R. Zembower,¹ Michael G. Ison,^1,3 Thomas H. Grant,⁴ Brian J. Hartigan,⁵ Michael Malczynski,⁶ and Valentina Stosor^1,3*

Division of Infectious Diseases, Department of Medicine,¹ Department of Pathology,² Division of Organ Transplantation, Department of Surgery,³ Department of Radiology,⁴ Department of Orthopaedic Surgery, Northwestern University Feinberg School of Medicine,⁵ Clinical Microbiology Laboratory, Northwestern Memorial Hospital, Chicago, Illinois⁶

Received 12 March 2008/ Returned for modification 2 May 2008/ Accepted 27 May 2008

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We report two cases of invasive infections caused by Panton-Valentine leukocidin-positive, community-associated, methicillin-resistant Staphylococcus aureus (CA-MRSA) after kidney transplantation. This report emphasizes the clinical importance of considering CA-MRSA as a causative agent in the differential diagnosis of infections of the skin and soft tissues in organ transplant recipients.

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Case 1. A 32-year-old African American male with hypertension and type I diabetes mellitus who had undergone living-donor kidney transplantation 28 months earlier was admitted with severe left-flank pain, subjective fevers, and a 20-lb weight loss over 1 month. Intermittent left-sided low-back pain had been present for 6 months. Fifteen, 11, and 7 months earlier, the patient had recurring furunculosis and cellulitis involving the buttocks. Cultures performed during the two most recent episodes revealed methicillin-resistant Staphylococcus aureus (MRSA) with the following susceptibility profile: resistance to oxacillin (MICs, >4 µg/ml) and erythromycin (>8 µg/ml) but susceptibility to vancomycin (1 µg/ml), trimethoprim-sulfamethoxazole (TMP-SMX) (0.5/9.5 µg/ml), tetracycline (1 µg/ml), gentamicin (0.5 µg/ml), rifampin (0.5 µg/ml), clindamycin (0.25 µg/ml), and linezolid (2 µg/ml). These infections were treated by his primary care physician with incision, drainage, and oral anti-infectives, including cephalexin, amoxicillin-clavulanate, and TMP-SMX. He underwent an attempt at decolonization with mupirocin applications to the anterior nares. He reported having had sex with men, and the human immunodeficiency virus antibody was nonreactive. The posttransplant course was otherwise uncomplicated, with good allograft function on a stable immunosuppression regimen that included tacrolimus, mycophenolate mofetil, and prednisone.

On examination, his vital signs were as follows: oral temperature, 36.9°C; pulse, 74/min; blood pressure, 100/68 mm Hg; and respirations, 19/min. Left-flank tenderness and a limping gait were present. The laboratory evaluation determined a white blood cell count of 20,200 cells/µl with 86% neutrophils, an erythrocyte sedimentation rate of 107 mm/hour, a C-reactive protein level of 21.5 mg/dl, and a serum creatinine level of 1.8 mg/dl. Computed tomography imaging of his pelvis demonstrated a 6.6-cm by 8.5-cm left iliopsoas abscess, and magnetic resonance spine imaging revealed osteomyelitis of the L5 vertebral body and left transverse process (Fig. 1A). The abscess was drained by interventional radiology, and monomicrobial MRSA was isolated from the abscess culture; anaerobic cultures were negative. Blood cultures were also negative. He completed 6 weeks of parenteral vancomycin therapy, followed by 2 weeks of linezolid therapy. Due to the patient's desire to return to work without an intravenous catheter, vancomycin was changed to linezolid to complete the intended 8-week course of therapy. TMP-SMX was administered for an additional 8 weeks of suppressive therapy. Follow-up testing demonstrated an erythrocyte sedimentation rate of 14 mm/h, a C-reactive protein level of 0.7 mg/dl, and resolving radiographic findings. No infection relapses have occurred more than 6 months after treatment completion.

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FIG. 1. Radiographic and clinical findings of invasive CA-MRSA infections in kidney transplant recipients. (A) Case 1. A T1-weighted axial postcontrast infusion magnetic resonance image of the patient's lumbosacral spine demonstrates osteomyelitis (arrow) of the L5 vertebral body and a large left psoas abscess (arrowheads). (B) Case 2. Photograph taken at initial presentation of the right upper extremity, demonstrating severe swelling, erythema, and bullous skin lesions. (C) Case 2. Intraoperative photograph from initial surgery, with drainage of purulence and thin grayish fluid tracking through fascial planes.

Case 2. A 53-year-old African American man with hypertension and type II diabetes mellitus who had undergone deceased-donor kidney transplantation 22 months earlier presented with progressive swelling and erythema of the right upper extremity 4 days after noticing an "insect bite" on his upper arm. Fever, chills and sweats, poor oral intake, and light-headedness were reported. Previously, renal allograft function was excellent on maintenance tacrolimus and mycophenolate mofetil, and no posttransplant complications were reported.

In the emergency department, he was profoundly ill, with an oral temperature of 38.4°C, a heart rate of 101/min, a blood pressure of 89/67 mm Hg, and 18 respirations/min. Examination was most notable for his faint right-radial pulse, marked circumferential erythema and edema of the right upper extremity, warmth and tenderness on palpation of this extremity, and multiple right upper arm bullae (Fig. 1B). The white blood cell count was initially 4,000 cells/µl with 66% neutrophils but declined to 1,200 cells/µl within the first 24 h. Abnormal serum chemistries included the following: sodium, 128 meq/liter; chloride, 91 meq/liter; bicarbonate, 23 meq/liter; glucose, 428 g/ml; creatinine, 1.7 mg/dl; and lactic acid, 6.2 mmol/liter. Computed tomography imaging demonstrated edema and scattered foci of gas within the subcutaneous soft tissues adjacent to the bicep muscle. The patient underwent immediate surgical debridement of necrotic skin, fascia, and muscle, as well as thrombosis of the cephalic vein (Fig. 1C). Empirical treatment of necrotizing fasciitis was initiated with vancomycin, piperacillin-tazobactam, clindamycin, amikacin, and intravenous immunoglobulin. During the perioperative period, the patient was resuscitated and supported with intravenous hydration, vasopressors, mechanical ventilation, and temporary discontinuation of immunosuppressive therapy. Histology showed skin and underlying subcutaneous tissue with acute and chronic inflammation, including abscess formation and fat necrosis. Monomicrobial MRSA was isolated from pre- and intraoperative wound and tissue cultures, while anaerobic wound and tissue cultures were negative. Blood culture done on admission was negative. The subsequent hospital course was marked by two additional debridement surgeries (hospital days 2 and 8) and wound closure with a split-thickness skin graft. He was weaned off vasopressors and extubated by hospital day 5. Antimicrobial therapy was changed to vancomycin monotherapy, and the patient was discharged on hospital day 10 and completed 3 weeks of vancomycin therapy. He had a complete recovery of limb and kidney allograft function.

Bacterial identification and susceptibility testing were performed using the Vitek 2 system (bioMérieux, Inc., Durham, NC). The presence of penicillin binding protein 2' was tested using latex agglutination (Oxoid Limited, United Kingdom).

Detection of staphylococcal chromosome cassette mec (SCCmec) type IV was performed by PCR amplification of class B mec and type 2 ccr gene complexes, and Panton-Valentine leukocidin (PVL) was detected with the lukS- and lukF-PV genes using previously published primers (10, 19). Two to three bacterial colonies were suspended in 50 µl distilled water, and rapid DNA extraction was performed by heating the suspension to 99°C for 5 min. After centrifugation at 13,000 x g for 10 min, 1 µl of the supernatant was used for 50 µl of PCR. Thermocycling conditions were followed as described previously (10, 19). ApaI pulsed-field gel electrophoresis analysis was performed with the CHEF-DR II system according to the manufacturer's recommendations. Case strains were compared to a reference strain of USA 300 from the Network on Antimicrobial Resistance (NRS384), and clonality was determined by previously defined criteria (17).

Both S. aureus isolates from cases 1 and 2 were resistant to oxacillin (MICs, >4 µg/ml). Vancomycin (MICs, 1 µg/ml), TMP-SMX (0.5/9.5 µg/ml), gentamicin (0.5 µg/ml), rifampin (0.5 µg/ml), clindamycin (0.25 µg/ml), and linezolid (2 µg/ml) had in vitro activities against both isolates. Isolate 1 was resistant to erythromycin (MICs, >8 µg/ml) but susceptible to tetracycline (1 µg/ml), while isolate 2 was susceptible to erythromycin (0.25 µg/ml) but resistant to tetracycline (>16 µg/ml). D testing was negative for inducible clindamycin resistance for isolate 1. PBP 2' was detected in both isolates.

Type IV SCCmec and PVL S/F bicomponent proteins were detected by PCR in both MRSA isolates (Fig. 2). Both isolates demonstrated clonality with strain USA 300 (Fig. 3).

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FIG. 2. Molecular detection of type IV SCCmec and PVL virulence genes. (A) PCR amplification with specific primers for the class B mec complex and type 2 ccr complex that confirms the presence of type IV SCCmec in S. aureus isolates from case 1 and case 2 and strain USA 300. (B) PCR amplification with specific primers for the detection of the PVL S/F bicomponent protein genes, lukS- and lukF-PV, confirms the presence of PVL in S. aureus isolates from cases 1 and 2 and strain USA 300. NC, negative control; M, 1-kb DNA molecular markers.

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FIG. 3. Molecular strain typing by ApaI pulsed-field gel electrophoresis. Staphylococcal isolates from an abscess culture of case 1 and a tissue culture of case 2 demonstrate clonality with strain USA 300 (NRS384) using criteria developed by Tenover et al. (17).

Infections remain one of the major problems that impact the outcomes of organ transplant recipients. Traditionally, MRSA infections are hospital-acquired complications that occur after transplantation. The emergence of MRSA within the community has become a major public health concern and has altered health care practices as it increasingly afflicts new segments of the population. USA 300 is the predominant MRSA clone that causes community-associated infections in the United States (4). Strains of USA 300 share the multilocus sequence type 8 profile and a common staphylococcal protein A gene-type motif (11, 18). Additionally, they carry the type IV SCCmec element and are resistant to beta-lactam antibiotics and, often, erythromycin (11). Community-associated MRSA (CA-MRSA) infections, however, have not previously complicated the course of kidney transplantation. To our knowledge, we report the first cases of invasive infections caused by PVL-positive CA-MRSA occurring after kidney transplantation. In both cases, we were able to confirm possession of type IV SCCmec and clonality with USA 300. From this series, however, we are unable to determine whether organ transplantation is a specific risk factor for CA-MRSA acquisition and the severity of infection, and further study is required to determine the epidemiology of CA-MRSA in this unique patient population. Additionally, since both organ recipients also had diabetes, a known risk factor for staphylococcal colonization and infection, we are unable to determine the contribution of each comorbid condition to the acquisition and the severe disease manifestations of CA-MRSA in these cases.

Linares and colleagues recently reported a low rate of MRSA infection among 416 kidney transplant patients who were prospectively followed for 3 years. In this study, 58 patients developed multiresistant bacterial infections, and only two of these infections were due to MRSA (9). Apart from limited data for liver transplant recipients, there are no data on the true incidence of MRSA colonization or infection in other transplant recipients (1). In this group of patients, MRSA infections typically occur in the first 3 months, and the commonly reported sites are the bloodstream (often catheter related), wounds, inside the abdomen, and the lower respiratory tract (1).

Obed and colleagues (14) reported fatal PVL-MRSA pneumonia complicating the postoperative course of a living-donor liver transplant recipient. Those authors reported donor transmission of this pathogen, either via the allograft or via nosocomial acquisition, since donor and recipient shared a hospital room postoperatively. In either scenario, this was a case of health care-associated PVL-MRSA.

Osteomyelitis is a difficult-to-treat infection characterized by progressive inflammatory destruction and new apposition of bone (8). S. aureus is the most common causative agent, but CA-MRSA is rarely implicated. Our first patient was treated for recurrent MRSA skin and soft tissue abscesses prior to presentation, and this most likely predisposed him to deep abscess and osteomyelitis. The abscess was drained, diagnosis was aided by culture, and, ultimately, a good clinical outcome was achieved by drainage and prolonged antimicrobial therapy. Gelfand et al. (7) speculated in their report of CA-MRSA osteomyelitis in patients presenting with pathological fractures that virulence factors specific for CA-MRSA may predispose patients to a complicated course of acute osteomyelitis.

Necrotizing fasciitis is characterized by extensive, rapidly progressing, and life-threatening gangrene of skin and subcutaneous tissue above the fascial layer. It is typically a polymicrobial infection, and streptococci are most commonly isolated (2). MRSA is not a commonly implicated pathogen and has been reported only once as a cause of necrotizing fasciitis after kidney transplantation (3). In that report, neither the presence of the PVL gene nor the type IV SCCmec gene was reported. Miller and colleagues (12) reported 100% survival for a series of 14 patients with CA-MRSA necrotizing fasciitis, 21% of whom had diabetes mellitus, just as with our case 2. Of note, Olsen and colleagues (15) reported the survival of an AIDS patient diagnosed with PVL-positive MRSA necrotizing fasciitis; likewise, Dehority et al. (5) reported the survival of a neonate with monomicrobial CA-MRSA necrotizing fasciitis. Our kidney recipient with necrotizing fasciitis also had monomicrobial infection and survived, supporting the concept that MRSA may be less virulent than other pathogens causing necrotizing fasciitis; further studies are needed to prove this hypothesis. Optimal management of CA-MRSA necrotizing fasciitis has not been defined; our patient had a good clinical outcome with an aggressive multidisciplinary approach, including early and multiple surgical debridements, antimicrobial therapies, and cardiopulmonary supportive measures.

PVL, a bicomponent, pore-forming toxin that has a specific lytic activity on human polymorphonuclear cells and monocytes, has been speculated to be a virulence factor (15, 16, 18). The presence of PVL in S. aureus is associated with increased disease severity, ranging from cutaneous infection requiring surgical drainage to severe chronic osteomyelitis and deadly necrotizing pneumonia (4, 10). Our patient received two therapies aimed at inhibiting the production and neutralization of PVL with clindamycin and intravenous immunoglobulin; however, the contribution of each of these to the successful treatment of our patient and other invasive CA-MRSA infections is unknown (6, 13, 16, 18).

In summary, kidney transplant recipients may acquire invasive infections with MRSA, including community-associated strains, in the late posttransplant period. As this pathogen becomes more pervasive in the community, its importance as a cause of potentially severe, life-threatening infections after organ transplantation will increase. The epidemiology of CA-MRSA infections specific to organ transplant recipients requires further study.

 
We thank Northwestern University Feinberg School of Medicine for providing financial support for this research.

We declare no potential conflicts of interest.

 
* Corresponding author. Mailing address: Divisions of Infectious Diseases and Organ Transplantation, Northwestern University Feinberg School of Medicine, 645 N. Michigan Avenue, Suite 900, Chicago, IL 60611. Phone: (312) 695-5085. Fax: (312) 695-5088. E-mail: v-stosor{at}northwestern.edu

Published ahead of print on 4 June 2008.

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Journal of Clinical Microbiology, August 2008, p. 2809-2813, Vol. 46, No. 8
0095-1137/08/$08.00+0     doi:10.1128/JCM.00494-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Adeyemi, O. A. Articles by Stosor, V. Search for Related Content PubMed PubMed Citation Articles by Adeyemi, O. A. Articles by Stosor, V.