J Infect Chemother 21 (2015) 695e699

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Case report

Staphylococcus saprophyticus native valve endocarditis in a diabetic patient with neurogenic bladder: A case report Hiroki Magarifuchi a, *, Koji Kusaba b, Hiroki Yamakuchi a, Yohei Hamada a, Toshiharu Urakami a, Yosuke Aoki a, c a b c

Division of Infectious Disease and Hospital Epidemiology, Saga University Hospital, Saga, Japan Division of Clinical Laboratory, Saga University Hospital, Saga, Japan Division of Clinical Infectious Diseases, Department of International Medicine, Faculty of Medicine, Saga University, Japan

a r t i c l e i n f o

a b s t r a c t

Article history: Received 10 January 2015 Received in revised form 24 May 2015 Accepted 26 May 2015 Available online 3 June 2015

A 61-year-old man was admitted to our hospital with 2-day history of malaise and dyspnea. He had mitral prolapse and type II diabetes mellitus with neurogenic bladder, which was cared for by catheterization on his own. On arrival the patient was in septic condition with hypoxemia, and physical examination revealed systolic murmur at the apex. Transthoracic echocardiography revealed vegetation of the mitral and the aortic valve. The presence of continuous bacteremia was confirmed by multiple sets of blood culture, whereby gram-positive cocci was retrieved and identified as Staphylococcus saprophyticus (S. saprophyticus) both phenotypically and genetically. Because two major criteria of the Modified Duke Criteria were met, the patient was diagnosed with native valve endocarditis due to S. saprophyticus. The urine culture was also positive for gram-positive cocci, phenotypically identified as Staphylococcus warneri, which was subsequently identified as S. saprophyticus with the use of 16S rRNA gene sequence analysis and MALDI-TOF MS (matrix-assisted laser desorption ionization time of flight mass spectrometry), indicating strongly that the intermittent catheterization-associated urinary tract infection resulted in bacteremia that eventually lead to infective endocarditis. This patient was treated with vancomycin and clindamycin. Because of multiple cerebral infarctions, the patient underwent mitral and aortic valve replacement on hospital day 5. Blood culture turned negative at 6th hospital day. Antibiotic therapy was continued for six weeks after surgery. The patient's clinical course was uneventful thereafter, and was discharged home. This is the first case report of native valve endocarditis caused by S. saprophyticus of confirmed urinary origin. © 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Keywords: Staphylococcus saprophyticus Coagulase-negative Staphylococcus Native valve endocarditis Urinary tract catheterization

1. Introduction Staphylococcus epidermidis (S. epidermidis), Staphylococcus lugdnensis (S. lugdnensis), and Staphylococcus saprophyticus (S. saprophyticus) among others are clinically important coagulasenegative Staphylococcus (CoNS) [1] that develop native valve endocarditis (NVE) with an incidence of 5%e8% except for those observed in injection drug users [2,3]. The majority of CoNS NVE is caused by S. epidermidis (85%), which is thought to originate from

* Corresponding author. 5-1-1, Nabeshima, Saga 849-8501, Japan. Tel.: þ81 952 34 3816; fax: þ81 952 34 3294. E-mail address: [email protected] (H. Magarifuchi).

hematogenous seeding as seen in catheter-related blood stream infections to the previously damaged or malformed heart valves or endocardium [1]. The clinical course of NVE due to CoNS is also often severe, with high rates of valvular destruction, heart failure, and death [4]. More than half of the cases require valve replacement [3]. Despite high rates of operability for cardiac surgery (60%) than NVE caused by Staphylococcus aureus, NVE due to CoNS is nonetheless associated with 25% mortality [4]. S. saprophyticus frequently colonizes within the rectum and the genitourinary tract, and is a well-documented causative pathogen of urinary tract infections (UTI), making it the second most common cause of uncomplicated cystitis among young women [5]. However, rare cases of NVE, endophthalmitis, and septicemia have

http://dx.doi.org/10.1016/j.jiac.2015.05.008 1341-321X/© 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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also been reported in the literature [6]. We report a case of NVE caused by S. saprophyticus of urinary origin that developed as healthcare-associated infection. 2. Case report A 61-year-old man was admitted to Saga University Medical Center with a 2-days’ history of dyspnea. He also complained of back pain and malaise which he reported to have occurred insidiously. He had suffered type II diabetes mellitus complicated by neurogenic bladder due to neuropathy, which had been managed by domiciliary self-catheterization, and mitral valve prolapse. On arrival at our hospital, his body temperature was 35.8  C, heart rate 86/min, blood pressure 108/60 mmHg, and respiratory rate 30/min. Physical examination revealed Levine III/VI systolic murmur at the apex. There was no possible stigma of infective endocarditis such as petechiae on palpebral conjunctiva, hemorrhagic streak beneath the nail plate, or discoloration of fingertip, suggestive of such as Osler's node, or Janeway lesion. Coarse crackle at both lung bases was heard. Laboratory investigation revealed white blood cell (WBC) count 17,000/mL with neutrophils being 84.5%. The serum concentration of C-reactive protein was 4.01 mg/dl, creatinine 2.00 mg/dL, brain natriuretic peptide 2397 pg/ml, and HbA1c 5.9%. The urinalysis was positive for leukocyte and nitrite, and the Gram-stain of urine also showed gram positive cocci in cluster. Chest radiography showed cardiomegaly with bilateral enhancement of the vascular marking consistent with lung congestion. Transthoracic echocardiography

revealed soft tissue structure attached to the mitral and aortic valve (Fig. 1). Magnetic resonance imaging (MRI) of the spine showed illdefined hyperintense signal abnormality and fluid accumulation of small volume by T2-weighted image at Th9/10 and L1/2. These findings were consistent with intervertebral discitis (Fig. 1). Five out of eight blood culture bottles (4 sets) that were drawn on admission prior to antibiotic therapy turned positive, showing gram positive cocci in cluster on Gram stain on the 3rd hospital day. The Vitek 2 GP card system (bioMerieux, Durham, NC) identified S. saprophyticus. Since the gram-positive cocci in the urine was phenotypically identified as Staphylococcus warneri, genetic analysis with the use of polymerase chain reaction (PCR) of 16S rRNA and mass spectrometric analysis with the use of matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS) were applied to the strains retrieved from the blood and urine, both of which methods identified S. saprophyticus (Table 1). In addition, a further analysis with the pulsed-field gel electrophoresis (PFGE) strongly suggested that these two strains of S. saprophyticus from the blood and urine were genetically identical (Fig. 2). Having fulfilled two major criteria of the modified Duke criteria [8], positive blood culture and echocardiographic findings, definitive diagnosis of NVE due to S. saprophyticus was made. The constellation of clinical syndromes of this patient, diabetes mellitus, bacteriuria associated with self-cared neurogenic bladder, multiple intervertebral discitis, and definite diagnosis of S. saprophyticus infective endocarditis, illustrates that the patient first contracted device-associated urinary tract infection due to S. saprophyticus, then complicated with S. saprophyticus bacteremia

Fig. 1. Clinical course. Transthoracic echocardiography (TTE) showed vegetations of the aortic and mitral valve (day 1: long arrows). Chest radiography showed bilateral lung congestion (day 1). MRI showed multiple cerebral infarctions in bilateral brain cerebral hemisphere (day 2: short arrows). Cefazolin (CEZ) and clindamycin (CLDM) were administrated empirically. After sensitivity of S. saprophyticus was available, CEZ was changed to vancomycin (VCM). Dosage of VCM was changed to 0.75g after therapeutic drug monitoring. Following antimicrobial treatment and valvular replacement (day 6), lung congestion subsided and blood culture was sterilized.

H. Magarifuchi et al. / J Infect Chemother 21 (2015) 695e699 Table 1 Results of species identification and antimicrobial susceptibility. Blood

Urine

Smear Gram-positive cocci Culture Positive Positive VITEK2 S. saprophyticus S. warneri MALDI-TOF MS S. saprophyticus S. saprophyticus 16s rRNA S. saprophyticus S. saprophyticus Antimicrobial susceptibility testing (mg/ml) MPIPC 0.5 (R) 4 (R) ABPC &0.25 (R) 0.5 (R) SBT/ABPC &1.0 (R) 1.0 (R) CEZ &1.0 (R) 2.0 (R) CLDM &0.25 (S) &0.25 (S) MINO &1.0 (S) &1.0 (S) VCM 1.0 (S) 1.0 (S)

Vegetation Negative e e S. saprophyticus Not available

Staphylococcal species were identified by the Vitek 2 GP card system (bioMerieux, Durham, NC), MALDI-TOF MS analysis (Bruker Daltonics, Bremen, Germany), and polymerase chain reaction of 16S rRNA. Antimicrobial susceptibility was determined by minimum inhibitory concentration (mg/ml) quantitated by the broth microdilution method. Susceptibility break points for Staphylococcal species were consistent with those of the Clinical and Laboratory Standards Institute for Staphylococcus spp [7]. (S; susceptible, R; resistant).

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that developed infective endocarditis and septic intervertebral discitis. The patient was first put on presumptive therapy for NVE complicated by septic spondylitis with intravenous cefazolin (CEZ) 2g q12H, to which clindamycin (CLDM) 600 mg q8H was coadministered expecting its higher penetration into the bone tissue than beta-lactam antibiotics [9]. On the hospital day 4, the antibiotic susceptibility results became available (Table 1). Even though S. saprophyticus strain from blood culture was considered susceptible to beta-lactam antibiotics, the urinary strain was considered sensitive to vancomycin (VCM), but not beta-lactam agents. Therefore CEZ was switched to VCM 1g QD, with CLDM being continued. Because the size of the mitral valve vegetation was large enough (21  6 mm) to warrant surgical repair [10], and MRI of the brain taken on the 2nd hospital day had shown multiple cerebral infarcts bilaterally which assumed to have resulted from septic dissemination (Fig. 1), and most importantly congestive heart failure was not responsive to medical treatment, the patient underwent cardiac surgery for aortic valve replacement, mitral valve repair, and tricuspid valve annuloplasty on the 5th hospital day. Gram staining of the resected valve also showed gram positive cocci in cluster. Although tissue culture of the infected valves remained negative, 16S rRNA gene sequence analysis applied to the surgical specimen identified S. saprophyticus (Table 1). Blood culture turned negative at 6th hospital day, and all the blood culture performed after the beginning of antibiotics remained negative. Antibiotic therapy was continued with VCM and CLDM for six weeks after surgery. The patient's clinical course was uneventful thereafter, and was discharged home (Fig. 1). Because of the patient's lifelong risk factors for UTI, such as the need for self-catheterization of the urine and being diabetic, which together keep this patient vulnerable to prosthetic valve endocarditis (PVE), the patient was instructed to secure aseptic techniques in urinary catheterization. During three years' follow-up after discontinuing antibiotics, no signs and symptoms suggesting UTI or endovascular source of infections have not been observed. 3. Discussion

Fig. 2. PFGE profiles of S. saprophyticus isolates from blood and urine. Chromosomal DNAs were digested with Sma Ⅰ restriction enzyme, and the fragments were fractionated on a 1% agarose gel. The pulse time was 5.3e34.9s over 20 h at 6 V/cm. Lane M contains the size standards Lambda ladder. 1. PFGE profiles of the isolate from blood. 2. PFGE profiles of the isolate from urine.

It has long been known since the report by Lee et al. [11] that Staphylococcus aureus (S. aureus) bacteremia manifests S. aureus bacteriuria as well in nearly 10%e25% of cases [11e14]. On the other hand, preceding staphylococcal colonization within the urinary tract is also known to potentially develop staphylococcal bacteremia [15]. In our case, although S. sapropyhticus was retrieved from both blood and urine, the portal of entry of S. saprophyticus is likely to be urinary tract given that the patient had been taking care of his own urination by self-catheterization, and was not exposed to apparent risk of primary bacteremia of staphylococci. MICs of the beta-lactam antibiotics, especially MPIPC, against S. sapropyticus strains that were deemed genetically identical by PFGE were different between the blood and urine. This may well be observed, however, given the antimicrobial susceptibility varies with the difference in culture condition, the inoculum size or the antimicrobial concentrations in a given organ to which bacteria were exposed in vivo, all of which are hardly or never be the same [16,17]. S. saprophyticus is second only to E. coli as the most frequent causative organism of uncomplicated UTI in women. Sexually active women have higher risk for UTI due to S. saprophyticus than general population, but male in any age such as young boy, male homosexuals, and the elderly with indwelling catheters can also be affected [1,18]. In patients with diabetes mellitus, which is one of the risk factors for contracting IE [19], innate neutrophil functions including adherence, chemotaxis, phagocytosis, oxidative burst, and

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Table 2 Clinical features of native valve endocarditis due to S. saprophyticus. Case 1 [26] Age Sex Underlying disease

41-year-old Male Alcohol-related cirrhosis, portal hypertension, intravenous drug abuse Symptom Nausea, vomiting, shortness of breath, fever Blood culture Positive (3 sets) Urine culture Negative Vegetation culture Negative (On autopsy) Suspected portal of entry Intravenous drug addict Infected valve Complication Operation Antibiotics Clinical outcome

Aortic valve (native valve) Progressive heart failure, renal insufficiency e Nafcillin Dead

Case 2 [27]

Present case

50-year-old 61-year-old Male Male Paranoid schizophrenia, surgery for cholelithiasis Type Ⅱ diabetes mellitus, neurogenic bladder, mitral valve prolapse Dyspnea, fever, malaise Dyspnea, malaise Positive (1 set) Positive (4 sets) e Positive Positive Negative (16S-rRNA positive) Unknown (no cutaneous source, Urinary tract no genitourinary tract procedure) Aortic valve (native valve) Aortic valve, mitral valve (native valve) Acute heart failure Acute heart failure, Intervertebral diskitis Valve replacement Valve replacement Vancomycin Vancomycin, clindamycin Cured Cured

intracellular killing have been studied and reported to be impaired in proportion to the degree and duration of hyperglycemia [20e22]. Therefore it is very likely in our patient that daily urethral catheterization resulted in transient, then intermittent bacteremia of urinary source because of the derangements of the mucosal architecture imposed by physical manipulation [23] in addition to the impaired anti-infective function of neutrohil. This in turn undoubtedly developed bacteremia of high grade nature, as demonstrated by multiple positivity of the blood culture, which is a hallmark of endovascular source of infection such as IE seen in our patient. Mitral valve prolapse which this patient had is the leading cause of natural valve endocarditis, and has been reportedly detected in 22%e29% of cases of infective endocarditis (IE) [10,24,25]. Thus, our patient is a typical case of community-acquired severe sepsis in diabetes with valvular cardiac disease, except that the causative organism, S. saprophyticus, was rare such that it could have been overlooked as a colonizer of the urinary tract. S. epidermidis, S. lugdnensis, and S. saprophyticus among others are clinically important CoNS [1] that develop NVE with an incidence of 5%e8% except for those observed in injection drug use [2,3]. The majority of CoNS NVE is caused by S. epidermidis (85%), which is thought to originate from hematogenous seeding as seen in catheter-related blood stream infections to the previously damaged or malformed heart valves or endocardium [1]. The clinical course of NVE due to CoNS is also often severe, with high rates of valvular destruction, heart failure, and death [4]. Mortality may be as high as 36%. More than half of these cases require valve replacement [3]. Despite high rates of operability for cardiac surgery (60%) than NVE caused by S. aureus, NVE due to CoNS is nonetheless associated with 25% mortality [4]. Only two cases of S. saprophyticus endocarditis have been so far reported in the literature [26,27]. The present case is the first case of S. saprophyticus NVE in whom the portal of entry was definitively the urinary tract (Table 2). All patients including the present case were male and had underlying diseases. In one case, the portal of entry was unclear. Aortic valve involvement was the common finding in these three cases. Most characteristically, all cases presented with dyspnea presumably due to acute heart failure and two cases needed valvular replacement. These features suggest that IE due to S. saprophyticus is a severe life-threatening infection. In the era of increasing population of aging and chronic diseases such as diabetes or immune dysfunction of any causes, the present case highlights the importance of making appropriate diagnosis in a timely fashion for those who are at increased risk of healthcareassociated infections.

Conflict of interest None.

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