Correspondence *Department of Internal Medicine, Cerrahpasa Medical Faculty, University of Istanbul, 34098 Istanbul, Turkey

Email isilbavunoglu@gmail.com

The case

A 26-year-old man was admitted to medical care with sudden-onset abdominal pain, nausea and diarrhea. He also presented with fever and fatigue, and reported a weight loss of 15 kg over the past 2 months. He had been diagnosed with membranous ventricular septal defect (VSD) during childhood, but had received no regular monitoring or treatment for this condition. There was no history of prolonged fever, and no notable hospital admissions, dental extractions or surgical procedures that could suggest an increased susceptibility to infective endocarditis (IE). At admission he was visibly unwell and had a temperature of 38.6 °C. On examination his respiratory rate was 20 breaths/min, his blood pressure was 100/60 mmHg, his pulse was 100 beats/min and regular, and all peripheral pulses were palpable. Examination of the abdomen revealed hepatosplenomegaly and diffuse abdominal tenderness, but no rebound tenderness. Cardiovascular examination revealed a thrill and a pansystolic murmur in the mitral area and left sternal border. Neurological and ophthalmological examinations were normal. No cutaneous or mucocutaneous lesions were noted. The patient was hospitalized to allow further evaluation of his fever.

Laboratory tests revealed a white blood cell count of 9.2 10⁹/l (proportion of polymorphonuclear neutrophils—0.85), a hemoglobin level of 87 g/l, a hematocrit of 0.274, a platelet count of 178 10⁹/l, an erythrocyte sedimentation rate of 46 mm/h, and a C-reactive protein level of 0.176 g/l. Urinalysis showed proteinuria, microscopic hematuria and granular casts. Electrolyte and blood glucose levels were normal, as were hepatic and renal function tests. Electrocardiography showed sinus tachycardia and a 1–2 mm ST depression in the anterior leads. Thoracic and abdominopelvic CT confirmed hepatosplenomegaly, but there were no other notable observations.

Two sets of blood cultures were produced, which grew -hemolytic Streptococci (incubation by BacT/ALERT^® 3D) subsequently identified as Streptococcus sanguis by Rapid ID 32 STREP tests (bioMérieux, Marcy l'Etoile, France). The strain was resistant to penicillin, with a minimal inhibitory concentration (MIC) of 3 g/ml (measured repeatedly by Etest^® [AB Biodisk, Solna, Sweden] and verified by agar dilution), but was sensitive to clindamycin, erythromycin, vancomycin and gentamicin (all measured by disk diffusion test; breakpoints for gentamicin are those specified for enterococci by the Clinical and Laboratory Standards Institute). Tests for -lactamase, using nitrocefin, were negative (Oxoid Limited, Basingstoke, UK).

Transthoracic echocardiography showed multiple vegetations on the anterior mitral leaflet, a 16 6 mm mobile vegetation on the surface of the aortic noncoronary cusp, and a small (<10 mm) vegetation on the tricuspid valve (Figures 1 and 2). Membranous VSD was also noted. A diagnosis of multiple valve S. sanguis endocarditis was made on the third day of hospitalization and treatment was initiated with 1 g vancomycin delivered intravenously every 12 h, and 80 mg gentamicin every 8 h.

Figure 1 Transthoracic echocardiogram during diastole (parasternal long axis view), showing multiple vegetations on the anterior leaflet of the patient's mitral valve (arrows 1 and 2) and a 16 6 mm mobile vegetation on the aortic noncoronary cusp (arrow 3)

Abbreviations: LA, left atrium; LV, left ventricle.

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Figure 2 M-mode echocardiogram of the patient's mitral valve, showing multiple echoes from vegetations on the anterior leaflet during diastole

This is a specific sign of cusp vegetations in infective endocarditis.

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A week later the patient's gastrointestinal symptoms and hepatosplenomegaly had resolved but he was still febrile, and was recommended for surgery. The mitral valve was explored following left atriotomy, but these vegetations turned out to be small, and no surgical procedure was performed. Initial exploration of the aortic valve suggested severe leaflet damage, and a 23 mm St Jude Medical^® prosthetic valve (St Jude Medical, St Paul, MN) was fitted. The vegetation on the tricuspid valve was removed. A 5 5 mm fistula, located 20 mm above the aortic root, was noted and repaired with a pericardial patch. Finally, the VSD (15 15 mm) was repaired using a Dacron^® patch (Invista North America S.A.R.L. Corporation, Wilmington, DE).

The patient remained in hospital on intravenous antibiotic therapy for 3 weeks. This period proved uneventful, and he was subsequently discharged after 30 days in hospital. He recovered well, and was still healthy when assessed 1 year later.

Discussion of diagnosis

IE is a lethal disease if not treated aggressively with parenteral antibiotics, often in combination with surgery.¹ Despite improvements in general health care, the incidence of the disease has not changed over the past 2 decades.² Recent increases in the antibiotic resistance of viridans Streptococci, the leading cause of IE, have made treatment problematic, and the number of serious complications has risen, along with associated mortality.^{3, 4, 5, 6} Streptococci have membrane-bound proteins that bind penicillin, and the increasing resistance is thought to be attributable to a decreased affinity of these receptors for -lactam.^{3, 4} Penicillin-resistant Streptococci are classified as having either intermediate-level (MIC 0.1–1 g/ml) or high-level resistance (MIC >1 g/ml).

The patient displayed symptoms of acute abdomen, but it was primarily the presence of a VSD that led toward a diagnosis of IE (it was also noted that his gastrointestinal symptoms improved following initial antibiotic therapy, yet the fever persisted). VSDs, along with most forms of congenital heart disease, alter the course of blood through the heart. As a result, cardiac tissue can become exposed to turbulent blood flow that can potentially damage the endocardium, making it vulnerable to bacteria that are present in the blood, and leading to infection.

The patient fulfilled the Duke criteria for IE,⁷ as he had two sets of positive blood cultures growing S. sanguis, an echocardiogram demonstrating vegetations, a predisposing condition for endocarditis (VSD), and fever (temperature >38 °C). The diagnosis was, therefore, confirmed as community-acquired, triple-valve IE, caused by S. sanguis with high-level penicillin resistance (MIC of 3 g/ml).

Although such resistance in Streptococci is increasing, very few cases of penicillin-resistant viridans streptococcal endocarditis have been reported in the literature.^{5, 6, 8, 9, 10, 11, 12} In 1979, Parrillo et al.⁸ described a woman receiving penicillin prophylaxis for rheumatic fever who developed endocarditis caused by S. mitis with a penicillin MIC of 2.7 g/ml. Six years later, Wilson and Geraci⁹ reported a patient with viridans streptococcal endocarditis with a penicillin MIC of 1 g/ml, as part of a series of 142 patients. In 2002¹¹ and 2004,¹² reports of two children with endocarditis caused by penicillin-resistant streptococci (MIC >1.5 g/ml) were published. Hsu et al.¹³ reported in 2006 that high-level penicillin resistance of the Streptococci responsible for IE was increasingly common, and that medical therapy with vancomycin was effective. The authors also emphasized that penicillin resistance was associated with a decreased risk of embolization, but was not associated with higher mortality.

The majority of IE cases occur on a single valve, and multiple valve involvement is rare; in a recent case series of 77 patients with IE the incidence of multivalvular endocarditis was 18%, with the mitral and aortic valves most commonly affected.¹⁴ No triple or quadruple valve IE cases were reported in the series. Echocardiography of the current patient showed multiple vegetations on his anterior mitral leaflet, aortic noncoronary cusp and tricuspid valve. These findings suggest that the involvement of multiple valves in this case could be attributed to left-to-right ventricular communication, caused by the membranous VSD. The infection on one side of the heart could have spread through the left-to-right shunt produced by the VSD, thus affecting valves on both sides of the heart.

Fever in patients with endocarditis due to viridans Streptococci usually lasts for less than 7 days.¹⁵ In this patient, however, it persisted beyond this point despite intensive therapy. The most common causes of persistent fever in IE are the spread of infection beyond the valve (often leading to myocardial abscess), focal metastatic infection, or drug hypersensitivity (particularly likely if the fever resolves and then recurs).¹⁵ Nosocomial infections, or other hospitalization-related complications such as pulmonary embolism, can also be responsible. These possibilities were excluded in this patient by clinical and radiological investigation. Fever most likely persisted simply because antibiotic treatment alone was unable to control such a highly resistant infection.

Treatment and management

The recommendations of the AHA for the treatment of IE have been updated to address the increasing penicillin resistance of viridans Streptococci.³ The optimum therapy for multivalvular endocarditis involving resistant strains, however, remains controversial. Available data suggest that early surgery is required for management of these patients.¹⁴ For strains with a penicillin MIC greater than 0.5 g/ml, the recommended treatment regimen is the same as that for enterococcal endocarditis,³ although there are few data to suggest that the response to therapy is analogous between these different types of bacteria.¹¹

In the case described by Parrillo et al.⁸ (S. mitis with a penicillin MIC of 2.7 g/ml), the patient relapsed after a 3-week course of moderate-dose penicillin alone, but was finally cured with a subsequent 6-week course of high-dose penicillin and gentamicin. These authors also reported a patient with IE (penicillin MIC of 0.7 g/ml) who was successfully treated over 7 weeks with gentamicin, initially in combination with moderate-dose, and subsequently high-dose, penicillin. Karchmer et al.¹⁶ reported a case with viridans streptococcal IE caused by an organism with a penicillin MIC of 0.7 g/ml who was treated successfully with 28 days of sequential single drug therapy. This therapy comprised high-dose penicillin for 6 days, followed by cefalotin for 13 days, and finally vancomycin for 9 days. The patient reported by Wilson and Geraci⁹ (penicillin MIC of 1 g/ml) was treated successfully with a 2-week course of penicillin and streptomycin.

Endocarditis caused by penicillin-resistant microorganisms has proven more problematic to treat than that caused by penicillin-susceptible strains.¹³ Alternatives to penicillin should be considered against highly resistant Streptococci, which are currently widely susceptible to vancomycin.^{1, 13} Martinez et al.¹⁷ used a rabbit model and penicillin-resistant S. sanguis (MIC 8 g/ml) to evaluate responses to therapy. They found that combinations of imipenem and gentamicin, and of teicoplanin and gentamicin, were both effective, but that the combination of vancomycin and gentamicin was the most successful therapy against IE in this animal model.

Demonstration of multivalvular involvement in patients with suspected IE is also important. Some reports suggest that patients with multiple valve infection are more likely to die or require early surgery for management of complications,¹⁸ while others suggest that the mortality is comparable between single-valve and multiple-valve IE.¹⁴ The most common etiological microorganism in patients with multivalvular endocarditis is reported to be Staphylococcus aureus, followed by viridans Streptococci.¹⁴ In terms of complications, only congestive heart failure seems to be statistically more common in multivalvular than univalvular endocarditis.¹⁴ The choice of antibiotics is usually based on the isolated strain and its resistance pattern, rather than the number of valves involved.

Recent studies show a relatively low operative mortality for patients with active IE, both of native and prosthetic valves, who were operated on during the course of antibiotic therapy.^{15, 19} The patient's preoperative hemodynamic status, rather than the duration of preoperative antibiotic therapy, seems to correlate with postoperative mortality. Although congestive heart failure was not detected in the patient described here, the involvement of multiple valves, the high resistance of the organism, evidence of large mobile vegetations, and persistent fever led to urgent surgical cardiac intervention.

Conclusions

Although multivalvular endocarditis due to penicillin-resistant viridans Streptococci is rare, the incidence of this condition is increasing. A combination of parenteral antibiotics and early surgery seems to be the optimum treatment modality.

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Subject areas under which this article appears: Infection | Intervention | Therapy