Infectious Disease Consult Service Case Presentation

1. Infectious Disease Consult Service Case Presentation October 10, 2007 Sarah Hubbell, MS4

2. History 30-year-old African American female, with PMH significant for congenital heart disease and previous episodes of endocarditis, presents with four day history of chills, fevers up to 103 F, myalgias, and dyspnea (increased over baseline).

3. History continued On the day prior to admission, she had emesis x 1, diarrhea x 2, nausea, and clear rhinorrhea. Admits to mild frontal headaches that worsen with chills, and occasional sharp pain over her sternum. The sternal pain seems to resolve with resolution of chills. She took Tylenol and TheraFlu with some relief.

4. Past Medical History Congenital cyanotic heart disease (ASD, VSD, pulmonary atresia), s/p Waterston shunt as a neonate, and Blalock Taussig shunt at age 12. Most recent echo (3/2006) showed EF 45-50%. Right basal ganglia abscess in 2005, s/p drainage. Culture negative. Streptococcus viridans endocarditis x 3, last episode in 2003. Paroxysmal atrial fibrillation since 1997. CVA, 1999 � related to line infection. No residual defects.

5. Brief cardiac detour� Waterston shunt: creation of a narrow opening between the ascending aorta and subjacent right pulmonary artery to increase pulmonary circulation. Blalock Taussig shunt: anastomosis of right or left subclavian artery to the right or left pulmonary artery � directing blood from the systemic circulation to the lungs.

6. Blalock-Taussig Shunt The left subclavian artery is divided and connected to the left pulmonary artery. This allows blood to flow to the lungs to pick up oxygen. View illustration at: http://images.healthcentersonline.com/heart/images/article/i14Blalock.jpg

7. Social/Family History Lives with 1 year-old daughter and fianc�. She stays at home. Denies tobacco, alcohol, or drug use. HIV negative in 2005. No recent travel or sick contacts, though her daughter did develop a dry cough after her illness began. Father and aunt have HTN. Family history of multiple cancers, including breast, lung, leukemia, melanoma. Aunt with enlarged heart.

8. Medications Home medications: Furosemide 20 mg po daily Lisinopril 5 mg po daily Digoxin 0.125 mg po daily Metoprolol ER 12.5 mg po daily ASA 81 mg po daily Allergies: Penicillin ? rash. Has tolerated cephalosporins and vancomycin in the past. Question of ceftriaxone-induced rash at Wake.

9. ROS Denies neck soreness/pain, sinus pain, sore throat, dysuria, hematuria, back pain, recent dental work, abdominal pain, arthralgias, skin infections, cough, altered mental status. Has had some palpitations.

10. Physical Exam Vital Signs: Tm 103.4, HR 111-168, RR 18-20, BP 110-126/38-57, O2 68-89% on non-rebreather mask. General: Awake, alert, in distress, struggling to breathe. HEENT: Sclerae anicteric, PERRL, EOMI, oropharynx without erythema or exudates, clear nares. Neck: No masses, nontender, full ROM, no JVD.

11. Physical Exam continued Lymph: No cervical, supraclavicular, or axillary adenopathy. CV: Irregularly irregular, tachycardic, III/VI systolic murmur best heard on left sternal border. Respiratory: Decreased breath sounds, particularly on the left. Scattered mild rales and rhonchi, increased work of breathing. Abdomen: Soft, non-tender, non-distended, no masses. Normoactive bowel sounds.

12. Physical Exam continued MSK: Normal tone and strength. Neuro: Full sensory and motor function, cranial nerves 2-12 intact. No focal deficits. Skin: No rashes or lesions, + cyanosis of hands and feet. No splinter hemorrhages, Janeway lesions, Osler�s nodes. Psych: Oriented x 3 with normal mental status. Appropriate mood and affect.

13. Admission Labs WBC 10.3, Hgb 18.2, Hct 54, Plt 133 Na 134, K 3.2, Cl 106, Bicarb 20, BUN 14, Cr 0.9, Gluc 109, Ca 8.6 Urine pregnancy negative U/A 13 RBC�s, 6 WBC�s, nitrite neg, leuk esterase neg, 2+ bacteria Albumin 2.5, tot. protein 5.8, t bili 4.7, ALT 54, AST 67, alk phos 78 CK 337, MB 2.2, trop I 0.05 CXR: moderate cardiomegaly, no acute changes, no opacities in lungs, + evidence of prior median sternotomy

14. Management Given ceftriaxone and vancomycin in the ED and admitted to Wake MICU on 10/4. Treated there with vancomycin, ceftriaxone (discontinued after a rash appeared), aztreonam, and levofloxacin. Transferred here from Wake at patient�s request, as her primary cardiologist is at UNC.

15. Discussion

16. And the blood cultures grew out� Gram positive cocci in chains

17. Granulicatella adiacens Nutritionally Variant Streptococci (NVS)

18. Nutritionally Variant Streptococci First described in 1961 as fastidious gram-positive bacteria that grow as satellite colonies around other bacteria, particularly Staph aureus. Found as normal flora of the upper respiratory, urogenital, and gastrointestinal tracts of humans. Like other bacterial residents of the oral cavity, NVS have been identified as an important cause of endocarditis. NVS can also cause primary bacteremia, particularly for neutropenic patients and patients with underlying hematological malignancies.

19. Other infections There are reports of NVS being isolated from patients with: Osteomyelitis Otitis media Wound infections Brain abscesses Septic arthritis Endophthalmitis Meningitis. Pancreatic abscess

20. A little history� On the basis of DNA-DNA hybridization studies, it was found that NVS fit the genus description of Streptococcus but were taxonomically unrelated to other viridans group organisms. The names S. adjacens and S. defectivus were proposed as new designations in 1989. In 1995, studies using 16S ribosomal RNA sequence analysis showed that these two species were actually not related to other members of the Streptococcus genus. They were placed in a new genus Abiotrophia, as A. adiacens and A. defectiva. In 2000, the genus Abiotrophia was taxonomically revised, reclassifying all species except A. defectiva to the new genus Granulicatella.

21. For the medical student� Streptococcus adjacens and S. defectivus? Abiotrophia adiacens and A. defectiva ? A. defectiva stays the same, everything else goes to genus Granulicatella.

22. NVS and Endocarditis Nutritionally variant streptococci cause approximately 5% of cases of bacterial endocarditis. Historically, NVS is believed to have accounted for most cases of culture-negative endocarditis. NVS endocarditis resembles that of viridans, primarily occurring in the setting of valvular disease and progressing indolently.

23. NVS and Endocarditis Vegetations are comparatively small, but commonly embolize (33% vs. 11% for other oral species). Two dimensional echocardiography visualizes vegetations in 64% of patients.

24. NVS and Endocarditis Granulicatella adiacens and Abiotrophia defectiva comprise the vast majority of NVS causing endocarditis (57% and 41% respectively) with Granulicatella elegans causing a small number (2%). The higher infectivity of G. adiacens and A. defectiva has been attributed to their capacity to bind to cardiac valvular tissue. G. adiacens is the NVS found in the greatest numbers in the oropharynx (ratio is 11:1:1 for G. adiacens: G. elegans: A. defectiva).

25. NVS and Endocarditis A comparison between patients with NVS endocarditis and patients with infection caused by other oral species revealed a higher mortality rate and more frequent complications of embolization for NVS. For NVS and viridans streptococci endocarditis, mortality rates have been reported as 14% and 5% respectively.

26. In the micro lab� NVS are recognized by their requirement for pyridoxal or thiol group supplementation for growth. Colonies of NVS are small and are either non-hemolytic or a-hemolytic on blood agar.

27. Micro lab continued In subculture, solid media must be supplemented with 0.001% pyridoxal or 0.01% l-cysteine to sustain growth. Alternatively, the subculture plate can be cross-streaked with S. aureus to provide these factors and permit growth as satellite colonies.

28. Pick your treatment!

29. Difficulties in treating NVS Relapse rates are approximately 17%, and bacteriological failure rates of 41% have been noted. Failure rate has been attributed in part to delay in starting therapy, due to increased length of time required to isolate and identify these bacteria.

30. Difficulties in treating NVS The growth rate of NVS is significantly slower than viridans, so longer treatment durations are suggested. NVS are less susceptible in vitro to penicillin than are other streptococci. Approximately 33% to 65% of strains are relatively resistant, and some isolates are highly resistant.

31. Treatment Synergy between penicillin or vancomycin in combination with an aminoglycoside is observed both in vitro and in experimental animal models of endocarditis. NVS has demonstrated 100% sensitivity to both vancomycin and rifampin. Rifampin has been observed to produce synergistic bactericidal activity when given in combination with vancomycin in time-kill studies.

32. Treatment continued Aminoglycosides show variable in vitro activity against NVS. High-level resistance has not been reported. Most NVS are also susceptible to clindamycin, chloramphenicol, and erythromycin The activity of the cephalosporins and tetracyclines are variable.

33. Treatment continued In vitro antimicrobial susceptibility testing of NVS is beyond the scope of many routine clinical laboratories. It is recommended that all patients with NVS endocarditis be treated with long-term combination therapy for 4 to 6 weeks. Even with this regimen, however, the rates of bacteriologic failure and relapse are high.

34. Our treatment selection Antibiotics we picked: Gentamicin, Vancomycin, and Rifampin This triple combination has been indicated as being the most synergistic in animal models, and was used successfully in case reports.

35. Hospital Course for our patient Respiratory status improved while here, and she remained afebrile. TEE results: large ASD, perimembranous VSD, degenerative mitral valve disease, trivial MR, mild TR, atretic appearing tricuspid and pulmonic valves. No vegetations or abscesses were noted.

36. Hospital Course continued Cardiac MRI for Morphology revealed: Low normal LV systolic function Functional Waterston' s shunt with flow from the ascending thoracic aorta to the right pulmonary artery Probable left pulmonary artery atresia Atrial septal defect Left subclavian artery atresia with recanalization within the axilla via subcostal arterial network No evidence for myocardial scar or infiltration The Blalock-Taussig shunt could not be identified

37. Hospital Course continued Blood cultures drawn here have remained negative. Isolate of NVS from Wake is being prepared for shipping to our lab for sensitivity testing.

38. Discharge Plan The patient will be discharged on vancomycin, rifampin, and gentamicin for treatment of bacteremia/endovascular infection. She will follow up with ID clinic in 2 weeks, at which time sensitivities of the Wake specimen are likely to be ready. She�s doing well!

39. Resources Jeng A, et al. Prosthetic valve endocarditis from Granulicatella adiacens (nutritionally variant streptococci). Journal of Infection (2005)51, e125-e129. Mandell, Bennett, & Dolin: Principles and Practice of Infectious Diseases, 6th ed. Book available online via the UNC-CH Libraries Perkins A, et al. A case of endocarditis due to Granulicatella adiacens. Clinical Microbiology and Infection (2003)9(6), 576�577. Ruoff KL. Nutritionally variant streptococci. Clinical Microbiology Review. 1991 Apr;4(2):184-90. Senn L, et al. Bloodstream and endovascular infections due to Abiotrophia defectiva and Granulicatella species. BMC Infectious Diseases 2006, 6:9.

40. Search PubMed Nutritionally Variant Streptococci Case Reports Reviews Differential Diagnosis Drug Therapy