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rins should constitute initial treatment of H. parainfluenzae endocarditis ... success in treatment with a long-acting ... cases of subacute bacterial endocarditis.
ANNALS O F C LIN IC A L AND LABORATORY S C IEN C E, Vol. 23, No. 3 C opyright © 1993, Institute for C linical Science, Inc.

H aem ophilus parainfluenzae Endocarditis in a Patient with Mitral Valve Prolapse* JOH N N. G R EEN E, M .D .,t RAMON L. SANDIN, M .D., M .S.,t LUIS VILLANUEVA, and JOH N T. SINN OTT IV, M .D .t Departments o f Internal Medicinet and Pathology,t University o f South Florida College o f Medicine, Tampa, Florida 33612

ABSTRACT H aem ophilus parainfluenzae is a frequent cause of “culture-negative” endocarditis {i.e., endocarditis owing to a fastidious organism w hich may require longer incubation periods and/or enrichm ent m edia for detection com pared to traditional pathogens). More cases will probably be identified w ith im provem ents in grow th and isolation techniques. A case of H. parainfluenzae endocarditis is presented in a patient w ith m itral valve prolapse, w hich illustrates the difficulty in diagnosing endocarditis w hen initial blood cultures are negative. Particularly, it em phasizes the difficulty in selecting appropriate antibiotic therapy since beta-lactam ase producing organisms are being isolated w ith increased frequency. This report is unique in that it docum ents successful treatm ent with a cephalosporin and w hat is, to our know ledge, the third reported case of a beta-lactam ase producing H. parainfluenzae causing endocarditis. The authors believe th a t b e ta -la c ta m ase sta b le seco n d or th ird g e n e ra tio n c e p h a lo sp o ­ rins should constitute initial treatm ent of H. parainfluenzae endocarditis until sensitivity studies becom e available, since beta-lactam ase produc­ tion by this organism w ould nullify the effect of the previous agent of choice, ampicillin.

form ing, p leo m o rp h ic , gram -n eg ativ e coccobacillus. It is a normal inhabitant of Endocarditis caused by H aem ophilus the nasopharynx and oropharynx, iso­ p a r a i n f l u e n z a e is a n u n c o m m o n lated in 5 to 25 percent of cultures from entity,2’ ’12,14 representing 0.5 to 1 p er­ normal subjects.7 This fastidious organ­ cent of all cases of endocarditis.10 The ism requires coenzym e 1 (NAD or V fac­ organism is a non-m otile, non spore- tor) for growth, and its isolation in blood cultures may take up to 18 days.6 Subcul­ ture onto chocolate agar and incubation * Address reprint requests to: Ramon L. Sandin, w ith C 0 2 e n ric h m e n t, h o w e v e r, can M.D., Room 2071 Pathology Service, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magno­ accomplish isolation in 18 to 24 hours. In lia Drive, Tampa, FL 33612-9497. fact, blood cultures m ight not be recog­ 203 Introduction

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nized as positive until there is subculture to suitable agar, either chocolate agar or Fildes peptic digest of blood agar.5 Some b e h av io u rs of th is p a rtic u la r m icrobe w hich m ay contribute to a decrease in isolation rates include adherence to glass at th e g la s s -flu id in te rfa c e in b ro th cu ltu re b o ttles w ith th e form ation of “p u ffb a lls,” and affinity for erythrocytes w ith w hich it settles to th e bottom of broth b ottles.11,13 T h e a d v e n t o f e ffe c tiv e a n tib io tic therapy has decreased m ortality from this entity from 100 percent prior to 1940, to 12 percent at present.11 T he first reported cure was in a 46-year-old wom an who was treated w ith penicillin and sulfadia­ zine by H unter and D w ane.9 D uring the su b seq u en t 40 years, p enicillin G and streptom ycin or a sulfa agent w ere most often used.3 Am picillin and streptom ycin becam e the drugs of choice during the last 10 years until Calio e t al1 reported success in treatm ent w ith a long-acting c e p h a lo s p o r in . T h e s e a u th o r s a lso r e p o r t e d th e s e c o n d c a se o f b e ta lactam ase production by H. parainfluen­ zae w hich rendered the organism resis­ tant to am picillin. It is hereby reported w hat is, to our knowledge, the third case of beta-lactam ase production by an H. p a ra in flu e n za e organism in v o lv e d in endocarditis and the second case of H. parainfluenzae endocarditis w hich was successfully treated with a cephalosporin. Case Report A 36-year old school teacher had mitral valve pro­ lapse diagnosed during a routine physical examina­ tion 13 years prior to admission and subsequently confirm ed by echocardiogram . She rem ained asymptomatic and was not on any therapy except for endocarditis prophylaxis during surgical or den­ tal procedures. During the next 13 years, her only complaint was that of occasional skipped beats. Approximately two months prior to admission, the patient underwent a routine dental procedure, pre­ ceded by the appropriate dose of penicillin V approximately two hours prior to and following the procedure. Following the dental work, the patient’s

only complaint was that of anxiety and some morn­ ing nausea prior to the beginning of a new school teaching position. About one month later, the patient developed a severe febrile illness with chills, headache, and backache. This occurred two days after her son experienced a similar illness, during which she spent two nights caring for the child. She was placed on oral penicillin without response and was then hospitalized for intravenous ampicillin admin­ istration. Once the patient defervesced, she was dis­ charged on oral cefaclor, which was subsequently changed to am oxicillin/clavulanate owing to a recurrence of fevers. Blood cultures subsequently became positive for H. parainfluenzae in three out of three sets, and she was readmitted to the hospital for intravenous anti­ biotics. Pertinent physical findings during hospi­ talization had included a regular heart beat with a systolic click but without murmurs, and a single splinter hemorrhage under the left third fingernail, in an otherwise well-nourished, white lady. Remarkable laboratory findings during hospi­ talization included a white blood cell count of 2.9 with 60 percent polymorphonuclear leucocytes, 2 percent bands, 26 percent lymphocytes and 8 per­ cent eosinophils. Hemoglobin was 12.2 grams and the erythrocyte sedimentation rate was 28. Chest X ray and urinalysis were normal. Echocardiogram revealed a redundant mitral valve with marked pro­ lapse of anterior and posterior leaflets, but without vegetations. The H. parainfluenzae was betalactamase positive and sensitive to erythromycin, tetracycline, aztreonam, ampicillin/sulbactam, gentamicin, and imipenem. It was resistant to penicil­ lin, ampicillin, and clindamycin. The patient was treated with I.V. cefamandole for six weeks. She remained asymptomatic afterwards, with no evi­ dence of recurrence.

Discussion The fastidious growth requirem ents of H. parainfluenzae have m ade it a fre­ q u e n t c a u se o f “ c u ltu r e n e g a tiv e ” endocarditis, accounting for 7 to 28 per­ cent of such cases.6 The infection is usu­ ally insidious in nature and is superim ­ p o se d on pre-ex istin g cardiac lesions associated with rheum atic or congenital heart disease, prosthetic valves, or m itral valve prolapse.13 Average age of onset is the 20 to 40 year-old age group w ith a 2:1 female to male ratio.11 This differs from the 2:1 m ale to fem ale ratio reported in cases of subacute bacterial endocarditis. F req u en t findings include: duration of symptoms in two-thirds of cases of less

H. PARAINF LU ENZAE ENDOCARDITIS

th a n tw o m onths b efo re diag n o sis is m ade, febrile illness, anem ia and hem a­ turia, and petechiae occurring in 50 p er­ c e n t o f the cases.11 Roth spots, O sier nodes and Janew ay lesions are uncom ­ m on findings. Sim ilar to fungal endocarditis, large vegetations may be produced w hich may lead to major occlusive disease, as noted in 29 to 85 p e rc e n t o f p a tie n ts .1 As re p o rte d by C h u n n e t al, m icroscopy dem onstrated H. parainfluenzae growing in long mat-like chains w hich resem bled th e lo n g b r a n c h in g h y p h a e a n d /o r p se u d o h y p h a e seen w ith C andida or A s p e r g illu s .3 C e re b ro v a sc u la r em b o li account for approxim ately 57 to 66 per­ cent of em bolic events in these patients, in whom it is the leading cause of mor­ t a l i t y . 11,13 T h is c o n tr a s ts w ith th e reported 6 to 25 percent risk of peripheral em bolization in cases of subacute bacte­ rial en d o card itis caused by m ore fre­ quently isolated organisms such as the viridans streptococci.13 A nother com pli­ cation is congestive heart failure second­ ary to dam aged heart valves, w here early surgical intervention may decrease mor­ tality from 80 percent to 35 p ercent.10 This case constitutes the second report of successful treatm ent of H. parainfluen­ zae endocarditis w ith a cephalosporin, and the third report of a beta-lactam ase positive, am picillin-resistant, H. parain­ flu e n z a e . S ev eral a sp ec ts a b o u t th is p a tie n t’s p rese n tatio n w ere sim ilar to o th e r re p o rts of H. p a r a in flu e n z a e endocarditis: (1) insidious onset of dis­ ease, w ith sym ptom s first d e v elo p in g m ore than a m onth following a routine dental procedure; (2) difficulty in isolat­ in g th e o ffe n d in g o rg a n is m , w h ic h requ ired from five to seven days before growth becam e detectable; and (3) the presence of mitral valve prolapse in this patient. In one series of patients w ith e n d o c ard itis, 11 p e rc e n t of cases had m itral valve prolapse.4 That the patient’s illness coincided with a sim ilar illness in

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h er child was probably incidental given th e sp e ed of o nset o f h er sym ptom s, w hich occurred w ithin one to two days of exposure to the sick child. T his p a tie n t’s p rese n tatio n d iffered significantly from prior reports in the a b se n c e o f v a lv u la r v e g e ta tio n s an d absence of em bolization, w ith its poten­ tial for high m orbidity and mortality. As a m em ber of the “HACEK” (H aem ophilus sp., A ctinobacillus actinom ycetem com itans, Cardiobacterium h o m in is , E ikenella corrodens, and Kingella kingae) group of etiological agents, which fre q u e n tly c a u se “ c u ltu r e - n e g a tiv e ” endocarditis, H. parainfluenzae can be difficult to diagnose and may cause sig­ nificant m orbidity and possibly mortality if not recognized promptly. In the past, am picillin plus gentam icin w a s th e t r e a t m e n t o f c h o ic e fo r endocarditis caused by the “ HA CEK” group. However, beta-lactam ase produc­ ing organisms in this group are occurring more frequently, prom pting a change in treatm ent strategy which w ould include a beta-lactam ase stable cephalosporin in place of ampicillin. References 1. 2. 3. 4.

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J., CUSUMANO, S., R e i s a , F., et al.: H aem ophilus parainfluenzae endocarditis. Infect. Dis. 16:222-223, 1987. C h r i s t e n s e n , I. and H j b j e r g , T .: Prosthetic valve endocarditis caused by Haemophilus parainfluenzae. Ugeskr. Laeger 152:168, 1990. C hunn, C. J., Jones, S. R., M c C u tc h an , J. A., et al.: Haemophilus parainfluenzae infective endocarditis. Medicine 56:99-113, 1977. C o r r i g a l l , D., B o l e n , J., H a n c o c k , E . W ., and P o p p , R. L.: Mitral valve prolapse and infective endocarditis. Amer. J. Med. 63:215222, 1977. D a h l g r e n , J., T a l l y , F. P., B r o t h e r s , F. P., et al.: Haemophilus parainfluenzae endocardi­ tis. Amer. J. Clin. Pathol. 62:607, 1974. E l l n e r , J. J., R o s e n t h a l , M. S., L e r n e r , P. I ., a n d M c H e n r y , M. C .: I n fe c tiv e endocarditis caused by slow-growing, fastidi­ ous, gram-negative bacteria. Medicine 58:145158, 1979. C a l io , A.

G e r a c i , J. E ., W i l k o w s k e , C . J ., W i l s o n , W . R., etal.: Haemophilus endocarditis: Report

of 14 patients. Mayo Clin. Proc. 52:209-215, 1977.

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K., K r o n i k , G ., et al.: Haemophilus parainfluenzae endocarditis on tricuspid valve. Cardiology 71:215-219, 1984. 9. H u n t e r , T. H . and D u a n e , R. B.: Subacute bacterial endocarditis due to gram-negative organisms. J. Amer. Med. Assoc. 132:209, 1940. 10. J e m s e k , J. G ., G r e e n b e r g , S. B., G e n t r y , L. O., et al.: H aem ophilus parainfluenzae endocarditis: Two cases and review of the lit­ erature in the past decade. Amer. J. Med. 6 6 : 51-57, 1979. 11. L y n n , D. J., K a n e , J. G., and P a r k e r , R. H.: Haemophilus parainfluenzae and influenzae 8

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endocarditis: A review of forty cases. Medicine 56:115-128, 1977. 12. O l l i v i e r , P ., L a f o r , D., H a i a t , R ., and T h e r o n , J. P .: Embolic retinitis in Haemo­ philus parainfluenzae endocarditis. J. Fr. D’Ophthalmologie 24:119-122, 1991. 13. P a r k e r , S. W ., A p i c e l l a , M. A., and F u l l e r , C. M.: H a em o p h ilu s e n d o c a rd itis: Two patients with complications. Arch. Int. Med. 143:48-51, 1983. 14. R a u c h e r , B., D o b k i n , J., M a n d e l , L ., et al.: Occult polymicrobial endocarditis with Hae­ mophilus parainfluenzae in intravenous drug abusers. Amer. J. Med. 86:169-172, 1989.