Haemophilus parainfluenzae Endocarditis Twa Cases and Review of the Literature in the Past Decade
JOSEPH G. JEMSEK, M.D. STEPHEN B. GREENBERG, M.D. LAYNE 0. GENTRY, M.D. DAVID E. WELTON, M.D. KENNETH L. MATTOX, M.D. Houston, Texas
From the Departments of Medicine and Surgery, Baylor College of Medicine, and Ben Taub General Hospital, Houston, Texas. Requests for reprints should be addressed to Dr. Joseph G. Jemsek, Infectious Diseases Section, Department of Medicine, Baylor College of Medicine, 1200 Moursund Avenue, Houston, Texas 77030. Manuscript accepted August 9, 1976.
Twenty-five cases of Haemophilus parainfluenzae endocarditis have been reported in the past 10 years, providing a better current perspective of this disease. We have recently diagnosed and treated two patients with H. parainfluenzae endocarditis, and both underwent surgical intervention for complications of their disease. H. parainfluenzae and the other Haemophilus species causing endocarditis often present with a subacute course, often escape early cultural detection and mimic fungal endocarditis in the propensity for large vessel embolization. Multiple emboli and occlusion of major arterial vessels are especially notable features of H. parainfluenzae endocarditis and have occurred in approximately 30 per cent of the cases reported in the past 10 years. In contradistinction to other types of bacterial endocarditis, the most common cause of death in this series has been neurologic complications following embolization. Development of large vegetations appears to be common and may be an intrinsic property of the Haemophilus species, but it is likely that it also reflects the duration of the disease. Delay in recovery of the organism from blood cultures is characteristic of H. parainfluenzae endocarditis and may be due to the strict requirement for V factor exhibited by some strains. Echocardiography has proved useful in suggesting the diagnosis of endocarditis when blood cultures are negative. Optimal antibiotic therapy of H. parainfluenzae endocarditis has not been determined, but the reported clinical experience suggests that combination therapy with ampicillin and an aminoglycoside is the current treatment of choice. Failure to eradicate the organism after a prolonged trial of appropriate antibiotic therapy is not unusual. Indications for surgery in H. parainfluenzae endocarditis may have to be amended to include potential embolization, especially if large vegetations are demonstrated on echocardiography. The Haemophilus species are an infrequent cause of endocarditis whose clinical characteristics recently have become better appreciated. The incidence of Haemophilus species causing endocarditis has been estimated to be approximately 0.5 to 1.0 per cent [l]. However, some investigators have suggested that the detection of Haemophilus endocarditis may be increasing due to improved culture technics [z]. Endocarditis has been described for several species of Haemophilus, including parainfluenzae, aphrophilus, paraphrophilus and influenzae [Z-J]. Twenty-five cases of H. parainfluenzae endocarditis presenting a broad spectrum of clinical features have been reported since 1969 [2,3,5-111.
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The Haemophilus genus consists of small, aerobic, facultative anaerobic coccobacilli with specific nutritional requirements. Species differentiation is based on varying requirements for X and V factors, ability to hemolyze sheep red blood cells and enhanced growth in carbon dioxide [X2]. H. parainfluenzae is a normal inhabitant of the upper respiratory tract with a carriage rate of approximately 10 per cent [9]. In the past year, we have diagnosed and treated two patients with H. parainfluenzae endocarditis. These case reports as well as a review of the recent literature will emphasize the distinctive features of this increasingly recognized disease. MATERIALS
AND METHODS
Bacteriology. Vented Lederle (Lederle Diagnostic, Pearl River, New York] and unvented Columbia blood culture media (Pfizer, New York, New York) are routinely employed at Ben Taub General Hospital. Blind subcultures to chocolate and blood agar are performed at 24 hours and seven days, and routine subcultures whenever turbidity or hemolysis is first detected. Isolates from blood cultures or heart valves were inoculated on trypticase soy agar (BBL, Cockeysville, Maryland) and paper discs (Difco, Detroit, Michigan] containing X (haemin) and V (nicotinamide adenine dinucleotidej factor, respectively, were applied to the agar surface. After overnight incubation in 5 per cent carbon dioxide, H. parainfluenzae was identified by its growth requirement for V but not X factor. Differentiation of H. parainfluenzae from H. parahaemolyticus was demonstrated by the latter’s ability to hemolyze rabbit blood agar [u]. Antibiotic Susceptibility Testing. After initial isolation, attempts were made to achieve visible growth in enriched broth. Minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) with selected antibiotics were determined using standard tube dilution technics [13] with the exception of incubation in 5 per cent carbon dioxide. Serum inhibitory concentrations and serum bactericidal concentrations were also determined by standard tube dilution technic
1141. CASE REPORTS Case 1. A 35 year old black man, a parenteral drug user, who had been in previous good health presented with a four week history of malaise, easy fatigability and weight loss. The patient had also noted fever and chills during the preceding one to two weeks as well as mild dyspnea on exertion. Physical examination on admission revealed a well developed, lethargic black man who was oriented to person, place and time. Temperature was 103’F orally, pulse rate was 96/min and regular, respirations 20/min and slightly labored, and blood pressure 100/65 mm Hg. Pertinent physical findings included coarse breath sounds bilaterally without dullness or egophony. A Z/6 systolic murmur that increased with inspiration was observed at the left lower sternal border and radiated both to the base and apex. Neurologic examination revealed generalized weakness but was otherwise unremarkable. Laboratory data on admission revealed a hemoglobin level of 9.7 g/l00 ml, a hematocrit value of 31.3 per cent and a white cell count of 31,90o/mms
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Case 1. Echocardiogram of the tricuspid valve showing anterior tricuspid valve (ATV), posterior tricuspid valve (PTV) and large vegetation (VEG).
with a shift to the left. Chest roentgenogram revaled a normal cardiac silhouette with diffuse bilateral pulmonary infiltrates. The electrocardiogram showed peaked T waves in leads Vs through Ve. The urinalysis was within normal limits except for the presence of l+ proteinuria and a few granular casts. Antibiotic therapy with nafcillin and gentamicin was begun and then discontinued at 48 hours when initial blood, sputum and urine cultures were reported as showing no growth. On the fourth hospital day, an echocardiogram revealed large vegetations on the tricuspid valve (Figure 1). Candida precipitins and teichoic acid antibody studies were reported as negative. Despite negative culture data, therapy with nafcillin and gentamicin was resumed. On the eighth hospital day, ventilation-perfusion studies of the lung revealed multipIe defects compatible with pulmonary emboli. On the following day, blood cultures taken on admission and subcultured on the fourth hospital day were smear positive for a gram-negative bacillus. Antibiotic therapy was empirically changed to ampicillin, 2 g every 3 hours, and gentamicin, 80 mg every 8 hours. The organism was identified as H. parainfluenzae and eventually grew from all six blood cultures taken on admission. MICs for both ampicillin and gentamicin were 0.2 pg/ml. Serum inhibitory and bactericidal levels during ampicillin and gentamicin therapy were 1:256 and 1:128, respectively. Serum trough gentamicin levels by radioimmunoassay on three subsequent occasions were greater than 1.5 pg/ml. The patient had daily spikes in temperature often accompanied with a moderate degree of mental confusion and tachypnea. Sequential chest roentgenograms demonstrated progression of the infiltrates. A repeat echocardiogram showed a decrease in the size of the right-sided vegetation. On the 30th hospital day, a right thoracentesis removed 500 cc of sanguineous nonclotting fluid that was culture-negative. Cardiac catheterization revealed 2+ to 3+ tricuspid insufficiency. On the 36th hospital day, blood cultures drawn 10 days earlier (after 17 days of ampicillin and gentamicin therapy] grew H. parainfluenzae. Because of persistent bacteremia and evidence of extensive embolization to the lung, total resection of
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the tricuspid valve was performed [on the 39th hospital day). Large vegetations were found involving the chordae tendineae and all three cusps without evidence of a perivalvular abscess, portions of the resected valve were cultured and were positive for H. parainfluenzae. Ampicillin and gentamicin therapy was continued for five days postoperatively, and the patient was discharged in good condition on the 10th postoperative day. Several months postoperatively, he remains well despite clinical evidence of tricuspid insufficiency.
Comment: Case 1 demonstrates the failure of response to adequate antibiotic therapy (according to serum bactericidal levels) previously demonstrated in this disease (25~). In addition, this case represents the first tricuspid valvulectomy performed for endocarditis due to Haemophilus parainfluenzae. Case 2. A 25 year old Caucasian man, a parenteral drug user, presented with a two week history of fever, malaise, arthralgias, irrational behavior, dyspnea on exertion, hematuria and pedal edema. He denied orthopnea, paroxysmal nocturnal dyspnea or previous history of a heart murmur. On admission, temperature was 1036’F orally, blood pressure 110/90 mm Hg, pulse rate I2O/min and respiratory rate 22/min. Conjunctival hemorrhages and scattered petechiae were present, and he had multiple dental caries and severe gingivitis. The neck was stiff on flexion. A ventricular gallop was present with a grade 3/6 holosystolic murmur radiating from the apex to the axilla. The spleen tip was palpable. The patient had 2+ peripheral edema. Neurologic examination was within normal limits except for mild lethargy. Laboratory data on admission revealed a hemoglobin level of 10.3 g/100 ml, a hematocrit value of 31 per cent, a white blood cell count of 16,400/mm3 with a shift to the left. Serum sodium was 120 meq/liter, potassium 4.4 meq/liter. chloride 70 meq/liter, carbon dioxide 21.2 meq/liter, blood urea nitrogen 116 mg/lOO ml and creatinine 2.1 mg/lOO ml. Urinalysis revealed 2+ protein and the presence of red and white cell casts. The chest roentgenogram was clear except for cardiomegaly, and the electrocardiogram showed a sinus tachycardia. Rheumatoid factor was positive, and the serum complement was reduced to 35 mg/IOO ml (normal = 55 to 120 mg/lOO ml, radial immunodiffusion). An echocardiogram revealed a large left atrium, an enlarged left ventricle with good ventricular function and mitral- valve vegetations on the posterior mitral leaflet. A lumbar puncture revealed 13 white cells (10 polymorphonuclear cells, 3 mononuclear cells), 115 red cells, protein 20 mg/lOO ml and glucose 70 mg/lOO ml with a simultaneous blood glucose of 123 mg/lOO ml. Bacteria were not seen on gram stain, and the cerebrospinal fluid culture was negative. Antibiotic therapy was begun with nafcillin and gentamicin, and then discontinued at 48 hours when initial blood and urine cultures were reported as negative. On the fourth hospital day, H. parainfluenzae was isolated from admission blood cultures, and therapy was begun with ampicillin and gentamicin. MICs of ampicillin and gentamicin to H. parainfluenzae were both 0.2 pg/ml. Serum peak and trough bactericidal levels during ampicillin and gentamicin therapy were 1:64 and 1:64, respectively. Close monitoring of serum gentamicin levels consistently demonstrated trough levels of approximately 2 pLg/ ml.
ET AL.
Peritoneal dialysis was instituted for treatment of uremia and volume overload. On the seventh hospital day, a grand ma1 seizure occurred and was followed by a persistent right-sided Babinski reflex and depressed mental status. An electroencephalogram revealed a !eft-sided focal lesion. On the eighth hospital day, the patient underwent mitral valve resection and replacement with a Beall prosthesis, A large vegetation discovered on the posterior mitral valve leaflet was culturenegative. The early postoperative period was marked by dependence on assisted ventilation, continued lethargy and development of Pseudomonas pneumonia. On the sixth postoperative day, the patient became unresponsive and manifested bilaterally dilated pupils which were unreactive to light. On the 17th hospital day he died. Autopsy revealed an intact mitral valve prothesis, glomerulonephritis, pulmonary edema and a ruptured mycotic aneurysm in the circle of Willis. In addition, there were several small areas of hemorrhage and infarction in the brain, particularly in the region of the left temporal and frontal lobes.
Case 2 illustrates a case of malignant enComment: docarditis marked by cerebral embolization, severe glomerulonephritis and rupture of a mycotic aneurysm as the terminal event. Although historically there was only a two week prodrome, features of chronic sepsis included a positive rheumatoid factor, advanced glomerulonephritis and the presence of a mycotic aneurysm. Case z represents the first case in which surgical intervention was undertaken in H. parainfluenzae endocarditis primarily for major vessel embolization. COMMENTS Clinical Features. Delay in recovery of the organism: In the previously published cases, one distinctive aspect of H. influenzae endocarditis is delay in the recovery of the organism from blood cultures. The initial isolation in Case 1 was not made until the ninth day of hospitalization, requiring five days for visible growth on chocolate agar after being subcultured from blood on the fourth day of incubation. Standard 24hour blind subcultures were negative. The isolate in Case 2 became positive on the fourth day of incubation. In the cases reported since 1969 in which the information was clearly provided, the mean duration between the time blood cultures were drawn and the organism detected was 6.3 days for left-sided endocarditis (15 cases) and 8.5 days for right-sided endocarditis (three cases) (Table I). Review of the other cases in which this information was not specifically mentioned suggests that the mean interval may actually be slightly shorter, especially if optimal bacteriologic technic is employed. The fastidious nature of the Haemophilus species probably represents the major reason for delay in detection with routine culture methods. Haemophilus species in standard blood culture media do not attain adequate concentration to demonstrate turbidity [x5] and tend to cluster at the blood-medium interface occasionally forming “puff balls.” The blood products inoculated into the medium at the time of venipuncture
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TABLE I
PARAINFLUENZAE
ENDOCARDITIS-JEMSEK
ET AL.
Bacteriologic and Clinical Response of Patients with Haemophilus parainfluenzae Endocarditis
Intervalto
Investigator
Mortality* (no.)
Chunn [5] Lynn [3,10,11] Dahlgren [ 61 Johnson [ 7] Geraci [2] Blair [8] Jemsek
l/7 l/5 o/3 l/3 o/4 l/3 l/2
Total
5127
Detection in Blood Culturesf Cases Range (days) (so.) 6 3
1-18 4-10
4 3 2
3-13 3-4 4-9
18
mean = 6.7
Blood or Valve CulturesPositive 10 days Post Antibiotics*
Clinically Evident Major Arte ial .I (no.) Embolr
(so.)
Persistent Fevers (so.)
l/6 o/3 o/3 l/2 II4 O/l l/2
416 013 l/2 O/l II3 213 o/o
617 213 l/3 213 214 l/3 ill
317 213 o/3 l/3 l/4 013 O/l
216 O/l o/3 o/2 o/4 l/2
4121
8118
15124
7124
3118
Multiple Emboli” (so.)
Permanent Neurologic Bsficitsft (no.)
Cause of death was intracerebral hemorrhage (two), cerebral emboli (one), congestive heart failure (one) and ruptured mycotic aneurysm (one). + Cases in which serial culture data provided-three cases were from tricuspid valve involvement. T Only patients receiving accepted antibiotic therapy are included, i.e., ampicillin, ampicillin plus an aminoglycoside or ampicillin, aminoglycoside plus chloramphenicol. 5 Only patients receiving accepted antibiotics for at least 10 days and having negative cultures. ‘1Only left-sided endocarditis included-seven patients had peripheral embolic occlusions. * Only left-sided endocarditis included. ff Excludes fatal and tricuspid endocarditis cases. l
l
presumably provide a source of V factor as well as X factor. However, the medium apparently is not sufficiently enriched to support growth to the concentration of 107-lo* organisms which is required for turbidity. In addition, subculture of blood culture specimens to chocolate agar [which must not be routinely discarded at 24 or 48 hours] may be necessary to provide visible colony growth. The widely varying requirements of H. parainfluenzae for V factor may mitigate against the recovery of a more nutritionally exacting strain despite optimal culture technic. The isolates from our two patients were titrated with varying concentrations of V factor and both isolates responded to increasing concentrations with enhanced growth (Jemsek, unpublished observation). Failure of bacteriologic cure: In the cases of H. parainfluenzae endocarditis in which serial culture data were specifically mentioned, 20 per cent of the patients (four of 20) had positive blood or valve cultures after a minimum of 10 days of appropriate antibiotic therapy (Table I). Another eight patients were described as having prolonged and often hectic febrile courses while cultures remained negative during antibiotic therapy. Thus, signs of persistent infection were present in over one half of the patients in whom the information could be evaluated. Despite the expected deleterious effect of poorly controlled infection, there was no significant difference in major morbidity or mortality between those patients with persistent fever and patients who became afebrile within 10 days of appropriate antibiotic therapy. The reasons for this are not clear, but the implication is that signs of persistent infection may not be
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a useful prognostic factor. Of the four patients whose cultures were persistently positive, two underwent valvular resection and survived; both suffered extensive embolization prior to surgery [5]. The other two patients received prolonged medical therapy and survived, but they also suffered major vessel embolization [2,7]. In Case 1 the patient had positive blood cultures on the 17th day of appropriate antibiotic therapy, despite trough serum bactericidal levels of 1:128 at the time that blqod for cultures was drawn. Poor correlation with serum bactericidal levels and eradication of bacteremia in H. parainfluenzae endocarditis has been previously noted [5]. Falsely elevated serum bactericidal titers have been observed with aminoglycoside therapy using serum which had become alkaline after standing [16]. Although in vivo studies show delayed antibiotic penetration into a fibrin clot, the levels attained are generally sufficient for inhibition [l7]. This suggests that altered metabolic properties of an organism in a vegetation may be responsible for a lack of antibiotic susceptibility. Embolic events: Since 1969,63 per cent of the patients with left-sided H. parainfluenzae endocarditis (15/24) have demonstrated clinically apparent major arterial embolization [Table I). Occlusion of a major peripheral vessel or multiple emboli, an uncommon event for bacterial endocarditis in the antibiotic era [l], occurred in seven of 24 (29 per cent) cases. In the five fatal cases reported since 1969,four deaths were directly related to neurologic complications following embolization. Of the survivors for whom the information was available, another seven of 18 suffered serious neurologic im-
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pairment, and in three patients, the deficits were permanent. The propensity for major embolization seen with certain organisms, especially fungi, may relate to the large vegetations characteristically seen with these organisms [U-21].The capacity to form large vegetations may be an intrinsic property of certain organisms. For example, the filamentous, hyphal-like morphology occasionally seen with H. parainfluenzae may be especially conducive to fibrin and platelet thrombus formation. The absence of fibrinolysin in other organisms has also been implicated as predisposing to formation of large vegetations [zz]. Physical factors have been demonstrated to be important in the genesis of a platelet and fibrin nidus on a diseased valve, and may play an important role in the propagation of the established thrombus [18]. It is also likely, however, that the duration of illness is one of the factors which determines vegetation size. Although serial echocardiographic studies of a variety of organisms in endocarditis have not as yet confirmed the relationship [23], support for this premise is indirectly provided by the reduced incidence of major embolization in endocarditis with the advent of the antibiotic era [l&19]. Valves affected-predisposing factors: Underlying heart disease has been suggested to be a prerequisite for development of H. parainfluenzae endocarditis [1,7]. However, the reported experience in the past 10 years shows that this feature is present in only 48 per cent of the cases. Although H. parainfluenzae is generally regarded as causing a subacute form of endocarditis, the ability to attack normal valves, and especially the tricuspid valve, attests to the virulence of the organism. Isolated tricuspid endocarditis with H. parainfluenzae has now been reported in three patients accounting for 11 per cent of the cases since 1969. Intravenous drug abuse, a positive historic feature in both of our patients, has now been seen in two of the three cases of isolated tricuspid endocarditis with H. parainfluenzae [3]. Echocardiography. As demonstrated in Case 1,the echocardiogram may identify vegetations before the diagnosis of endocarditis is even suspected [23] and can support the diagnosis of endocarditis in the absence of positive blood cultures [~a]. In contrast, cardiac cathete ization has proved unreliable in the demonstration of vegetations [26]. In selected reviews of positive echocardiograms in endocarditis, as many as 90 per cent of the patients died or required surgery for refractive congestive heart failure [23,25,27] and approximately 60 per cent sustained large vessel embolization [23,28]. Some investigators have noted an inverse relationship between the size of the vegetation seen on echocardiography and favorable clinical response [8], but this correlation has not been adequately substantiated. During the course of endocarditis, some vegetations become more dense with healing and calcification whereas others do not change [23,28]. In Case 1, the vegetation actually di-
PARAINFLUENZAE
ENDOCARDITIS-]EMSEK
ET AL.
minished in size as the patient’s condition steadily deteriorated. This presumably represented, fragmentation and subsequent embolization of the vegetation. Including the two cases reported in this paper, five patients with H. parainfluenzae endocarditis have had echocardiograms, and vegetations were identified in four cases. Although little echocardiographic data have been collected in cases of endocarditis due to other gram-negative organisms, the 80 per cent incidence of vegetations seen with H. parainfluenzae is much higher than that reported for a variety of gram-positive organisms [23]. The one patient who did not have evidence for a vegetation on an echocardiogram was also the only patient who did not suffer large vessel embolization. In addition, three of four patients with vegetations demonstrated by echocardiography underwent surgery. Thus, in this small series it appears that the presence of echocardiographic vegetations in H. parainfluenzae correlates with the potential for embolization and the need for eventual surgical intervention. Therapy. Recommendations for medical therapy: Because there have been no large series of cases at any single institution, no definitive recommendations can be made as to optimal antibiotic therapy in H. parainfluenzae endocarditis. In the past 10 years, successful antibiotic therapy has been reported with ampicillin alone [5-81. In addition, cures in isolated cases have been reported with ampicillin, gentamicin and chloramphenicol in combination [5], tetracycline and streptomycin [3], and cephalothin and chloramphenicol[5]. Although in vitro sensitivity by disc diffusion is invariably demonstrated, treatment of H. parainfluenzae endocarditis with chloramphenicol as a single agent has been disappointing [9,12]. Of the four antibiotic failures listed in Table I, prolonged therapy with ampicillin alone was utilized in two [5,7], ampicillin and streptomycin in one [2], and in our first case a total of 30 days of therapy with ampicillin and gentamicin. Despite these treatment failures with combination ampicillin and aminoglycoside therapy, the current consensus favors ampicillin plus gentamicin for initial therapy. The addition of an aminoglycoside following several days of penicillin therapy has been noted to markedly improve the clinical course in several instances [5,10]. In addition, killing curves performed on two isolates showed combination ampicillin and gentamicin therapy to be superior to ampicillin therapy alone [5]. Some investigators, however, maintain that ampicillin alone is adequate initial therapy [2]. In vitro sensitivities of H. parainfluenzae to a wide variety of antibiotics has recently been reported [29]. Fifty strains were randomly collected from the oropharynx of healthy volunteers. Three of 50 isolates resistant to ampicillin (MIC greater than 8 Mg/ml) were shown to possess beta-lactamase. Gentamicin inhibited all strains at 1 pg/ml whereas chloramphenicol inhibited all strains at 2 pg/ml. Carbenicillin was the most effective antibiotic inhibiting 88 per cent of strains at 0.03
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pg/ml. Based on the current data, however, treatment with ampicillin and gentamicin should be initiated unless this combination is shown by killing curves to be inferior to ampicillin alone or if the clinical course is judged to be so benign as to obviate the addition of an aminoglycoside. Antibiotic therapy for the penicillinallergic patient remains a serious problem, particularly in view of the poor experience with chloramphenicol as single agent therapy. An aminoglycoside in addition to another agent should probably be administered and serious consideration given for penicillin desensitization. Indications for surgical therapy: The current indications for surgery in endocarditis include congestive heart failure, major or repeated embolization, persistent infection or a combination of these [30-361. Congestive heart failure currently represents the leading cause for surgical intervention and is the reason for surgery in 50 to 90 per cent of the patients [31,32,36]. Surgical intervention has reduced the mortality of severe heart failure due to acute valvular insufficiency in endocarditis from 80 per cent to less than 35 per cent [31,36]. Boyd et al. [3l] make a strong point for early surgical intervention in those cases with clinically uncontrolled infection or embolization. In a collection of 175 cases, 16 patients who had bacterial endocardjtis on nonprosthetic valves were considered to have clinically uncontrolled sepsis. In the assessment of early and late surgical intervention for continued sepsis (all patients treated medically at least 10 days), a marked increase in mortality was observed for those patients in whom surgery was deferred until four to six weeks of antibiotic therapy had been completed. Excluding our cases, only three patients with H. parainfluenzae endocarditis have undergone valvular surgery for complications related to the infection. The indicatioas for surgery in two of these patients was congestive heart failure [5,7] whereas the other patient had an antibiotic failure involving a prosthetic valve [5]. Despite the high incidence of repeated embolization and its attendant morbidity and mortality in this disease, Case 2 represents the first instance in which the primary reason for surgery was an embolic event. The mortality rate in those patients with
ET AL.
major embolic events who did not undergo surgery was 25 per cent [3 of 121, and in two fatal cases multiple emboli were involved. Another three patients in this category suffered permanent neurologic sequelae on medical therapy alone. Two of the five patients in whom surgery has been formed have died postoperatively, one with irreversible complications of multiple emboli and renal failure [7] and.the other [Case 2) with a ruptured mycotic aneurysm. Central nervous system embolization was the major factor in determining the course in seven of the eight patients who either died or suffered permanent neurologic deficits [5,7,8,11]. Critical review of these cases suggests that early surgical intervention in five patients (two with permanent neurologic sequelae, three with fatal cases] could have possibly avoided the complications encountered [5,8,11]. Hazards of surgical intervention are appreciable, exposing the patient to intraoperative and postoperative complications as well as the lifelong risks associated with a prosthetic valve. Most surgical data, however, are based on subjects with suboptimal hemodynamic status, and there are no carefully controlled studies reported which assess the feasibility of surgical intervention in those cases of endocarditis in which a high risk for major embolization is recognized. Further experience with echocardiography or other devices in the study of H. parainfluenzae and other types of endocarditis may eventually allow the prediction of which patients are at high risk for embolization. This would then provide a more rational approach to selection of patients as candidates for surgery. ACKNOWLEDGMENT We gratefully acknowledge the technical assistance of Edward Mason, Ph.D. and the critical review and encouragement of R. Russell Martin, M.D. This research was supported by research grants from the National Institutes of Health [CA-15784 and HL16938) and a grant from the Council for Tobacco Research ( #ICKM). Computational assistance was provided by the CLINFO project and funded by National Institutes of Health Division of Research Resources, Contract NOl-RR-5-2188.
REFERENCES 1. Weinstein L. Rubin RH: Infective endocarditis-1973. Prog Cardiovasc Dis 16:239,1973. 2. Geraci JE, Wilkowske CJ. Wilson WR, et al.: Haemophilus endocarditis. Report of 14 cases. Mayo Clinic Proc 52: 209. 1977. 3. Lynn DJ, Kane JG, Parker RH: Haemophilus parainfluenzae and influenzae endocarditis. A review of 40 cases. Meditine [Baltimore) 56: 115,1977. 4. Elster SK, Mattes LM, Meyers BR, et al.: Haemophilus aphrophilus endocarditis. Review of 23 cases. Am J Cardiol 35: 72, 1975. 5. Chunn CJ. Jones SR. McCutchan JA, et al.: Haemophilus parainfluenzae infective endocarditis. Medicine (Baltimore) 56: 99, 1977. 6. Dahlgren J. Tally FP. Brother G, et al.: Haemophilus par-
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ainfluenzae endocarditis. Am 1Clin Path 62: 807, 1974. RH, Kcnncdy RP. Marton KI, et al.: Hacmophilus endocarditis. New cases, literature review and recommendations for management. S Med J 70: 1098, 1977. Blair DC, Walker W, Sodeman T, et al: Bacterial endocarditis due to Haemophilus parainfluenzae. Chest 71: 146,1977. Hable KA, Logan GB, Washington II ]A: Three haemophilus species-pathogenic activity. Am J Dis Child 121: 35, 1971. Gordon AM, Love WC: Endocarditis due to Haemophilus parainfluenzae. J Med Microbial 3: 550,197O. Hodge JLR, Brenner DA: Haemophilus endocarditis and the isolation of haemophilic bacteria in blood culture-case report. N 2 Med J 79: 824, 1974.
7. Johnson
8. 9. 10. 11.
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12.
13. 14.
15. 16.
17.
18.
Young VM: Haemophilus, in Manual of Clinical Microbiology, Second Edition [Lennette EH, Spaulding EH, Traunt JP, eds). Washington, D.C., American Society for Microbiology, 1974. Barry AL: Methods for Testing Antimicrobic Combinations, in The Antimicrobic Susceptibility Test: Principles and Practices. 1st ed, Philadelphia, Lea and Febiger, 1976. Schlichter JG, Maclean H: A method of determining the effective therapeutic level in the treatment of subacute bacterial endocarditis with penicillin. Am Heart J 34: 209, 1947. Wallace RI. Musher DM. Martin RR: Haemoohilus influenzae’pneumonia in adults. Am J Med 64: S?‘,1978. Brvan CS. Marnev SR, Alford RH. et al.: Gram-negative bacillary endocarditis-Interpretation of the seru; bactericidal test. Am J Med 58: 209, 1975. Barza M, Samuelson T, Weinstein L: Penetration of antibiotics into fibrin loci in vivo. II Comparison of nine antibiotics: Effect of dose and degree of protein binding. J Inf Dis 129: 66. 1974. Weinstein L. Schlesinger JJ: Pathoanatomic. pathophysiologic and clinical correlations in endocarditis. N Enell Med 291: 1122,1974. Cherubin CE. Neu HC: Infective endocarditis at the Presbyterian Hospital in New York City from 1938-1967. Am I Med 51: 83.1971. Gdmes JAC. Calderon J, Lejam F, et al.: Echocardiographic detection of funnal vegetations in Candida naraosilosis endocarditis. Am J Med 61: 273.1976. ’ ’ Gottlieb S, Khuddus SA, Balooki H. et al.: Echocardiographic diagnosis of aortic valve vegetations in Candida endocarditis. Circulation 50: 826, 1974. Vilde JL, Roujeau JC, Bure A, et al.: Severe infection and septicemia due to Group B streptococci in adults. Sem Hop P&is 50: 355,1974. _ Wann LS, Dillon JC, Wagmann AE, et al.: Echocardiography in bacterial endocarditis. N Engl J Med 295: 135, 1976. Gleckman R: Culture negative cndocarditis: confirming the v
19. 20. 21. 22. 23. 24.
diagnosis. Am Heart J 94: 125, 1977. 25. Andy JJ. Shiekh MN, Wagab A, et al.: Echocardiographic observation in opiate addicts with active infective endocarditis-frequency of involvement in various valves and comparison of echocardiographic features of right- and left-sided cardiac valve endocarditis. Am J Cardiol40: 17, 1977. 26. 27. 28.
29.
30.
31.
I
32.
Mills J, Abbott J, Utley JR, et al.: Role of cardiac catheterization in infective endocarditis. Chest 72: 576, 1977. Sutton R. Petih M, Parker J: Echocardiography in infective endocarditis. Proc Br Cardiac Sot 38: 312,1976. Roy P, Tajik AJ. Giuliani ER, et al.: Spectrum of echocardiographic findings in bacterial endocarditis. Circulation 53: 474, 1976. Mayo JB, McCarthy LR: Antimicrobial susceptibility of Haemophilus parainfluenzae. Antimicrob Agents Chemotheril: 844; 1977. Black S, O’Rourke RA, Karliner JS: Role of surgery in the treatment of primary infective endocarditis. Am J Med 56: 357,1974. Boyd AD, Spencer FC. Isom WO, et al.: Infective endocarditis-An analysis of 54 surgically treated patients. J Thorac Cardiovasc Surg 73: 23.1977. Manhas DR, Mohri H, Hessel EA. et al.: Experience with surgical management of primary infective endocarditis. A collected review of 139 patients. Am Heart J 84: 738, 1972.
33.
Okies JE, Williams TW. Howell JF, et al.: Valvular replacement in bacterial endocarditis. Card Res Ctr Bulletin 8: 126.
34.
Okies IE. Bradshaw MW. Williams TW: Valve renlacement in becterial endocarditis. Chest 63: 898, 1973. . Mills I, Utlev J, Abbott J: Heart failure in infective endocarditis: predisposing factors, course and treatment. Chest 65:
1970.
35.
151,1974.
36. Parrott JC, Hill JD, Keith WJ. et al.: The surgical management of bacterial endocarditis-a review. Ann Surg 183: 289, 1976.
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JOSEPH G. JEMSEK, M.D. STEPHEN B. GREENBERG, M.D. LAYNE 0. GENTRY, M.D. DAVID E. WELTON, M.D. KENNETH L. MATTOX, M.D. Houston, Texas
From the Departments of Medicine and Surgery, Baylor College of Medicine, and Ben Taub General Hospital, Houston, Texas. Requests for reprints should be addressed to Dr. Joseph G. Jemsek, Infectious Diseases Section, Department of Medicine, Baylor College of Medicine, 1200 Moursund Avenue, Houston, Texas 77030. Manuscript accepted August 9, 1976.
Twenty-five cases of Haemophilus parainfluenzae endocarditis have been reported in the past 10 years, providing a better current perspective of this disease. We have recently diagnosed and treated two patients with H. parainfluenzae endocarditis, and both underwent surgical intervention for complications of their disease. H. parainfluenzae and the other Haemophilus species causing endocarditis often present with a subacute course, often escape early cultural detection and mimic fungal endocarditis in the propensity for large vessel embolization. Multiple emboli and occlusion of major arterial vessels are especially notable features of H. parainfluenzae endocarditis and have occurred in approximately 30 per cent of the cases reported in the past 10 years. In contradistinction to other types of bacterial endocarditis, the most common cause of death in this series has been neurologic complications following embolization. Development of large vegetations appears to be common and may be an intrinsic property of the Haemophilus species, but it is likely that it also reflects the duration of the disease. Delay in recovery of the organism from blood cultures is characteristic of H. parainfluenzae endocarditis and may be due to the strict requirement for V factor exhibited by some strains. Echocardiography has proved useful in suggesting the diagnosis of endocarditis when blood cultures are negative. Optimal antibiotic therapy of H. parainfluenzae endocarditis has not been determined, but the reported clinical experience suggests that combination therapy with ampicillin and an aminoglycoside is the current treatment of choice. Failure to eradicate the organism after a prolonged trial of appropriate antibiotic therapy is not unusual. Indications for surgery in H. parainfluenzae endocarditis may have to be amended to include potential embolization, especially if large vegetations are demonstrated on echocardiography. The Haemophilus species are an infrequent cause of endocarditis whose clinical characteristics recently have become better appreciated. The incidence of Haemophilus species causing endocarditis has been estimated to be approximately 0.5 to 1.0 per cent [l]. However, some investigators have suggested that the detection of Haemophilus endocarditis may be increasing due to improved culture technics [z]. Endocarditis has been described for several species of Haemophilus, including parainfluenzae, aphrophilus, paraphrophilus and influenzae [Z-J]. Twenty-five cases of H. parainfluenzae endocarditis presenting a broad spectrum of clinical features have been reported since 1969 [2,3,5-111.
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PARAINFLUENZAE
ENDOCARDITIS-JEMSEK
ET AL.
The Haemophilus genus consists of small, aerobic, facultative anaerobic coccobacilli with specific nutritional requirements. Species differentiation is based on varying requirements for X and V factors, ability to hemolyze sheep red blood cells and enhanced growth in carbon dioxide [X2]. H. parainfluenzae is a normal inhabitant of the upper respiratory tract with a carriage rate of approximately 10 per cent [9]. In the past year, we have diagnosed and treated two patients with H. parainfluenzae endocarditis. These case reports as well as a review of the recent literature will emphasize the distinctive features of this increasingly recognized disease. MATERIALS
AND METHODS
Bacteriology. Vented Lederle (Lederle Diagnostic, Pearl River, New York] and unvented Columbia blood culture media (Pfizer, New York, New York) are routinely employed at Ben Taub General Hospital. Blind subcultures to chocolate and blood agar are performed at 24 hours and seven days, and routine subcultures whenever turbidity or hemolysis is first detected. Isolates from blood cultures or heart valves were inoculated on trypticase soy agar (BBL, Cockeysville, Maryland) and paper discs (Difco, Detroit, Michigan] containing X (haemin) and V (nicotinamide adenine dinucleotidej factor, respectively, were applied to the agar surface. After overnight incubation in 5 per cent carbon dioxide, H. parainfluenzae was identified by its growth requirement for V but not X factor. Differentiation of H. parainfluenzae from H. parahaemolyticus was demonstrated by the latter’s ability to hemolyze rabbit blood agar [u]. Antibiotic Susceptibility Testing. After initial isolation, attempts were made to achieve visible growth in enriched broth. Minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) with selected antibiotics were determined using standard tube dilution technics [13] with the exception of incubation in 5 per cent carbon dioxide. Serum inhibitory concentrations and serum bactericidal concentrations were also determined by standard tube dilution technic
1141. CASE REPORTS Case 1. A 35 year old black man, a parenteral drug user, who had been in previous good health presented with a four week history of malaise, easy fatigability and weight loss. The patient had also noted fever and chills during the preceding one to two weeks as well as mild dyspnea on exertion. Physical examination on admission revealed a well developed, lethargic black man who was oriented to person, place and time. Temperature was 103’F orally, pulse rate was 96/min and regular, respirations 20/min and slightly labored, and blood pressure 100/65 mm Hg. Pertinent physical findings included coarse breath sounds bilaterally without dullness or egophony. A Z/6 systolic murmur that increased with inspiration was observed at the left lower sternal border and radiated both to the base and apex. Neurologic examination revealed generalized weakness but was otherwise unremarkable. Laboratory data on admission revealed a hemoglobin level of 9.7 g/l00 ml, a hematocrit value of 31.3 per cent and a white cell count of 31,90o/mms
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Case 1. Echocardiogram of the tricuspid valve showing anterior tricuspid valve (ATV), posterior tricuspid valve (PTV) and large vegetation (VEG).
with a shift to the left. Chest roentgenogram revaled a normal cardiac silhouette with diffuse bilateral pulmonary infiltrates. The electrocardiogram showed peaked T waves in leads Vs through Ve. The urinalysis was within normal limits except for the presence of l+ proteinuria and a few granular casts. Antibiotic therapy with nafcillin and gentamicin was begun and then discontinued at 48 hours when initial blood, sputum and urine cultures were reported as showing no growth. On the fourth hospital day, an echocardiogram revealed large vegetations on the tricuspid valve (Figure 1). Candida precipitins and teichoic acid antibody studies were reported as negative. Despite negative culture data, therapy with nafcillin and gentamicin was resumed. On the eighth hospital day, ventilation-perfusion studies of the lung revealed multipIe defects compatible with pulmonary emboli. On the following day, blood cultures taken on admission and subcultured on the fourth hospital day were smear positive for a gram-negative bacillus. Antibiotic therapy was empirically changed to ampicillin, 2 g every 3 hours, and gentamicin, 80 mg every 8 hours. The organism was identified as H. parainfluenzae and eventually grew from all six blood cultures taken on admission. MICs for both ampicillin and gentamicin were 0.2 pg/ml. Serum inhibitory and bactericidal levels during ampicillin and gentamicin therapy were 1:256 and 1:128, respectively. Serum trough gentamicin levels by radioimmunoassay on three subsequent occasions were greater than 1.5 pg/ml. The patient had daily spikes in temperature often accompanied with a moderate degree of mental confusion and tachypnea. Sequential chest roentgenograms demonstrated progression of the infiltrates. A repeat echocardiogram showed a decrease in the size of the right-sided vegetation. On the 30th hospital day, a right thoracentesis removed 500 cc of sanguineous nonclotting fluid that was culture-negative. Cardiac catheterization revealed 2+ to 3+ tricuspid insufficiency. On the 36th hospital day, blood cultures drawn 10 days earlier (after 17 days of ampicillin and gentamicin therapy] grew H. parainfluenzae. Because of persistent bacteremia and evidence of extensive embolization to the lung, total resection of
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the tricuspid valve was performed [on the 39th hospital day). Large vegetations were found involving the chordae tendineae and all three cusps without evidence of a perivalvular abscess, portions of the resected valve were cultured and were positive for H. parainfluenzae. Ampicillin and gentamicin therapy was continued for five days postoperatively, and the patient was discharged in good condition on the 10th postoperative day. Several months postoperatively, he remains well despite clinical evidence of tricuspid insufficiency.
Comment: Case 1 demonstrates the failure of response to adequate antibiotic therapy (according to serum bactericidal levels) previously demonstrated in this disease (25~). In addition, this case represents the first tricuspid valvulectomy performed for endocarditis due to Haemophilus parainfluenzae. Case 2. A 25 year old Caucasian man, a parenteral drug user, presented with a two week history of fever, malaise, arthralgias, irrational behavior, dyspnea on exertion, hematuria and pedal edema. He denied orthopnea, paroxysmal nocturnal dyspnea or previous history of a heart murmur. On admission, temperature was 1036’F orally, blood pressure 110/90 mm Hg, pulse rate I2O/min and respiratory rate 22/min. Conjunctival hemorrhages and scattered petechiae were present, and he had multiple dental caries and severe gingivitis. The neck was stiff on flexion. A ventricular gallop was present with a grade 3/6 holosystolic murmur radiating from the apex to the axilla. The spleen tip was palpable. The patient had 2+ peripheral edema. Neurologic examination was within normal limits except for mild lethargy. Laboratory data on admission revealed a hemoglobin level of 10.3 g/100 ml, a hematocrit value of 31 per cent, a white blood cell count of 16,400/mm3 with a shift to the left. Serum sodium was 120 meq/liter, potassium 4.4 meq/liter. chloride 70 meq/liter, carbon dioxide 21.2 meq/liter, blood urea nitrogen 116 mg/lOO ml and creatinine 2.1 mg/lOO ml. Urinalysis revealed 2+ protein and the presence of red and white cell casts. The chest roentgenogram was clear except for cardiomegaly, and the electrocardiogram showed a sinus tachycardia. Rheumatoid factor was positive, and the serum complement was reduced to 35 mg/IOO ml (normal = 55 to 120 mg/lOO ml, radial immunodiffusion). An echocardiogram revealed a large left atrium, an enlarged left ventricle with good ventricular function and mitral- valve vegetations on the posterior mitral leaflet. A lumbar puncture revealed 13 white cells (10 polymorphonuclear cells, 3 mononuclear cells), 115 red cells, protein 20 mg/lOO ml and glucose 70 mg/lOO ml with a simultaneous blood glucose of 123 mg/lOO ml. Bacteria were not seen on gram stain, and the cerebrospinal fluid culture was negative. Antibiotic therapy was begun with nafcillin and gentamicin, and then discontinued at 48 hours when initial blood and urine cultures were reported as negative. On the fourth hospital day, H. parainfluenzae was isolated from admission blood cultures, and therapy was begun with ampicillin and gentamicin. MICs of ampicillin and gentamicin to H. parainfluenzae were both 0.2 pg/ml. Serum peak and trough bactericidal levels during ampicillin and gentamicin therapy were 1:64 and 1:64, respectively. Close monitoring of serum gentamicin levels consistently demonstrated trough levels of approximately 2 pLg/ ml.
ET AL.
Peritoneal dialysis was instituted for treatment of uremia and volume overload. On the seventh hospital day, a grand ma1 seizure occurred and was followed by a persistent right-sided Babinski reflex and depressed mental status. An electroencephalogram revealed a !eft-sided focal lesion. On the eighth hospital day, the patient underwent mitral valve resection and replacement with a Beall prosthesis, A large vegetation discovered on the posterior mitral valve leaflet was culturenegative. The early postoperative period was marked by dependence on assisted ventilation, continued lethargy and development of Pseudomonas pneumonia. On the sixth postoperative day, the patient became unresponsive and manifested bilaterally dilated pupils which were unreactive to light. On the 17th hospital day he died. Autopsy revealed an intact mitral valve prothesis, glomerulonephritis, pulmonary edema and a ruptured mycotic aneurysm in the circle of Willis. In addition, there were several small areas of hemorrhage and infarction in the brain, particularly in the region of the left temporal and frontal lobes.
Case 2 illustrates a case of malignant enComment: docarditis marked by cerebral embolization, severe glomerulonephritis and rupture of a mycotic aneurysm as the terminal event. Although historically there was only a two week prodrome, features of chronic sepsis included a positive rheumatoid factor, advanced glomerulonephritis and the presence of a mycotic aneurysm. Case z represents the first case in which surgical intervention was undertaken in H. parainfluenzae endocarditis primarily for major vessel embolization. COMMENTS Clinical Features. Delay in recovery of the organism: In the previously published cases, one distinctive aspect of H. influenzae endocarditis is delay in the recovery of the organism from blood cultures. The initial isolation in Case 1 was not made until the ninth day of hospitalization, requiring five days for visible growth on chocolate agar after being subcultured from blood on the fourth day of incubation. Standard 24hour blind subcultures were negative. The isolate in Case 2 became positive on the fourth day of incubation. In the cases reported since 1969 in which the information was clearly provided, the mean duration between the time blood cultures were drawn and the organism detected was 6.3 days for left-sided endocarditis (15 cases) and 8.5 days for right-sided endocarditis (three cases) (Table I). Review of the other cases in which this information was not specifically mentioned suggests that the mean interval may actually be slightly shorter, especially if optimal bacteriologic technic is employed. The fastidious nature of the Haemophilus species probably represents the major reason for delay in detection with routine culture methods. Haemophilus species in standard blood culture media do not attain adequate concentration to demonstrate turbidity [x5] and tend to cluster at the blood-medium interface occasionally forming “puff balls.” The blood products inoculated into the medium at the time of venipuncture
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HAEMOPHILUS
TABLE I
PARAINFLUENZAE
ENDOCARDITIS-JEMSEK
ET AL.
Bacteriologic and Clinical Response of Patients with Haemophilus parainfluenzae Endocarditis
Intervalto
Investigator
Mortality* (no.)
Chunn [5] Lynn [3,10,11] Dahlgren [ 61 Johnson [ 7] Geraci [2] Blair [8] Jemsek
l/7 l/5 o/3 l/3 o/4 l/3 l/2
Total
5127
Detection in Blood Culturesf Cases Range (days) (so.) 6 3
1-18 4-10
4 3 2
3-13 3-4 4-9
18
mean = 6.7
Blood or Valve CulturesPositive 10 days Post Antibiotics*
Clinically Evident Major Arte ial .I (no.) Embolr
(so.)
Persistent Fevers (so.)
l/6 o/3 o/3 l/2 II4 O/l l/2
416 013 l/2 O/l II3 213 o/o
617 213 l/3 213 214 l/3 ill
317 213 o/3 l/3 l/4 013 O/l
216 O/l o/3 o/2 o/4 l/2
4121
8118
15124
7124
3118
Multiple Emboli” (so.)
Permanent Neurologic Bsficitsft (no.)
Cause of death was intracerebral hemorrhage (two), cerebral emboli (one), congestive heart failure (one) and ruptured mycotic aneurysm (one). + Cases in which serial culture data provided-three cases were from tricuspid valve involvement. T Only patients receiving accepted antibiotic therapy are included, i.e., ampicillin, ampicillin plus an aminoglycoside or ampicillin, aminoglycoside plus chloramphenicol. 5 Only patients receiving accepted antibiotics for at least 10 days and having negative cultures. ‘1Only left-sided endocarditis included-seven patients had peripheral embolic occlusions. * Only left-sided endocarditis included. ff Excludes fatal and tricuspid endocarditis cases. l
l
presumably provide a source of V factor as well as X factor. However, the medium apparently is not sufficiently enriched to support growth to the concentration of 107-lo* organisms which is required for turbidity. In addition, subculture of blood culture specimens to chocolate agar [which must not be routinely discarded at 24 or 48 hours] may be necessary to provide visible colony growth. The widely varying requirements of H. parainfluenzae for V factor may mitigate against the recovery of a more nutritionally exacting strain despite optimal culture technic. The isolates from our two patients were titrated with varying concentrations of V factor and both isolates responded to increasing concentrations with enhanced growth (Jemsek, unpublished observation). Failure of bacteriologic cure: In the cases of H. parainfluenzae endocarditis in which serial culture data were specifically mentioned, 20 per cent of the patients (four of 20) had positive blood or valve cultures after a minimum of 10 days of appropriate antibiotic therapy (Table I). Another eight patients were described as having prolonged and often hectic febrile courses while cultures remained negative during antibiotic therapy. Thus, signs of persistent infection were present in over one half of the patients in whom the information could be evaluated. Despite the expected deleterious effect of poorly controlled infection, there was no significant difference in major morbidity or mortality between those patients with persistent fever and patients who became afebrile within 10 days of appropriate antibiotic therapy. The reasons for this are not clear, but the implication is that signs of persistent infection may not be
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a useful prognostic factor. Of the four patients whose cultures were persistently positive, two underwent valvular resection and survived; both suffered extensive embolization prior to surgery [5]. The other two patients received prolonged medical therapy and survived, but they also suffered major vessel embolization [2,7]. In Case 1 the patient had positive blood cultures on the 17th day of appropriate antibiotic therapy, despite trough serum bactericidal levels of 1:128 at the time that blqod for cultures was drawn. Poor correlation with serum bactericidal levels and eradication of bacteremia in H. parainfluenzae endocarditis has been previously noted [5]. Falsely elevated serum bactericidal titers have been observed with aminoglycoside therapy using serum which had become alkaline after standing [16]. Although in vivo studies show delayed antibiotic penetration into a fibrin clot, the levels attained are generally sufficient for inhibition [l7]. This suggests that altered metabolic properties of an organism in a vegetation may be responsible for a lack of antibiotic susceptibility. Embolic events: Since 1969,63 per cent of the patients with left-sided H. parainfluenzae endocarditis (15/24) have demonstrated clinically apparent major arterial embolization [Table I). Occlusion of a major peripheral vessel or multiple emboli, an uncommon event for bacterial endocarditis in the antibiotic era [l], occurred in seven of 24 (29 per cent) cases. In the five fatal cases reported since 1969,four deaths were directly related to neurologic complications following embolization. Of the survivors for whom the information was available, another seven of 18 suffered serious neurologic im-
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pairment, and in three patients, the deficits were permanent. The propensity for major embolization seen with certain organisms, especially fungi, may relate to the large vegetations characteristically seen with these organisms [U-21].The capacity to form large vegetations may be an intrinsic property of certain organisms. For example, the filamentous, hyphal-like morphology occasionally seen with H. parainfluenzae may be especially conducive to fibrin and platelet thrombus formation. The absence of fibrinolysin in other organisms has also been implicated as predisposing to formation of large vegetations [zz]. Physical factors have been demonstrated to be important in the genesis of a platelet and fibrin nidus on a diseased valve, and may play an important role in the propagation of the established thrombus [18]. It is also likely, however, that the duration of illness is one of the factors which determines vegetation size. Although serial echocardiographic studies of a variety of organisms in endocarditis have not as yet confirmed the relationship [23], support for this premise is indirectly provided by the reduced incidence of major embolization in endocarditis with the advent of the antibiotic era [l&19]. Valves affected-predisposing factors: Underlying heart disease has been suggested to be a prerequisite for development of H. parainfluenzae endocarditis [1,7]. However, the reported experience in the past 10 years shows that this feature is present in only 48 per cent of the cases. Although H. parainfluenzae is generally regarded as causing a subacute form of endocarditis, the ability to attack normal valves, and especially the tricuspid valve, attests to the virulence of the organism. Isolated tricuspid endocarditis with H. parainfluenzae has now been reported in three patients accounting for 11 per cent of the cases since 1969. Intravenous drug abuse, a positive historic feature in both of our patients, has now been seen in two of the three cases of isolated tricuspid endocarditis with H. parainfluenzae [3]. Echocardiography. As demonstrated in Case 1,the echocardiogram may identify vegetations before the diagnosis of endocarditis is even suspected [23] and can support the diagnosis of endocarditis in the absence of positive blood cultures [~a]. In contrast, cardiac cathete ization has proved unreliable in the demonstration of vegetations [26]. In selected reviews of positive echocardiograms in endocarditis, as many as 90 per cent of the patients died or required surgery for refractive congestive heart failure [23,25,27] and approximately 60 per cent sustained large vessel embolization [23,28]. Some investigators have noted an inverse relationship between the size of the vegetation seen on echocardiography and favorable clinical response [8], but this correlation has not been adequately substantiated. During the course of endocarditis, some vegetations become more dense with healing and calcification whereas others do not change [23,28]. In Case 1, the vegetation actually di-
PARAINFLUENZAE
ENDOCARDITIS-]EMSEK
ET AL.
minished in size as the patient’s condition steadily deteriorated. This presumably represented, fragmentation and subsequent embolization of the vegetation. Including the two cases reported in this paper, five patients with H. parainfluenzae endocarditis have had echocardiograms, and vegetations were identified in four cases. Although little echocardiographic data have been collected in cases of endocarditis due to other gram-negative organisms, the 80 per cent incidence of vegetations seen with H. parainfluenzae is much higher than that reported for a variety of gram-positive organisms [23]. The one patient who did not have evidence for a vegetation on an echocardiogram was also the only patient who did not suffer large vessel embolization. In addition, three of four patients with vegetations demonstrated by echocardiography underwent surgery. Thus, in this small series it appears that the presence of echocardiographic vegetations in H. parainfluenzae correlates with the potential for embolization and the need for eventual surgical intervention. Therapy. Recommendations for medical therapy: Because there have been no large series of cases at any single institution, no definitive recommendations can be made as to optimal antibiotic therapy in H. parainfluenzae endocarditis. In the past 10 years, successful antibiotic therapy has been reported with ampicillin alone [5-81. In addition, cures in isolated cases have been reported with ampicillin, gentamicin and chloramphenicol in combination [5], tetracycline and streptomycin [3], and cephalothin and chloramphenicol[5]. Although in vitro sensitivity by disc diffusion is invariably demonstrated, treatment of H. parainfluenzae endocarditis with chloramphenicol as a single agent has been disappointing [9,12]. Of the four antibiotic failures listed in Table I, prolonged therapy with ampicillin alone was utilized in two [5,7], ampicillin and streptomycin in one [2], and in our first case a total of 30 days of therapy with ampicillin and gentamicin. Despite these treatment failures with combination ampicillin and aminoglycoside therapy, the current consensus favors ampicillin plus gentamicin for initial therapy. The addition of an aminoglycoside following several days of penicillin therapy has been noted to markedly improve the clinical course in several instances [5,10]. In addition, killing curves performed on two isolates showed combination ampicillin and gentamicin therapy to be superior to ampicillin therapy alone [5]. Some investigators, however, maintain that ampicillin alone is adequate initial therapy [2]. In vitro sensitivities of H. parainfluenzae to a wide variety of antibiotics has recently been reported [29]. Fifty strains were randomly collected from the oropharynx of healthy volunteers. Three of 50 isolates resistant to ampicillin (MIC greater than 8 Mg/ml) were shown to possess beta-lactamase. Gentamicin inhibited all strains at 1 pg/ml whereas chloramphenicol inhibited all strains at 2 pg/ml. Carbenicillin was the most effective antibiotic inhibiting 88 per cent of strains at 0.03
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pg/ml. Based on the current data, however, treatment with ampicillin and gentamicin should be initiated unless this combination is shown by killing curves to be inferior to ampicillin alone or if the clinical course is judged to be so benign as to obviate the addition of an aminoglycoside. Antibiotic therapy for the penicillinallergic patient remains a serious problem, particularly in view of the poor experience with chloramphenicol as single agent therapy. An aminoglycoside in addition to another agent should probably be administered and serious consideration given for penicillin desensitization. Indications for surgical therapy: The current indications for surgery in endocarditis include congestive heart failure, major or repeated embolization, persistent infection or a combination of these [30-361. Congestive heart failure currently represents the leading cause for surgical intervention and is the reason for surgery in 50 to 90 per cent of the patients [31,32,36]. Surgical intervention has reduced the mortality of severe heart failure due to acute valvular insufficiency in endocarditis from 80 per cent to less than 35 per cent [31,36]. Boyd et al. [3l] make a strong point for early surgical intervention in those cases with clinically uncontrolled infection or embolization. In a collection of 175 cases, 16 patients who had bacterial endocardjtis on nonprosthetic valves were considered to have clinically uncontrolled sepsis. In the assessment of early and late surgical intervention for continued sepsis (all patients treated medically at least 10 days), a marked increase in mortality was observed for those patients in whom surgery was deferred until four to six weeks of antibiotic therapy had been completed. Excluding our cases, only three patients with H. parainfluenzae endocarditis have undergone valvular surgery for complications related to the infection. The indicatioas for surgery in two of these patients was congestive heart failure [5,7] whereas the other patient had an antibiotic failure involving a prosthetic valve [5]. Despite the high incidence of repeated embolization and its attendant morbidity and mortality in this disease, Case 2 represents the first instance in which the primary reason for surgery was an embolic event. The mortality rate in those patients with
ET AL.
major embolic events who did not undergo surgery was 25 per cent [3 of 121, and in two fatal cases multiple emboli were involved. Another three patients in this category suffered permanent neurologic sequelae on medical therapy alone. Two of the five patients in whom surgery has been formed have died postoperatively, one with irreversible complications of multiple emboli and renal failure [7] and.the other [Case 2) with a ruptured mycotic aneurysm. Central nervous system embolization was the major factor in determining the course in seven of the eight patients who either died or suffered permanent neurologic deficits [5,7,8,11]. Critical review of these cases suggests that early surgical intervention in five patients (two with permanent neurologic sequelae, three with fatal cases] could have possibly avoided the complications encountered [5,8,11]. Hazards of surgical intervention are appreciable, exposing the patient to intraoperative and postoperative complications as well as the lifelong risks associated with a prosthetic valve. Most surgical data, however, are based on subjects with suboptimal hemodynamic status, and there are no carefully controlled studies reported which assess the feasibility of surgical intervention in those cases of endocarditis in which a high risk for major embolization is recognized. Further experience with echocardiography or other devices in the study of H. parainfluenzae and other types of endocarditis may eventually allow the prediction of which patients are at high risk for embolization. This would then provide a more rational approach to selection of patients as candidates for surgery. ACKNOWLEDGMENT We gratefully acknowledge the technical assistance of Edward Mason, Ph.D. and the critical review and encouragement of R. Russell Martin, M.D. This research was supported by research grants from the National Institutes of Health [CA-15784 and HL16938) and a grant from the Council for Tobacco Research ( #ICKM). Computational assistance was provided by the CLINFO project and funded by National Institutes of Health Division of Research Resources, Contract NOl-RR-5-2188.
REFERENCES 1. Weinstein L. Rubin RH: Infective endocarditis-1973. Prog Cardiovasc Dis 16:239,1973. 2. Geraci JE, Wilkowske CJ. Wilson WR, et al.: Haemophilus endocarditis. Report of 14 cases. Mayo Clinic Proc 52: 209. 1977. 3. Lynn DJ, Kane JG, Parker RH: Haemophilus parainfluenzae and influenzae endocarditis. A review of 40 cases. Meditine [Baltimore) 56: 115,1977. 4. Elster SK, Mattes LM, Meyers BR, et al.: Haemophilus aphrophilus endocarditis. Review of 23 cases. Am J Cardiol 35: 72, 1975. 5. Chunn CJ. Jones SR. McCutchan JA, et al.: Haemophilus parainfluenzae infective endocarditis. Medicine (Baltimore) 56: 99, 1977. 6. Dahlgren J. Tally FP. Brother G, et al.: Haemophilus par-
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ainfluenzae endocarditis. Am 1Clin Path 62: 807, 1974. RH, Kcnncdy RP. Marton KI, et al.: Hacmophilus endocarditis. New cases, literature review and recommendations for management. S Med J 70: 1098, 1977. Blair DC, Walker W, Sodeman T, et al: Bacterial endocarditis due to Haemophilus parainfluenzae. Chest 71: 146,1977. Hable KA, Logan GB, Washington II ]A: Three haemophilus species-pathogenic activity. Am J Dis Child 121: 35, 1971. Gordon AM, Love WC: Endocarditis due to Haemophilus parainfluenzae. J Med Microbial 3: 550,197O. Hodge JLR, Brenner DA: Haemophilus endocarditis and the isolation of haemophilic bacteria in blood culture-case report. N 2 Med J 79: 824, 1974.
7. Johnson
8. 9. 10. 11.
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12.
13. 14.
15. 16.
17.
18.
Young VM: Haemophilus, in Manual of Clinical Microbiology, Second Edition [Lennette EH, Spaulding EH, Traunt JP, eds). Washington, D.C., American Society for Microbiology, 1974. Barry AL: Methods for Testing Antimicrobic Combinations, in The Antimicrobic Susceptibility Test: Principles and Practices. 1st ed, Philadelphia, Lea and Febiger, 1976. Schlichter JG, Maclean H: A method of determining the effective therapeutic level in the treatment of subacute bacterial endocarditis with penicillin. Am Heart J 34: 209, 1947. Wallace RI. Musher DM. Martin RR: Haemoohilus influenzae’pneumonia in adults. Am J Med 64: S?‘,1978. Brvan CS. Marnev SR, Alford RH. et al.: Gram-negative bacillary endocarditis-Interpretation of the seru; bactericidal test. Am J Med 58: 209, 1975. Barza M, Samuelson T, Weinstein L: Penetration of antibiotics into fibrin loci in vivo. II Comparison of nine antibiotics: Effect of dose and degree of protein binding. J Inf Dis 129: 66. 1974. Weinstein L. Schlesinger JJ: Pathoanatomic. pathophysiologic and clinical correlations in endocarditis. N Enell Med 291: 1122,1974. Cherubin CE. Neu HC: Infective endocarditis at the Presbyterian Hospital in New York City from 1938-1967. Am I Med 51: 83.1971. Gdmes JAC. Calderon J, Lejam F, et al.: Echocardiographic detection of funnal vegetations in Candida naraosilosis endocarditis. Am J Med 61: 273.1976. ’ ’ Gottlieb S, Khuddus SA, Balooki H. et al.: Echocardiographic diagnosis of aortic valve vegetations in Candida endocarditis. Circulation 50: 826, 1974. Vilde JL, Roujeau JC, Bure A, et al.: Severe infection and septicemia due to Group B streptococci in adults. Sem Hop P&is 50: 355,1974. _ Wann LS, Dillon JC, Wagmann AE, et al.: Echocardiography in bacterial endocarditis. N Engl J Med 295: 135, 1976. Gleckman R: Culture negative cndocarditis: confirming the v
19. 20. 21. 22. 23. 24.
diagnosis. Am Heart J 94: 125, 1977. 25. Andy JJ. Shiekh MN, Wagab A, et al.: Echocardiographic observation in opiate addicts with active infective endocarditis-frequency of involvement in various valves and comparison of echocardiographic features of right- and left-sided cardiac valve endocarditis. Am J Cardiol40: 17, 1977. 26. 27. 28.
29.
30.
31.
I
32.
Mills J, Abbott J, Utley JR, et al.: Role of cardiac catheterization in infective endocarditis. Chest 72: 576, 1977. Sutton R. Petih M, Parker J: Echocardiography in infective endocarditis. Proc Br Cardiac Sot 38: 312,1976. Roy P, Tajik AJ. Giuliani ER, et al.: Spectrum of echocardiographic findings in bacterial endocarditis. Circulation 53: 474, 1976. Mayo JB, McCarthy LR: Antimicrobial susceptibility of Haemophilus parainfluenzae. Antimicrob Agents Chemotheril: 844; 1977. Black S, O’Rourke RA, Karliner JS: Role of surgery in the treatment of primary infective endocarditis. Am J Med 56: 357,1974. Boyd AD, Spencer FC. Isom WO, et al.: Infective endocarditis-An analysis of 54 surgically treated patients. J Thorac Cardiovasc Surg 73: 23.1977. Manhas DR, Mohri H, Hessel EA. et al.: Experience with surgical management of primary infective endocarditis. A collected review of 139 patients. Am Heart J 84: 738, 1972.
33.
Okies JE, Williams TW. Howell JF, et al.: Valvular replacement in bacterial endocarditis. Card Res Ctr Bulletin 8: 126.
34.
Okies IE. Bradshaw MW. Williams TW: Valve renlacement in becterial endocarditis. Chest 63: 898, 1973. . Mills I, Utlev J, Abbott J: Heart failure in infective endocarditis: predisposing factors, course and treatment. Chest 65:
1970.
35.
151,1974.
36. Parrott JC, Hill JD, Keith WJ. et al.: The surgical management of bacterial endocarditis-a review. Ann Surg 183: 289, 1976.
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The American Journal of Medicine
Volume 66
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