Acta Medica Scandinavica. Vol. 166, fasc. 2,1960

From the Department of Bacteriology (Head: R. Grubb, M.D.) and the Department of Medicine (Head: H. Malmros, M.D.), University of Lund, Sweden

Subacute Bacterial Endocarditis Due to Coagulase-Negative Staphylococcus Albus

BY

LARS BRANDT and BENGT SWAHN

Colonies of coagulase-negative staphylo- coccus albus are extremely common findings in various forms of bacteriologic culture, for the simple reason that it is one of the commonest contaminating species in our laboratories. Such colonies are therefore usually and justly regarded as contaminants. But occasionally S. albus may be responsible €or a case of septi- caemia. As early as 1901 Lenhartz de- scribed a case of such septicaemia with consequent septic endocarditis. In 195 1 Matthew reported 2 cases, both fatal, of subacute bacterial endocarditis due to infection with S. albus. With the expan- sion of the range of indications for cardiac and vascular surgery during the last decade some cases of endocarditis due to infection with S. albus in association with thoracic operations have been re- ported. Thus, Fleming & Seal (1955) de- scribed 9 cases of post-operative bacterial endocarditis, 3 of which were caused by Streptococcus viridans, 3 by Staphylo- coccus aureus and 3 by Staphylococcus albus. Five of these 9 cases were fatal. In Submitted for publication July 2, 1959.

one of the fatal cases blood culture had given growth of S. albus. The growth had, however, been regarded as a con- taminant with the result that effective therapy was not instituted. In 1958 Smith et al. reported a few personal cases of S. albus septicaemia and gave a detailed survey of all cases of subacute bacterial endocarditis in which' blood culture had repeatedly given growth of S. albus. They were able to trace 90 such cases published since 1900. Smith also believed S. albus to be responsible for 1 % of all cases of bac- terial endocarditis. Judging from his sur- vey during the last decade the incidence of such cases is on the increase.

During a relatively short period in the autumn of 1958 in the Department of Medicine, University Hospital, Lund, we saw a few patients with symptoms of subacute bacterial endocarditis in whom the blood culture gave growth of coagu- lase-negative S. albus repeatedly. This prompted inspection of the protocols of all blood cultures performed that year a t the Institute of Bacteriology, Lund.

125

126 LARS BRANDT AND BENGT SWAHN

Perusal of the records revealed a few cases from other hospitals in the south of Sweden in which the repeated finding of coagulase-negative S. albus in blood culture could hardly be dismissed simply as a contaminant. In addition a further case from 1955 with postoperative endo- carditis was included.

The increasing frequency with which S. albus has been held responsible for cases of bacterial endocarditis on record together with the discovery of several cases of endocarditis due to S. albus in a fairly limited receiving area in the south of Sweden prompted the present report. In view of the wide belief that S. albus is non-pathogenic and that the presence of such bacteria in cultures may be ignored or regarded as being due to contamina- tion, reinvestigation of the bacteriology and clinical course of endocarditis due to S. albus was considered justified.

Material

A total of 5 cases ofsepticaemia were traced (table) in which culture had given growth of S. albus on at least 2 occasions. Of these patients, 3 had undergone an operation on the heart with digital commissurotomy, 2 of them died in the post-operative phase. The remaining 3 re- ceived antibiotic therapy and recovered. In 5 other cases traced, but in which blood culture had given growth of S. albus on 1 occasion only, perusal of the record sheets did not suggest that their occurrence had been of pathogenic im- portance.

Report of cases

Case 1. The patient was a school teacher, aged 66. At 10 years he had had rheumatic fever with possible cardiac involvement. At 20 years affection of the mitral and aortic valves had been diagnosed. He had been

exempted from military service, but he had not been advised to rest or limit physical activity. He then felt well until the summer of 1952, when he developed fever, cough and chills. He received a short course of penicillin by mouth, but without success. He was ad- mitted to hospital for investigation. Examina- tion there revealed: E. S. R. 70 mm/l hour (Westergren), Hb. 10.8 g/100 ml, Strepto- coccal agglutination was positive and agglutin- ation of sensitized sheep blood cells was strongly positive. Repeated blood cultures gave no growth. Heart: harsh systolic murmur and prolonged conduction. Apart from ar- thritic symptoms in the right shoulder the patient had no joint pains. Rheumatic myo- carditis was assumed and the patient was given 1,700,000 units of penicillin daily for 1 month. The pathological serological reactions persisted throughout treatment, but the E. S. R. fell to 17 mm/l hour. Three months later routine examination during supervised con- valescence showed that the E. s. R. had dropped to 9 mm/l hour and that the agglutin- ation reaction of sensitized sheep cells had become negative.

The patient then felt well until April 1958, when muscle pain developed, particularly in the upper arni and thigh. He nevertheless continued his work and he did not take his body temperature. In June 1958 he sought advice at the outpatient department, where the E. S. R. was found to be 35 mm/l hour and the Hb. 12.2 g/100 ml. He then felt fairly well until the end of August, when the symptoms recurred. They were also more severe than before. During August and September the patient lost 5 kg in weight. He was admitted to hospital on Sept. 30. The E. S. R. was then 57 mm/l hour and the Hb. 10.3 g/100 ml. Thrre was, as before, a harsh systolic murmur loudest over the apex. On Oct. 7 the E. S. R. had risen to 70 mm/l hour and the Hb. had fallen to 8.8 g/100 ml. The serum iron was 33 gamma/l00 ml. A malig- nant tumour was suspected, but roentgen examination of the colon, stomach, oesoph- agus, kidneys (plain films), skull, chest and skeleton failed to reveal any evidence of such a growth. Histological examination of a sternal punctate showed nothing remarkable. No L. E. cells were found. A fractional test meal suggested hyposecretion and the pa- tient’s symptoms were interpreted as anae-

COAGULASE-NEGATIVE STAPHYLOCOCCUS ALBUS 127

Table I. Clinical data on cases of subacute bacterial endocarditis due to coagulase-negatiue S. albus

Case Age Operation 1:; ' Clinical symptoms -_ Fever

- + +

+ +

- Car- diovas cular in- volvc- rncnt

f + -1-

+ +

-

High E. S.R

mia secondary to achylia. Iron therapy was given, but with little success. Electrophoresis showed a pronounced reduction of the albumin and a moderate increase in the alpha, fraction. Reactions for antistreptolysin and antistaphylolysin showed low titres. Strep- tococcal agglutination tests were also per- formed and showed slightly positive agglutina- tion in L- and 0-antigen. The agglutination of sensitized sheep blood cells was strongly positive. Blood culture on Oct. 4 gave growth of S. albus, which was, however, regarded as a contaminant. During his stay in hospital the patient had no fever and he was sent home. On follow-up examination on Oct. 27 the E. S. R. was 54 mm/l hour and the Hb. 9.5 g/100 ml. Blood cultured on that occasion also gave growth of S. albus. Culture was re- peated on Nov. 10 and 11 and with the samc result. The strain was sensitive to all anti- biotics tried. The patient was re-admitted on Nov. 17. I n a search for the source of the in- fection the only finding was a granuloma of a tooth root. The tooth was extracted under penicillin cover. The white blood-cell count was 6,200/mm3 and the antistaphylolysin titre showed a borderline value of 2.5 (pre- viously 0.9). The patient was given benzyl penicillin in a daily close of 6 mill. units

- Anae mia

t- + +

-

+

-

Num- ber 01

posi- tive blood Clll-

tures

for 1 month.

Antibiotics used Remarks

Penicillin Penicillin Penicillin Streptomycin Erythromycin Chlorarnphenicol Ristocetin Penicillin Erythromycin Penicillin Streptomycin Erythromycin

Dead

Dead

lur ing treatment the seIo- - logical reactions became negative, as did the blood cultures. The E. S. R. dropped to 12 mm/l hour and the Hb. rose to 13.2 g/lOO ml without iron therapy. During the first few months after the penicillin course blood was cultured on 6 occasions and was regularly negative. The patient now feels well.

Case 2. The patient was a woman, aged 71. I n 1953 she had been admitted to hospital because of mild hypertension and symptoms of cardiac incompetence. O n that occasion a systolic murmur had been noted. The blood pressure was 200/100 mm Hg. She afterwards felt well until 1957, when she was admitted to the department of medicine because of sidero- paenic anaemia. A systolic murmur was heard on that occasion, too. Her anaemia responded well to oral iron therapy.

O n Dec. 15, 1958, she was again admitted to hospital, this time because of severe neck pain, pain in the left thumb and fever. On admission: Temp. 38.6" C. E. S. R. 48 mm/l hour. Hb. 10.6 g/100 ml. White blood-cell count 6,300/mms. Streptococcal agglutina- tion reaction negative. Agglutination of sensitized sheep cells: Negative. Antistrepto- lysin titre 65. Antistaphylolysin titre 3.7. Blood cultured on Dec. 18 and 27 gave

128 LARS BRANDT AND BENGT SWAHN

growth of coagulase-negative S. albus. Re- peated cultures on Dec. 30 and 31 and on Jan. 1, 1959 were negative. The body tem- perature, which had fluctuated daily between 37" and 38" C became normal after in- stitution of benzyl penicillin (1,000,000 units x 4). The E. S. R. was 16 mm/l hour. Blood cultures on Jan. 26, 27 and 28 were negative, and the patient was sent home on Jan. 30, She then felt well. The neck pain, which she had had on admission and which disappeared on immobilisation, might be ascribed to ar- thritic changes with decalcification of the cer- vical column.

Case 3. The patient was a woman, aged 48. In 1927, she was then 18, valvular disease of heart was diagnosed and tonsillectomy was performed because of repeated infections of the throat. In 1938 the patient had had re- peated attacks of dyspnoea, and in 1941 treat- ment with digitalis was started because of in- creasing symptoms of cardiac incompetence. During the following 10 years she also had episodes of symptoms that were interpreted as manifestations of pulmonary embolism. In 1951 she was admitted to hospital for bi- lateral pneumonia and signs of embolism of the lower left leg. In March 1958 she entered the department of medicine because of fever and symptoms of dyspnoea and the following month she had a relapse. The patient was referred to the department of cardiology on July 1958 with a request as to the advis- ability of valvulotomy. The cardiologist re- ported mitral stenosis and slight aortic stenosis. Though the case was judged as advanced, it was suggested that commissurot- omy might provide some relief.

On Aug. 29, 1958 the patient was submitted to digital commissurotomy. Operation re- vealed severe valvular involvement with fusion, particularly in the anterior commis- sure, and calcified deposits. The post-operative course was smooth during the first 2 days, but on the third day chills developed and the temperature rose to 39.5" C. During the following few days temperature peaks of 40" C were noted and leucocytosis with white blood cell counts of about 17,000/mm3. Penicillin (benzyl + procaine penicillin) in a daily dose of 10,000,000 units was started, and within a few days the temperature became steady at about 38" C. After 10 days' treat- ment the patient felt well, and the penicillin

course was discontinued. Blood culture on Sept. 1, 2 and 9 was negative. On Sept. 20 the temperature again rose to 40" C. Blood culture on that occasion was also negative. On Sept. 25 chills again developed and chloramphenicol (0.5 g x 4) was given. Culture of 2 samples drawn that day gave growth of coagulase-negative S. albus. From Sept. 26 until Oct. 3 temperature peaks were noted daily. Blood culture in Sept. 26 gave growth of S. albus. Blood culture on Sept. 29 was negative. The temperature then be- came normal within few days. Erythromycin was discontinued on Oct. 6, after which the patient again received chloramphenicol (0.5 g x 4). On Nov. 1 temperature peaks recur- red and culture again gave growth of S. albus. On Nov. 8 benzyl penicillin (2,000,000 units x 3) was again given and on Oct. 11 strepto- mycin (0.5 g x 3) also. The patient then felt fairly well, but on Nov. 16 chills recurred, the temperature rose to 38.8" C, and a pale exanthema developed over the entire body. On Nov. 17 she deteriorated rapidly, had symptoms of shock, lost consciousness, and died.

Postmortem examination showed the lesions usually seen after rheumatic endocarditis: Slight aortic stenosis + mitral stenosis and severe massive calcifications. There was cardiac hypertrophy with right sided pre- ponderance. Signs of verrucose bacterial endocarditis were seen in the mitral valve. Multiple infarcts were found in the kidneys with almost total infarction of the right kidney. Infarcts were also observed in the spleen and myocardium.

Histological examination of the mitral valves showed fibrosis with calcified deposits and polypose thrombi. These thrombus for- mations were covered with clusters of bac- teria resembling staphylococci. Sections from the left auricle showed fibrosis and cellular infiltrates but no bacterial foci. Unfortunately no necropsy specimens were cultured for bacterial growth.

Case 4. The patient was a woman, aged 29. She had had scarlet fever as a child, but to her knowledge she had not had rheumatic fever. In 1952 valvular disease was diagnosed. During pregnancy in 1953 she had often had attacks of breathlessness, and cough with blood stained expectorate. After parturition, which was uncomplicated, she felt better. In

COAGULASE-NEGATIVE STAPHYLOCOCCUS ALBUS 129

1955 she was referred to the cardiologist for examination as to the advisability of valvulo- tomy. Mitral stenosis with aortic incompetence was diagnosed, but the stenosis was not con- sidered severe, and expectant treatment was recommended.

Dyspnoea recurred during pregnancy in 1957 and on June 2, 1958, the patient was operated upon with digital commissurotomy. The post-operative course was smooth and the patient was sent home on June 19. During follow-up at the outpatient department of her local hospital she felt well and was in a good general condition. On Oct. 26, however, the patient presented herself complaining of cough and headache which she had had for a couple of weeks. On Oct. 29 chills developed, the temperature rose to 39" C, and she was admitted to hospital on Nov. 3. Her body temperature was then 38.6" C, the E. S. R. was 30 mm/l hour and the Hb. 11.6g/ 100 ml. Blood culture on Nov. 4 and 5 gave growth of coagulase-negative S. albus. On Nov. 6 treatment with benzyf penicillin procaine in a dose of 600,000 units was started. On Nov. 13 benzyl penicillin procaine was replaced by benzyl penicillin, and the dose was increased to 1,000,000 units x 2. Antibiotic treatment was continued until Nov. 27. Blood culture was repeated on Dec. 10, 11 and 12 and regularly showed growth of S. albus. Body temperature was now normal. On Dec. 19 erythromycin, in a dose of 2 g daily, was started and con- tinued until Jan. 10, 1959. On Dec. 29 and 30 blood cultures again gave growth of S. albus. Body temperature was still normal. During the last few weeks the E. S. R. had fluctuated between 25 and 45 mm/l hour. On Jan. 13 chills recurred, the temperature rose to 39.8" C and culture of two blood samples drawn on that day and the next 2 days were positive.

The patient was given benzyl penicillin in a dose of 2,000,000 units x 3 and erythro- mycin in a dose of 0.5 g x 4. Cultures on Jan. 30 and Feb. 9 were negative. The fever disappeared and the patient felt well.

Case 5. The patient was a police official, who had felt well until 1941, since when he had had pneumonia almost every year. In the beginning he had received domiciliary treatment, but since 1951 he had been ad- mitted on various occasions to the department for infectious diseases and to the department 9-593789. Acta M e d . S c a d . Vol. 166.

of medicine. In 1952 mitral stenosis was diagnosed. Since it could not be decided whether the pulmonary affection was due to some systemic disease or to his mitral stenosis, he was in 1955 referred to the department of cardiology for investigation. Examination there revealed mitral stenosis, and com- missurotomy was felt to be indicated. The patient was transferred to the department of thoracic surgery and was operated upon Oct. 17, 1955. The first few days after opera- tion the body temperature persisted at about 39" C before it returned to normal, but on Oct. 29 it again rose, chills developed and the patient was mentally hazy. Every time the patient had a chill a blood sample was drawn for culture. The first 3 cultures were negative. Penicillin (2,500,000 units x 4) was given for 10 days. At the beginning of the course the patient had no chills, but they returned on Nov. 8, and he was then given streptomycin as well. This combined therapy appeared to have no effect and was therefore discontinued on Nov. 12. Since culture of the blood and of the urine had given no growth, no new antibiotics were given. On Nov. 17 the patient became much worse and respira- tion was forced, but without signs of pul- monary oedema. The blood values dropped, and the Hb. was 6.2 g/100 ml. He had pro- nounced leucocytosis. The presence of a focal infection in the operative field was considered improbable, and the anaemia was believed to be due to some haemolytic mechanism. This belief was supported by a reticulocyte value of 6.3 per cent, and the agglutination of trypsin treated blood cells. The pulmonary symptoms contraindicated blood transfusions. In view of the desperate situation the patient was given cortisone and erythromycin. New culture on Nov. 16 gave growth of S. albus. Electrophoresis in Nov. 21 showed a marked reduction of the albumin and a considerable increase in the alpha, and gamma globulins. Sternal punctate showed hyperplastic erythro- poiesis. The patient improved somewhat during treatment with cortisone and erythro- mycin. He was subfebrile and had no chills, but he was still fairly dyspnoeic. No certain haemolytic factor could be found to explain the anaemia, and since the sternal punctate had contained abundant bacteria resembling lanceolate cocci, new blood samples were cultured on Nov. 29 and 30 and Dec. 2, and

130 LARS BRANDT AND BENGT SWAHN

all gave growth of S. albus. The patient gradually deteriorated with increasing dys- pnoea and died on Dec. 2.

Postmortem examination showed old throm- bi in the left atrium and ventricle with in- fected, recent superimposed thrombi in the left atrium. Emboli were found in various arteries, infarcts in the spleen, a thrombus in the right femoral vein, and multiple haemor- rhagic infarcts in the lungs. Necropsy speci- mens from the bone marrow, lung, heart thrombi and spleen were cultured and all gave growth of S. albus.

Bacteriology As mentioned, a diagnosis of endocarditis

due to infection with S. albus can only be made on the basis of repeated positive blood cultures. Since S. albus can almost always be isolated from the skin and upper airways from healthy subjects, the risk of contamina- tion of blood cultures is obvious. I t is there- fore important that all samples be collected and handled under conditions as sterile as possible. In the present material the samples have been drawn with a sterilr vacuum blood collector.

The S. albus strains isolated from the blood in the cases under consideration regularly gave growth of porcelain white colonies on blood agar. In a few of the cases signs of haemolysis were observed in accordance with the report of O'Hare & Stevenson (1953). Unlike the 3 cases of mixed infection of Strept. viridans and Staphylococcus albus (and aureus) described by Fleming & Seal (1955), our cases gave no growth of other bacteria.

In all of the cases the coagulase test was negative. Neither did any of the strains ferment mannite. The S. albus strains isolated from the blood cultures were tested for sensitivity to antibiotics by the agar cup method de- scribed by Erlanson (1951). All of the strains were found to be sensitive to penicillin, strep- tomycin, sulphonamides, aureomycin, terra- mycin, tetracyclin, chloramphenicol, eryth- romycin, oleandomycin and novobiocin. Most of the S. albus strains described as responsible for subacute bacterial endocarditis in the cases on record, however, were resistant to at least one of these antibiotics.

In 2 of the cases described (cases 3 and 4) we were able to compare the sensitivity

spectrum before and after institution of treat- ment with antibiotics. No increase in these- sistance of the bacteria could be demon'- strated. In another case (No. 5) the sensitivity spectrum could not be studied until after antibiotic therapy had bcen started, and in that case no earlier positive blood culture was available for comparison. In this case all of the strains were also found to be sensitive to all of, the antibiotics tried.

Discussion

Bacterial endocarditis is an important group of diseases and is the most common heart affection after coronary, hyper- tensive and rheumatic heart disease. Two types of endocarditis are generally rec- ognised, an acute bacterial or ulcerative form, usually due to infection with pyo- genic bacteria, and a sub-acute form due to non-pyogenic bacteria. There is no clear-cut bacteriological or clinical dif- ference between the two types, and Wood (1950) regards the classification as arti- ficial. According to him, the course of the disease depends on the virulence of the bacteria and the resistance of the host. Though the cases described in the present paper were due to the non-pyogenic bacteria, S. albus, the clinical course varied from one patient to another.

Of all cases of bacterial endocarditis, 75-85 yo are due to the occurrence of Strept. viridans, and 5-15 yo to entero- cocci. Staphylococci, mainly S. aureus, are responsible for about 5 yo. In their analysis of the 90 published cases of septicaemia due to S. albus Smith et al. (1958) found S. albus to be the cause of 1 yo of the cases of bacterial endocarditis. In view of the increasing incidence of endocarditis because of infection with S. albus and the decline in the frequency of streptococcal endocarditis because of the now wide use of antibiotics, there

132 LARS BRANDT AND BENGT SWAHN

The prognosis of untreated endo- carditis due to infection with S. albus is extremely poor. Though it runs a slowly progressive and initially mild course, it claims a mortality of about 80 yo, which is about the same as that of septicaemia due to infection with S. aureus. Even in cases treated with antibiotics the prog- nosis is often poor, and unexpected deaths have been reported in patients with finally sterile blood cultures. In such cases death was usually due to focal septic emboli.

Snmmary

The finding of coagulase-negative Staphylococcus albus is usually dismissed as contamination or non-pathogenic. Du- ring a relatively short period 5 cases of subacute bacterial endocarditis due to S. albus were diagnosed in a relatively limited receiving area in the south of Sweden. These 5 cases are described against the background of the clinical picture, treatment and the apparently

increasing frequency of the condition. AlI of the patients had predisposing heart changes in their history. Three had undergone digital commissurotomy with post-operative death in 2 of them. The other 3 patients recovered after a long period of antibiotic therapy. Treatment with benzyl penicillin in a daily dosage of 6-10 million units for 4 weeks is rec- ommended.

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FLEMING, H. A. & SEAL, R. M. E.: Thorax 10:

LENHARTZ, H.: Munchen Med. Wchnschr. 48:

MATTHEW, H.: Lancet I: 146, 1951. @HARE, M. M. & STEVENSON, J. S.: Brit. Med.

J. 2: 1086, 1953. SMITH, I. M., BEALS, P. O., KINGSBURY, K. R. &

HASENCLEVER, H. F.: Arch. Int. Med. 102: 375, 1958.

WOOD, P. : Diseases of the Heart and Circulation. Eyre and Spottiswoode, London 1950.

85, 1951.

327, 1955.

1123, 1901.