Journal of Infection (1991) 22, 161-169
CASE REPORT V a n c o m y c i n - r e s i s t a n t Corynebacterium species c a u s i n g p r o s t h e t i c valve e n d o c a r d i t i s s u c c e s s f u l l y treated with i m i p e n e m * and ciprofloxacin Stella Barnass, Karen Holland and Soad Tabaqchali Department of Medical Microbiology, St Bartholomew's Hospital, West Smithfield, London ECIA 7BE, U.K. Accepted for publication 9 July I99o Summary Endocarditis caused by a Corynebacterium sp. resistant to vancomycin, penicillin G, erythromycin, gentamicin and rifampicin arose in a 44-year-old woman 4 months after replacement of the mitral valve with a prosthesis. She was successfully treated with a 79-day course of intravenous imipenem and ciprofloxacin and replacement of the prosthesis 48 days after treatment began.
Introduction Resistance of Gram-positive bacteria to vancomycin, although rare, is increasingly being described and there are now several reports of clinically significant isolates among Leuconostoc spp., 1 Lactobacillus spp. 2-4 and enterococci. 5-9 F r o m the blood of a patient with prosthetic valve endocarditis we isolated a Corynebacterium sp. resistant to vancomycin. To the best of our knowledge, this has not previously been reported. T h e organism was also resistant to penicillin G, erythromycin, rifampicin and gentamicin but susceptible to imipenem and ciprofloxacin. T h e patient was successfully treated with imipenem and ciprofloxacin. Their role in the treatment of endocarditis is discussed.
Case report T h e patient was a 44-year-old female community research worker who presented in March I989 with a 2 days' history of fever, anorexia and feeling unwell. She had been born with congenital heart disease which included coarctation of the aorta that had been repaired at the age of I I years. Her past history included a pulmonary embolus in I976 and pericarditis of presumed viral origin in April I988. Her mitral valve had been replaced with a No. 2 Start-Edwards prosthesis under cover of flucloxacillin and gentamicin in November r988 because of congenital mitral stenosis with pulmonary hypertension which had caused symptoms during pregnancy. * Imipenem refers throughout to Primaxin (Merck, Sharp & Dohme), which contains equal quantities of imipenem and cilastatin. oi63-4453/9I/O2OI6I +09 $03.00/0
© 1991 The British Society for the Study of Infection
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On examination, the patients' temperature was 37"6 °C. Her pulse rate was 88/rain. with regular but occasional extra beats; her blood pressure was 8o/5o m m H g . T h e jugular venous pressure was not raised and the apex beat not displaced. A systolic m u r m u r was unchanged. T h e haemoglobin concentration was I I'7 g/dl and the WBC count 8"I × IO9/1 with a normal differential count. T h e ESR was II m m in I h. Microscopy of the patient's urine did not reveal any red cells. An echocardiogram showed a normal mitral valve prosthesis without vegetations or regurgitation, but with good left ventricular function. Titres of complement-fixing antibodies to Mycoplasma pneumoniae, Chlamydia psittaci and Coxiella burnetii were I6, < 8 and < 8 respectively, both on the patient's admission to hospital and 8 days later. T h r e e days after admission, three splinter haemorrhages were noted and empirical therapy for endocarditis was started. This comprised ampicillin 5oo mg q.d.s., flucloxacillin 5oo mg q.d.s, and gentamicin 8o mg t.d.s. Iv. After I week, 6 / I 4 blood culture bottles inoculated on admission and 4/4 bottles inoculated 4 days later yielded a Corynebacterium sp. T h e r a p y was therefore changed empirically to vancomycin I g b.d. and gentamicin 8o mg t.d.s. Iv. Clinically, there was no response to therapy, despite adequate therapeutic concentrations of vancomycin and gentamicin. Furthermore, the white cell count had risen to I2 x io9/1 (9o % neutrophils, 8% lymphocytes and 2 % monocytes) and the E S R had risen to 3o m m in I h. Also, bactericidal activity of the serum at this time was unsatisfactory. Therefore, in accord with results of in vitro tests (see below) treatment was changed to Iv ciprofloxacin zoo m g b . d , and imipenem 5 o o m g q.d.s, on day I4 after the patient's admission to hospital. Four days later, she became apyrexial for the first time, and serum bactericidal activity was satisfactory. Nausea associated with imipenem was prevented by prior administration of an antiemetic. Her clinical course was complicated by the development of supraventricular tachyarrhythmias which required cardioversion on day I6. An episode of fever on day I8 responded to removal of the central venous pressure line although the tip proved to be sterile on culture. On day I9, Janeway's lesions of the feet developed but resolved spontaneously during the next week. On day 5 I, the mitral valve prosthesis was replaced with a No. 3 Starr-Edwards prosthesis. T h e excised prosthesis remained sterile on culture. Imipenem and ciprofloxacin were continued for a total of 79 days. Blood cultures taken on days zI, 39, 6o and 86 remained sterile. T h e patient was finally discharged from hospital without any antibiotics 86 days after admission and remained well with sterile blood cultures when seen 4 months later.
Laboratory methods Preliminary testing of the isolate was by routine laboratory methods. 1° It was further identified by M r H. Malnick of the National Collection of T y p e Cultures (NCTC), Central Public Health Laboratory, Colindale. Susceptibility of the organism to various antibiotics was determined by Stokes' comparative method on lysed blood agar (Becton Dickinson).
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T a b l e I Results of identification tests performed on the isolate Test Growth on blood agar (5 % COs) Growth on blood agar (anaerobic) Growth on MacConkey agar Growth on tellurite agar Growth in MRS lactobacillus broth Growth on lecithovitellin agar Opalescence on lecithovitellin agar Growth on Tween 2o Hydrolysis of Tween 2o Growth on Tween 8o Hydrolysis of Tween 8o Catalase Oxidase Fermentation of: glucose sucrose maltose lactose arabinose galactose ribose mannitol sorbitol salicin raffinose Hydrolysis of: starch urea casein Indole Methyl red Nitrate reduction Nitrite reduction Voges-Proskauer Aesculin hydrolysis Motility Gelatin stab Haemolysis on 5 % horse blood agar Phosphatase ONPG Ornithine decarboxylase Lysine decarboxylase
Result + + + + + + + + + +
+ +
+ +
+ +
B e t a - l a c t a m a s e p r o d u c t i o n was d e t e c t e d w i t h a c h r o m o g e n i c c e p h a l o sporinase (Nitrocefm, Oxoid). M i n i m u m inhibitory concentrations ( M I C ) and m i n i m u m bactericidal c o n c e n t r a t i o n s ( M B C ) w e r e d e t e r m i n e d b y a m a c r o d i l u t i o n technique.11 S e r u m inhibitory and bactericidal dilutions ( M I D and M B D ) were d e t e r m i n e d b y a m a c r o d i l u t i o n t e c h n i q u e 11 a p p l i e d to ' p e a k ' a n d ' t r o u g h '
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Table II AIICs and M B C s of antimicrobial agents in respect of the Corynebacterium sp. isolated Antimicrobial agent
M I C (mg/1)
Vancomycin Vancomycin +gentamicin 3 mg/1 Rifampicin Imipenem Ciprofloxacin
M B C (mg/1)
32 32
32 32
> 64 o'5 o'5
N.T.• I o'5
*N.T. = No t tested.
samples of serum taken immediately before and 2o min after administration of antimicrobial agents. Results
T e n of 18 blood culture bottles yielded a Gram-positive bacillus. T h e results of identification tests are shown in Table I. Identification beyond Corynebacterium sp. was not possible according to M r H. Malnick of the U.K. National Collection of T y p e Culture. When tested by Stokes' method, the isolate was resistant to vancomycin, penicillin G, ampicillin, erythromycin, rifampicin and gentamicin, but susceptible to ciprofloxacin and imipenem. It was found to produce betalactamase. M I C s and MBCs of the antibiotics tested against the isolate are shown in Table II. T h e combination of ciprofloxacin and imipenem was indifferent in vitro. Serum bactericidal activity against the isolate is shown in Table III.
Discussion
Reports of resistance to vancomycin among Gram-positive bacteria are increasing. Clinically significant infection caused by vancomycin-resistant lactobacilli 2-4 and vancomycin-resistant enterococci5-9 have been recorded. Emergence o f vancomycin resistance in coagulase-negative staphylococci during antimicrobial therapy has been described also. 12 Furthermore, vancomycin resistance has been reported in Leuconostoc spp. and Pediococcus spp., bacteria used in the dairy and food industries and which may occasionally infect h u m a n beings. L18'14 As far as we are aware, there have not been any previous reports of vancomycin-resistant corynebacteria. T h e possibility that the organism which we isolated was a lactobacillus was considered but biochemical tests placed it firmly in the genus Corynebacterium. T h e source of the organism could not be found. Therapeutic problems posed by vancomycin resistance have until now been resolved by the use of erythromycin, a penicillin alone or a penicillin combined
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T a b l e I I I Serum bactericidal activity against the C o r y n e b a c t e r i u m sp.
isolated Antimicrobial therapy Vancomycin and gentamicin ' Trough' titre 'Peak' titre Imipenem and ciprofloxacin 'Trough' titre 'Peak' titre
MID
MBD
Undiluted I in 4
Undiluted I in 4
I in 4 I in 64
I in 4 I in 64
MID, Maximum inhibitory dilution. MBD, Maximum bactericidal dilution.
with an aminoglycoside or rifampicin. 1'4'5'7'12-~4 In this case, the organism was resistant to all the antimicrobial agents previously available for treating infections caused b y G r a m - p o s i t i v e bacteria. In particular, the combination of v a n c o m y c i n and gentamicin was not effective in vitro or in vivo. M o s t G r a m - p o s i t i v e bacteria are sensitive to vancomycin with an M I C b e t w e e n I - 5 mg/1 and M I C s for Corynebacterium spp. normally up to 0.8 mg/11~. Strains o f enterococci 8'9'1G'17 and occasional strains of Leuconostoc spp., 14'1s Streptococcus sanguis, 1~ lactobacilli 4 and enterococci 7 have shown a high degree of resistance to vancomycin with M I C s > I g/1. E v e n so, T h o r n s b e r r y and Facklam 2° d o u b t the existence of vancomycin-resistant streptococci and have suggested that the isolate of Shlaes et al., 19m a y also have been a Leuconostoc sp. T h e isolate described here showed an intermediate degree of resistance to vancomycin with an M I C and an M B C of 32 mg/1, concentrations greater than those clinically sustainable. Recent work on Enterococcus faecalis and E. faecium has shed light on the m e c h a n i s m of resistance to v a n c o m y c i n and its genetic basis. Synthesis of a 39 k D a cytoplasmic m e m b r a n e protein is t h o u g h t to prevent access of v a n c o m y c i n to its peptidoglycan target. This resistance is inducible and transferable. 6'7'16'17 Both plasmid and chromosomal loci for the vancomycinresistance determinant have been described and translocation m a y be b y means o f a transposon.9 Studies on enterococci 6'9'16'17 as well as on Leuconostoc spp. 21 and lactobacilli 4 have shown that antibiotic inactivation is not important. T h e m e c h a n i s m o f resistance in our isolate is not known. T h e M I C s of o'5 mg/1 of both ciprofloxacin and i m i p e n e m for our isolate were similar to those determined in a study of 25 blood culture isolates of Corynebacterium sp. from patients with prosthetic valve endocarditis and in which the MICg0 of ciprofloxacin was o'5 mg/1 and that of imipenem was o'I25 mg/1. 22 Seventeen strains of C. jeikeium, although susceptible to ciprofloxacin ( M I C s of o - o 6 - i m g / 1 ) , were all resistant to i m i p e n e m ( M I C s t> 32 mg/1). ~a Corynebacterium spp. cannot therefore be a s s u m e d to be susceptible to both agents. H o w e v e r , peak serum concentrations, attainable with the doses of i m i p e n e m and ciprofloxacin used, were considerably higher than the M I C values for the isolate.
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S. B A R N A S S E T
AL.
T a b l e I V R e p o r t e d use o f i m i p e n e m in e n d o c a r d i t i s Number of patients (number with prosthetic Reference valve) 25
19 (o) 3 (o) 2 (o) I (o) I (o)
26
IO (o) I (o)
Causative organisms
Dose of imipenem
Mean duration of treatment
Staphylococcus aureus
500 mg q.d.s. 500 mg q.d.s.
30 days 30 days
18 cured Cured
5oo mg q.d.s. 500 mg q.d.s.
3o days 30 days
Cured Cured
I g q.d.s.
30 days
Cured
500 mg q.d.s. 500 mg q.d.s.
29 days 28 days
Cured Cured
500 mg q.d.s.
28 days
Cured
500 mg q.d.s.
28 days
Cured
500 mg q.d.s.
28 days
Cured
50o mg q.d.s.
27 days
Cured
5oo mg q.d.s.
56 days
Cured
0"75--4 g/day 750 mg q.d.s.
N.s. 7 weeks
1"5 g q.d.s.
13 weeks
Cured Cured (+ new valve) Cured (+ amikacin + new valve)
Viridans streptococcus Gp D streptococcus Streptococcus pneumoniae Pseudomonas aeruginosa Staphylococcus aureus Staphylococcus
Outcome
aur eus +
2 (o) I (o) I (0) I (0)
I (o)
Gp B streptococcus Viridans streptococcus Neisseria sp Eikenella sp + Gp. G streptococcus Sta-phylococcus epidermidis Haemophilus aphrophilus Enterobacter aerogenes
II (N.S.) N.S. I (I) Escherichia coli
27 28 29
I (i)
Nocardia asteroides
*N.s. = Not stated. T h e s u s c e p t i b i l i t y o f o u r isolate to i m i p e n e m , d e s p i t e r e s i s t a n c e to o t h e r b e t a - l a c t a m agents, m a y h a v e b e e n d u e to r e s i s t a n c e o f i m i p e n e m to d e g r a d a t i o n b y t h e b e t a - l a c t a m a s e p r o d u c e d b y t h e isolate. I t m a y also h a v e b e e n d u e , in p a r t , to t h e e n h a n c e d affinity o f i m i p e n e m f o r cell w a l l - b i n d i n g p r o t e i n s . H o p e f u l l y , s u s c e p t i b i l i t y to i m i p e n e m will c o n t i n u e s h o u l d m o r e widespread vancomycin resistance develop. T h e p e a k s e r u m b a c t e r i c i d a l t i t r e o f 64 in o u r p a t i e n t d u r i n g t r e a t m e n t w i t h c i p r o f l o x a c i n a n d i m i p e n e m was c o n s i d e r e d to b e satisfactory. I n a s t u d y o f 129 p a t i e n t s w i t h e n d o c a r d i t i s , p e a k titres > / 6 4 w e r e a s s o c i a t e d w i t h IOO % b a c t e r i o l o g i c a l c u r e ratesfl 4 T h e r e are f e w r e p o r t s o f t h e use o f i m i p e n e m o r c i p r o f l o x a c i n in e n d o c a r d i t i s ; t h e y are s u m m a r i s e d in T a b l e s I V a n d V r e s p e c t i v e l y . M o s t r e p o r t s are o f single p a t i e n t s b u t i m i p e n e m has b e e n u s e d in t w o series o f
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T a b l e V R e p o r t e d use of ciprofloxacin in endocarditis Number of patients (number with prosthetic Reference valve)
Causative organisms
Dose of ciprofloxacin
Mean duration of treatment
N.S.*
7 r days
3°
I (0)
Streptococcus mitis
3I
i (I) i (i)
Escheriehia coli Pseudomonas aeruginosa
N.S. 20o mg t.d.s.I.v. 75o mg b.d. orally
32
I (x)
Legionella pneumophila
6oo rag/day I.V.
33
I (o)
Pseudomonas aeruginosa
I'5- 3 g/day orally
I (I)
Pseudomonas aeruginosa
I-2 g/day orally
Outcome
Cured (+ new valve) 4z days Cured 9 weeks Death from 3 weeks heart failure; blood cultures sterile Io weeks Cured ( + rifampicin + new valve) 22 months Death from heart failure 14 weeks Death from bacteraemia on stopping treatment
*N.S. = Not stated.
patients, m o s t l y with endocarditis caused by S. aureus. A l t h o u g h i m i p e n e m has b e e n used as a single agent in endocarditis, a c o m b i n a t i o n o f two agents was t h o u g h t desirable in o u r case so as to p r e v e n t e m e r g e n c e o f resistance to either agent since e m e r g e n c e o f resistance to ciprofloxacin d u r i n g t h e r a p y o f infections caused by Pseudomonas spp. m a y be as high as 26 %.3~ T w o agents were also used in o r d e r to p r o m o t e m o r e rapid and c o m p l e t e killing o f the organism. P u b l i s h e d r e p o r t s on the use o f ciprofloxacin and i m i p e n e m in treating endocarditis give little g u i d a n c e on the dose or d u r a t i o n o f therapy. T h e r e f o r e , in keeping with the general principles for t h e r a p y o f endocarditis, we gave m a x i m u m doses, based on the patient's weight and renal function. Similarly, a l e n g t h y course o f t r e a t m e n t was given, in view o f the multiple antibiotic resistance o f the organism, in o r d e r to p r e v e n t e m e r g e n c e o f resistance and because the affected valve was a p r o s t h e t i c one. O u r aim was to treat for a m i n i m u m o f 6 weeks and to c o n t i n u e t r e a t m e n t for 4 weeks after r e p l a c e m e n t o f the p r o s t h e s i s ; this was achieved. U n d o u b t e d l y , the patient's age and general fitness t o g e t h e r with r e p l a c e m e n t o f the prosthesis c o n t r i b u t e d to the favourable o u t c o m e . T h i s case d e m o n s t r a t e s the need, firstly, to m o n i t o r G r a m - p o s i t i v e isolates for v a n c o m y c i n susceptibility and, secondly, to consider the use o f n e w e r u n c o n v e n t i o n a l antimicrobial agents for t h e r a p y w h e n necessary.
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(We thank D r D. D y m o n d and M r G. M. Rees for permission tO report on their patient and M r H. Malnick of the National Collection of T y p e Cultures for identifying the organism.) References
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24. Weinstein MP, Stratton CW, Ackley A. Multicenter collaborative evaluation of a standardised serum bactericidal test as a prognostic indicator in infective endocarditis. A m J Med I985; 78: 262-269. z5. Donabedian H, Freimer EH. Pathogenesis and treatment of endocarditis. A m J M e d I985; 78 (Suppl 6A) : 1 I9-I25. z6. Dickinson G, Rodriguez K, Arcey S, Alea A, Greenman R. Efficacy of imipenem/cilastatin in endocarditis. Am J Med I985 ; 78 (Suppl 6A) : I o 9 - I I3. z7. Eron LJ. Imipenem/cilastatin therapy of bacteraemia. Am J Med I985; 78 (Suppl 6A): 87-9 I. 28. Garau J, Martin R, Bouza E et al. Imipenem in the treatment of severe bacterial infections in seriously ill patients. J Antimicrob Chemother I986; I8 (Suppl E): I3I-I4O. 29. Ertl G, Schaal KP, Kochsiek K. Nocardial endocarditis of an aortic valve prosthesis. Br HeartJ I987; 57: 384-386. 3o. Lode H. New aspects in the antibiotic treatment of infective endocarditis. Eur Heart J I987; 8 (Suppl J): 341-345. 3I. Breuer J, Bragman S G L , Sahathevan M D , Philpott-Howard JN, Casewell M W . T h e possible role of ciprofloxacin in the treatment of endocarditis caused by Pseudomonas aeruginosa. J Infect I988; I6: IO6-Io7. 32. Tompkins LS, Roessler BJ, Redd SC, Markowitz LE, Cohen M L . Legionella prosthetic valve endocarditis. N Engl J Med I988; 3*8:530-535 • 33. Daikos G L , Kathpalia SB, Lolans VT, Jackson G G , Fosslein E. Long-term oral ciprofloxacin : experience in the treatment of incurable infective endocarditis. Am J Med I988; 84: 786-79o. 34. Scully BE, Neu H C , Parry M F , Mandell W. Oral ciprofloxacin therapy of infection due to Pseudomonas aeruginosa. Lancet I986; i : 8 I9-8z2.
CASE REPORT V a n c o m y c i n - r e s i s t a n t Corynebacterium species c a u s i n g p r o s t h e t i c valve e n d o c a r d i t i s s u c c e s s f u l l y treated with i m i p e n e m * and ciprofloxacin Stella Barnass, Karen Holland and Soad Tabaqchali Department of Medical Microbiology, St Bartholomew's Hospital, West Smithfield, London ECIA 7BE, U.K. Accepted for publication 9 July I99o Summary Endocarditis caused by a Corynebacterium sp. resistant to vancomycin, penicillin G, erythromycin, gentamicin and rifampicin arose in a 44-year-old woman 4 months after replacement of the mitral valve with a prosthesis. She was successfully treated with a 79-day course of intravenous imipenem and ciprofloxacin and replacement of the prosthesis 48 days after treatment began.
Introduction Resistance of Gram-positive bacteria to vancomycin, although rare, is increasingly being described and there are now several reports of clinically significant isolates among Leuconostoc spp., 1 Lactobacillus spp. 2-4 and enterococci. 5-9 F r o m the blood of a patient with prosthetic valve endocarditis we isolated a Corynebacterium sp. resistant to vancomycin. To the best of our knowledge, this has not previously been reported. T h e organism was also resistant to penicillin G, erythromycin, rifampicin and gentamicin but susceptible to imipenem and ciprofloxacin. T h e patient was successfully treated with imipenem and ciprofloxacin. Their role in the treatment of endocarditis is discussed.
Case report T h e patient was a 44-year-old female community research worker who presented in March I989 with a 2 days' history of fever, anorexia and feeling unwell. She had been born with congenital heart disease which included coarctation of the aorta that had been repaired at the age of I I years. Her past history included a pulmonary embolus in I976 and pericarditis of presumed viral origin in April I988. Her mitral valve had been replaced with a No. 2 Start-Edwards prosthesis under cover of flucloxacillin and gentamicin in November r988 because of congenital mitral stenosis with pulmonary hypertension which had caused symptoms during pregnancy. * Imipenem refers throughout to Primaxin (Merck, Sharp & Dohme), which contains equal quantities of imipenem and cilastatin. oi63-4453/9I/O2OI6I +09 $03.00/0
© 1991 The British Society for the Study of Infection
162
S. BARNASS E T A L .
On examination, the patients' temperature was 37"6 °C. Her pulse rate was 88/rain. with regular but occasional extra beats; her blood pressure was 8o/5o m m H g . T h e jugular venous pressure was not raised and the apex beat not displaced. A systolic m u r m u r was unchanged. T h e haemoglobin concentration was I I'7 g/dl and the WBC count 8"I × IO9/1 with a normal differential count. T h e ESR was II m m in I h. Microscopy of the patient's urine did not reveal any red cells. An echocardiogram showed a normal mitral valve prosthesis without vegetations or regurgitation, but with good left ventricular function. Titres of complement-fixing antibodies to Mycoplasma pneumoniae, Chlamydia psittaci and Coxiella burnetii were I6, < 8 and < 8 respectively, both on the patient's admission to hospital and 8 days later. T h r e e days after admission, three splinter haemorrhages were noted and empirical therapy for endocarditis was started. This comprised ampicillin 5oo mg q.d.s., flucloxacillin 5oo mg q.d.s, and gentamicin 8o mg t.d.s. Iv. After I week, 6 / I 4 blood culture bottles inoculated on admission and 4/4 bottles inoculated 4 days later yielded a Corynebacterium sp. T h e r a p y was therefore changed empirically to vancomycin I g b.d. and gentamicin 8o mg t.d.s. Iv. Clinically, there was no response to therapy, despite adequate therapeutic concentrations of vancomycin and gentamicin. Furthermore, the white cell count had risen to I2 x io9/1 (9o % neutrophils, 8% lymphocytes and 2 % monocytes) and the E S R had risen to 3o m m in I h. Also, bactericidal activity of the serum at this time was unsatisfactory. Therefore, in accord with results of in vitro tests (see below) treatment was changed to Iv ciprofloxacin zoo m g b . d , and imipenem 5 o o m g q.d.s, on day I4 after the patient's admission to hospital. Four days later, she became apyrexial for the first time, and serum bactericidal activity was satisfactory. Nausea associated with imipenem was prevented by prior administration of an antiemetic. Her clinical course was complicated by the development of supraventricular tachyarrhythmias which required cardioversion on day I6. An episode of fever on day I8 responded to removal of the central venous pressure line although the tip proved to be sterile on culture. On day I9, Janeway's lesions of the feet developed but resolved spontaneously during the next week. On day 5 I, the mitral valve prosthesis was replaced with a No. 3 Starr-Edwards prosthesis. T h e excised prosthesis remained sterile on culture. Imipenem and ciprofloxacin were continued for a total of 79 days. Blood cultures taken on days zI, 39, 6o and 86 remained sterile. T h e patient was finally discharged from hospital without any antibiotics 86 days after admission and remained well with sterile blood cultures when seen 4 months later.
Laboratory methods Preliminary testing of the isolate was by routine laboratory methods. 1° It was further identified by M r H. Malnick of the National Collection of T y p e Cultures (NCTC), Central Public Health Laboratory, Colindale. Susceptibility of the organism to various antibiotics was determined by Stokes' comparative method on lysed blood agar (Becton Dickinson).
Imipenem and ciprofloxacin in endocarditis
I63
T a b l e I Results of identification tests performed on the isolate Test Growth on blood agar (5 % COs) Growth on blood agar (anaerobic) Growth on MacConkey agar Growth on tellurite agar Growth in MRS lactobacillus broth Growth on lecithovitellin agar Opalescence on lecithovitellin agar Growth on Tween 2o Hydrolysis of Tween 2o Growth on Tween 8o Hydrolysis of Tween 8o Catalase Oxidase Fermentation of: glucose sucrose maltose lactose arabinose galactose ribose mannitol sorbitol salicin raffinose Hydrolysis of: starch urea casein Indole Methyl red Nitrate reduction Nitrite reduction Voges-Proskauer Aesculin hydrolysis Motility Gelatin stab Haemolysis on 5 % horse blood agar Phosphatase ONPG Ornithine decarboxylase Lysine decarboxylase
Result + + + + + + + + + +
+ +
+ +
+ +
B e t a - l a c t a m a s e p r o d u c t i o n was d e t e c t e d w i t h a c h r o m o g e n i c c e p h a l o sporinase (Nitrocefm, Oxoid). M i n i m u m inhibitory concentrations ( M I C ) and m i n i m u m bactericidal c o n c e n t r a t i o n s ( M B C ) w e r e d e t e r m i n e d b y a m a c r o d i l u t i o n technique.11 S e r u m inhibitory and bactericidal dilutions ( M I D and M B D ) were d e t e r m i n e d b y a m a c r o d i l u t i o n t e c h n i q u e 11 a p p l i e d to ' p e a k ' a n d ' t r o u g h '
I64
S. B A R N A S S E T A L .
Table II AIICs and M B C s of antimicrobial agents in respect of the Corynebacterium sp. isolated Antimicrobial agent
M I C (mg/1)
Vancomycin Vancomycin +gentamicin 3 mg/1 Rifampicin Imipenem Ciprofloxacin
M B C (mg/1)
32 32
32 32
> 64 o'5 o'5
N.T.• I o'5
*N.T. = No t tested.
samples of serum taken immediately before and 2o min after administration of antimicrobial agents. Results
T e n of 18 blood culture bottles yielded a Gram-positive bacillus. T h e results of identification tests are shown in Table I. Identification beyond Corynebacterium sp. was not possible according to M r H. Malnick of the U.K. National Collection of T y p e Culture. When tested by Stokes' method, the isolate was resistant to vancomycin, penicillin G, ampicillin, erythromycin, rifampicin and gentamicin, but susceptible to ciprofloxacin and imipenem. It was found to produce betalactamase. M I C s and MBCs of the antibiotics tested against the isolate are shown in Table II. T h e combination of ciprofloxacin and imipenem was indifferent in vitro. Serum bactericidal activity against the isolate is shown in Table III.
Discussion
Reports of resistance to vancomycin among Gram-positive bacteria are increasing. Clinically significant infection caused by vancomycin-resistant lactobacilli 2-4 and vancomycin-resistant enterococci5-9 have been recorded. Emergence o f vancomycin resistance in coagulase-negative staphylococci during antimicrobial therapy has been described also. 12 Furthermore, vancomycin resistance has been reported in Leuconostoc spp. and Pediococcus spp., bacteria used in the dairy and food industries and which may occasionally infect h u m a n beings. L18'14 As far as we are aware, there have not been any previous reports of vancomycin-resistant corynebacteria. T h e possibility that the organism which we isolated was a lactobacillus was considered but biochemical tests placed it firmly in the genus Corynebacterium. T h e source of the organism could not be found. Therapeutic problems posed by vancomycin resistance have until now been resolved by the use of erythromycin, a penicillin alone or a penicillin combined
Imipenem and ciprofloxacin in endocarditis
I65
T a b l e I I I Serum bactericidal activity against the C o r y n e b a c t e r i u m sp.
isolated Antimicrobial therapy Vancomycin and gentamicin ' Trough' titre 'Peak' titre Imipenem and ciprofloxacin 'Trough' titre 'Peak' titre
MID
MBD
Undiluted I in 4
Undiluted I in 4
I in 4 I in 64
I in 4 I in 64
MID, Maximum inhibitory dilution. MBD, Maximum bactericidal dilution.
with an aminoglycoside or rifampicin. 1'4'5'7'12-~4 In this case, the organism was resistant to all the antimicrobial agents previously available for treating infections caused b y G r a m - p o s i t i v e bacteria. In particular, the combination of v a n c o m y c i n and gentamicin was not effective in vitro or in vivo. M o s t G r a m - p o s i t i v e bacteria are sensitive to vancomycin with an M I C b e t w e e n I - 5 mg/1 and M I C s for Corynebacterium spp. normally up to 0.8 mg/11~. Strains o f enterococci 8'9'1G'17 and occasional strains of Leuconostoc spp., 14'1s Streptococcus sanguis, 1~ lactobacilli 4 and enterococci 7 have shown a high degree of resistance to vancomycin with M I C s > I g/1. E v e n so, T h o r n s b e r r y and Facklam 2° d o u b t the existence of vancomycin-resistant streptococci and have suggested that the isolate of Shlaes et al., 19m a y also have been a Leuconostoc sp. T h e isolate described here showed an intermediate degree of resistance to vancomycin with an M I C and an M B C of 32 mg/1, concentrations greater than those clinically sustainable. Recent work on Enterococcus faecalis and E. faecium has shed light on the m e c h a n i s m of resistance to v a n c o m y c i n and its genetic basis. Synthesis of a 39 k D a cytoplasmic m e m b r a n e protein is t h o u g h t to prevent access of v a n c o m y c i n to its peptidoglycan target. This resistance is inducible and transferable. 6'7'16'17 Both plasmid and chromosomal loci for the vancomycinresistance determinant have been described and translocation m a y be b y means o f a transposon.9 Studies on enterococci 6'9'16'17 as well as on Leuconostoc spp. 21 and lactobacilli 4 have shown that antibiotic inactivation is not important. T h e m e c h a n i s m o f resistance in our isolate is not known. T h e M I C s of o'5 mg/1 of both ciprofloxacin and i m i p e n e m for our isolate were similar to those determined in a study of 25 blood culture isolates of Corynebacterium sp. from patients with prosthetic valve endocarditis and in which the MICg0 of ciprofloxacin was o'5 mg/1 and that of imipenem was o'I25 mg/1. 22 Seventeen strains of C. jeikeium, although susceptible to ciprofloxacin ( M I C s of o - o 6 - i m g / 1 ) , were all resistant to i m i p e n e m ( M I C s t> 32 mg/1). ~a Corynebacterium spp. cannot therefore be a s s u m e d to be susceptible to both agents. H o w e v e r , peak serum concentrations, attainable with the doses of i m i p e n e m and ciprofloxacin used, were considerably higher than the M I C values for the isolate.
I66
S. B A R N A S S E T
AL.
T a b l e I V R e p o r t e d use o f i m i p e n e m in e n d o c a r d i t i s Number of patients (number with prosthetic Reference valve) 25
19 (o) 3 (o) 2 (o) I (o) I (o)
26
IO (o) I (o)
Causative organisms
Dose of imipenem
Mean duration of treatment
Staphylococcus aureus
500 mg q.d.s. 500 mg q.d.s.
30 days 30 days
18 cured Cured
5oo mg q.d.s. 500 mg q.d.s.
3o days 30 days
Cured Cured
I g q.d.s.
30 days
Cured
500 mg q.d.s. 500 mg q.d.s.
29 days 28 days
Cured Cured
500 mg q.d.s.
28 days
Cured
500 mg q.d.s.
28 days
Cured
500 mg q.d.s.
28 days
Cured
50o mg q.d.s.
27 days
Cured
5oo mg q.d.s.
56 days
Cured
0"75--4 g/day 750 mg q.d.s.
N.s. 7 weeks
1"5 g q.d.s.
13 weeks
Cured Cured (+ new valve) Cured (+ amikacin + new valve)
Viridans streptococcus Gp D streptococcus Streptococcus pneumoniae Pseudomonas aeruginosa Staphylococcus aureus Staphylococcus
Outcome
aur eus +
2 (o) I (o) I (0) I (0)
I (o)
Gp B streptococcus Viridans streptococcus Neisseria sp Eikenella sp + Gp. G streptococcus Sta-phylococcus epidermidis Haemophilus aphrophilus Enterobacter aerogenes
II (N.S.) N.S. I (I) Escherichia coli
27 28 29
I (i)
Nocardia asteroides
*N.s. = Not stated. T h e s u s c e p t i b i l i t y o f o u r isolate to i m i p e n e m , d e s p i t e r e s i s t a n c e to o t h e r b e t a - l a c t a m agents, m a y h a v e b e e n d u e to r e s i s t a n c e o f i m i p e n e m to d e g r a d a t i o n b y t h e b e t a - l a c t a m a s e p r o d u c e d b y t h e isolate. I t m a y also h a v e b e e n d u e , in p a r t , to t h e e n h a n c e d affinity o f i m i p e n e m f o r cell w a l l - b i n d i n g p r o t e i n s . H o p e f u l l y , s u s c e p t i b i l i t y to i m i p e n e m will c o n t i n u e s h o u l d m o r e widespread vancomycin resistance develop. T h e p e a k s e r u m b a c t e r i c i d a l t i t r e o f 64 in o u r p a t i e n t d u r i n g t r e a t m e n t w i t h c i p r o f l o x a c i n a n d i m i p e n e m was c o n s i d e r e d to b e satisfactory. I n a s t u d y o f 129 p a t i e n t s w i t h e n d o c a r d i t i s , p e a k titres > / 6 4 w e r e a s s o c i a t e d w i t h IOO % b a c t e r i o l o g i c a l c u r e ratesfl 4 T h e r e are f e w r e p o r t s o f t h e use o f i m i p e n e m o r c i p r o f l o x a c i n in e n d o c a r d i t i s ; t h e y are s u m m a r i s e d in T a b l e s I V a n d V r e s p e c t i v e l y . M o s t r e p o r t s are o f single p a t i e n t s b u t i m i p e n e m has b e e n u s e d in t w o series o f
I m i p e n e m and ciprofloxacin in endocarditis
r67
T a b l e V R e p o r t e d use of ciprofloxacin in endocarditis Number of patients (number with prosthetic Reference valve)
Causative organisms
Dose of ciprofloxacin
Mean duration of treatment
N.S.*
7 r days
3°
I (0)
Streptococcus mitis
3I
i (I) i (i)
Escheriehia coli Pseudomonas aeruginosa
N.S. 20o mg t.d.s.I.v. 75o mg b.d. orally
32
I (x)
Legionella pneumophila
6oo rag/day I.V.
33
I (o)
Pseudomonas aeruginosa
I'5- 3 g/day orally
I (I)
Pseudomonas aeruginosa
I-2 g/day orally
Outcome
Cured (+ new valve) 4z days Cured 9 weeks Death from 3 weeks heart failure; blood cultures sterile Io weeks Cured ( + rifampicin + new valve) 22 months Death from heart failure 14 weeks Death from bacteraemia on stopping treatment
*N.S. = Not stated.
patients, m o s t l y with endocarditis caused by S. aureus. A l t h o u g h i m i p e n e m has b e e n used as a single agent in endocarditis, a c o m b i n a t i o n o f two agents was t h o u g h t desirable in o u r case so as to p r e v e n t e m e r g e n c e o f resistance to either agent since e m e r g e n c e o f resistance to ciprofloxacin d u r i n g t h e r a p y o f infections caused by Pseudomonas spp. m a y be as high as 26 %.3~ T w o agents were also used in o r d e r to p r o m o t e m o r e rapid and c o m p l e t e killing o f the organism. P u b l i s h e d r e p o r t s on the use o f ciprofloxacin and i m i p e n e m in treating endocarditis give little g u i d a n c e on the dose or d u r a t i o n o f therapy. T h e r e f o r e , in keeping with the general principles for t h e r a p y o f endocarditis, we gave m a x i m u m doses, based on the patient's weight and renal function. Similarly, a l e n g t h y course o f t r e a t m e n t was given, in view o f the multiple antibiotic resistance o f the organism, in o r d e r to p r e v e n t e m e r g e n c e o f resistance and because the affected valve was a p r o s t h e t i c one. O u r aim was to treat for a m i n i m u m o f 6 weeks and to c o n t i n u e t r e a t m e n t for 4 weeks after r e p l a c e m e n t o f the p r o s t h e s i s ; this was achieved. U n d o u b t e d l y , the patient's age and general fitness t o g e t h e r with r e p l a c e m e n t o f the prosthesis c o n t r i b u t e d to the favourable o u t c o m e . T h i s case d e m o n s t r a t e s the need, firstly, to m o n i t o r G r a m - p o s i t i v e isolates for v a n c o m y c i n susceptibility and, secondly, to consider the use o f n e w e r u n c o n v e n t i o n a l antimicrobial agents for t h e r a p y w h e n necessary.
168
S. BARNASS E T A L .
(We thank D r D. D y m o n d and M r G. M. Rees for permission tO report on their patient and M r H. Malnick of the National Collection of T y p e Cultures for identifying the organism.) References
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