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Left-sided endocarditis caused by Pseudomonas aeruginosa: successful treatment with meropenem and tobramycin
Diagnostic Microbiology and Infectious Disease 47 (2003) 427– 430
www.elsevier.com/locate/diagmicrobio
Case reports
Left-sided endocarditis caused by Pseudomonas aeruginosa: successful treatment with meropenem and tobramycin P. J. Gavina,*, M. T. Susenob, F. V. Cookc, L. R. Petersona, R. B. Thomson, Jra a
Departments of Laboratory Medicine and Pathology, Evanston Northwestern Healthcare, Evanston and Feinberg School of Medicine, Northwestern University, Chicago, IL, USA b Pharmacy, Evanston Northwestern Healthcare, Evanston and Feinberg School of Medicine, Northwestern University, Chicago, IL, USA c Internal Medicine, Evanston Northwestern Healthcare, Evanston and Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Received 7 April 2003; received in revised form 17 May 2003
Abstract Medical treatment alone is rarely successful in left-sided infective endocarditis caused by Pseudomonas aeruginosa. We report the cure of such a case with high-dose meropenem in combination with tobramycin. © 2003 Elsevier Inc. All rights reserved. Keywords: Pseudomonas endocarditis; Meropenem
1. Introduction Infective endocarditis caused by Pseudomonas aeruginosa is uncommon. However, associated morbidity and mortality rates are high despite optimal use of available antimicrobials (Komshian et al., 1990; Reyes & Lerner, 1983; Wieland et al., 1986). Most reports concern rightsided disease, which is characteristically associated with injection drug use, is sub-acute in onset and carries a better prognosis (Reyes & Lerner, 1983). Left-sided endocarditis caused by Pseudomonas aeruginosa is a more serious disease and remains an especially difficult therapeutic problem. Reports of cure of left-sided infection with medical treatment alone are rare. Mortality rates of 67% to 85% among patients who received medical treatment alone have led to recommendations for treatment with immediate valve replacement accompanied by a 6-week course of high-dose combined -lactam and aminoglycoside antimicrobials (Komishian et al., 1990; Reyes & Lerner, 1983; Wieland et al., 1986). We report successful medical treatment of leftsided endocarditis caused by Pseudomonas aeruginosa using a combination of meropenem plus tobramycin, both given in high-dose for 6-weeks, following the initial failure
* Corresponding author. Tel.: ⫹1-847-570-2744; Fax: ⫹1-847-7335314. E-mail address: [email protected] (P. J. Gavin). 0732-8893/03/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0732-8893(03)00135-4
of combination regimens with both ceftazidime or piperacillin-tazobactam plus tobramycin. A 35-year-old severely mentally handicapped man was admitted to hospital with a 1 day history of passing bright red blood per rectum and vomiting. This was associated with low-grade tactile fevers and nonproductive cough for 3 days. He had been ill for the previous month with weakness, anorexia and an 8 pound weight loss. Three weeks earlier he had received a 5 day course of oral antibiotics for otitis externa. His past medical history was notable for essential hypertension, a cardiac murmur, and an episode of pneumonia 5 years earlier. Severe mental handicap of unknown cause was evident from 6 months of age. He required assistance with activities of daily living and had lived in a nursing home for the previous 16 years. There was no history of central i.v. access or injection drug use. Examination revealed fever of 38.5°C, pulse of 93/min, respirations of 20/min, blood pressure of 115/66 mm Hg, and chronic bilateral otitis externa. Cardiac examination revealed a grade II/VI holosystolic murmur at the apex with radiation to the axilla. There was no clubbing, splinter hemorrhages, rash or splenomegaly. Laboratory studies showed: hemoglobin, 10g/dL; white blood cell count, 8,900/mm3 (82% neutrophils, 10% monocytes, 8% lymphocytes); platelets, 228,000/mm3, and serum creatinine, 1.0 mg/dL. Blood and urine cultures were obtained. Chest radiography showed a left perihilar infiltrate and treatment
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P.J. Gavin et al. / Diagnostic Microbiology and Infectious Disease 47 (2003) 427– 430
was initiated with azithromycin (500 mg orally q24h) and ceftriaxone (2g iv q12h) for presumed pneumonia. He remained febrile, and 2 days later both sets of blood cultures from admission were positive for Pseudomonas aeruginosa. Gram’s stain of a swab from his right external ear revealed Gram-positive rods and no white blood cells, and culture was positive for light growth of Pseudomonas aeruginosa, coagulase-negative Staphylococcus species and Corynebacterium species. Antimicrobial susceptibilities of the Pseudomonas aeruginosa isolates were determined by standard disc diffusion (NCCLS Standard M2-A7, 35°C) (NCCLS, 2002). Minimum inhibitory concentration values (MICs) were extrapolated from zone-diameters interpreted by the BIOMIC Video Reader System (Giles Scientific, Inc., Santa Barbara, CA.) as previously described (D’Amato et al., 1985). Antibiograms of Pseudomonas aeruginosa isolates from blood and ear cultures were identical: resistant to gentamicin, ciprofloxacin and levofloxacin but susceptible to other antipseudomonal antimicrobials. Specifically, MICs were as follows: amikacin ⬍8 g/ml; aztreonam ⬍4 g/ml; ceftazidime ⬍4 g/ml; ciprofloxacin ⱖ4 g/ml; gentamicin ⱖ8 g/ml; levofloxacin ⱖ8 g/ml; meropenem ⬍0.5 g/ml; piperacillin-tazobactam ⬍1 g/ml; ticarcillin-clavulanate ⬍16 g/ml; and tobramycin ⬍2 g/ml. Antimicrobial treatment was changed to piperacillin-tazobactam (3.375g iv q4h) and tobramycin (400 mg iv q24h). Transesophageal echocardiography revealed a large vegetation (7 mm by 7 mm) on the posterior annulus of the mitral valve, and moderate mitral regurgitation without heart failure. Electrocardiogram showed normal sinus rhythm. Tobramycin was changed to 300 mg q 12h. The patient’s fevers continued and blood cultures were persistently positive for Pseudomonas aeruginosa on hospital Days 3, 4, 5 and 7. On hospital Day 9, he developed intermittent rapid atrial fibrillation, which responded to oral digoxin treatment. Piperacillin-tazobactam was discontinued and treatment with ceftazidime (2g iv q6h) started (tobramycin was continued). Three days later, on hospital Day 12, peak and trough serum inhibitory titers were 1:32 and 1:8, respectively, while peak and trough serum bactericidal titers were 1:16 and 1:8, respectively (NCCLS Standard M21-A) (NCCLS, 1999). However, fevers persisted and repeat blood cultures on hospital Days 10, 11, 14 and 15 remained positive for Pseudomonas aeruginosa. Antimicrobial susceptibilities of Pseudomonas aeruginosa isolates from all repeat positive blood cultures were identical and remained unchanged throughout therapy. Although replacement valve surgery was considered, his guardians declined consent. On hospital Day 17, ceftazidime was discontinued, treatment with meropenem (2g iv q8h) was started, and tobramycin was continued. Repeat blood cultures from the following day, hospital Day 18, and Days 22 and 38 remained sterile. On hospital Day 19, after 2 days of meropenem
treatment, peak serum inhibitory and bactericidal titers were 1:64, while trough inhibitory and bactericidal titers were 1:32 (NCCLS Standard M21-A) (NCCLS, 1999). Tobramycin levels, which were closely monitored during the hospital stay (on 17 occasions at approximately 3-day intervals), demonstrated mean peak and trough levels of 11.8 g/ml (range, 7.5-17.5 g/ml) and 1.09 g/ml (range, 0.3-1.7 g/ml), respectively. Serum creatinine levels were normal throughout. On hospital Day 24, fever finally resolved and thereafter he was afebrile. At this stage, the patient was discharged to a skilled nursing facility to receive a total of 6 weeks of meropenem (2g iv q8h) and tobramycin (300 mg iv q12h). Follow-up transesophageal echocardiogram, after 5 weeks of meropenem treatment, revealed moderate mitral valve regurgitation without evidence of vegetation, and left atrial enlargement without ventricular dysfunction. Two weeks after cessation of antimicrobial therapy, follow-up blood cultures were sterile. Although formal audiometry was not performed, auditory or vestibular toxicity were not apparent. One year later, the patient remains symptom-free and in his usual state of health.
2. Discussion The present report of infective endocarditis caused by Pseudomonas aeruginosa is notable for several reasons. Firstly, the majority of reports of Pseudomonas aeruginosa endocarditis involve iv drug users (more than 90% of reported cases) or prosthetic heart valves (Komshian et al., 1990; Reyes & Lerner, 1983; Wieland et al., 1986). Secondly, it is one of few to document cure of left-sided endocarditis caused by Pseudomonas aeruginosa with medical treatment alone. And finally, to our knowledge, it is the first to describe successful use of high-dose meropenem in this disease. Management of endocarditis caused by Pseudomonas aeruginosa is difficult, particularly so in left-sided disease where medical cure rates may be as low as 12% to 15% (Komshian et al., 1990; Wieland et al., 1986). Treatment failures have been characterized by lack of correlation between in vitro and in vivo susceptibilities, extremely large numbers of organisms present in infected vegetations, and frequent development of resistance on therapy (Diaz et al., 1977; Jimenez-Lucho et al., 1986; Reyes & Lerner, 1983; Wieland et al., 1986). It is believed that slow bactericidal action and lack of post-antibiotic effect of -lactam antimicrobials selects for or induces antibiotic resistant mutants and may lead to treatment failure (Diaz et al., 1977; Jimenez-Lucho et al., 1986). Antimicrobial regimens used in medically cured cases of left-sided endocarditis caused by Pseudomonas aeruginosa are summarized in Table 1. Additional reports of apparent medical successes were not evaluable because either the diagnosis of endocarditis was not definitive or later valvereplacement surgery was required. Most authorities now
P.J. Gavin et al. / Diagnostic Microbiology and Infectious Disease 47 (2003) 427– 430
429
Table 1 Cases of left-sided endocarditis caused by Pseudomonas aeruginosa cured by medical treatment alone Reference (Year)
Antimicrobial regimen (duration)
No. of patients
Serum bactericidal titers
Lloyd & Gordon (1961)
Polymixin plus tetracycline, colistin, kanamycin, sulfisoxazole (6 wks) Carbenicillin plus polymixin (6 wks) Ticarcillin plus tobramycin (6 wks) Ticarcillin plus tobramycin (6 wks) Ceftazidime plus tobramycin (6 wks) Ticarcillin plus tobramycin or amikacin (mean, 6 wks) Meropenem plus tobramycin (6 wks)
1
NR
1 3 of 9 1 of 6 1 1 of 7
Peak, 1:10; trough, 1:5 NR Peak, 1:4; trough, ⬍1:2 Peak, 1:32; trough, 1:8 NR
1
Peak, 1:64; trough, 1:32
Diaz et al. (1977) Reyes & Lerner, (1983) Wieland et al., (1986) Cabinian & Kaatz, (1987) Komshian et al., (1990) Present report Note: NR, not recorded.
recommend treatment of left-sided endocarditis caused by Pseudomonas aeruginosa with immediate valve replacement accompanied by a 6 week course of high-dose combined extended spectrum -lactam plus aminoglycoside antimicrobials (Komshian et al., 1990; Reyes & Lerner, 1983; Wieland et al., 1986). Such a combined surgical/medical approach is associated with improved survival (Komshian et al., 1990; Wieland et al., 1986). In the present case, surgical treatment was not feasible and optimal medical treatment was required. In contrast to other -lactam antimicrobials, carbapenems, have demonstrated rapid bactercidal action and post-antibiotic effect against Pseudomonas aeruginosa (Bustamente et al., 1984; Bowker et al., 1996). Meropenem was chosen for its documented activity against Pseudomonas aeruginosa and good safety profile in high-dose. Meropenem has the broadest antibacterial spectrum of any -lactam agent available and has greater intrinsic activity in vitro against clinical isolates of Pseudomonas aeruginosa than aminoglycoside, quinolone and comparable -lactam antimicrobials, including imipenem, ceftazidime and piperacillin (Iaconis et al., 1997; Pfaller & Jones, 1997). It is highly active against most Gram-negative bacilli including Pseudomonas aeruginosa, and is less likely to induce seizures than is imipenem (Craig, 1997; Norrby & Gildon, 1999). Furthermore, low protein binding provides a good pharmacodynamic profile (Moon et al., 1997; Astra-Zeneca Pharmaceuticals, 2001). In animal models of endocarditis caused by Pseudomonas aeruginosa, sustained high concentrations of -lactam antimicrobials within vegetations are important for treatment success (Bayer et al., 1988; Ingerman et al., 1986). Specifically, it is proposed that reduced antibiotic penetrance within left-sided Pseudomonas aeruginosa-infected vegetations contributes to the strikingly higher mortality in left-sided relative to right-sided endocarditis (Bayer et al., 1988). In addition, very large concentrations of antimicrobial are required to saturate the polyanionic glycocalyx biofilm of Pseudomonas aeruginosa before antimicrobial penetration to the bacterial cell can occur (Costerton, 1984). The usual dosage of meropenem in adults is 500 mg to 1g iv q8h. To maximize serum concentrations we elected to use the highest recommended dose of meropenem (2g iv q8h),
which is normally reserved for patients with meningitis (Astra-Zeneca Pharmaceuticals, 2001). In previous series of left-sided endocarditis caused by Pseudomonas aeruginosa, measurement of serum inhibitory or bactericidal activity was of no predictive value (Wieland et al., 1986). Similarly, in the present report, earlier treatment with ceftazidime failed despite apparently effective serum bactericidal activity in vitro. However, subsequent treatment with meropenem, which was associated with a somewhat more favorable serum bactericidal profile, was successful. Aminoglycoside and -lactam antibiotics, including meropenem, have demonstrated in vitro synergy in endocarditis caused by Pseudomonas aeruginosa (Reyes & Lerner, 1983; Reyes & Lerner, 1979). Reyes et al. suggest a target serum C max for the aminoglycoside of 12-20 g/ml, with values for tobramycin toward the lower end of the range (Reyes & Lerner, 1983). In the present case, tobramycin given in high-dose was chosen as the combination treatment, with frequent monitoring of tobramycin levels to minimize the risk of toxicity. We conclude that in select cases of left-sided endocarditis caused by Pseudomonas aeruginosa, where surgery may not be feasible, medical treatment alone with meropenem plus an aminoglycoside, both in high-dose, is a therapeutic option.
References Astra-Zeneca Pharmaceuticals. (2001). Merrem. (Meropenem). Prescribing information. Wilmington, DE. Bayer, A. S., Crowell, D. J., Yih, J., Bradley, D. W., & Norman, D. C. (1988). Comparative pharmacokinetics and pharmacodynamics of amikacin and ceftazidime in tricuspid and aortic vegetations in experimental Pseudomonas endocarditis. J Infect Dis 158 (2), 355–359. Bowker, K. E., Holt, H. A., Reeves, D. S., & MacGowan, A. P. (1996). Bactericidal activity, post-antibiotic effect and modified controlled effective regrowth time of meropenem at high concentrations. J Antimicrobiol Chemother 38, 1055–1060. Bustamente, C., Drusano, G., Tatem, B., & Standiford, H. (1984). Postantibiotic effect of imipenem on Pseudomonas aeruginosa. Antmicrob Agents Chemother 26, 678 – 682.
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Cabinian, A. E., & Kaatz, G. W. (1987). Successful therapy of Pseudomonas aeruginosa endocarditis with ceftazidime. Amer J Med 83, 366 –367. Costerton, J. (1984). The etiology and persistence of cryptic bacterial infections: A hypothesis. Rev Infect Dis 6 (Supplement 3), S608 –S616. Craig, W. A. (1997). The pharmacology of meropenem, a new carbepenem antibiotic. Clin Infect Dis 24 (Suppl 2), S266 –S275. D’Amato, R. F., Hochstein, L., Vernaleo, J. R., Cleri, D. J., Wallman, A. A., Gradus, M. S., & Thornsberry, C. (1985). Evaluation of the BIOGRAM antimicrobial susceptibility test system. J Clin Microbiol 22, 793–798. Diaz, C. R., Fossieck, B. E., & Parker, R. H. (1977). Pseudomonas endocarditis: Cure with carbenicillin and polymyxin B. South Med J 70, 869 – 871. Iaconis, J. P., Pitkin, D. H., Sheikh, W., & Nadler, H. L. (1997). Comparison of antibacterial activities of meropenem and six other antimicrobials against Pseudomonas aeruginosa isolates from North American studies and clinical trials. Clin Infect Dis 24 (Suppl 2), S191–A196. Ingerman, M. J., Pitsakis, P. G., Rosenberg, A. F., & Levison, M. E. (1986). The importance of pharmacodynamics in determining the dosing interval in therapy for experimental Pseudomonas endocarditis in the rat. J Infect Dis 153 (4), 707–714. Jimenez-Lucho, V. E., Saravolatz, L. D., Medieros, A. A., & Pohlod, D. (1986). Failure of therapy in Pseudomonas endocarditis: selection of resistant mutants. Clin Infect Dis 154 (1), 64 – 68. Komshian, S. V., Tablan, O. C., Palutke, W., & Reyes, M. P. (1990). Characteristics of left-sided endocarditis due to Pseudomonas aeruginosa in the Detroit medical Center. Rev Infect Dis 12 (4), 693–702.
Lloyd, K. M., & Gordon, J. N. (1961). Bacterial endocarditis due to Pseudomonas aeruginosa. Ann Intern Med 55, 814 – 817. Moon, Y. S., Chung, K. C., & Gill, M. A. (1997). Pharmacokinetics of meropenem in animals, healthy volunteers, and patients. Clin Infect Dis 24 (Suppl 2), S249 –S255. National Committee for Clinical Laboratory Standards (2002). Performance standards for antimicrobial susceptibility testing; Twelfth Informational Supplement. NCCLS document M 100-S12. National Committee for Clinical Laboratory Standards (1999). Methodology for the Serum Bactericidal Test; Approved Guideline; NCCLS document M 21-A. Norrby, S. R., & Gildon, K. M. (1999). Safety profile of meropenem: A review of nearly 5, 000 patients treated with meropenem. Scand J Infect Dis 31, 3–10. Pfaller, M. A., & Jones, R. N. (1997). A review of the in vitro activity of meropenem and comparative antimicrobial agents tested against 30,254 aerobic and anaerobic pathogens isolated worldwide. Diagn Microbiol Infect Dis 28, 157–163. Reyes, M. P., & Lerner, A. M. (1983). Current problems in the treatment of infective endocarditis due to Pseudomonas aeruginosa. Clin Infect Dis 5 (2), 314 –321. Reyes, M. P., & Lerner, A. (1979). Synergy between carbenicillin and an aminoglycoside (gentamicin or tobramycin) against Pseudomonas aeruginosa isolated from patients with endocarditis and sensitivity of isolates to normal human serum. J Infect Dis 140 (2), 192–202. Wieland, M., Lederman, M. M., Kline-King, C., Keys, T. F., Lerner, P. I., Bass, S. N., Chmielewski, R., Banks, V. D., & Ellner, J. J. (1986). Left-sided endocarditis due to Pseudomonas aeruginosa. Medicine 65 (3), 180 –189.
www.elsevier.com/locate/diagmicrobio
Case reports
Left-sided endocarditis caused by Pseudomonas aeruginosa: successful treatment with meropenem and tobramycin P. J. Gavina,*, M. T. Susenob, F. V. Cookc, L. R. Petersona, R. B. Thomson, Jra a
Departments of Laboratory Medicine and Pathology, Evanston Northwestern Healthcare, Evanston and Feinberg School of Medicine, Northwestern University, Chicago, IL, USA b Pharmacy, Evanston Northwestern Healthcare, Evanston and Feinberg School of Medicine, Northwestern University, Chicago, IL, USA c Internal Medicine, Evanston Northwestern Healthcare, Evanston and Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Received 7 April 2003; received in revised form 17 May 2003
Abstract Medical treatment alone is rarely successful in left-sided infective endocarditis caused by Pseudomonas aeruginosa. We report the cure of such a case with high-dose meropenem in combination with tobramycin. © 2003 Elsevier Inc. All rights reserved. Keywords: Pseudomonas endocarditis; Meropenem
1. Introduction Infective endocarditis caused by Pseudomonas aeruginosa is uncommon. However, associated morbidity and mortality rates are high despite optimal use of available antimicrobials (Komshian et al., 1990; Reyes & Lerner, 1983; Wieland et al., 1986). Most reports concern rightsided disease, which is characteristically associated with injection drug use, is sub-acute in onset and carries a better prognosis (Reyes & Lerner, 1983). Left-sided endocarditis caused by Pseudomonas aeruginosa is a more serious disease and remains an especially difficult therapeutic problem. Reports of cure of left-sided infection with medical treatment alone are rare. Mortality rates of 67% to 85% among patients who received medical treatment alone have led to recommendations for treatment with immediate valve replacement accompanied by a 6-week course of high-dose combined -lactam and aminoglycoside antimicrobials (Komishian et al., 1990; Reyes & Lerner, 1983; Wieland et al., 1986). We report successful medical treatment of leftsided endocarditis caused by Pseudomonas aeruginosa using a combination of meropenem plus tobramycin, both given in high-dose for 6-weeks, following the initial failure
* Corresponding author. Tel.: ⫹1-847-570-2744; Fax: ⫹1-847-7335314. E-mail address: [email protected] (P. J. Gavin). 0732-8893/03/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0732-8893(03)00135-4
of combination regimens with both ceftazidime or piperacillin-tazobactam plus tobramycin. A 35-year-old severely mentally handicapped man was admitted to hospital with a 1 day history of passing bright red blood per rectum and vomiting. This was associated with low-grade tactile fevers and nonproductive cough for 3 days. He had been ill for the previous month with weakness, anorexia and an 8 pound weight loss. Three weeks earlier he had received a 5 day course of oral antibiotics for otitis externa. His past medical history was notable for essential hypertension, a cardiac murmur, and an episode of pneumonia 5 years earlier. Severe mental handicap of unknown cause was evident from 6 months of age. He required assistance with activities of daily living and had lived in a nursing home for the previous 16 years. There was no history of central i.v. access or injection drug use. Examination revealed fever of 38.5°C, pulse of 93/min, respirations of 20/min, blood pressure of 115/66 mm Hg, and chronic bilateral otitis externa. Cardiac examination revealed a grade II/VI holosystolic murmur at the apex with radiation to the axilla. There was no clubbing, splinter hemorrhages, rash or splenomegaly. Laboratory studies showed: hemoglobin, 10g/dL; white blood cell count, 8,900/mm3 (82% neutrophils, 10% monocytes, 8% lymphocytes); platelets, 228,000/mm3, and serum creatinine, 1.0 mg/dL. Blood and urine cultures were obtained. Chest radiography showed a left perihilar infiltrate and treatment
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P.J. Gavin et al. / Diagnostic Microbiology and Infectious Disease 47 (2003) 427– 430
was initiated with azithromycin (500 mg orally q24h) and ceftriaxone (2g iv q12h) for presumed pneumonia. He remained febrile, and 2 days later both sets of blood cultures from admission were positive for Pseudomonas aeruginosa. Gram’s stain of a swab from his right external ear revealed Gram-positive rods and no white blood cells, and culture was positive for light growth of Pseudomonas aeruginosa, coagulase-negative Staphylococcus species and Corynebacterium species. Antimicrobial susceptibilities of the Pseudomonas aeruginosa isolates were determined by standard disc diffusion (NCCLS Standard M2-A7, 35°C) (NCCLS, 2002). Minimum inhibitory concentration values (MICs) were extrapolated from zone-diameters interpreted by the BIOMIC Video Reader System (Giles Scientific, Inc., Santa Barbara, CA.) as previously described (D’Amato et al., 1985). Antibiograms of Pseudomonas aeruginosa isolates from blood and ear cultures were identical: resistant to gentamicin, ciprofloxacin and levofloxacin but susceptible to other antipseudomonal antimicrobials. Specifically, MICs were as follows: amikacin ⬍8 g/ml; aztreonam ⬍4 g/ml; ceftazidime ⬍4 g/ml; ciprofloxacin ⱖ4 g/ml; gentamicin ⱖ8 g/ml; levofloxacin ⱖ8 g/ml; meropenem ⬍0.5 g/ml; piperacillin-tazobactam ⬍1 g/ml; ticarcillin-clavulanate ⬍16 g/ml; and tobramycin ⬍2 g/ml. Antimicrobial treatment was changed to piperacillin-tazobactam (3.375g iv q4h) and tobramycin (400 mg iv q24h). Transesophageal echocardiography revealed a large vegetation (7 mm by 7 mm) on the posterior annulus of the mitral valve, and moderate mitral regurgitation without heart failure. Electrocardiogram showed normal sinus rhythm. Tobramycin was changed to 300 mg q 12h. The patient’s fevers continued and blood cultures were persistently positive for Pseudomonas aeruginosa on hospital Days 3, 4, 5 and 7. On hospital Day 9, he developed intermittent rapid atrial fibrillation, which responded to oral digoxin treatment. Piperacillin-tazobactam was discontinued and treatment with ceftazidime (2g iv q6h) started (tobramycin was continued). Three days later, on hospital Day 12, peak and trough serum inhibitory titers were 1:32 and 1:8, respectively, while peak and trough serum bactericidal titers were 1:16 and 1:8, respectively (NCCLS Standard M21-A) (NCCLS, 1999). However, fevers persisted and repeat blood cultures on hospital Days 10, 11, 14 and 15 remained positive for Pseudomonas aeruginosa. Antimicrobial susceptibilities of Pseudomonas aeruginosa isolates from all repeat positive blood cultures were identical and remained unchanged throughout therapy. Although replacement valve surgery was considered, his guardians declined consent. On hospital Day 17, ceftazidime was discontinued, treatment with meropenem (2g iv q8h) was started, and tobramycin was continued. Repeat blood cultures from the following day, hospital Day 18, and Days 22 and 38 remained sterile. On hospital Day 19, after 2 days of meropenem
treatment, peak serum inhibitory and bactericidal titers were 1:64, while trough inhibitory and bactericidal titers were 1:32 (NCCLS Standard M21-A) (NCCLS, 1999). Tobramycin levels, which were closely monitored during the hospital stay (on 17 occasions at approximately 3-day intervals), demonstrated mean peak and trough levels of 11.8 g/ml (range, 7.5-17.5 g/ml) and 1.09 g/ml (range, 0.3-1.7 g/ml), respectively. Serum creatinine levels were normal throughout. On hospital Day 24, fever finally resolved and thereafter he was afebrile. At this stage, the patient was discharged to a skilled nursing facility to receive a total of 6 weeks of meropenem (2g iv q8h) and tobramycin (300 mg iv q12h). Follow-up transesophageal echocardiogram, after 5 weeks of meropenem treatment, revealed moderate mitral valve regurgitation without evidence of vegetation, and left atrial enlargement without ventricular dysfunction. Two weeks after cessation of antimicrobial therapy, follow-up blood cultures were sterile. Although formal audiometry was not performed, auditory or vestibular toxicity were not apparent. One year later, the patient remains symptom-free and in his usual state of health.
2. Discussion The present report of infective endocarditis caused by Pseudomonas aeruginosa is notable for several reasons. Firstly, the majority of reports of Pseudomonas aeruginosa endocarditis involve iv drug users (more than 90% of reported cases) or prosthetic heart valves (Komshian et al., 1990; Reyes & Lerner, 1983; Wieland et al., 1986). Secondly, it is one of few to document cure of left-sided endocarditis caused by Pseudomonas aeruginosa with medical treatment alone. And finally, to our knowledge, it is the first to describe successful use of high-dose meropenem in this disease. Management of endocarditis caused by Pseudomonas aeruginosa is difficult, particularly so in left-sided disease where medical cure rates may be as low as 12% to 15% (Komshian et al., 1990; Wieland et al., 1986). Treatment failures have been characterized by lack of correlation between in vitro and in vivo susceptibilities, extremely large numbers of organisms present in infected vegetations, and frequent development of resistance on therapy (Diaz et al., 1977; Jimenez-Lucho et al., 1986; Reyes & Lerner, 1983; Wieland et al., 1986). It is believed that slow bactericidal action and lack of post-antibiotic effect of -lactam antimicrobials selects for or induces antibiotic resistant mutants and may lead to treatment failure (Diaz et al., 1977; Jimenez-Lucho et al., 1986). Antimicrobial regimens used in medically cured cases of left-sided endocarditis caused by Pseudomonas aeruginosa are summarized in Table 1. Additional reports of apparent medical successes were not evaluable because either the diagnosis of endocarditis was not definitive or later valvereplacement surgery was required. Most authorities now
P.J. Gavin et al. / Diagnostic Microbiology and Infectious Disease 47 (2003) 427– 430
429
Table 1 Cases of left-sided endocarditis caused by Pseudomonas aeruginosa cured by medical treatment alone Reference (Year)
Antimicrobial regimen (duration)
No. of patients
Serum bactericidal titers
Lloyd & Gordon (1961)
Polymixin plus tetracycline, colistin, kanamycin, sulfisoxazole (6 wks) Carbenicillin plus polymixin (6 wks) Ticarcillin plus tobramycin (6 wks) Ticarcillin plus tobramycin (6 wks) Ceftazidime plus tobramycin (6 wks) Ticarcillin plus tobramycin or amikacin (mean, 6 wks) Meropenem plus tobramycin (6 wks)
1
NR
1 3 of 9 1 of 6 1 1 of 7
Peak, 1:10; trough, 1:5 NR Peak, 1:4; trough, ⬍1:2 Peak, 1:32; trough, 1:8 NR
1
Peak, 1:64; trough, 1:32
Diaz et al. (1977) Reyes & Lerner, (1983) Wieland et al., (1986) Cabinian & Kaatz, (1987) Komshian et al., (1990) Present report Note: NR, not recorded.
recommend treatment of left-sided endocarditis caused by Pseudomonas aeruginosa with immediate valve replacement accompanied by a 6 week course of high-dose combined extended spectrum -lactam plus aminoglycoside antimicrobials (Komshian et al., 1990; Reyes & Lerner, 1983; Wieland et al., 1986). Such a combined surgical/medical approach is associated with improved survival (Komshian et al., 1990; Wieland et al., 1986). In the present case, surgical treatment was not feasible and optimal medical treatment was required. In contrast to other -lactam antimicrobials, carbapenems, have demonstrated rapid bactercidal action and post-antibiotic effect against Pseudomonas aeruginosa (Bustamente et al., 1984; Bowker et al., 1996). Meropenem was chosen for its documented activity against Pseudomonas aeruginosa and good safety profile in high-dose. Meropenem has the broadest antibacterial spectrum of any -lactam agent available and has greater intrinsic activity in vitro against clinical isolates of Pseudomonas aeruginosa than aminoglycoside, quinolone and comparable -lactam antimicrobials, including imipenem, ceftazidime and piperacillin (Iaconis et al., 1997; Pfaller & Jones, 1997). It is highly active against most Gram-negative bacilli including Pseudomonas aeruginosa, and is less likely to induce seizures than is imipenem (Craig, 1997; Norrby & Gildon, 1999). Furthermore, low protein binding provides a good pharmacodynamic profile (Moon et al., 1997; Astra-Zeneca Pharmaceuticals, 2001). In animal models of endocarditis caused by Pseudomonas aeruginosa, sustained high concentrations of -lactam antimicrobials within vegetations are important for treatment success (Bayer et al., 1988; Ingerman et al., 1986). Specifically, it is proposed that reduced antibiotic penetrance within left-sided Pseudomonas aeruginosa-infected vegetations contributes to the strikingly higher mortality in left-sided relative to right-sided endocarditis (Bayer et al., 1988). In addition, very large concentrations of antimicrobial are required to saturate the polyanionic glycocalyx biofilm of Pseudomonas aeruginosa before antimicrobial penetration to the bacterial cell can occur (Costerton, 1984). The usual dosage of meropenem in adults is 500 mg to 1g iv q8h. To maximize serum concentrations we elected to use the highest recommended dose of meropenem (2g iv q8h),
which is normally reserved for patients with meningitis (Astra-Zeneca Pharmaceuticals, 2001). In previous series of left-sided endocarditis caused by Pseudomonas aeruginosa, measurement of serum inhibitory or bactericidal activity was of no predictive value (Wieland et al., 1986). Similarly, in the present report, earlier treatment with ceftazidime failed despite apparently effective serum bactericidal activity in vitro. However, subsequent treatment with meropenem, which was associated with a somewhat more favorable serum bactericidal profile, was successful. Aminoglycoside and -lactam antibiotics, including meropenem, have demonstrated in vitro synergy in endocarditis caused by Pseudomonas aeruginosa (Reyes & Lerner, 1983; Reyes & Lerner, 1979). Reyes et al. suggest a target serum C max for the aminoglycoside of 12-20 g/ml, with values for tobramycin toward the lower end of the range (Reyes & Lerner, 1983). In the present case, tobramycin given in high-dose was chosen as the combination treatment, with frequent monitoring of tobramycin levels to minimize the risk of toxicity. We conclude that in select cases of left-sided endocarditis caused by Pseudomonas aeruginosa, where surgery may not be feasible, medical treatment alone with meropenem plus an aminoglycoside, both in high-dose, is a therapeutic option.
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