Infective Endocarditis Caused by Enterococcus faecalis treated with Continuous Infusion of Ampicillin without Adjunctive Aminoglycosides

Transcription

1 CASE REPORT Infective Endocarditis Caused by Enterococcus faecalis treated with Continuous Infusion of Ampicillin without Adjunctive Aminoglycosides Taku Ogawa, Masatoshi Sato, Shinsuke Yonekawa, Chiyo Nakagawa, Kenji Uno, Kei Kasahara, Koichi Maeda, Mitsuru Konishi and Keiichi Mikasa Abstract Aminoglycosides are useful antimicrobial agents for treating infective endocarditis; however, they occasionally cause troublesome side effects, such as nephrotoxicity and ototoxicity. We herein report a case of infective endocarditis caused by Enterococcus faecalis that was treated successfully with continuous infusion of ampicillin without adjunctive aminoglycosides. The serum ampicillin concentrations were higher than the minimal inhibitory concentration for the target strain. Although the use of ampicillin monotherapy is currently avoided because double β-lactam therapy is reportedly more effective, continuous penicillin administration remains an effective therapeutic choice for treating infective endocarditis. Key words: infective endocarditis, Enterococcus faecalis, ampicillin, continuous infusion, concentration () () Introduction Infective endocarditis is an important differential diagnosis for a fever of unknown origin. It should be diagnosed as quickly as possible and treated appropriately because it occasionally causes severe complications, such as vertebral osteomyelitis, infective aneurysms and abdominal abscesses. Frequently, penicillin places a burden on patients, doctors and nurses because the drug may be administered up to six times per day. Consequently, treatment with the continuous intravenous infusion of β-lactam antibiotics has recently attracted attention; however, few studies have so far reported the antibiotic concentrations in patients sera. The American Heart Association statement on Infective endocarditis: diagnosis, antimicrobial therapy and management of complications (1) recommends the use of the continuous infusion of penicillin G as an alternative to intermittent administration; however, continuous infusion of ampicillin is not currently recommended. Because there is no clear evidence regarding the inferiority of continuous infusion relative to intermittent administration, we therefore decided to evaluate continuous ampicillin infusion in a patient with infective endocarditis caused by Enterococcus faecalis. We measured the patient s serum ampicillin concentrations and performed blood cultures frequently to ensure the efficacy and safety of this therapy. We herein report a case of infective endocarditis caused by E. faecalis that was successfully treated with the continuous intravenous infusion of ampicillin alone. Case Report A 73-year-old man was admitted to our hospital in March 2008 presenting with a fever of unknown origin. The patient reported a history of a left cerebral infarction that had occurred 16 years previously followed by right hemiplegia. He was under prolonged anticoagulation therapy with warfarin for chronic atrial fibrillation. He had no remarkable family medical history and reported no smoking or alcohol consumption. The patient had previously been hospitalized for approximately five months for a right femoral neck fracture. He underwent right total hip arthroplasty, and gait rehabilitation Center for Infectious Diseases, Nara Medical University, Japan Received for publication June 20, 2012; Accepted for publication February 1, 2013 Correspondence to Dr. Taku Ogawa, t_ogawa@naramed-u.ac.jp 1131

2 Table 1. Laboratory Findings on the Day of Admission Table 2. The Susceptibility Test Results of the E. faecalis Obtained from the Patient Susceptibility of gentamicin and streptomycin was tested using the disc diffusion method. Other agents were tested using the microdilution. was initiated because no postoperative complications were observed. Approximately four months before being admitted to our hospital, he experienced gradual improvement in his daily activities. However, he simultaneously developed a fever of approximately 38. Initially, pyelonephritis was suspected due to macroscopic pyuria; however, no urine culture tests were performed. 81 and 61 days before admission to our hospital, blood culture results revealed the presence of E. faecalis. Piperacillin at a dose of 2 g twice daily was administered one day after diagnosis, which was changed five days later to flomoxef at a dose of 1 g twice daily after piperacillin failed to show any effects. When flomoxef failed to improve the patient s condition after three days, vancomycin was initiated at a dose of 0.5 g twice daily. However, vancomycin was also ineffective, and sulbactam-ampicillin at a dose of 3 g (1 g of sulbactam plus 2 g of ampicillin) twice daily was administered 43 days before the patient was admitted to our hospital. Despite these therapies, the patient s fever persisted. Gallium scintigraphy revealed an abnormal uptake in the patient s thoracic vertebra that was suggestive of vertebral osteomyelitis. His spinal tissue was collected and investigated pathologically and microbiologically. The pathological examination revealed severe inflammation; however, no organisms were detected on microbiological examinations. In view of the persistent fever, the patient was transferred to our hospital with a diagnosis of fever of unknown origin under ongoing sulbactam-ampicillin therapy. On admission, the patient had a body temperature of 38.0, a heart rate of 92 beats/min (irregular), a blood pressure of 104/56 mmhg and an oxygen saturation level of 97% (room air). Although the patient s respiratory rate was not measured precisely, it did not appear to be markedly elevated. The patient was conscious, without any evidence of mental disturbance; however, right hemiplegia was apparent. No signs of hemorrhage in the conjunctiva were observed, and the cervical lymph nodes were not palpable. No crackling sounds during inspiration or expiration, excessive heart sounds or murmurs or abnormalities in the abdomen were detected. An examination of the patient s entire skin did not reveal any signs indicative of infective endocarditis, and no evidence of spinal pain or heat was observed. The psoas sign was negative. The blood examination and urinalysis results showed some abnormalities (Table 1). Electrocardiography revealed atrial fibrillation. On day 2 of hospitalization, E. faecalis was detected in two sets of blood samples that were obtained on the day of admission. We initiated vancomycin at a dose of 1 g twice daily and gentamicin at a dose of 50 mg thrice daily as an empirical therapy for enterococcal bacteremia. However, after the susceptibility test results (Table 2) were obtained on day 3 of hospitalization, we decided to deescalate the antibiotic therapy and switch to a continuous infusion of ampicillin alone. On the seventh day of hospitalization, transthoracic echocardiography was performed to detect valve vegetation. We observed an abnormal echo around the mitral valve, which we suspected was due to vegetation. Accordingly, transesophageal echocardiography was performed on the following day. An oscillating vegetation measuring approximately 1132

3 Discussion Figure. Vegetation on anterior mitral valve leaflet with rapid swaying (size: approximately 11 mm in diameter). 11 mm in diameter attached to the anterior leaf of the mitral valve was observed (Figure). The patient was diagnosed with infective endocarditis caused by E. faecalis based on the modified Duke criteria (2). We confirmed the susceptibility of the targeted strain of E. faecalis to aminoglycosides using disc diffusion in accordance with the Clinical Laboratory and Standards Institute manual statement, Performance Standards for Antimicrobial Susceptibility Testing (M100-S21) (3). We found that the strain was highly resistant to gentamicin and sensitive to streptomycin (Table 2). We therefore decided to treat the patient with a continuous infusion of ampicillin alone at a dose of 12 g/d. The treatment protocol consisted of a continuous ampicillin infusion for 24 hours, followed by ampicillin (6 g) dissolved in 18 ml of saline administered at a rate of 1.7 ml/h using an infusion pump. The solution was changed twice per day. The patient s fever was alleviated within three days of initiating this treatment, and his blood cultures became negative after one week. We continued the treatment for 59 days until the erythrocyte sedimentation rate stabilized. Blood cultures were performed every week, and all culture results, except for those obtained on the day of admission, were negative. Transesophageal echocardiography was repeated on day 51 of hospitalization, which revealed that the vegetation had disappeared. No side effects, such as hyperkalemia, venous phlebitis or neutropenia, were observed during the course of treatment. The patient s serum ampicillin concentrations on days 33 and 40 of hospitalization (days 30 and 37 from the initiation of the continuous infusion) were 13.4 μg/ml and 15.0 μg/ ml, respectively. The serum ampicillin concentrations were measured using high performance liquid chromatography and were well above the minimum inhibitory concentration for the target E. faecalis. After completing the treatment, the patient underwent rehabilitation and was discharged from our hospital. Enterococcus spp. is one of the most important pathogens of infective endocarditis. In the American Heart Association s guidelines regarding infective endocarditis published in 2005 (1), the combined use of penicillin antibiotics and aminoglycoside antibiotics is recommended when no highlevel resistance to aminoglycosides is found. Administering 24 million units of penicillin G per day divided into six doses or via continuous infusion or 12 g of ampicillin per day divided into six doses is recommended. In the case reported here, E. faecalis exhibited high-level resistance to gentamicin and sensitivity to streptomycin. According to the guidelines, combination therapy with streptomycin plus ampicillin was recommended (1, 4). However, the frequent administration of streptomycin via intramuscular injection under anticoagulation entailed the possibility of complications, such as hematoma formation. For this reason, we avoided using streptomycin. The American Heart Association guidelines (1) recommend the use of continuous infusion of penicillin G. This recommendation is supported by animal studies, in which continuous infusion has been found not to be inferior to intermittent administration (5); however, there are no studies comparing continuous administration with intermittent infusion of ampicillin. We feared that penicillin G infusion into our patient s very thin vessels could easily cause phlebitis. Moreover, one study reported a tendency for missed doses to occur more frequently in nonintensive care unit settings than in intensive care unit settings when the doses are prescribed every four hours (6). The continuous infusion of β- lactam antibiotics in general does not appear to be inferior to intermittent administration (7-10). Furthermore, the effects correlate with the time above the minimum inhibitory concentration (11, 12). We came to the conclusion that a continuous infusion of ampicillin would be an acceptable method of treating this patient. Some reports state that the combined use of penicillin antibiotics and ceftriaxone is effective against infective endocarditis caused by Enterococcus spp. that exhibits high-level resistance to aminoglycosides (13-15). We did not adopt this double β-lactam treatment for this patient. However, considering the high failure rate of treatment of enterococcal infective endocarditis with ampicillin alone (16), adopting double β-lactam therapy could be worth considering at the present time. Generally, when continuous infusion is performed, the peaks and troughs of the serum concentration disappear and become consistently uniform; thus, the theoretical time above the minimal inhibitory concentration would be either 0% or 100%. Continuous infusion of penicillin antibiotics is considered to be effective only when the appropriate dosage is set. In our case, the serum ampicillin concentration accurately exceeded the minimal inhibitory concentration. It would therefore be useful in the future to study more such 1133

4 cases in order to examine the relationship between the serum concentration and the ampicillin dosage using the continuous infusion method. In cases treated with quinolones, maintaining a serum concentration within the mutant selection window (between the minimal inhibitory concentration and the mutant prevention concentration) for a long time can induce drug resistance (17, 18). In our treatment method, the serum concentration was above the minimal inhibitory concentration but was not very high compared with the intermittent method. The relationship between the mutant selection window and resistance induction to β-lactams is uncertain at this time; therefore, it is still impossible to assess whether this administration method contributes to resistance induction. We believe that further research is needed into the relationship between the serum concentrations of β-lactams and resistance formation. The guidelines regarding valvular disease issued by the American Heart Association in 2006 (19) state that early surgical intervention reduces the recurrence of infective endocarditis. In 2012, there were reports of randomized trials that support this view (20). However, even in the infective endocarditis clinical practice guidelines issued by the European Society of Cardiology in 2009 (21), early surgical intervention was deemed to be at an evidence level of IIb, which is not very high. Furthermore, a diameter 10 mm, which is a general indication for surgical intervention, is not a definitive criterion supported by randomized trials, and the standards applied to surgical intervention are not absolute. Taking this into account, we judged that our patient did not have a definite indication for surgical intervention. In addition, the heart surgery department of our hospital did not recommend immediate surgical intervention because there was no evidence of heart failure. Since the vegetation was found to have disappeared without any symptoms of embolism on the second transesophageal echocardiogram, we considered that surgery was not necessary. In the case reported herein, we successfully treated enterococcal infective endocarditis using continuous infusion of ampicillin only. We believe that continuous infusion is effective as an alternative administration method; however, it may still cause some problems. When the dosage is too low, the time above the minimal inhibitory concentration theoretically becomes 0%. Therefore, the relationship between the dosage of ampicillin and the serum concentration needs to be clarified in a larger group of patients. In conclusion, our findings indicate that continuous infusion of ampicillin at a sufficient dosage is an acceptable method when ampicillin is used as an antibiotic agent to treat infective endocarditis caused by Enterococcus spp. The authors state that they have no Conflict of Interest (COI). References 1. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 111: e394-e434, Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med 96: , Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing, M100-S21, Henry NK, Wilson WR, Geraci JE. Treatment of streptomycinsusceptible enterococcal experimental endocarditis with combinations of penicillin and low- or high-dose streptomycin. Antimicrob Agents Chemother 30: , Eagle H, Fleischman R, Levy M. Continuous vs. discontinuous therapy with penicillin: the effect of the interval between injections on therapeutic efficacy. N Engl J Med 248: , Hughes DW, Frei CR, Maxwell PR, et al. Continuous versus intermittent infusion of oxacillin for treatment of infective endocarditis caused by methicillin-susceptible Staphylococcus aureus. Antimicrob Agents Chemother 53: , Roberts JA, Webb S, Paterson D, Ho KM, Lipman J. A systematic review on clinical benefits of continuous administration of β- lactam antibiotics. Crit Care Med 37: , Buck C, Bertram N, Ackermann T, et al. Pharmacokinetics of piperacillin-tazobactam: intermittent dosing versus continuous infusion. Int J Antimicrob Agents 25: 62-67, Lau WK, Mercer D, Itani KM, et al. Randomized, open-label, comparative study of piperacillin-tazobactam administered by continuous infusion versus intermittent infusion for treatment of hospitalized patients with complicated intra-abdominal infection. Antimicrob Agents Chemother 50: , Pédeboscq S, Dubau B, Frappier S, et al. Comparison of 2 administration protocol (continuous or discontinuous) of a timedependent antibiotic, Tazocin. Pathol Biol (Paris) 49: , Nicolau DP. Pharmacodynamic optimization of beta-lactams in the patient care setting. Crit Care 12 (Suppl 4): S2, Chain E, Florey HW, Adelaide MB, et al. Penicillin as a chemotherapeutic agent. Lancet 236: , Gavaldà J, Torres C, Tenorio C, et al. Efficacy of ampicillin plus ceftriaxone in treatment of experimental endocarditis due to Enterococcus faecalis strains highly resistant to aminoglycosides. Antimicrob Agent Chemother 43: , Gavaldà J, Len O, Miró JM, et al. Brief communication: treatment of Enterococcus faecalis endocarditis with ampicillin plus ceftriaxone. Ann Intern Med 146: , Euba G, Lora-Tamayo J, Murillo O, et al. Pilot study of ampicillin-ceftriaxone combination for treatment of orthopedic infections due to Enterococcus faecalis. Antimicrob Agents Chemother 53: , Geraci JE, Martin WJ. Antibiotic therapy of bacterial endocarditis. VI. Subacute enterococcal endocarditis: clinical, pathologic and therapeutic consideration of 33 cases. Circulation 10: , Zhao X, Drlica K. Restricting the selection of antibiotic-resistant mutants: a general strategy derived from fluoroquinolone studies. Clin Infect Dis 33: S147-S156, Zhao X, Drlica K. Restricting the selection of antibiotic-resistant mutants: measurement and potential uses of the mutant selection window. J Infect Dis 185: , Bonow RO, Carabello B, Chatterjee K, et al. ACC/AHA

5 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients with Valvular Heart Disease). Circulation 114: e84-e231, Kang DH, Kim YJ, Kim SH, et al. Early surgery versus conventional treatment for infective endocarditis. N Engl J Med 28: , Habib G, Hoen B, Tornos P, et al. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009). Eur Heart J 30: , The Japanese Society of Internal Medicine