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Brief Communication: Treatment of Enterococcus faecalis Endocarditis with Ampicillin plus Ceftriaxone

Joan Gavaldà, MD; Oscar Len, MD; José M. Miró, MD; Patricia Muñoz, MD; Miguel Montejo, MD; Aristides Alarcón, MD; Julián de la Torre-Cisneros, MD; Carmen Peña, MD; Xavier Martínez-Lacasa, MD; Cristina Sarria, MD; Germán Bou, MD; José M. Aguado, MD; Enrique Navas, MD; Joan Romeu, MD; Francesc Marco, MD; Carmen Torres, MD; Pilar Tornos, MD; Ana Planes, MD; Vicenç Falcó, MD; Benito Almirante, MD; and Albert Pahissa, MD
[+] Article and Author Information

From the Hospital Universitari Vall d'Hebron, Institut d'Investigacions Biomediques August Pi i Sunyer, Hospital de Bellvitge, Mutua de Terrassa, and Hospital Germans Tries i Pujol, Barcelona, Spain; Hospital Gregorio Marañón, Hospital Universitario de La Princesa, Hospital Doce de Octubre, and Hospital Ramón y Cajal, Madrid, Spain; Hospital de Cruces, Barakaldo, Spain; Hospital Virgen del Rocío, Seville, Spain; Hospital Reina Sofía, Córdoba, Spain; Hospital Juan Canalejo, La Coruña, Spain; and Universidad de La Rioja, Logroño, Spain.


Note: Presented in part at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Illinois, 16–19 December 2001 (abstract 1342).

Acknowledgment: The authors thank Celine Cavallo for Englishlanguage assistance.

Grant Support: Dr. Len received a research grant from Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, Spanish Network for the Research in Infectious Diseases (REIPI RD06/0008), and Dr. Miró received a research grant from Institut d'Investigacions Biomediques August Pi i Sunyer.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Joan Gavaldà, MD, Servei de Malalties Infeccioses, Hospital Universitari Vall d'Hebron, Paseo Vall d'Hebron 119-129, 08035 Barcelona, Spain; e-mail, jgavalda@ir.vhebron.net.

Current Author Addresses: Drs. Gavaldà, Len, Tornos, Planes, Falcó, Almirante, and Pahissa: Hospital Universitari Vall d'Hebron, Paseo Vall d'Hebron 119-129, 08035 Barcelona, Spain.

Drs. Miró and Marco: Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer, Calle Villarroel, 170, 08036 Barcelona, Spain.

Dr. Muñoz: Hospital Gregorio Marañón, Calle Doctor Esquerdo, 46, 28007 Madrid, Spain.

Dr. Montejo: Hospital de Cruces, Plaza de Cruces, s/n, 48903 Cruces/Barakaldo, Spain.

Dr. Alarcón: Hospital Virgen del Rocío, Avenida Manuel Siurot, s/n, 41013 Sevilla, Spain.

Dr. de la Torre-Cisneros: Hospital Reina Sofía, Menéndez Pidal, s/n, 14004 Córdoba, Spain.

Dr. Peña: Hospital de Bellvitge, Feixa Llarga, s/n, 08907 Hospitalet de Llobregat, Barcelona, Spain.

Dr. Martínez-Lacasa: Hospital Mutua de Terrassa, Plaça Dr. Robert, 5, 08221 Terrassa, Barcelona, Spain.

Dr. Sarria: Hospital Universitario de La Princesa, Diego de León, 62, 28006 Madrid, Spain.

Dr. Bou: Hospital Juan Canalejo, Lugar Jubias de Arriba, La Coruña, Spain.

Dr. Aguado: Hospital Doce de Octubre, Avenida de Córdoba, s/n, 28041 Madrid, Spain.

Dr. Navas: Hospital Ramón y Cajal, Carretera de Colmenar Viejo, Km 9, 1, 28034 Madrid, Spain.

Dr. Romeu: Hospital Germans Tries i Pujol, Carretera de Canyet s/n, 08916 Badalona, Barcelona, Spain.

Dr. Torres: Universidad de La Rioja, Avenida de La Paz, 93, 26006 Logroño, Spain.

Author Contributions: Conception and design: J. Gavaldà, O. Len.

Analysis and interpretation of the data: J. Gavaldà, O. Len.

Drafting of the article: J. Gavaldà, O. Len.

Critical revision of the article for important intellectual content: J. Gavaldà, O. Len, V. Falcó, B. Almirante, A. Pahissa.

Final approval of the article: J. Gavaldà, O. Len, J.M. Miró, P. Muñoz, M. Montejo, A. Alarcón, J. de la Torre-Cisneros, C. Peña, X. Martínez-Lacasa, C. Sarria, G. Bou, J.M. Aguado, E. Navas, J. Romeu, F. Marco, C. Torres, P. Tornos, A. Planes, V. Falcó, B. Almirante, A. Pahissa.

Provision of study materials or patients: J. Gavaldà, O. Len, J.M. Miró, P. Muñoz, M. Montejo, A. Alarcón, J. de la Torre-Cisneros, C. Peña, X. Martínez-Lacasa, C. Sarria, G. Bou, J.M. Aguado, E. Navas, J. Romeu, F. Marco, C. Torres, P. Tornos, A. Planes, V. Falcó, B. Almirante.

Collection and assembly of data: J. Gavaldà, O. Len.


Ann Intern Med. 2007;146(8):574-579. doi:10.7326/0003-4819-146-8-200704170-00008
Text Size: A A A

The institutional review boards of the participating institutions approved the study. Patients were eligible if they had definite endocarditis due to HLAR E. faecalis (highly resistant to gentamicin and streptomycin); were susceptible to ampicillin (minimal inhibitory concentration, 1 to 4 µg/mL) as described elsewhere (11), defined according to the modified Duke criteria (13); and provided written informed consent. Patients were consecutively enrolled between 1995 and 2003. In January 2000, a protocol amendment was approved to include patients with non-HLAR enterococcal infection and renal failure or a risk for nephrotoxicity. We enrolled a total of 43 patients from 13 centers throughout Spain. Data were previously presented in part elsewhere (14).

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Grahic Jump Location
Figure.
Kaplan–Meier curve of time to failure for any reason.

HLAR = high-level aminoglycoside resistance.

Grahic Jump Location

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Ampicillin plus Ceftriaxone for HLAR E. faecalis Endocarditis
Posted on April 22, 2007
Akashdeep Singh
Christian Medical College and Hospital
Conflict of Interest: None Declared

The antimicrobial synergism of ampicillin plus ceftriaxone for the treatment of Enterococcus faecalis endocarditis as shown by Joan Gavalda and collegues is appreciable. There are certain basic quires which need to be answered before it can be incorporated into the day to day practice. First, enterococci are inherentally resistant to cephalosporins including ceftriaxone. Second, ampicillin and ceftriaxone are both β-lactam antibiotics having a common mechanism of action - inhibition of synthesis of the bacterial peptidoglycan cell wall. Antimicrobial agents acting at different targets may enhance the overall antimicrobial activity. Then how can it be believed that there will be synergism between these two drugs. Treatment of HLAR E. faecalis depends on precise determination of antibiotic susceptibilities, testing for bactericidal activity, ascertainment of the serum inhibitory and bactericidal titres, and monitoring of drug concentrations in the serum. Although aminoglycoside- resistance is often present, these drugs can still synergize with cell- wall inhibitors provided that the aminoglycoside's MIC is 1000 mg/L or less.1 Streptomycin is worth testing because it can be active against enterococci that are resistant to other aminoglycosides.2

The cure rates for HLAR E. faecalis in the present study was 52% with the ampicillin plus ceftriaxone combination therapy which is not different from cure rate with a cell wall susceptible agent alone.3 (40- 50%)

References

1. F Caron, M Pestel, MD Kitzis, JF Lemeland, G Humbert and L Gutmann, Comparison of different beta-lactam-glycopeptide-gentamicin combinations for an experimental endocarditis caused by a highly beta- lactam-resistant and highly glycopeptide-resistant isolate of Enterococcus faecium, J Infect Dis 171 (1995), pp. 106"“112.

2. B Hoen, F Alla and C Selton-Suty et al., Changing profile of infective endocarditis, results of a 1-year survey in France, JAMA 288 (2002), pp. 75"“81.

3. Eliopoulos GM: Aminoglycoside-resistant enterococcal endocarditis. Infectious Disease Clinics of North America. 1993, 7: 117- 133.

Conflict of Interest:

None declared

Re: Ampicillin plus Ceftriaxone for HLAR E. faecalis Endocarditis
Posted on June 19, 2007
Joan Gavaldà
Servei Malalties Infeccioses. Hospital Vall d'Hebron.
Conflict of Interest: None Declared

We read with interest the letter by Dr. Singh [1] regarding our article "Brief communication: treatment of Enterococcus faecalis endocarditis with ampicillin plus ceftriaxone" [2]. First of all, we would like to clarify that the cure rate for HLAR E. faecalis endocarditis was 71.4%, far away from the best cure rate reached with a cell wall susceptible agent alone or in combination. Carefully reading the article we did not find any figure or data that could address anyone to confussion. Second; considering the limitations of space established by Annals of Internal Medicine, we could not give detailed information about Dr. Singh's concerns [1]. In any case, the first Singh's question about the sinergic effect of ampicillin plus ceftriaxone was evaluated in vitro by Mainardi et al (3) and by our group in different studies in the experimental endocardis model (4,5). Mainardi et al (3), with amoxicillin and cefotaxime, proposed that "at low amoxicillin concentrations, the low- molecular-weight penicillin-binding proteins (PBPs) 4 and 5 would be partially saturated, but the nonessential PBPs 2 and 3 could participate in building the cell wall; the combination with cefotaxime would totally saturate PBPs 2 and 3, producing the bactericidal synergistic effect". Thereafter, our group showed that the combination of ampicillin plus ceftriaxone was as effective as ampicillin plus gentamicin for the treatment of experimental endocarditis due to E.faecalis without high resistance to Ags (4) and a greater efficacy than ampicillin alone in the experimental endocarditis model due to HLRAg E.faecalis (5). Third, although we agree with Dr. Singh's about the possible usefulness of the combination of ampicillin plus gentamicin if the aminoglycoside's MIC is between 500 and 1000 mg/L it may be only a theoretical question and probably with the results of our study the combination of ampicillin plus ceftriaxone would be more successful. Potential conflicts of interest. All authors: no conflicts. References

1. Singh A. Ampicillin plus ceftriaxone for HLAR E. faecalis endocarditis (letter). Ann Intern Med 2007;146:56

2. Gavalda J, Len O, Miro JM, et al. Brief communication: treatment of Enterococcus faecalis endocarditis with ampicillin plus ceftriaxone. Ann Intern Med 2007;146:574-9.

3. Mainardi JL, Gutmann L, Acar JF, Goldstein FW. Synergistic effect of amoxicillin and cefotaxime against Enterococcus faecalis. Antimicrob Agents Chemother. 1995;39:1984-7. Erratum in: Antimicrob Agents Chemother 1995;39:2835

4. Gavalda J, Onrubia PL, Gomez MT, Gomis X, Ramirez JL, Len O, Rodriguez D, Crespo M, Ruiz I, Pahissa A. Efficacy of ampicillin combined with ceftriaxone and gentamicin in the treatment of experimental endocarditis due to Enterococcus faecalis with no high-level resistance to aminoglycosides. J Antimicrob Chemother. 2003;52:514-7

5. Gavalda J, Torres C, Tenorio C, Lopez P, Zaragoza M, Capdevila JA, Almirante B, Ruiz F, Borrell N, Gomis X, Pigrau C, Baquero F, Pahissa A. Efficacy of ampicillin plus ceftriaxone in treatment of experimental endocarditis due to Enterococcus faecalis strains highly resistant to aminoglycosides. Antimicrob Agents Chemother. 1999;43:639-46

Conflict of Interest:

None declared

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Summary for Patients

Successful Treatment of Aminoglycoside-Resistant Endocarditis with Ampicillin and Ceftriaxone

The summary below is from the full report titled “Brief Communication: Treatment of Enterococcus faecalis Endocarditis with Ampicillin plus Ceftriaxone.” It is in the 17 April 2007 issue of Annals of Internal Medicine (volume 146, pages 574-579). The authors are J. Gavaldà, O. Len, J.M. Miró, P. Muñoz, M. Montejo, A. Alarcón, J. de la Torre-Cisneros, C. Peña, X. Martínez-Lacasa, C. Sarria, G. Bou, J.M. Aguado, E. Navas, J. Romeu, F. Marco, C. Torres, P. Tornos, A. Planes, V. Falcó, B. Almirante, and A. Pahissa.

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