Treatment of infective endocarditis
Infective endocarditis is a potentially lethal disease and requires prolonged antibiotic therapy. The aim of antibiotic therapy is to eradicate infection which includes sterilization of the vegetations. But there are certain challenges in the sterilization of vegetations. There is a high microbial density in the vegetations, with slow rate of growth and consequently low metabolic activity of the microorganisms. Stationary phase organisms lose penicillin binding proteins which are the target sites for β-lactam antibiotics. In addition microbes are surrounded by a biofilm which protects them against the action of antimicrobials [1]. All these translate into a need for prolonged parenteral therapy with its own problems like maintaining safe vascular access.
Discussion of whole list of options of antimicrobials for different varieties of endocarditis is quite a large topic. This discussion is only a broad outline of the antimicrobial treatment of infective endocarditis, meant mainly for exam purpose rather than actual clinical treatment. References to more detailed guidelines have been provided for those who wish to learn more.
Inoculum Effect
High microbial density as in vegetations cause less antimicrobial activity of some antimicrobial agents. This is known as inoculum effect and has been documented with β-lactams and glycopeptides but not linezolid, in the treatment of Staphylococcus aureus [2]. Inoculum effect is less with fluoroquinolones and aminoglycosides [1,3].
Need for bactericidal drugs
Bactericidal drugs are needed to sterilize the vegetations of infective endocarditis which have high microbial density. Combination of β-lactams with aminoglycosides is useful in this context. Sometimes bactericidal effect can be obtained by the synergistic effect of bacteriostatic drugs.
Need for prolonged therapy
Need for prolonged antimicrobial therapy has been highlighted initially. This is needed because of the slow activity of most drugs against high bacterial density. But when the organisms are quite sensitive, shorter duration may be sufficient. One study has demonstrated that a 2 week course of ceftriaxone plus netilmicin can be useful in the treatment of streptococcal endocarditis [4]. But potential nephrotoxicity and ototoxicity of netilmicin have to be kept in mind. Two week therapy and even monotherapy with β-lactam antibiotic have been used successfully in right sided endocarditis [1]. But these are exceptions rather than the rule. Right sided vegetations tend to have lower bacterial densities.
Treatment of infective endocarditis is often empirical in the initial phase because of delay in getting appropriate culture and sensitivity reports. Choice of antibiotics depend on the clinical scenario in which endocarditis has occurred. Important factors include injection drug abuse, the presence of indwelling catheters or indwelling medical devices, associated genitourinary disorders, infection or procedure, including pregnancy, delivery and abortion, chronic skin infections, dental sepsis and procedures, cirrhosis, burns, diabetes mellitus, prosthetic valves, immunodeficiency, immunosuppression, and gastrointestinal lesions [1]. In each of these situations, there is a list of probable organisms and it is better to check available reference tables rather than memorize the options.
It has been suggested that if positive blood cultures are obtained, repeat cultures at 24-48 hour intervals be taken to document clearance of organisms from the blood stream. Counting of duration of antibiotic therapy may be from the day on which it becomes negative when it was positive initially [1].
While treating streptococcal endocarditis with highly sensitive organisms, 4 week course of penicillin G or ceftriaxone has been shown to have good efficacy [5]. Ceftriaxone had the advantage of being a once daily dosage. Ceftriaxone plus gentamicin for 2 weeks or vancomycin for 4 weeks are other options. Other potential nephrotoxic medications like non-steroidal anti inflammatory agents should be avoided while using gentamicin. When the streptococci are not highly sensitive, penicillin for 4 weeks is combined with gentamicin for 2 weeks. Vancomycin for 4 weeks is the alternative option. Ceftriaxone may be considered if the organisms are sensitive to it. In the presence of a prosthetic valve or prosthetic valve material, duration of therapy is 6 weeks.
Staphylococcus aureus is now the most common causative organism for infective endocarditis in most of the industrialized nations [1]. This has been primarily attributed to healthcare contact in the form of intravascular catheters, surgical wounds, prosthetic devices and hemodialysis. But it is interesting to note that most patients with health care associated Staphylococcus aureus infective endocarditis (60.1%), acquired the infection outside of the hospital [6].
Coagulase-Negative Staphylococci are important in the setting of prosthetic valve endocarditis and a small but significant number of cases of native valve endocarditis.
Right sided endocarditis
Gentamicin is not recommended for staphylococcal infection in right sided native valve endocarditis [1]. Shorter duration of 2 week therapy with parenteral β-lactam or daptomycin is enough for uncomplicated right sided methicillin sensitive staphylococcal endocarditis. Longer duration of therapy is needed for methicillin resistant staphylococci with glycopeptide antibiotics [1].
Prosthetic valve endocarditis
Duration of treatment for prosthetic valve endocarditis is 6 weeks or more. Rifampicin is an important drug in this situation. For oxacillin-susceptible strains of staphylococci, rifampicin and oxacillin for a minimum of 6 weeks along with gentamicin for initial 2 weeks are recommended. In case of oxacillin resistance, vancomycin and rifampicin for a minimum of 6 weeks and gentamicin for initial 2 weeks are considered. 2015 ESC guidelines mention that rifampicin should be started only after 3-5 days of effective antibiotic therapy once the bacteremia has been cleared. Rationale mentioned is the likely antagonistic effect of the antibiotic combinations with rifampicin against replicating bacteria. Synergy is seen against dormant bacteria within biofilms [7].
Indications for surgery in prosthetic valve endocarditis has been discussed earlier [1].
Linezolid and daptomycin are two drugs useful in resistant enterococcal endocarditis. Fluoroquinolones are another group of drugs considered in the treatment of susceptible strains of staphylococci and HACEK group of organisms.
Fungal endocarditis
Fungal endocarditis is an important consideration in early prosthetic valve endocarditis, immunosuppressed persons and in those with injection drug abuse. High mortality rates have been noted in fungal endocarditis. Surgery has to be considered early in fungal endocarditis. After an initial 6 week course of parenteral antifungal therapy, life long suppressive therapy with an oral azole is considered [1].
Oral step down therapy for infective endocarditis
Due to the problems of maintaining intravenous access for a long period, oral step down therapy for infective endocarditis is an attractive option. A narrative review published in May 2020 examined this aspect [8]. They found 21 observational studies on this aspect. None found oral step down therapy after initial intravenous therapy to be inferior to continuing intravenous therapy. Several studies had described improved clinical cure rate and improved mortality among those treated with oral step down therapy. Three randomized clinical trials also demonstrated that oral step down therapy was as good as intravenous only therapy in right sided, left sided or prosthetic valve endocarditis. In the largest trial, significantly improved cure rate and mortality rate was documented with oral step down therapy compared to intravenous only therapy. Authors recommended that highly orally bioavailable antibiotics can be considered as oral step down therapy after clearing bacteremia and achieving clinical stability with intravenous regimens.
References
- Baddour LM, Wilson WR, Bayer AS, Fowler VG Jr, Tleyjeh IM, Rybak MJ, Barsic B, Lockhart PB, Gewitz MH, Levison ME, Bolger AF, Steckelberg JM, Baltimore RS, Fink AM, O’Gara P, Taubert KA; American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Stroke Council. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association. Circulation. 2015 Oct 13;132(15):1435-86.
- LaPlante KL, Rybak MJ. Impact of high-inoculum Staphylococcus aureus on the activities of nafcillin, vancomycin, linezolid, and daptomycin, alone and in combination with gentamicin, in an in vitro pharmacodynamic model. Antimicrob Agents Chemother. 2004 Dec;48(12):4665-72.
- Mizunaga S, Kamiyama T, Fukuda Y, Takahata M, Mitsuyama J. Influence of inoculum size of Staphylococcus aureus and Pseudomonas aeruginosa on in vitro activities and in vivo efficacy of fluoroquinolones and carbapenems. J Antimicrob Chemother. 2005 Jul;56(1):91-6.
- Francioli P, Ruch W, Stamboulian D. Treatment of streptococcal endocarditis with a single daily dose of ceftriaxone and netilmicin for 14 days: a prospective multicenter study. Clin Infect Dis. 1995 Dec;21(6):1406-10.
- Francioli P, Etienne J, Hoigné R, Thys JP, Gerber A. Treatment of streptococcal endocarditis with a single daily dose of ceftriaxone sodium for 4 weeks. Efficacy and outpatient treatment feasibility. JAMA. 1992 Jan 8;267(2):264-7.
- Fowler VG Jr, Miro JM, Hoen B, Cabell CH, Abrutyn E, Rubinstein E, Corey GR, Spelman D, Bradley SF, Barsic B, Pappas PA, Anstrom KJ, Wray D, Fortes CQ, Anguera I, Athan E, Jones P, van der Meer JT, Elliott TS, Levine DP, Bayer AS; ICE Investigators. Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA. 2005 Jun 22;293(24):3012-21.
- Habib G, Lancellotti P, Antunes MJ, Bongiorni MG, Casalta JP, Del Zotti F, Dulgheru R, El Khoury G, Erba PA, Iung B, Miro JM, Mulder BJ, Plonska-Gosciniak E, Price S, Roos-Hesselink J, Snygg-Martin U, Thuny F, Tornos Mas P, Vilacosta I, Zamorano JL; ESC Scientific Document Group. 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J. 2015 Nov 21;36(44):3075-3128.
- Spellberg B, Chambers HF, Musher DM, Walsh TL, Bayer AS. Evaluation of a Paradigm Shift From Intravenous Antibiotics to Oral Step-Down Therapy for the Treatment of Infective Endocarditis: A Narrative Review. JAMA Intern Med. 2020 May 1;180(5):769-777.