ANTIBIOTIC THERAPY

Principles:

                Effective antimicrobial therapy of infective endocarditis optimally requires identification of the specific pathogen and assessment of its susceptibility to various antimicrobial agents. Therefore every effort must be made to isolate the pathogen prior to initiation of antimicrobial therapy, if clinically feasible. In septic patients suspected of having infective endocarditis, empiric antibiotic therapy should be targeted at the most likely pathogens in that particular clinical setting and should include an anti-staphylococcal agent. Standardized regimens have been recommended by the American Heart Association for the most common pathogens, which include viridans streptococci, enterococci, staphylococci and HACEK organisms on native and prosthetic valves (Table 6a and 6b). The minimal requirements for an effective antimicrobial regimen include:

Bactericidal Activity:

                Antimicrobial drugs that only inhibit microbial growth (bacteriostatic agents) are not able to clear pathogens from infected tissues if unaided by host defenses, such as polymorphonuclear leukocytes, antibody and complement. Because these host defenses are thought not to operate within vegetations (except in tricuspid valve vegetations, where polymorphonuclear leukocytes may aid the effect of an antimicrobial agent), clearance of bacteria from these vegetations requires a bactericidal antibiotic. In fact, eradication of all pathogens from the vegetation is thought to be essential to cure endocarditis. If any bacteria remain after completion of antibiotic therapy, the residual organisms will resume growth and result in relapse. If the pathogen cannot be eliminated completely by antimicrobial therapy, e.g., if relapse occurs or the patient has persistent bacteremia, the infected vegetation may need to be excised surgically to obtain a cure. For microorganisms without predictable susceptibility, bactericidal activity of an antimicrobial agent for the particular patient’s pathogen must be assessed by determination of the minimal inhibitory (MIC) and minimal bactericidal concentrations (MBC) of the antimicrobial agents in vitro (Table 5).

Table 5. In Vitro Assays

^a The infecting strain of enterococcus recovered from patients with endocarditis should be tested for susceptibility to high levels of both gentamicin and streptomycin but not other aminoglycosides. Strains that are resistant to high levels of gentamicin are resistant to other aminoglycosides, except some of these strains may be susceptible to high levels of streptomycin.

    Choice of an aminoglycoside for synergy should be based on in vitro high-level aminoglycoside susceptibility testing. If the strain is susceptible to high levels of both gentamicin and streptomycin, gentamicin is preferred because determination of gentamicin serum levels is more generally available. If the strain exhibits high-level resistance to one of these aminoglycosides, use only the aminoglycoside to which the strain is sensitive. If the strain is resistant to high levels of both gentamicin and streptomycin, no aminoglycoside is available to synergize with a cell wall-active antibiotic.  

^b  MIC/MBC testing may be useful for nonstandard antimicrobial regimens or unusual pathogens

^c  Vancomycin “peak” serum levels should be obtained 1 h after completion of a 1-2h infusion and should be in the range of 30-45 ug/ml. Vancomycin trough levels obtained just before the next dose should be 10-15 ug/ml.

^d Gentamicin “peak” serum levels obtained 1 h after start of a 20-30 min IV infusion or IM injection of 1 mg/kg should be about 3-4 ug/ml and trough level should be <1 ug/ml. Streptomycin peak serum level 1h after IM administration of 7.5 mg/kg is about 15-20 ug/ml and trough should be about 5 ug/ml.        

MIC, minimal inhibitory concentration; MBC, minimal bactericidal concentration; MRSA, methicillin-resistant S. aureus; MRCNS, methicillin-resistant coagulase-negative staphylococci; TMP/SMX, trimethoprim/sulfamethoxazole;

Enterococci:

                Unlike streptococci, enterococci are inhibited but not killed by cell wall-active antibiotics such as vancomycin and the anti-enterococcal beta-lactam antibiotics (e.g., penicillin, ampicillin, amoxicillin, and piperacillin) when these drugs are used alone. Ticarcillin, aztreonam, the anti-staphylococcal penicillins, e.g., nafcillin and methicillin, the cephalosporins, and the carbapenem meropenem have no or limited activity against enterococci. In addition, enterococci are intrinsically resistant to low concentrations of all aminoglycosides, but usually will be killed by either very high concentrations of aminoglycoside alone (concentrations that are too high to achieve clinically without toxicity) or by a combination of a cell wall-active antibiotic plus low concentrations of the aminoglycoside that can be achieved in patients without excessive toxicity. The bactericidal activity of the cell wall-active antibiotic plus aminoglycoside combination (termed synergy) is due to enhanced intracellular penetration of the aminoglycoside caused by the cell wall–active agent. Either gentamicin or streptomycin may be used in combination with an anti-enterococcal beta-lactam or vancomycin to treat enterococcal infective endocarditis that exhibit synergism with these combinations. However, some strains of enterococci exhibit high-level resistance (HLR) in vitro to aminoglycosides (2000 mcg/ml of streptomycin or 500 mcg/ml of gentamicin).

                HLR is usually due to plasmid- or transposon-mediated aminoglycoside–modifying enzymes. Strains of enterococci that exhibit HLR to gentamicin or streptomycin will not exhibit synergy when exposed to the cell wall-active antibiotic combined with the corresponding aminoglycoside at low aminoglycoside concentrations. Therefore the strain of enterococcus causing infective endocarditis should be tested for HLR to both gentamicin and streptomycin. Strains with HLR to gentamicin will be resistant to all other aminoglycosides, but may still be sensitive to high levels of streptomycin and strains with HLR to streptomycin may still be sensitive to high levels of gentamicin. If the strain exhibits HLR to only one of these two aminoglycosides, only the particular aminoglycoside to which the strain is sensitive should be used in the cell wall-active antibiotic/aminoglycoside treatment regimen. If the strain is sensitive to high levels of both gentamicin and streptomycin, gentamicin is usually the preferred aminoglycoside for combination therapy because of the greater availability of laboratories that will perform assays of serum concentrations of gentamicin. Also, combinations of a beta-lactam/gentamicin are preferable to vancomycin/gentamicin because of the increased risk of nephrotoxicity with the vancomycin/gentamicin combination. E. faecium strains produce low levels of an aminoglycoside-modifying enzyme that inactivates kanamycin, tobramycin and netilmicin, which results in loss of synergy when these aminoglycosides are combined with cell wall-active antibiotics, even in the absence of HLR to these drugs. If there is HLR to both gentamicin and streptomycin, no reliable bactericidal antibiotic or combination of antibiotics is currently available with a successful clinical track record.

               Based on studies in animal models of enterococcal endocarditis, once daily dosing of the aminoglycoside is not as efficacious as daily divided aminoglycoside dosing. Streptomycin dosing is divided into 2 and gentamicin into 3 equally divided doses every 24 hours for 4 to 6 weeks, the longer duration being reserved for those patients with duration of symptomatic illness > 3 months, or prosthetic valve endocarditis (see Table 6a and 6b). Lower doses of gentamicin (3mg/kg daily) are equally efficacious as higher doses and nephrotoxicity is less common with lower gentamicin dosing regimens.

               Rare strains of enterococcus are beta-lactamase-positive. Routine MIC-testing of beta-lactamase-positive strains may fail to disclose this type of penicillin-resistance; use of a higher than standard bacterial inoculum for MIC testing or nitrocefin-disk may detect the presence beta-lactamase in these strains. Infective endocarditis caused by beta-lactamase-positive enterococci can be treated with ampicillin/sulbactam or vancomycin. If these strains are also high-level-aminoglycoside-resistant, as is commonly the case, ampicillin/sulbactam or vancomycin is used alone for 8-12 weeks (see see Table 6a and 6b), but relapse rate is high.

               E. faecium (MIC 4-32 ug/ml) are more resistant to penicillin than E. faecalis MIC 1-4 ug/ml). At one center, one third of the E. faecium were highly resistant to penicillin [MIC > 200 micrograms/mol) but did not produce beta-lactamase; this high-level intrinsic penicillin resistance resulted in the loss synergism when an aminoglycoside antibiotic agent was combined with penicillin in vitro and in an experimental rat model of endocarditis If the enterococcus has high-level intrinsic penicillin-resistance, vancomycin can be used in combination with an aminoglycoside, if the strain is high-level-aminoglycoside-susceptible.

               Enterococci have developed vancomycin-resistance (MIC >4ug/ml) as a result of modification of the drug’s target. Of the five phenotypes described, vanA, vanB and vanC are most common: vanA (high level-vancomycin resistance, MIC >64 ug/ml) is more common in E. faecium than E. faecalis; vanB (intermediate to high level resistance, MIC 16-512 ug/ml) is found in both of these species; and vanC (low level resistance. MIC 2-32 ug/ml) is found intrinsically in E. casseliflavus and E. gallinarum. If E. faecium is vancomycin-resistant, infectious disease consultation should be sought, as these strains are usually multidrug-resistant. However, E. faecalis, E. casseliflavus and E. gallinarum are usually penicillin-susceptible. Linezolid and quinupristin/dalfopristin have only inhibitory activity against enterococci, and the activity of quinupristin/dalfopristin is limited to E. faecium , but success has been reported for these antibiotics in some patients with enterococcal infective endocarditis. Daptomycin, the only available lipopeptide antibiotic, exhibits concentration-dependent bactericidal activity against both E. faecalis and E. faecium. Although, daptomycin has been reported to be effective in experimental vancomycin-resistant enterococcal endocarditis, clinical data thus far are limited Double beta-lactam combinations (imipenem/ampicillin or cephalosporin/ampicillin) have been successful in experimental models, but clinical experience is limited.

Streptococci:

                Synergistic combinations of aminoglycoside and beta-lactam are also used to shorten the course of therapy for viridans streptococcal infective endocarditis due to a penicillin-sensitive strain (MIC < 0.1 mcg/ml) from 4 weeks when the beta-lactam (ceftriaxone 2 g IV or IM once daily) is used alone to 2 weeks for the combination therapy (ceftriaxone 2 g IV or IM plus gentamicin 3 mg/kg IV each given as a single daily dose) with comparable results as a result of more rapid bactericidal activity from the combination therapy. A single daily dose of ceftriaxone is an attractive alternate to penicillin; because of its long half-life and good potency against these streptococci; serum levels of ceftriaxone unbound to serum protein remain well above the MIC and MBC for over 24 hour. Indeed, two weeks of combined therapy with ceftriaxone plus gentamicin once daily allows outpatient therapy for stable patients with uncomplicated disease due to penicillin-susceptible strains (MIC <0.1 mcg/ml); however, use of the 2-week combination regimen that includes gentamicin is not intended for patients with renal or 8th cranial nerve impairment, and is not preferred for patients >65 years of age. Synergistic combination is also used for treatment of infective endocarditis due to penicillin-intermediate susceptible viridans streptococcal strains (MIC 0.2-0.5 mcg/ml) and infective endocarditis due Abiotrophia and Granulicatella (NVS), and Gemella species (see Table 6a and 6b). Infective endocarditis due to NVS, Gemella species , and viridans streptococcal strains more resistant to penicillin (MIC >1.0 mcg/ml) are treated with the regimens recommended for enterococcal infective endocarditis (see Table 6a and 6b).

               Although there are limited clinical data evaluating therapeutic regimens for infective endocarditis caused by S. pneumoniae, S. pyogenes, and Groups B, C, and G streptococci, high-dose penicillin or ceftriaxone for 4 weeks is recommended, even for infective endocarditis caused by strains of S. pneumoniae with MIC 0.1 to 4 ug/ml. Vancomycin therapy should be administered only to patients with infective endocarditis due to these microorganisms who are unable to tolerate a ß-lactam antibiotic. In general, strains of group B, C, and G streptococci are slightly more resistant to penicillin than are strains of group A streptococci. Some authorities recommend the addition of gentamicin to penicillin for at least the first 2 weeks of a 4- to 6-week course of antimicrobial therapy for group B, C, and G streptococcal infective endocarditis. Early cardiac surgical intervention may improve survival rates of patients with S. pneumoniae or ß-hemolytic streptococcal endocarditis.

Staphylococci:  

                Staphylococci that are sensitive to methicillin and oxacillin can be treated with vancomycin or an anti-staphylococcal beta-lactam, such as nafcillin or cefazolin, but a beta-lactam is always preferable over vancomycin, as illustrated by the poor response to glycopeptides (teicoplanin or vancomycin) for S. aureus infective endocarditis. Glycopeptides may be less effective because of poor penetration into vegetations, more rapid clearance in certain patients, relatively slow bactericidal action of vancomycin and the longer duration of S. aureus bacteremia on vancomycin therapy, i.e., 7-9 days for vancomycin versus 3 days for nafcillin. Vancomycin is recommended for patients with methicillin (or oxacillin)-resistant staphylococci (MRSA or ORSA) infective endocarditis and for patients with a history of immediate-type reaction to penicillin. A first generation cephalosporin, such as cefazolin, is recommended for patients with non-immediate-type reactions to penicillin. Ceftriaxone has relatively poor anti-staphylococcal activity (i.e., the short duration that serum drug levels not protein-bound exceed the MICs that are higher for S. aureus than for other ceftriaxone-sensitive gram-positive pathogens and should not be used for this indication, despite the ease of its once daily administration.

               MRSA are cross-resistant to all currently available beta-lactams, including cephalosporins and carbapenems; MRSA that are hospital-acquired are also frequently resistant to other classes of antibiotics, except the glycopeptides, the lipopeptide daptomycin, the oxazolidinone linezolid, and the streptogramins (quinupristin/dalfopristin combination), although occasional emergence of resistance to these antibiotics has been documented. However, in the past decade MRSA have been noted to be increasingly community-acquired. These strains unlike nosocomial MRSA, have a distinctive staphylococcal chromosomal cassette (SCC type IV) that encodes methicillin-resistance, have a potent virulence factor (Panton-Valentine toxin), frequently cause severe skin and soft tissue infections, and are usually sensitive to other classes of antibiotics, including the macrolides and clindamycin, although resistance to these and other antibiotics (e.g., the fluoroquinolones) is now emerging.

               Because each class of antibiotics has a unique target in the bacterial cell, there will not be cross-resistance with other classes unless there is a common microbial target. For example, macrolides (e.g., erythromycin), the lincosamide clindamycin and the streptogramin b quinupristin (the so-called macrolide-lincosamide-streptogramin b or MLSb group of antibiotics) share the same ribosomal target. Resistance to these antibiotics can be caused by inducible methylation of the ribosomal target. Only erythromycin induces MLSb resistance in S. aureus, so that strains with inducible MLSb resistance will be erythromycin-resistance and clindamycin-sensitive, and will be killed by quinupristin/dalfopristin, as will S. aureus strains that lack MLSb resistance. However, constitutive MLSb-type resistance is a frequent finding in MRSA; these strains are both erythromycin- and clindamycin-resistant, and resistant to the streptogramin b component quinupristin. Quinupristin/dalfopristin will not be bactericidal against these strains that are constitutive MLSb-resistant, and clinical experience with MRSA infective endocarditis treated with quinupristin/dalfopristin is limited Even for clindamycin-sensitive S. aureus, clindamycin therapy of infective endocarditis has a high relapse rate.

               Both MSSA and nosocomial or community-acquired MRSA are sensitive to daptomycin and linezolid. Daptomycin exhibits concentration-dependent bactericidal activity against S. aureus, and has been reported to be effective in right-sided S. aureus endocarditis, but emergence of daptomycin-resistance was noted on daptomycin therapy. In addition, daptomycin penetrates lung poorly, and may not be effective if there is hematogenous spread of S. aureus to the lung. Also, although linezolid penetrates the lung well, it has only limited bactericidal activity, and clinical experience is limited. Clinical experience with doxycycline or minocycline for S. aureus infective endocarditis is limited. Many strains of MRSA are sensitive to trimethoprim-sulfamethoxazole, which has been shown to be effective in one series of cases, in the event that vancomycin is not tolerated. Strains should be tested for susceptibility to rifampin or gentamicin, if their use is planned as adjunctive therapy in an attempt to enhance bactericidal activity of vancomycin or an anti-staphylococcal beta-lactam to treat staphylococcal PVE; however, the effectiveness of gentamicin or rifampin used in this manner for staphylococcal NVE has been questioned, although their use combined with vancomycin is substantiated in experimental endocarditis and clinical experience for PVE due to methicillin-resistant coagulase-negative staphylococci and by analogy combined with methicillin for PVE due to MSSA and methicillin-sensitive coagulase-negative staphylococci. The clinical efficacy of various treatment regimens (e.g., daptomycin, linezolid, quinupristin/dalfopristin, etc) for infective endocarditis due to staphylococcal strains partially or fully resistant to vancomycin has not been established.

               Six weeks of antibiotic therapy is usually recommended for S. aureus infective endocarditis, because of the common presence of purulent complications, such as perivalvular abscess or extracardiac metastatic abscesses, although 4 weeks may be sufficient for uncomplicated infection.

Other Pathogens:

             Therapy for endocarditis due to gram-negative bacilli other than the HACEK group, anaerobes, and diphtheroids should be developed in consultation with an infectious diseases specialist. Bactericidal activity for anaerobic gram-negative bacilli can frequently be achieved with metronidazole; for diphtheroids with vancomycin-aminoglycoside combination: and for aerobic enteric gram-negative bacilli or P. aeruginosa with a beta-lactam-aminoglycoside combination or a fluoroquinolone such as ciprofloxacin, but emergence of resistance during antimicrobial therapy may be a problem. Gram-negative bacilli known to be expressing AmpC beta-lactamase or an extended-spectrum beta-lactamase are best treated with a carbapenem or fluoroquinolone, although resistance to these drugs is also increasing. Bartonella endocarditis can be treated with doxycycline 100 mg every 12h for 6 weeks plus gentamicin 1 mg/kg every 8h for the first 2 weeks, or if gentamicin cannot be used plus rifampin 300 mg po or IV every 12h.

Blood Culture-Negative Infective Endocarditis:

            Blood culture-negative NVE in patients who have received antibiotic before blood cultures are obtained is generally treated empirically with antibiotic regimens that will cover S. aureus, viridans streptococci, enterococci and HACEK microorganisms: ampicillin/sulbactam 12g/24h IV in 4 equally divided doses plus gentamicin 3mg/kg/24h in 3 equally divided doses for 4-6 weeks or in patients unable to tolerate penicillins vancomycin 15 mg/kg every 12h, ciprofloxacin 500 -750 mg po or 400 mg IV every 12h, and gentamicin 3mg/kg/24h in 3 equally divided doses for 4-6 weeks. Blood culture-negative early PVE is treated empirically with vancomycin 15 mg/kg every 12h IV plus cefepime 2g every 8h IV and rifampin 300 mg po or IV every 8h for at least 6 weeks and gentamicin 3mg/kg/24h in 3 equally divided doses for the first 2 weeks. Blood culture-negative late PVE is treated empirically with the same regimens recommended for blood culture-negative NVE above for at least 6 weeks.

Fungal Infective Endocarditis

            Aspergillus more commonly than Candida can cause blood culture-negative endocarditis, usually in patients with central venous catheters or prosthetic valves. When this diagnosis is suspected, treatment includes amphotericin B for 6 weeks and valve replacement. After an initial clinical response, long-term suppression with an oral azole should be considered after completion of combined medical/surgical management or after medical therapy alone if the patient is not a surgical candidate.

2) High concentrations of the antimicrobial agent in the vegetation: Optimally the antimicrobial agent should have a minimal “inoculum effect,” i.e., should exhibit the least reduction in potency when tested against high microbial densities of 108-11 CFU/g that exist in vegetations; these microbial densities are higher than the standard inocula of 105-6 CFU/ml used to perform the MIC and MBC test. Large doses of beta-lactam antibiotics must be used to overcome the inoculum effect, a characteristic of these antibiotics. Doses of the antimicrobial agent must also be large enough to achieve high concentrations of the antimicrobial agent in the blood that will facilitate passive diffusion of the antimicrobial agent into the depths of the vegetation where the microcolonies of the pathogen are located. Despite high concentrations in blood, some antimicrobial agents fail to penetrate vegetations deeply enough, e.g., amphotericin B, or penetrate vegetations unevenly, e.g., teicoplanin. Since amphotericin B is the only fungicidal agent, cure of fungal endocarditis usually requires surgery or chronic suppressive therapy after an initial response to an anti-fungal agent in patients who are too ill to undergo valve replacement.

3) Prolonged duration of antimicrobial therapy: Duration of therapy varies with the specific pathogen, the site of the infection, and type of antibiotic. For example, bacterial clearance is more rapid for viridans streptococci than staphylococci, in tricuspid versus aortic vegetations, with anti-staphylococcal beta-lactams than vancomycin or with combinations of cell wall-active agent plus aminoglycoside than cell wall-active agent alone. More rapid clearance in these special circumstances may permit a shorter course of therapy to achieve cure (see above).

               Over 90% of the microbial population in the vegetation is non-growing and metabolically inactive once the infection has become well established. Non-growing organisms are more likely to be found in the central portions of the microcolonies in the deeper regions of the vegetation. Because the beta-lactams are only active against growing microorganisms, which express the targets of these antibiotics (penicillin-binding proteins), each dose is only able to reduce the microbial count in that small portion (less than 10%) of the population that happens to be growing at the time of drug administration, which results in a slow rate of bactericidal action. The duration of drug therapy therefore must be prolonged in order to result in complete clearance of the pathogen from the vegetation.

               The duration of antimicrobial therapy after valve replacement depends to some extent on evidence for active infection at the time of surgery. In patients with positive intraoperative cultures or gram stain, a full course of post-operative therapy is reasonable, otherwise an additional 2 weeks and for those operated near the end of the standard period of treatment, simply completing the time remaining on the regimen for that type endocarditis.

4) Dosing should be frequent enough to prevent resumption of microbial growth between doses: The microorganisms that remain after a brief in vitro exposure to an antibiotic frequently exhibit a post-exposure delay in further growth, the so-called post-antibiotic effect. Unfortunately, no such effect occurs with enterococci or P. aeruginosa in the rat model of endocarditis, despite in vitro demonstration of a post-antibiotic effect. Thus, even though a bactericidal effect can achieved in the vegetation in the early portions of a dosing interval when vegetation levels of the drug are high, if antibiotic vegetation levels are not maintained at least above the MIC during the rest of the dosing interval, resumption of growth of residual organisms may occur and efficacy may be compromised. This requires relatively short dosing intervals for drugs with short serum half lives, especially for microorganisms with high MICs.  

SHORTER INPATIENT THERAPY/OUTPATIENT THERAPY

               Use of shorter courses of antibiotic therapy, administration of parenteral antibiotic therapy at home, and oral regimens have been investigated in selected groups of patients to shorten the length of hospitalization. Before considering outpatient therapy, most patients should first be evaluated and stabilized in the hospital; only very rarely can some patients be managed entirely as outpatients. Patients can be selected for administration of parenteral therapy at home by their being at low risk for complications of endocarditis: The presence of poorly controlled CHF, neurological findings that may result from systemic emboli or bleeding MAs, cardiac conduction abnormalities, valve ring abscesses (usually detected by TEE), persistent fever, positive blood cultures, and prosthetic valve endocarditis preclude home intravenous therapy. Having a focal infection that in itself would require more than 2 weeks of antimicrobial therapy, PVE, and renal or eighth nerve impairment would preclude use of short-course beta-lactam-aminoglycoside combination therapy for streptococcal or uncomplicated tricuspid valve S. aureus infective endocarditis. Patients with penicillin-susceptible viridans streptococcal endocarditis (penicillin MIC <0.1 µg/mol) whose disease is apparent for <3 months and is uncomplicated at the time of admission generally do well with outpatient intravenous therapy (i.e., 2 weeks of ß-lactam plus an aminoglycoside or 4 weeks of a ß-lactam such as ceftriaxone) alone. Because of the unreliable absorption of orally administered agents, oral therapy is generally not recommended. However, use of central intravenous catheters in patients, especially intravenous drug users, with infective endocarditis places them at risk of IV line sepsis and superinfection infective endocarditis. While on home antimicrobial therapy, patients must be monitored closely by a home infusion team and patients must have ready access to experienced physicians to monitor periodically (e.g., weekly) for development of complications of infective endocarditis and drug-related side effects of antimicrobial therapy (e.g., vestibular, auditory, and nephrotoxicity from aminoglycosides, leukopenia and thrombocytopenia from ß-lactams and vancomycin, and nephrotoxicity from the combination of vancomycin and gentamicin). The standard regimens used to treat penicillin-sensitive streptococcal infective endocarditis require either continuous infusion of penicillin or frequent intravenous administration.

RESPONSE TO THERAPY

               Once on appropriate antimicrobial therapy, most patients will note a sense of well-being, lessened fatigue, and improved appetite, and the temperature will usually fall to normal levels within 2-5 days; the ESR, anemia and renal function may take weeks to months to improve. Circulating immune complexes and related serologic findings that include hypocomplementemia, mixed cryoglobulinemia and rheumatoid factor, also tend to resolve gradually with effective antibiotic therapy. A variety of tests are done to monitor both the antimicrobial effects (see below) and the potential adverse reactions to the drugs used to treat the infection, which include neutropenia (beta-lactams, vancomycin, linezolid), thrombocytopenia (beta-lactams, vancomycin, linezolid), azotemia (aminoglycosides and much less commonly vancomycin, trimethoprim/sulfamethoxazole, and beta-lactams), elevated CPK (daptomycin) and hyperkalemia (trimethoprim/sulfamethoxazole). Drug interactions are also problematic for vancomycin with gentamicin (azotemia) and rifampin with multiple drugs, e.g., diminished prothrombin time with warfarin.

               After antimicrobial therapy is started, blood cultures should be repeated daily or every other day until sterile to assess for clearance of bacteremia. Blood cultures for streptococci and enterococci should become sterile after 1-2 days of appropriate therapy and for S. aureus, after 3-5 days; however, with vancomycin therapy as noted above, blood cultures for S. aureus may take 1 to 2 weeks to become sterile. If no organism is isolated from blood, but there is a good clinical response to the antimicrobial regimen, these antibiotics should be continued. If no organism is isolated and there is no clinical response to empiric therapy after 1-2 weeks, infective endocarditis due to a fastidious pathogen, e.g., fungi, anaerobes, etc., or a diagnosis other than infective endocarditis should be considered, such as antiphospholid antibody syndrome (APA); APA, which is frequently complicated by cerebral emboli, requires anticoagulant, rather than antibiotic therapy.

               If the pathogen is initially isolated from blood, and appropriate antimicrobial therapy started, but fever persists or recurs, blood cultures should be repeated to assess persistent or relapsing infection; other possibilities (Table 8), which include most commonly pulmonary or systemic embolization. Blood cultures are repeated two and four weeks after therapy has been completed, because relapse is most common within one month. Relapse rate for native valve endocarditis caused by penicillin-susceptible viridans streptococci is <1-2%, for aminoglycoside-susceptible enterococci, 8-12%, and higher for S. aureus, other pathogens, and PVE treated by the recommended regimens (Tables 6a and 6b).

Table 8. Reasons For Inadequate Clinical Response

Inadequate therapy: wrong drug, wrong dose Infarcts secondary to emboli Metastatic abscesses of the spleen, kidney, brain, etc., which may require surgical drainage Suppurative thrombophlebitis at site of an IV catheter, with or without superinfecting endocarditis. Other superinfections: e.g., C. difficile colitis, urinary tract infection Febrile reaction to the antimicrobial agent or other another drug Another unrelated febrile illness, e.g., deep vein thrombophlebitis

Table 6a. Standard Antibiotic Therapy for Native Valve Endocarditis due to Common Pathogens (Doses are for Adults with Normal Renal Function) 

⁰ PCN can be dosed via continuous infusion or every 4 hrs

¹Gentamicin should not be used in patients with creatinine clearance <30 ml/min, or patients with impaired 8^th cranial nerve function. Other potentially nephrotoxic drugs, e.g., non-steroidal anti-inflammatory drugs, should be used with caution in patients receiving gentamicin.  Caution when using gentamicin with vancomycin due to increased risk of nephrotoxicity.  Adjust dose of gentamicin based on renal function.

²Vancomycin is used only for patients with immediate type penicillin-allergic reactions, i.e., urticaria, angioedema, or anaphylaxis, to penicillin. Caution when using gentamicin with vancomycin due to risk of nephrotoxicity.   Vancomycin is inferior to beta-lactams for the treatment of methicillin-sensitive Staphylococcus aureus.

³ Enterococcus sensitive to penicillin, vancomycin and aminoglycosides.

⁴Because of technical difficulties in susceptibility testing of Abiotrophia species and virulence of these organisms, many experts recommend treating endocarditis due to these strains with the standard regimen recommended for enterococci.  Strongly consider dual antibiotic therapy.

⁵Cefazolin is used for patients with a non-immediate-type penicillin allergy

⁶Uncomplicated right-sided IE: normal renal function, no extra-pulmonary metastatic infection, no left-sided valvular IE.

⁷HACEK: Haemophilus parainfluenzae, H. aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae

⁸Enterococcus faecium only!

⁹Daptomycin is equivalent to beta-lactam antibiotics for the treatment of methicillin-sensitive Staphylococcus aureus.   Endocarditis data is for Staphylococcal aureus only.

Table 6b. Standard Antibiotic Therapy for Prosthetic Valve Endocarditis due to Common Pathogens

(Doses are for Adults with Normal Renal Function) 

⁰ PCN can be dosed via continuous infusion or every 4 hrs

¹Gentamicin should not be used in patients with creatinine clearance <30 ml/min, or patients with impaired 8^th cranial nerve function. Other potentially nephrotoxic drugs, e.g., non-steroidal anti-inflammatory drugs, should be used with caution in patients receiving gentamicin.  Caution when using gentamicin with vancomycin due to increased  risk of nephrotoxicity.  Adjust dose of gentamicin based on renal function.

²Vancomycin is used only for patients with immediate type penicillin-allergic reactions, i.e., urticaria, angioedema, or anaphylaxis, to penicillin. Caution when using gentamicin with vancomycin due to risk of nephrotoxicity.   Vancomycin is inferior to beta-lactams for the treatment of methicillin-sensitive Staphylococcus aureus.

³ Enterococcus sensitive to penicillin, vancomycin and aminoglycosides.

⁴Because of technical difficulties in susceptibility testing of Abiotrophia species and virulence of these organisms, many experts recommend treating endocarditis due to these strains with the standard regimen recommended for enterococci.  Strongly consider dual antibiotic therapy.

⁵Cefazolin is used for patients with a non-immediate-type penicillin allergy

⁶Uncomplicated right-sided IE: normal renal function, no extra-pulmonary metastatic infection, no left-sided valvular IE.

⁷HACEK: Haemophilus parainfluenzae, H. aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae

⁸Enterococcus faecium only!

⁹Daptomycin is equivalent to beta-lactam antibiotics for the treatment of methicillin-sensitive Staphylococcus aureus.  Only data for daptomycin in prosthetic valve infections is anecdotal case reports.  Endocarditis data is for Staphylococcal aureus only.

¹⁰ Oxacillin and nafcillin can be used interchangeably.