Incidence of infective endocarditis (IE) continues to increase, with an estimated 15 cases per 100,000 people in the United States in 2018. Gram-positive cocci are most frequently the source of infection, including streptococcus, staphylococcus, and enterococcus species. IE secondary to cardiac implanted devices, intravenous drug use (IVDU), and health-care exposures comprises an increasing number of cases. As a result, Staphylococcus aureus is the most common causative agent of IE, making up approximately 40% of all cases in “high-income countries” [ , ]. Due to the high morbidity and mortality associated with IE, prompt diagnosis and pharmacologic management is crucial to avoid complications such as death, embolic events, abscess formation, heart failure, and metastatic foci of infection [ ].
Empiric antimicrobial therapy should be initiated as soon as possible where clinical suspicion is high, ideally after collection of blood cultures. If blood culture collection is delayed, antimicrobial therapy should not be withheld. Furthermore, antimicrobial therapy can be initiated before echocardiography without altering the findings of the procedure. The intent of antimicrobial therapy is to eradicate infection, including sterilization of vegetations [ , ].
Identification and administration of optimal antimicrobials for IE is complex and does not come without challenges. Penetration to the site of infection, ability to overcome the high burden of bacteria, and tolerance and management of adverse drug events must be considered when selecting empiric agent(s) [ ]. Commonly utilized antimicrobials such as beta-lactams and glycopeptides may have decreased efficacy due to the highly dense bacterial populations present in many cases of IE. Table 7.1 reviews the mechanism of action of common classes of antimicrobial therapy used to treat IE. The “inoculum effect” describes this scenario of highly dense bacteria. Furthermore, reduced metabolic activity resulting in greater difficulty killing the bacterial colonies has been reported. Because of these factors, duration of therapy is prolonged for weeks or even months to ensure eradication of infection [ , ].
|Drug class||Mechanism of action|
|Beta-lactams||Inhibit cell wall formation [ ]|
|Glycopeptides||Inhibit cell wall formation [ ]|
|Aminoglycosides||Inhibit protein synthesis [ ]|
|Cyclic lipopeptides||Inhibit protein, DNA, and RNA synthesis [ ]|
|Fluoroquinolones||Inhibit DNA synthesis [ ]|
|Oxazolidinones||Inhibit protein synthesis [ ]|
Pharmacokinetics and pharmacodynamics
An understanding of the pharmacokinetic and pharmacodynamic properties of antimicrobial agents is necessary to determine appropriate treatment options. Pharmacokinetics refers to the body’s effect on a drug and includes the properties of absorption, distribution, metabolism, and excretion. Pharmacodynamics describes what a drug does to the body at the site of action and refers to pharmacologic or toxicologic effects.
Antimicrobial agents can be classified into two categories based on pharmacodynamic principles: time-dependent killing and concentration-dependent killing ( Table 7.2 ). Time-dependent killing requires that the antimicrobial concentration must be above the minimum inhibitory concentration (MIC) for at least 40%–50% of the dosing interval to effectively kill the organism. Concentration-dependent killing requires maximal peak concentrations in the serum and at the site of infection to effectively kill the organism [ ].
|Time-dependent killing||Concentration-dependent killing|
Bactericidal versus bacteriostatic
Antibiotics can be classified as either bactericidal or bacteriostatic ( Table 7.3 ). While the strict definitions of bactericidal killing and bacteriostatic inhibition are clear, there is a needed nuance when understanding these properties as they relate to IE. MIC is the concentration that inhibits visible microbial growth at 24 h. This is dependent upon specific conditions (e.g., media, temperature, and carbon dioxide concentration). Minimum bactericidal concentration (MBC) is the concentration that results in a 1000-fold reduction in microbial growth. Bacteriostatic is defined as a ratio of MBC to MIC of >4 and bactericidal is a ratio ≤4. An antibiotic that causes a 1000-fold reduction in microbial growth but does not do this at concentration that is < 4 times the MIC will be labeled as bacteriostatic [ , ]. The definitions of bacteriostatic and bactericidal are based on in vitro determinations and not on specific clinical principles. The laboratory definition for bactericidal is >99.9% growth inhibition at 24 h; some bacteriostatic antibiotics are highly effective at growth inhibition (90%–99%) but do not satisfy this definition [ ]. Some antibiotics can possess both properties (e.g., linezolid is bacteriostatic against staphylococci and enterococci, but bactericidal against streptococci) [ ]. In infections with a large inoculum size, such as IE, bactericidal killing can be inhibited resulting in a pattern more consistent with bacteriostatic growth inhibition.
It has long been thought that bactericidal antibiotics display increased efficacy. A systematic literature review identified 56 randomized controlled trials (RCTs) since 1985 that compared bacteriostatic antimicrobials to bactericidal antimicrobials in a head-to-head design for patients with invasive bacterial infections [ ]. Forty-nine (87.5%) trials found no significant difference in efficacy between bacteriostatic and bactericidal antimicrobials. Six (10.7%) trials found the bacteriostatic antibiotic, linezolid, to be superior in comparison to bactericidal agents, cephalosporins or vancomycin. Unfortunately, none of the 56 RCTs reviewed evaluated IE, making it difficult to draw conclusions in this patient population.
The inoculum effect occurs as microbial density increases at the site of infection and the efficacy of some antimicrobials decreases. It has been reported with a number of antimicrobials but is most frequently reported with beta-lactams [ ]. The MIC obtained from an antimicrobial susceptibility testing assay using a standard inoculum (10 5 colony-forming units per milliliter) can be much lower than the actual MIC at the site of infection where microbial densities can be 10 8 –10 10 organisms per gram of tissue [ ]. High microbial densities are more likely to have microbes in the stationary growth phase which can decrease the effectiveness of beta-lactams that target penicillin-binding proteins (PBPs). Of note, S. aureus is associated with a high inoculum of 10 8 –10 11 /g [ ].
Antimicrobial class review
Beta-lactams, comprised of penicillins, cephalosporins, and carbapenems, provide activity against a range of gram-positive and gram-negative pathogens, including streptococcus, staphylococcus, and enterococcus species, among others. Agents such as aqueous penicillin G, ampicillin, oxacillin, nafcillin, cefazolin, and ceftriaxone, as well as beta-lactams in combination with beta-lactamase inhibitors, such as ampicillin-sulbactam, are frequently used for treatment of IE [ ]. Through inhibition of PBPs, beta-lactams inhibit formation of peptidoglycan and subsequently cell wall formation [ , ]. Various resistance mechanisms to beta-lactams have been reported, including alteration of PBPs resulting in decreased binding or inability to bind to the proteins altogether, reduced permeability or complete impenetrability of the outer membranes, efflux pumps, and production of beta-lactamases [ , ], so it is important to obtain susceptibilities once a pathogen has been identified to ensure appropriate therapy is selected.
These agents are identified as time-dependent antibiotics, and therefore extended infusions or, in certain scenarios, continuous infusions are preferred over traditional intermittent dosing to optimize therapy [ ]. Common adverse reactions associated with this class of antibiotics include hypersensitivity reactions ranging from mild to life-threatening; neurotoxicity, including seizures, most often occurring secondary to cefepime or imipenem-cilastatin at high doses; gastrointestinal upset, most commonly observed in relation to amoxicillin and ampicillin; acute interstitial nephritis, associated most often with nafcillin; and increased risk of Clostridioides difficile infection [ , ].
Members of the glycopeptide class include vancomycin, oritavancin, telavancin, and dalbavancin [ ]. These agents inhibit cell wall formation by interfering with late-stage peptidoglycan synthesis [ ]. Often considered first-line for methicillin-resistant Staphylococcus aureus (MRSA) infections, vancomycin provides coverage against gram-positive pathogens, including staphylococci, streptococci, and enterococci. However, several mechanisms of resistance to vancomycin have been identified, including vancomycin-resistant S. aureus and vancomycin-resistant enterococci (VRE). Enterococci resistance to vancomycin is most commonly mediated by the vanA gene, which alters the synthesis of peptidoglycan. This gene can be transmitted from enterococci to staphylococci via plasmids, resulting in vancomycin-resistant staphylococci [ , ].
Nephrotoxicity and ototoxicity are associated with vancomycin use. While ototoxicity has not been identified as a dose-dependent adverse effect, development of nephrotoxicity is associated with higher doses of vancomycin [ ]. For this reason, vancomycin serum levels should be monitored for both safety and efficacy purposes. The ratio of area under the curve over 24 h to the minimum inhibitory concentration (AUC/MIC) provides the most accurate measurement of effective vancomycin therapy, though this level has historically been challenging to measure. For this reason, the current IE guidelines recommend a serum trough level of 10–15 mcg/mL [ ]; however, institutions may be targeting a trough range of 15–20 mcg/mL based on the recommendation that this trough range should achieve an AUC/MIC of 400 mg/L h which has been identified as the optimal target for vancomycin therapy [ ]. Most recently, the ability to calculate the AUC has become more feasible due to development of calculating software. Additionally, AUC can be calculated by two serum levels that are obtained: one at least 1 hour postinfusion and the second as a predose trough. Therefore, current guidelines for therapeutic monitoring of serious MRSA infections, including IE, recommend AUC-based monitoring with a target range of 400–600 mg/L h [ , ].
Dalbavancin and oritavancin are two novel long-acting lipoglycopeptides with activity against gram-positive pathogens [ ]. These agents present an attractive alternative to traditional antimicrobial therapy given their weekly or biweekly dosing schedule; however, they are not currently recommended in the guidelines.
A retrospective study evaluated the efficacy of dalbavancin in patients with gram-positive IE. A total of 27 patients were included in the analysis, 16 with native-valve IE, 6 with prosthetic-valve IE, and 5 with cardiac device–related endocarditis. Dalbavancin dosing regimens consisted of either a 1000 mg loading dose followed by 500 mg weekly or 1500 mg loading dose followed by 1000 mg biweekly. The majority of patients (88.9%) received alternative antimicrobial therapy prior to dalbavancin. Microbiological and clinical successes were reached in 25 (92.6%) of the 27 patients who received dalbavancin as a primary or sequential treatment for IE [ ].
In another retrospective study, clinical response to dalbavancin as consolidation therapy was assessed in patients with gram-positive IE and/or bloodstream infection (BSI). A total of 83 patients were included, 59% had BSI, and 49% IE (44% prosthetic-valve IE, 32.4% native-valve IE, 23.5% pacemaker lead). A variety of dosing strategies were used, with doses ranging from 500 to 1500 mg. Clinical response at 12 months was 96.7% in patients with IE [ ]. Oritavancin may have an advantage over dalbavancin in treating VRE infections due to its broader in vitro activity; however clinical data are limited to a single case report thus far [ , ].
Current literature shows promising outcomes; however, prospective studies are warranted to determine the efficacy and safety of long-acting lipoglycopeptides in the treatment of gram-positive IE.
Alternative anti-MRSA therapy
Daptomycin is an agent of the cyclic lipopeptide class. The mechanism of action in which daptomycin produces bactericidal effect is not fully understood, though the resultant effect is inhibition of protein, DNA, and RNA synthesis. Providing antibacterial coverage against S. aureus , including MRSA, various species of streptococci, and enterococcal infections, including VRE, daptomycin serves as an alternative agent for multidrug resistant (MDR) gram-positive pathogens [ ]. Daptomycin use may result in increased serum creatine kinase and associated myositis [ ]. Therefore, baseline and periodic serum creatine kinase levels should be monitored for the duration of therapy.
Linezolid, the first agent of the class of oxazolidinones, inhibits protein synthesis via binding to ribosomal RNA on the 30S and 50S ribosomal subunits. Linezolid is often used for MDR gram-positive organisms, such as MRSA and VRE; however, it remains active against other staphylococci and streptococci [ ]. Adverse reactions associated with linezolid include peripheral neuropathy, anemia and thrombocytopenia, increased serum lactate, and hypoglycemia. Additionally, linezolid inhibits monoamine oxidase, and therefore can result in serotonin syndrome when combined with other serotonergic agents [ ]. Close monitoring for signs and symptoms of aforementioned adverse effects is necessary throughout the duration of linezolid therapy.
Adjunctive antibacterial therapy
Gentamicin, the most commonly used agent of its class, in addition to tobramycin, amikacin, and streptomycin are members of the aminoglycoside class. Aminoglycosides interfere with protein synthesis through uptake into the bacterial cell and subsequent binding to the 16S rRNA of the 30S ribosomal subunit [ ]. Aminoglycosides have a wide range of use since they are active against many gram-positive pathogens, including staphylococci and enterococci, and gram-negative pathogens, including Enterobacteriaceae species, as well as MDR organisms.
Aminoglycosides have a concentration-dependent effect on bacterial killing and are dosed via one of two dosing strategies: conventional dosing or extended-interval dosing [ ]. Conventional dosing describes the strategy of dosing an aminoglycoside on a two to three times a day regimen. When using aminoglycosides for gram-positive synergy in IE, a conventional dosing strategy is used. In patients with normal renal function (e.g., creatinine clearance >60 mL/min) the typical dose for gentamicin is 3 mg/kg per 24 h given in two or three equally divided doses. If using an aminoglycoside for the treatment of IE caused by a gram-negative pathogen an extended-interval dosing strategy can be used for most patients with creatinine clearances greater than 30 mL/min. Extended-interval dosing regimens for gentamicin and tobramycin utilize either 5 or 7 mg/kg doses given every 24–48 h, depending on calculated creatinine clearance. Therapeutic drug monitoring is indicated for both dosing strategies and provides information regarding both safety and efficacy [ ].
When using conventional dosing for gram-positive synergy, a serum peak level should be obtained 30 min after administration of the intravenous dose with a target level of 3–5 mg/L. The target serum trough level is < 1 mg/L and should be obtained 30 min prior to the subsequent dose. At low/undetectable trough concentrations, aminoglycosides still inhibit the growth of targeted organisms, a phenomenon called the postantibiotic effect [ ]. Initial levels should be ordered at steady state (e.g., after the first or second dose of the regimen). Follow-up levels should be obtained biweekly to guide further dose adjustments, with additional level assessment after new steady state is achieved. Serum levels should also be obtained in response to changing renal function and volume status. Strategies for therapeutic drug monitoring of extended-interval dosing include measuring serum random levels and using a nomogram (such as the Hartford nomogram) [ , ]. In addition to serum drug levels, monitoring for renal impairment and ototoxicity, both of which are dose-dependent effects, is necessary [ ].
The fluoroquinolone class is comprised of several agents, including ciprofloxacin, levofloxacin, and moxifloxacin. Fluoroquinolones inhibit DNA replication and transcription via interaction with DNA gyrase, leading to inhibition of the topoisomerase II enzyme. Additionally, these agents inhibit topoisomerase IV, resulting in cell apoptosis. Spectrum of activity differs between agents, with varying activity against gram-positive and gram-negative pathogens [ ].
Adverse drug reactions related to fluoroquinolones include mental health disturbances, ranging from disorientation to memory impairment, as well as increased risk of hypoglycemia, peripheral neuropathy, aortic ruptures and tears, tendinitis, and tendon rupture. This class of agents should be avoided in patients with history of tendinitis or tendon rupture, as well as in patients with myasthenia gravis as agents can worsen symptoms [ ].
Rifampin, an RNA polymerase inhibitor, is recommended as an adjunct agent in the management of prosthetic-valve IE caused by Staphylococcus spp. [ , ]. This recommendation is based on the sterilizing mechanism rifampin has on foreign bodies infected by staphylococci. Combination with a cell wall inhibitor and rifampin results in a synergistic effect leading to improved bacterial killing [ ]. Adverse reactions associated with rifampin include gastrointestinal side effects including anorexia, hepatotoxicity, myelosuppression, and flu-like symptoms. Rifampin has significant effects on drug metabolism as it is a potent cytochrome P450 inducer, resulting in multiple drug–drug interactions. Careful review of patients’ medication profiles should be completed prior to initiation of rifampin therapy. Rifampin should also not be initiated until blood cultures have cleared due to resistance concerns [ ]. Common dosing strategies, monitoring parameters, and clinical pearls for antimicrobials used in the treatment of infective endocarditis are listed in Table 7.4 .
|Antimicrobial||Dosing (based on normal renal function)||Monitoring parameters||Clinical pearls|
|Aqueous penicillin G||12–30 million units IV/24h as continuous infusion (preferred) or divided doses q4h||Hypersensitivity reactions, renal function||Dosing is dependent on level of susceptibility|
|Ampicillin||2 g IV q4h||Hypersensitivity reactions, renal function, GI upset|
|Nafcillin||12 g IV/24h as continuous infusion (preferred) or divided doses q4h||Hypersensitivity reactions, renal function||No renal dose adjustments recommended, though AIN may occur|
|Oxacillin||12 g IV/24h as continuous infusion (preferred) or divided doses q4h||Hypersensitivity reactions||No renal dose adjustments recommended|
|Cefazolin||2 g IV q8h||Hypersensitivity reactions||Does not share the same side chain as any other penicillin, may be considered for nonanaphylactic allergies to penicillin|
|Cefotaxime||2 g IV q4–6h||Hypersensitivity reactions|
|Ceftriaxone||2 g IV q24h |
Double beta-lactam regimen: 2g IV q12h
|Hypersensitivity reactions||No renal dose adjustments recommended|
|Amikacin||Gram-negative infections: |
15 mg/kg DW IV q24h
|Nephrotoxicity, ototoxicity |
Gram-positive synergy: Gentamicin target peak = 3–5 mcg/mL and target trough = <1 mcg/mL; streptomycin target peak = 20–35 mcg/mL and target trough <10 mcg/mL
Extended-interval dosing for gram-negative infections: Gentamicin, tobramycin, and amikacin: Target random levels per nomogram [ , ]
|Gentamicin||Gram-positive synergy: |
3 mg/kg DW IV or IM per 24 h in 2–3 equally divided doses
Viridans group streptococci or Staphylococcus gallolyticus :
3 mg/kg DW IV or IM q24h
5 mg/kg or 7 mg/kg DW IV q24h
|Streptomycin||Gram-positive synergy: |
15 mg/kg IBW IV or IM per 24h in 2 equally divided doses
|Tobramycin||Gram-negative infections: |
5 mg/kg or 7 mg/kg DW IV q24h
|Vancomycin||15–20 mg/kg IV q8–24h||Nephrotoxicity, ototoxicity; target trough = 15–20 mcg/mL, target AUC = 400–600 mg/L h||Trough levels should be obtained 30 min prior to the next dose after reaching steady state|
|Daptomycin||Staphylococci: > 8 mg/kg IV q24h |
Enterococci: 10–12 mg/kg IV q24h
|Baseline and weekly CPK, muscle breakdown/weakness, renal function||Discontinue daptomycin if CPK > 1000 units/L (symptomatic) or > 2000 units/L (asymptomatic) [ ]|
|Ciprofloxacin||400 mg IV or 500 mg PO q12h||Altered mental status, blood glucose levels, tendinitis/tendon rupture, renal function, QTc interval||Avoid use in patients with a history of tendinitis/tendon rupture. May cause QTc prolongation—close monitoring is recommended|
|Levofloxacin||750 mg IV q24h|
|Moxifloxacin||400 mg IV q24h|
|Linezolid||600 mg IV or PO q12h||Serotonin syndrome, thrombocytopenia, peripheral neuropathy||Should not be used with >1 serotonergic agent due to increased risk of serotonin syndrome|
|Rifampin||900 mg IV or PO q24h in 3 divided doses||GI upset, myelosuppression, hepatotoxicity, flu-like symptoms||Rifampin is associated with many drug–drug interactions. Close evaluation of the patient’s medication list is indicated prior to therapy initiation. Counseling regarding bodily fluids, including tears and urine, are discolored (red) by rifampin is necessary|
Empiric therapy for IE should be initiated as soon as clinical suspicion for disease exists. The selected antimicrobial regimen should broadly cover all suspected pathogens until pathogen identification and susceptibilities are available, at which point the regimen can be deescalated to the narrowest agent(s). Many empiric regimens provide coverage for gram-positive cocci, including MRSA, as well as gram-negative bacilli such as Pseudomonas aeruginosa . Risk factors for IE should be considered in selecting the appropriate regimen; therefore, there is not a “standard empiric regimen,” but rather each empiric regimen should be individualized for each patient. Risk factors associated with various pathogens and appropriate empiric regimens are listed in Table 7.5 .