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 [ ].

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.

Inoculum effect

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 [ ].

Beta-lactams

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 [ , ].

Glycopeptides

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