Microbiology of endocarditis

Staphylococcus aureus

S. aureus is a ubiquitous gram-positive coccus with a classic “grape-like” cluster morphology on Gram stain. The name is derived from the Latin word aureus meaning golden after the yellow-gold appearance of the colonies on culture media. This organism grows aerobically but is also a facultative anaerobe. All staphylococci are catalase positive, which distinguishes them from streptococci. The coagulase test is used to differentiate S. aureus (coagulase positive) from most other clinically relevant staphylococci, collectively known as coagulase-negative staphylococcus (CoNS) [ ]. Staphylococci, including S. aureus , are common commensals of the skin and mucus membranes. Humans serve as the primary reservoir with approximately 30% of the population being colonized with S. aureus . The widespread prevalence coupled with several virulence factors make S. aureus the common cause of IE [ ]. These characteristics highlight why a blood culture positive for S. aureus is serious medical event. S. aureus , except in the rarest of rare circumstances, should never be considered a contaminant when recovered from the blood. S. aureus bacteremia should always prompt the clinician to consider the possibility of IE.

Methicillin-sensitive Staphylococcus aureus

Prior to the discovery and widespread utilization of penicillin for the treatment of S. aureus bacteremia, the mortality rates exceeded 80% [ ]. Following the introduction of penicillin, mortality rates fell precipitously; however, resistance followed shortly thereafter. First recognized in 1942 [ ], S. aureus produces a β-lactamase enzyme encoded by the blaZ gene which hydrolyzes the β-lactam ring permanently inactivating the compound [ ]. Penicillin, aminopenicillins (amoxicillin, ampicillin), and ureidopenicillins (piperacillin) are all effectively hydrolyzed by these extracellular β-lactamases.

In an effort to combat the development penicillin resistance, methicillin was introduced in 1961 [ ]. Methicillin belongs to a subclass of penicillins, known as anti-staphylococcal penicillins, which are immune to blaZ -encoded β-lactamase hydrolyzation. Methicillin has fallen out of favor due to toxicity concerns, specifically the development of interstitial nephritis. However, oxacillin and nafcillin (also anti-staphylococcal penicillins) remain in widespread use.

Established literature further supports that patients treated with β-lactams experience improved outcomes as compared to vancomycin as definitive therapy for MSSA bacteremia and endocarditis [ ]. However, not all β-lactams are created equal. First-generation cephalosporins, such as cefazolin, have been found to be non-inferior to anti-staphylococcal penicillins. However, some evidence suggests that cefazolin has improved tolerability compared to nafcillin [ ]. Still, the choice of β-lactam agent for MSSA is a continued debate in the infectious disease community. Of noted importance, retrospective evidence suggests that β-lactam/β-lactamase inhibitor combinations (ampicillin/sulbactam and piperacillin/tazobactam) may have higher mortality rates when compared to oxacillin, nafcillin, and cefazolin [ ].

Methicillin-resistant Staphylococcus aureus

Methicillin resistance was first reported in Britain in 1961, shortly after the introduction of anti-staphylococcal penicillins [ ]. As discussed, S. aureus becomes resistant to penicillin due to the production of a β-lactamase whereas it becomes resistant to anti-staphylococcal penicillins and cephalosporins via an altered binding site on the target penicillin-binding proteins (PBPs). PBPs are essential enzymes required for bacterial cell wall synthesis and specifically function during the cross-linking stage of cell wall synthesis. S. aureus produces four PBPs, PBP1-4. The mecA gene encodes for an altered PBP2 named PBP2a. This altered protein has a decreased binding affinity for most β-lactams which results in high-level resistance [ ]. Vancomycin remains a mainstay in the treatment of severe MRSA infections, but given its nephrotoxicity and dosing challenges, there has been a push to discover and utilize newer, safer alternatives.

Vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus

Resistance finds a way. Vancomycin has been a mainstay in the treatment armamentarium against MRSA since the 1950s. Vancomycin-resistant S. aureus was first encountered in the United States in 2002. However, it remains quite rare with less than 20 cases reported [ ]. Resistance is conferred by the vanA operon acquired from enterococcal plasmids during distinct conjugation events. Vancomycin binds to the D-Ala-D-Ala peptidoglycan precursors which ultimately interfere with cell wall synthesis. vanA alters the cell wall synthesis by encoding for D-Ala-D-Lac which is not susceptible to vancomycin binding and thus confers resistance [ ].

A more frequently encountered isolate than VRSA is vancomycin-intermediate S. aureus (VISA). These organisms experience reduced susceptibility to vancomycin without full resistance. This phenotype is often preceded by a mixed population of vancomycin-susceptible and vancomycin-intermediate isolates termed heterozygous VISA (hVISA) [ ].The mechanisms behind the development of VISA and the transition to hVISA are outside the scope of this text and remain an area of investigation. The important takeaway is that populations of hVISA exposed to prolonged glycopeptides (vancomycin) are associated with the progression to VISA [ ]. Thus, when hVISA is suspected, alternative therapies such as daptomycin, ceftaroline, or linezolid are often employed.