**9. Antimicrobial therapy that may be used for MRSA bacteremia**

#### **9.1. Clindamycin**

Clindamycin is not specifically approved for treatment of MRSA infection, but it has been used for skin infections and invasive susceptible community‐acquired MRSA infections in children. It is bacteriostatic and, as such, is not recommended for bacteremia, endovascular infections like infective endocarditis or septic thrombophlebitis. Clindamycin has excellent tissue penetration, particularly in bone and abscesses, but has poor penetration into the CSF. Community‐acquired MRSA infections are more susceptible to Clindamycin than hospi‐ tal‐acquired isolates. It is important to have a D‐zone test to look for inducible clindamycin resistance in erythromycin‐resistant, clindamycin‐susceptible isolates. Side effects include diarrhea and *Clostridium difficile‐*associated disease. Clindamycin is pregnancy category B.

#### **9.2. Daptomycin**

staphylococcal chromosome cassette (SCCmec) [14]. If methicillin‐resistant *S. aureus* bacte‐ remia is identified, vancomycin and daptomycin are generally recommended for treatment based on current guidelines. Glycopeptides are a class of antibiotics that include vancomycin and work by binding to bacterial cell wall precursors and interfering with penicillin‐binding protein enzymes, causing cessation of cell wall synthesis and later cell death. Daptomycin is a lipopeptide that is approved for the treatment of *S. aureus‐*complicated skin or soft tis‐ sue infection, bacteremia and right‐sided infective endocarditis [15]. Daptomycin diffuses through the peptidoglycan layer of Gram‐positive organisms to the plasma membrane where it caused rapid depolarization resulting in the loss of membrane potential leading to loss of

In the case of uncomplicated bacteremia that is determined by the absence of endocarditis, artificial hardware, multiple sites of infection, and for which repeated blood cultures do not grow MRSA and patients are clinically well, vancomycin or daptomycin 6 mg/kg/dose IV once daily can be given for at least 2 weeks. However, in the case of complicated bacteremia, a duration of 4–6 weeks of therapy is recommended, depending on the extent of infection. Sometimes, higher dosages of daptomycin at 8–10 mg/kg/dose IV once daily may be needed. When MRSA bacteremia becomes complicated with infective endocarditis, IV vancomycin or daptomycin 6–10 mg/kg/dose IV once daily for 6 weeks is recommended. It is not recom‐ mended to add gentamicin or rifampin to vancomycin for bacteremia or native valve infective

It is also important to identify the source and extent of the infection with removal and debride‐ ment or drainage of other sites of infection to decrease the bulk of the infection. Blood cul‐ tures need to be collected every 2–4 days after initial positive cultures until documentation of the clearance of bacteremia. And echocardiography is recommended for all adult patients with bacteremia to eliminate the possibility of associated endocarditis; transesophageal echo‐ cardiography (TEE) being preferred over transthoracic echocardiography (TTE). In the cases of large vegetations that exceed 10 mm in diameter, occurrence of more than one embolic event during the first 2 weeks of therapy, severe valvular insufficiency, valvular perforation or dehiscence, decompensated heart failure, perivalvular or myocardial abscess, new heart block, or persistent fevers or bacteremia, evaluation for replacement of the affected valve

In conditions that are characterized by MRSA bacteremia complicated with infective endocar‐ ditis of a prosthetic valve, administration of IV vancomycin plus rifampin 300 mg PO/IV every 8 h for at least 6 weeks plus gentamicin 1 mg/kg/dose IV every 8 h for 2 weeks is recommended, along with early evaluation for valve replacement surgery to decrease the risk of embolization.

Clindamycin is not specifically approved for treatment of MRSA infection, but it has been used for skin infections and invasive susceptible community‐acquired MRSA infections in children. It is bacteriostatic and, as such, is not recommended for bacteremia, endovascular

**9. Antimicrobial therapy that may be used for MRSA bacteremia**

protein, DNA, and RNA synthesis and resulting in cell death [16].

should be considered in consultation with cardiothoracic surgery.

endocarditis.

124 Frontiers in Frontiers in Staphylococcus Aureus *Staphylococcus aureus*

**9.1. Clindamycin**

This is a lipopeptide class antibiotic that destroys cell membrane function through calcium‐ dependent binding, leading in a bactericidal activity in a concentration‐dependent manner. It is FDA approved for adults with *S. aureus* bacteremia, right‐sided infective endocarditis, and complicated skin infections. It is not supposed to be given in nonhematogenous MRSA pneu‐ monia because its activity is inhibited by pulmonary surfactant. The susceptibility breakpoint for daptomycin for *S. aureus* is ≤1 μg/mL. It appears that prior use of vancomycin and elevated vancomycin minimal inhibitory concentrations (MICs) has been associated with increases in daptomycin MICs and the emergence of nonsusceptible isolates. Monitoring creatinine phos‐ phokinase (CPK) while on daptomycin is necessary to avoid rhabdomyolysis, which is seen with higher doses. Therapy with daptomycin may be complicated with daptomycin‐induced eosinophilic pneumonia. Daptomycin is pregnancy category B.

#### **9.3. Linezolid**

Linezolid is a synthetic oxazolidinone and inhibits initiation of protein synthesis at the 50S ribosome. It is FDA‐approved for treatment of skin infections and nosocomial pneumonia due to MRSA. It has a 100% oral bioavailability. Resistance to linezolid is rare, but has been reported. An outbreak with linezolid‐resistant and methicillin‐resistant *S. aureus* in an inten‐ sive care unit has been reported in Spain. Resistance to linezolid was mediated by the *cfr* gene, as all isolates ended up carrying this gene. It is not approved for the treatment of MRSA bacteremia, although it has been used for this condition on several occasions. Long‐term use is not advisable as it may be complicated with hematologic toxicity, thrombocytopenia, ane‐ mia, neutropenia, peripheral and optic neuropathy, and lactic acidosis. Peripheral and optic neuropathy may not be reversible. Since it is a weak, nonselective, reversible inhibitor of monoamine oxidase, it may cause serotonin syndrome in patients taking concurrent selective serotonin‐receptor inhibitors. It is considered pregnancy category C.

#### **9.4. Tedizolid**

Tedizolid is an oxazolidinone drug. It has the advantage of oral and parenteral formulations, similar to linezolid. It was approved for the treatment of acute bacterial skin and skin struc‐ ture infections in 2014 and is administered once daily. Its use in bacteremia has not been recommended at this point.

#### **9.5. Quinupristin‐dalfopristin**

Quinupristin‐dalfopristin is constituted of two streptogramin antibiotics and inhibits protein synthesis. It is FDA approved for skin and soft tissue infections in adults and children >16 years of age. It has been used as salvage therapy for invasive MRSA infections in the setting of vancomycin treatment failure. It can have several side effects such as arthralgias, myalgias, and infusion‐related reactions that may limit its use. Quinupristin‐dalfopristin is considered pregnancy category B.

#### **9.6. Rifampin**

Rifampin is bactericidal against *S. aureus* and achieves high intracellular levels and good pen‐ etration in biofilms. It cannot, however, be used as monotherapy and is recommended to be used in combination with another antibiotic. It can be given at doses ranging from 600 mg daily in a single dose or in two divided doses to 900 mg daily in two or three divided doses. Rifampin is usually used in the setting of a *S. aureus* hardware infection.

#### **9.7. Telavancin**

Telavancin is an intravenous lipoglycopeptide. It inhibits cell wall synthesis by binding to peptidoglycan chain precursors and causing cell membrane depolarization. It has bactericidal activity against MRSA, vancomycin intermediate *S. aureus* (VISA), and vancomycin‐resistant *S. aureus* (VRSA). It is FDA approved for complicated skin and soft tissue infections in adults and is pregnancy category C. Nephrotoxicity was more commonly reported among patients treated with telavancin than among those treated with vancomycin, however, unlike vancomy‐ cin, there is no need to monitor telavancin levels in the serum. It may be given in bacteremia, but would be an off label use.

#### **9.8. Tetracyclines**

Doxycycline is a tetracycline that is approved for the treatment of skin and soft tissue infec‐ tions due to *S. aureus*. There is lack of data to support its use in more invasive infections like bacteremia. Tetracycline and doxycycline resistance in CA‐MRSA is associated with *tetK* gene, but does not affect minocycline susceptibility. Minocycline is available in oral and parenteral formulations. A newer tetracycline named tigecycline is a glycylcycline and is a derivative of the tetracyclines. It is FDA approved in adults for skin and soft tissue infec‐ tions and intraabdominal infections. It has a bacteriostatic activity against MRSA, thus it is not used in bacteremia; however, it was found that its use was associated with an increase in all‐cause mortality. Tetracyclines are pregnancy category D and are not recommended for children <8 years of age due to the potential for tooth enamel discoloration and decreased bone growth.

#### **9.9. Trimethoprim‐sulfamethoxazole**

TMP‐SMX is not FDA‐approved for the treatment of any staphylococcal infection, but since the majority of community‐acquired MRSA strains are susceptible to it *in vitro*, it has become widely used for skin and soft tissue infections. It may also be used in bone and joint infections. For more invasive cases such as staphylococcal bacteremia and endocarditis, it can be used, though not as a first line drug. In addition, its use in the elderly must be done in conjunction with close monitoring of creatinine and potassium levels. It is not recommended in pregnant women in the third trimester (pregnancy category C/D).

#### **9.10. Ceftaroline**

years of age. It has been used as salvage therapy for invasive MRSA infections in the setting of vancomycin treatment failure. It can have several side effects such as arthralgias, myalgias, and infusion‐related reactions that may limit its use. Quinupristin‐dalfopristin is considered

Rifampin is bactericidal against *S. aureus* and achieves high intracellular levels and good pen‐ etration in biofilms. It cannot, however, be used as monotherapy and is recommended to be used in combination with another antibiotic. It can be given at doses ranging from 600 mg daily in a single dose or in two divided doses to 900 mg daily in two or three divided doses.

Telavancin is an intravenous lipoglycopeptide. It inhibits cell wall synthesis by binding to peptidoglycan chain precursors and causing cell membrane depolarization. It has bactericidal activity against MRSA, vancomycin intermediate *S. aureus* (VISA), and vancomycin‐resistant *S. aureus* (VRSA). It is FDA approved for complicated skin and soft tissue infections in adults and is pregnancy category C. Nephrotoxicity was more commonly reported among patients treated with telavancin than among those treated with vancomycin, however, unlike vancomy‐ cin, there is no need to monitor telavancin levels in the serum. It may be given in bacteremia,

Doxycycline is a tetracycline that is approved for the treatment of skin and soft tissue infec‐ tions due to *S. aureus*. There is lack of data to support its use in more invasive infections like bacteremia. Tetracycline and doxycycline resistance in CA‐MRSA is associated with *tetK* gene, but does not affect minocycline susceptibility. Minocycline is available in oral and parenteral formulations. A newer tetracycline named tigecycline is a glycylcycline and is a derivative of the tetracyclines. It is FDA approved in adults for skin and soft tissue infec‐ tions and intraabdominal infections. It has a bacteriostatic activity against MRSA, thus it is not used in bacteremia; however, it was found that its use was associated with an increase in all‐cause mortality. Tetracyclines are pregnancy category D and are not recommended for children <8 years of age due to the potential for tooth enamel discoloration and decreased

TMP‐SMX is not FDA‐approved for the treatment of any staphylococcal infection, but since the majority of community‐acquired MRSA strains are susceptible to it *in vitro*, it has become widely used for skin and soft tissue infections. It may also be used in bone and joint infections. For more invasive cases such as staphylococcal bacteremia and endocarditis, it can be used, though not as a first line drug. In addition, its use in the elderly must be done in conjunction

Rifampin is usually used in the setting of a *S. aureus* hardware infection.

pregnancy category B.

126 Frontiers in Frontiers in Staphylococcus Aureus *Staphylococcus aureus*

**9.6. Rifampin**

**9.7. Telavancin**

but would be an off label use.

**9.8. Tetracyclines**

bone growth.

**9.9. Trimethoprim‐sulfamethoxazole**

Ceftaroline is a fifth‐generation cephalosporin. It is bactericidal against Gram‐positive and Gram‐negative pathogens and has activity against MRSA and VISA strains. It is recom‐ mended for skin and skin tissue infections and community‐acquired pneumonia. Its use in cases of *S. aureus* bacteremia is still under investigation.

#### **9.11. Dalbavancin**

Dalbavancin is a semisynthetic lipoglycopeptide that inhibits cell wall synthesis. Its half‐life is 147‐258 hours, which allows use at once weekly dosing. It was approved in 2014 for treatment of acute bacterial skin and skin structure infections due to Gram‐positive organisms, includ‐ ing MRSA. It is not yet approved for cases of *S. aureus* bacteremia.

#### **9.12. Oritavancin**

Oritavancin is a semisynthetic glycopeptide that also inhibits cell wall synthesis. Its half‐life is 100 hours, allowing for single dose therapy. It was approved for treatment of acute bacterial skin and skin structure infections in 2014.

#### **9.13. Vancomycin**

Vancomycin has been the mainstay of parenteral therapy for MRSA infections; it has slow bactericidal activity. There is evidence of emerging resistant strains. Vancomycin kills staphy‐ lococci more slowly than β‐lactams do *in vitro* and is inferior to β‐lactams for MSSA bactere‐ mia and infective endocarditis. Tissue penetration is highly variable and depends upon the degree of inflammation. Vancomycin's minimum inhibitory concentration breakpoints were changed in 2006 to improve the detection of intermediate susceptible strains (susceptible: MIC of 2 μg/mL or lower; intermediate: MIC of 4–8 μg/mL; and resistant: MIC 16 μg/mL or greater). The concept of MIC creep has arisen due to decrease in susceptibility to vancomycin among *S. aureus* isolates. *S. aureus* strains have been reported to "creep" up and approach the breakpoint of 2 with increasing frequency. This has been associated with worse clinical outcomes when vancomycin is used as therapy, when the MRSA isolate has a higher MIC to vancomycin. Vancomycin is considered pregnancy category C.
