Key Words
Objectives
- 1.Recommend appropriate antimicrobial regimens for a given MRSA infection.
- 2.Describe the mechanisms, dosing, and monitoring parameters of antibiotics used to treat MRSA infections.
- 3.Explain the mechanisms and implications of antibiotic resistance among Staphylococcus aureus.
Staphylococcus aureus is a common pathogen that can infect a variety of body sites, causing skin and soft tissue infections (SSTIs), bacteremia and endocarditis, bone and joint infections, pneumonia, and infections of the central nervous system (
Liu et al., 2011
, - Liu C.
- Bayer A.
- Cosgrove S.E.
- Daum R.S.
- Fridkin S.K.
- Gorwitz R.J.
- Chambers H.F.
Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
Clinical Infectious Diseases. 2011; 53: e18-e55
Lowy, 1998
). A working knowledge of the management of S. aureus infections is important to provide prompt and optimal care, because S. aureus is associated with significant morbidity and mortality and is highly prevalent in both hospital and community settings, and because treatment involves a variety of antibiotics with different mechanisms and toxicities. Antibiotic selection for children is further complicated by unique toxicities and a relative lack of dosing guidance and supporting data.Microbiology and Epidemiology
Staphylococci are Gram-positive cocci that grow most commonly in irregular clusters. All Staphylococcus species typically produce the enzyme catalase and are facultative anaerobes (
Que and Moreillon, 2015
). S. aureus may be differentiated from other Staphylococcus species by its production of the enzyme coagulase and is referred to as “coagulase-positive.” Aside from S. aureus, all other staphylococci found in humans are coagulase-negative and, when pathogenic, are generally less virulent (Que and Moreillon, 2015
, Rupp and Fey, 2015
).S. aureus commonly colonizes skin and mucosa. Asymptomatic nasal colonization, occurring in approximately 30% of the population, has contributed to the spread and persistence of S. aureus (
Chambers and DeLeo, 2009
). Such persistence, as well as enhanced pathogenesis, may also be attributed to a variety of microbiological factors. Surface adhesions and biofilm production promote adherence to host proteins and medical devices (Que and Moreillon, 2015
). Additionally, S. aureus produces a number of enzymes and toxins including hemolysins and the Panton-Valentine leukocidin that may be associated with more severe infections (Chambers and DeLeo, 2009
, Que and Moreillon, 2015
). Historically, all strains of S. aureus were susceptible to penicillin, but development of penicillin resistance, followed by methicillin resistance, spread during the 1970s and 1980s, followed by the substantial presence of methicillin-resistant S. aureus (MRSA) in both hospital and community settings by the 1990s (Chambers and DeLeo, 2009
, Iwamoto et al., 2013
). MRSA continues to represent a significant health care challenge today.Pharmacotherapy of Common MRSA infections
Beyond the type of infection caused by MRSA, antibiotic selection also depends on the patient's overall clinical status and severity of infection. For example, MRSA SSTIs may range from uncomplicated impetigo likely to resolve without any antimicrobial therapy to a life-threatening extensive infection progressing to toxic shock needing broad-spectrum antibiotics. When managing bacteremia, a positive blood culture result alone is insufficient to guide antibiotic selection, and the source of the bloodstream infection must be considered. For example, rapidly resolving bacteremia attributable to an SSTI or acute hematogenous osteomyelitis (AHO) is treated differently than complicated bacteremia with an intravascular source of infection as in endocarditis. Although the following sections focus on pharmacotherapy, many nonpharmacologic interventions such as radiographic imaging, incision and drainage, removal of infected hardware, and identification and management of any predisposing conditions like immune system deficiencies are critical to successful treatment. Antibiotic options that may be suitable for each infection type reviewed below are also summarized in Box 1.
Box 1
Antibiotic options for selected MRSA infections
- Skin and skin structure infections
- •Clindamycin
- •SMX-TMP
- •Vancomycin
- •Linezolid
- •Ceftarolinea
- •Daptomycinb
- •Doxycyclinec
- •
- Osteomyelitis
- •Clindamycin
- •Vancomycin
- •Daptomycinb
- •Linezolid
- •
- Pneumonia
- •Vancomycin
- •Linezolid
- •Clindamycin
- •Ceftarolinea
- •
- CNS infection
- •Vancomycin
- •Linezolid
- •SMX-TMP
- •
- Bacteremia and infective endocarditis (IE)
- •Vancomycin (+rifampin + gentamicin for prosthetic valve IE)
- •Daptomycinb
- •Ceftarolinea
- •
Note. CNS, central nervous system; FDA, U.S. Food and Drug Administration; MRSA, methicillin-resistant Staphylococcus aureus; SMX-TMP, sulfamethoxazole/trimethoprim.
aCeftaroline is approved only for use in skin and soft tissue infections and non-MRSA community acquired pneumonia.
bNot FDA-approved for use in children.
cAvoid use in children younger than 8 years of age.
Skin and Soft Tissue Infections
Purulent skin infection, or the presence of pus within an abscess or other wound, is suggestive of a staphylococcal infection, and drainage should be sent for culture and susceptibility testing. Current guidelines for SSTI management recommend topical mupirocin for bullous and nonbullous impetigo, but systemic therapy is recommended in the setting of an outbreak for patients with multiple lesions (
Stevens et al., 2014
). Systemic antibiotic therapy is additionally recommended for more complicated or extensive skin abscesses, including failure to improve after incision and drainage, associated septic phlebitis or spreading cellulitis, incomplete drainage, or systemic illness (Liu et al., 2011
). In the outpatient setting, a variety of oral antibiotics may be used for MRSA SSTIs, including sulfamethoxazole/trimethoprim (SMX-TMP), clindamycin, doxycycline, or linezolid. Antibiotic selection requires consideration of regional or institutional susceptibility patterns, patient age, and drug costs and toxicities. For example, doxycycline is not used in children under 8 years of age, and linezolid is more expensive than other treatment options. Drug-specific considerations are reviewed in greater detail later.- Liu C.
- Bayer A.
- Cosgrove S.E.
- Daum R.S.
- Fridkin S.K.
- Gorwitz R.J.
- Chambers H.F.
Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
Clinical Infectious Diseases. 2011; 53: e18-e55
Children hospitalized for a complicated SSTI should be treated with vancomycin, particularly in the setting of bacteremia, hemodynamic instability, or other signs of systemic illness. Clindamycin may also be used empirically for clinically stable patients without persistent bacteremia or endocarditis, if the institutional rate of clindamycin resistance among S. aureus is less than 10% to 15%.
Staphylococcal scalded skin syndrome and toxic shock syndrome (TSS) are toxin-mediated disease states. Although TSS typically presents with a rash early and later desquamation, it is a multisystem illness, including hypotension and multiorgan failure. TSS has been associated with tampon use but may present in association with skin lesions or surgery, or without any clear infection source (
Kimberlin et al., 2015
). In addition to supportive care measures like hydration and vasopressor therapy, prompt antibiotic treatment with a cell wall active agent, typically vancomycin, in combination with a protein synthesis inhibitor like clindamycin to reduce toxin production is critical (Kimberlin et al., 2015
).Because staphylococcal SSTIs often recur in patients and family members, there is interest in eradicating asymptomatic colonization or carriage of S. aureus as a means of reducing spread and continued infections (
Creech et al., 2015
). This practice is referred to as decolonization, and it most often involves topical antimicrobial therapy including intranasal mupirocin and chlorhexidine washes (Stevens et al., 2014
). Reported outcomes of topical MRSA decolonization are varied. Although most studies comparing decolonization to either placebo or standard hygiene practices identified greater S. aureus eradication in the treatment groups, the impact on later incidence of SSTI was varied and not consistently reduced among patients who had undergone decolonization (Ellis et al., 2007
, - Ellis M.W.
- Griffith M.E.
- Dooley D.P.
- McLean J.C.
- Jorgensen J.H.
- Patterson J.E.
- Hospenthal D.R.
Targeted intranasal mupirocin to prevent colonization and infection by community-associated methicillin-resistant Staphylococcus aureus strains in soldiers: A cluster randomized controlled trial.
Antimicrobial Agents and Chemotherapy. 2007; 51: 3591-3598
Fritz et al., 2011
, - Fritz S.A.
- Camins B.C.
- Eisenstein K.A.
- Fritz J.M.
- Epplin E.K.
- Burnham C.A.
- Storch G.A.
Effectiveness of measures to eradicate Staphylococcus aureus carriage in patients with community-associated skin and soft-tissue infections: A randomized trial.
Infection Control & Hospital Epidemiology. 2011; 32: 872-880
Raz et al., 1996
, Whitman et al., 2010
). Additionally, later development of resistance to topical therapies has been reported (- Whitman T.J.
- Herlihy R.K.
- Schlett C.D.
- Murray P.R.
- Grandits G.A.
- Ganesan A.
- Tribble D.R.
Chlorhexidine-impregnated cloths to prevent skin and soft-tissue infection in Marine recruits: A cluster-randomized, double-blind, controlled effectiveness trial.
Infection Control & Hospital Epidemiology. 2010; 31: 1207-1215
Fritz et al., 2013
, McNeil et al., 2011
, McNeil et al., 2013
) but was not confirmed in a recent randomized controlled trial (Hayden et al., 2016
). Consistent with existing literature and current national consensus guidelines, decolonization should be prioritized for patients with recurrent SSTIs or for settings where S. aureus is continually being spread among household members (Creech et al., 2015
, Liu et al., 2011
, - Liu C.
- Bayer A.
- Cosgrove S.E.
- Daum R.S.
- Fridkin S.K.
- Gorwitz R.J.
- Chambers H.F.
Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
Clinical Infectious Diseases. 2011; 53: e18-e55
Stevens et al., 2014
).Pneumonia
MRSA pneumonia is most commonly a health care–associated or hospital-acquired infection and is rarely implicated in community-acquired pneumonia (CAP). MRSA CAP has been described in association with previous or concurrent influenza and among patients with diabetes or those requiring hemodialysis (
Self et al., 2016
). Although not confirmed in a recent case–control study to be unique to MRSA, it remains prudent to empirically cover MRSA in severe cases of CAP, such as patients requiring admission to an intensive care unit or presenting with empyema or cavitation on radiograph (Liu et al., 2011
, - Liu C.
- Bayer A.
- Cosgrove S.E.
- Daum R.S.
- Fridkin S.K.
- Gorwitz R.J.
- Chambers H.F.
Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
Clinical Infectious Diseases. 2011; 53: e18-e55
Self et al., 2016
). The recommended treatment of MRSA pneumonia in children is vancomycin, with the alternative option of clindamycin for clinically stable patients without persistent bacteremia at practice at sites where less than 10% of S. aureus are resistant to clindamycin. Other treatment options include linezolid or, potentially, ceftaroline. Recent consensus guidelines for the treatment of hospital-acquired pneumonia in adults recommend only vancomycin or linezolid for the empiric treatment of MRSA pneumonia (Kalil et al., 2016
). Daptomycin serves no role in the management of pneumonia because it is inactivated by pulmonary surfactant (- Kalil A.C.
- Metersky M.L.
- Klompas M.
- Muscedere J.
- Sweeney D.A.
- Palmer L.B.
- Brozek J.L.
Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society.
Clinical Infectious Diseases. 2016; 63: e61-e111
Merck & Co., Inc, 2015
). CAP in children is typically treated for 7 to 10 days, although longer treatment courses may be prescribed depending on the severity and improvement of the infection.Bone and Joint Infections
Acute hematogenous osteomyelitis (AHO) is common in young children because of open epiphyses with capillaries providing nutrients to growing bones. A transient bacteremia can lead to a bone infection more easily in a child than in an adult (
Gutierrez, 2012
). Osteomyelitis may also occur secondary to injury like an open fracture or puncture wound, or an untreated local infection such as a periodontal abscess progressing to facial osteomyelitis.In addition to surgical debridement when indicated (particularly in the setting of septic arthritis), treatment involves either vancomycin or clindamycin. Current guidelines recommend either vancomycin or clindamycin, with the same stipulations as described for clindamycin with respect to patient status, blood culture results, and institutional susceptibility data. Linezolid, SMX-TMP, and daptomycin are additional alternatives. Daptomycin is currently being studied for AHO in children, and investigational dosing regimens are reviewed later. The recommended duration of therapy for MRSA osteomyelitis is dependent on patient progress, often involving repeated imaging, monitoring of C-reactive protein concentrations, and evaluation of clinical response. At a minimum, septic arthritis is typically treated for 3 to 4 weeks and AHO for 4 to 6 weeks (
Erickson et al., 2016
, Keren et al., 2015
, Liu et al., 2011
). These prolonged durations of therapy may require long-term intravenous (IV) antibiotics, but equivalent outcomes have been observed after oral treatment with clindamycin (- Liu C.
- Bayer A.
- Cosgrove S.E.
- Daum R.S.
- Fridkin S.K.
- Gorwitz R.J.
- Chambers H.F.
Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
Clinical Infectious Diseases. 2011; 53: e18-e55
Erickson et al., 2016
, Keren et al., 2015
) without the inconvenience or associated risks of IV treatment like thrombosis or infection.Bacteremia and Endocarditis
Infections described earlier like SSTIs, pneumonia, or bone and joint infections may present with transient bacteremia, but bloodstream infections related to intravascular catheters or endovascular tissue represent unique disease states requiring different approaches to management.
Bloodstream infections are a common complication of intravascular catheters, and management depends on characteristics of both the patient and the infected line. In contrast to abscesses, which can be promptly drained, or short-term catheter lines, which can be readily removed, source control is a more complicated treatment decision in the setting of long-term central venous IV catheters. Many children depend on this type of IV access for survival, such as those with short bowel syndrome requiring parenteral nutrition or those with renal failure requiring hemodialysis. In these patients, the availability and accessibility of alternative catheter insertion sites must be carefully considered in addition to patient, pathogen, and infection characteristics, and greater efforts to salvage catheters may be warranted. To retain an infected catheter, sterilization must be achieved through strategies like infusing IV antibiotics directly through the infected catheter or locking the IV line with antibiotics or ethanol (
Mermel et al., 2009
, Oliveria et al., 2012
, Pitts et al., 2014
, Restrepo et al., 2015
, Schoot et al., 2015
). In general, MRSA intravascular catheter-related bloodstream infection may be treated for as short as 2 weeks after the first negative blood culture result if fever and bacteremia resolve within 72 hours of treatment and the child does not have comorbid conditions like diabetes, immunosuppression, neutropenia, intravascular prosthetic material (e.g., artificial valve or pacemaker), evidence of endocarditis, or suppurative thrombophlebitis. Children with these complicating features, or more severe or persistent infections, may require 4 to 6 weeks of antibiotics (- Schoot R.A.
- van Ommen C.H.
- Stijnen T.
- Tissing W.J.E.
- Michiels E.
- Abbink F.C.H.
- van de Wetering M.D.
Prevention of central venous catheter-associated bloodstream infections in paeditric oncology patients using 70% ethanol locks: A randomized controlled mutli-centre trial.
European Journal of Cancer. 2015; 51: 2021-2038
Mermel et al., 2009
).Infective endocarditis is a serious infection involving the endocardium, or innermost layer of the heart (
Cabell et al., 2003
). Treatment of MRSA endocarditis requires prolonged treatment, typically 6 weeks, with high doses of antibiotics to overcome the characteristically high bacterial inocula and biofilm formation that allows for slower bacterial growth and division, resulting in reduced antibiotic effectiveness (Baltimore et al., 2015
).Vancomycin remains the preferred agent for management of MRSA bacteremia and endocarditis. Potential alternative options include daptomycin or ceftaroline. Clindamycin and linezolid should be avoided because they exert bacteriostatic effects against S. aureus, and bactericidal agents are generally preferred in this clinical situation (
Baltimore et al., 2015
, Liu et al., 2011
). When treating MRSA endocarditis for patients with prosthetic cardiac material, vancomycin should be combined with both gentamicin for synergistic bacterial killing and rifampin for enhanced biofilm penetration (- Liu C.
- Bayer A.
- Cosgrove S.E.
- Daum R.S.
- Fridkin S.K.
- Gorwitz R.J.
- Chambers H.F.
Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
Clinical Infectious Diseases. 2011; 53: e18-e55
Baltimore et al., 2015
, Hall Snyder et al., 2015
).- Hall Snyder A.D.
- Vidaillac C.
- Rose W.
- McRoberts J.P.
- Rybak M.J.
Evaluation of high-dose daptomycin versus vancomycin alone or combined with clarithromycin or rifampin against Staphylococcus aureus and S. epidermidis in a novel in vitro PK/PD model of bacterial biofilm.
Infectious Diseases and Therapy. 2015; 4: 51-65
Infections of the Central Nervous System
Although MRSA is not a traditional meningitis pathogen, it commonly causes central nervous system (CNS) infections in association with trauma and neurosurgery (e.g., instrumentation for cerebrospinal fluid shunts). Vancomycin is the preferred treatment for MRSA CNS infections; alternative agents include linezolid or SMX-TMP (
Liu et al., 2011
, - Liu C.
- Bayer A.
- Cosgrove S.E.
- Daum R.S.
- Fridkin S.K.
- Gorwitz R.J.
- Chambers H.F.
Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
Clinical Infectious Diseases. 2011; 53: e18-e55
Tunkel et al., 2004
). Rifampin is not added routinely but may be considered in selected situations, such as a slower than expected clinical or microbiological response or an inability to remove infected hardware (Tunkel et al., 2004
). Higher vancomycin doses and troughs are recommended for the management of CNS infections, and therapy generally lasts at least 2 weeks for meningitis but may be significantly longer, up to 6 weeks or more, for brain or spinal abscesses (Liu et al., 2011
). Duration of antibiotic treatment may also be prolonged in the setting of retained infected hardware or persistent clinical symptoms or positive culture results.- Liu C.
- Bayer A.
- Cosgrove S.E.
- Daum R.S.
- Fridkin S.K.
- Gorwitz R.J.
- Chambers H.F.
Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
Clinical Infectious Diseases. 2011; 53: e18-e55
Antimicrobial Agents
Vancomycin
Vancomycin, a glycopeptide antibiotic, exerts bactericidal effects on S. aureus by binding to the d-alanyl–d-alanine terminus of the peptidoglycan molecules that make up the bacterial cell wall. These subunits are then unavailable for cell wall incorporation, and synthesis is halted (
Lexi-Comp, 2015
, Murray et al., 2015
). Vancomycin has long been a drug of choice against MRSA and is included in national guidelines for serious MRSA infections of all body sites.- Murray B.E.
- Arias C.A.
- Nannini E.C.
Glycopeptides (vancomycin and teicoplanin), streptogramins (quinupristin-dalfopristin), lipopeptides (daptomycin), and lipoglycopeptides.
in: Mandell G.L. Bennett J.E. Dolin R. Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Saunders, Elsevier Inc,
Philadelphia, PA2015: 377-400
The typical starting approach to vancomycin dosing in pediatric patients with normal renal function is the administration of a 15-mg/kg dose every 6 hours (
Lexi-Comp, 2015
, Liu et al., 2011
). To ensure clinical efficacy and safety, serum vancomycin concentrations are routinely monitored at the third dose. The pharmacodynamic parameter most closely associated with vancomycin efficacy is the ratio between the area under the concentration–time curve (AUC) and the vancomycin minimum inhibitory concentration (MIC). In adult patients, an AUC-to-MIC ratio of at least 400 has been correlated with successful treatment of MRSA bacteremia (- Liu C.
- Bayer A.
- Cosgrove S.E.
- Daum R.S.
- Fridkin S.K.
- Gorwitz R.J.
- Chambers H.F.
Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
Clinical Infectious Diseases. 2011; 53: e18-e55
Kullar et al., 2011
). Because this calculation is mathematically cumbersome to perform at the bedside, serum trough concentrations of vancomycin are often used as surrogate markers for AUC. When treating an infection caused by a MRSA isolate with a vancomycin MIC of 1 mg/L, serum trough concentrations between 15 and 20 mg/L correlate with an AUC-to-MIC ratio of 400 in adult patients (Rybak et al., 2009
). Pharmacokinetic modeling studies in children describe different relationships between trough concentrations and AUC-to-MIC ratios. The targeted AUC-to-MIC ratio of 400 or greater was achieved with attainment of vancomycin trough concentrations as low as 7 to 10 mg/L in modeling studies using pharmacokinetic parameters derived from pediatric patients (- Rybak M.
- Lomaestro B.
- Rotschafer J.C.
- Moellering R.
- Craig W.
- Billeter M.
- Levine D.P.
Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists.
American Journal of Health-System Pharmacy. 2009; 66: 82-98
Frymoyer et al., 2013
, Le et al., 2013
).The maintenance of trough concentrations above a minimum of 10 mg/L is desirable to avoid the development of vancomycin resistance (
Howden et al., 2004
, Sakoulas et al., 2006
). Ideal therapeutic drug monitoring targets for vancomycin in children continue to be an area of debate. Although institutional protocols vary, serum trough concentrations between 10 and 15 mg/L are generally targeted for superficial infections and troughs between 15 and 20 mg/L for more severe or invasive infections. Lower concentrations are usually targeted in neonates, depending on institutional practice and unique patient characteristics like gestational age, weight, renal function, and infection severity.Nephrotoxicity is a well-described adverse effect of vancomycin therapy, especially when used at high doses or in conjunction with other nephrotoxins. This risk is minimized when trough concentrations are kept below 20 mg/L (
Rybak et al., 2009
). A common patient complaint is the development of flushing or tachycardia during vancomycin infusion, commonly referred to as “red man syndrome” (- Rybak M.
- Lomaestro B.
- Rotschafer J.C.
- Moellering R.
- Craig W.
- Billeter M.
- Levine D.P.
Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists.
American Journal of Health-System Pharmacy. 2009; 66: 82-98
Healy et al., 1990
). This reaction is associated with histamine release and can be managed in most patients by slowing the rate of infusion or premedicating with an antihistaminergic agent such as diphenhydramine.Clindamycin
Clindamycin is a lincosamide antibiotic that inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit (
Lexi-Comp, 2015
). As a protein synthesis inhibitor able to reduce toxin release, clindamycin is an important adjuvant therapy for toxin-mediated illnesses like staphylococcal TSS. Because it lacks bactericidal effects against MRSA, clindamycin is not recommended for use in patients with persistent bacteremia or endovascular infections, but it is commonly used for skin and bone infections (Baltimore et al., 2015
). Clindamycin is also limited by its inability to cross the blood–brain barrier, negating its utility for CNS infections (Lexi-Comp, 2015
).Clindamycin has high oral bioavailability and can be readily transitioned from the IV to oral route of administration. When studied in the setting of musculoskeletal infections including osteomyelitis, conversion to oral clindamycin yielded equivalent outcomes and eliminated risks associated with long-term IV therapy (
Erickson et al., 2016
, Keren et al., 2015
). Typical IV dosing for serious infections is a dose of 10 mg/kg every 6 hours, which is usually transitioned to 10 mg/kg orally every 8 hours (Bradley et al., 2011
, - Bradley J.S.
- Byington C.L.
- Shah S.S.
- Alverson B.
- Carter E.R.
- Harrison C.
- Swanson J.T.
The management of community-acquired pneumonia in infants and children older than 3 months of age: Clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America.
Clinical Infectious Diseases. 2011; 53: e25-e76
Erickson et al., 2016
, Lexi-Comp, 2015
). These two dosing schemes were deemed equally effective when compared for the management of musculoskeletal infections (Erickson et al., 2016
). The most commonly reported adverse effect after clindamycin administration is gastrointestinal distress. Clindamycin commonly causes diarrhea and, as with all antibiotics, confers a risk for antibiotic-associated Clostridium difficile diarrhea.Linezolid
Linezolid is an oxazolidinone antibiotic that inhibits bacterial protein synthesis by binding to the 50S subunit of the bacterial ribosome (
Cox & Donowitz, 2015
). Linezolid is approved by the U.S. Food and Drug Administration (FDA) for use in adults and children of all ages for MRSA SSTIs and pneumonia (Pfizer, 2015
). Linezolid is not recommended for MRSA bacteremia or endocarditis because of its bacteriostatic effects and an observed mortality imbalance in a noninferiority study (Wilcox et al., 2009
) comparing linezolid to vancomycin for catheter-related bloodstream infections. A 21.5% mortality rate was reported for patients who received linezolid, compared with 16% of patients who received vancomycin; however, it is noted that this imbalance appeared to have been driven by concomitant Gram-negative pathogens (Liu et al., 2011
, - Liu C.
- Bayer A.
- Cosgrove S.E.
- Daum R.S.
- Fridkin S.K.
- Gorwitz R.J.
- Chambers H.F.
Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
Clinical Infectious Diseases. 2011; 53: e18-e55
Wilcox et al., 2009
). Adolescents may receive the adult dose of 600 mg every 12 hours, whereas doses of 10 mg/kg every 8 hours are recommended for younger patients (Pfizer, 2015
). Prolonged use of linezolid increases the incidence of drug-induced thrombocytopenia and other myelosuppressive effects, which generally normalize after stopping linezolid but must be considered, particularly in children who have blood dyscrasias at baseline (Garazzino et al., 2011
). Other adverse effects, including neuropathies and lactic acidosis, have been described. Linezolid is a monoamine oxidase inhibitor and thus should not be administered with foods rich in tyramine like smoked meats, red wine, or aged cheese. Additionally, concomitant administration of serotonin or norepinephrine reuptake inhibitors like citalopram or duloxetine can lead to neuroleptic malignant syndrome or serotonin syndrome (Pfizer, 2015
).Daptomycin
Daptomycin is a lipopeptide antibiotic that exerts its bactericidal activity by inserting its lipophilic tail into membranes of Gram-positive pathogens, causing a loss of potassium ions with subsequent depolarization leading to cell death, among other losses to membrane viability (
Hobbs, Miller, O'Neill, & Chopra, 2008
, Jung et al., 2004
). Given its broader Gram-positive spectrum activity, higher cost, and FDA approval for use in adults only, daptomycin is typically reserved for second-line treatment of MRSA bacteremia, usually in the setting of vancomycin failure or intolerance. Additionally, there is an increasing role for daptomycin in the management of bacteremia cause by strains of MRSA with vancomycin MICs greater than 1 mg/L, with evidence suggesting improved clinical outcomes with daptomycin over vancomycin in adult patients (Moore et al., 2012
, - Moore C.L.
- Osaki-Kyan P.
- Haque N.Z.
- Perri M.
- Donabedian S.
- Zervos M.J.
Daptomycin versus vancomycin for bloodstream infections due to methicillin-resistant Staphylococcus aureus with a high vancomycin minimum inhibitory concentration: A case-control study.
Clinical Infectious Diseases. 2012; 54: 51-58
Murray et al., 2013
). Although the manufacturer recommends daptomycin dosing for the treatment of S. aureus bacteremia in adult patients of 6 mg/kg once daily, many clinicians use higher doses, up to 8 mg/kg or greater, particularly in the setting of concomitant endocarditis (Kullar, Davis, Levine, Zhao et al., 2011
). Daptomycin is not currently approved for use in children. Pharmacokinetic data indicate more rapid daptomycin clearance and overall reduced drug exposure among younger children compared with adolescents and adults; alternative doses of daptomycin have been investigated in some small pediatric studies. Available evidence suggests daily doses of 8- to 10-mg/kg yield serum concentrations, similar to those attained by a 4- to 6-mg/kg dose in adults (Abdel-Rahman et al., 2008
, Abdel-Rahman et al., 2011
, - Abdel-Rahman S.M.
- Chandorkar G.
- Akins R.L.
- Bradley J.S.
- Jacobs R.F.
- Donovan J.
- Benziger D.P.
Single-dose pharmacokinetics and tolerability of daptomycin 8 to 10 mg/kg in children aged 2 to 6 years with suspected or proved gram-positive infections.
The Pediatric Infectious Disease Journal. 2011; 30: 712-714
Antachopoulos et al., 2012
). Daptomycin is currently being studied for the treatment of children with AHO in children ages 1 to 7 years receiving daily doses of 12 mg/kg, children between the ages of 7 and 12 years receiving 9 mg/kg, and children ages 12 years and older receiving 7 mg/kg (Cubist Pharmaceuticals, 2013
). Because of nervous system and/or muscular system adverse effects, the package insert warns against use in patients younger than 12 months (Merck & Co., Inc, 2015
).Ceftaroline
Ceftaroline is a novel advanced-generation cephalosporin, and it is the first β-lactam with activity against MRSA. Ceftaroline inhibits bacterial cell wall synthesis by binding to a transpeptidase enzyme involved in cell wall formation, even in the presence of mutations rendering other β-lactams ineffective (
Kosowka-Shick et al., 2010
). Ceftaroline was approved for use in adults by the FDA in 2010 for the treatment of acute bacterial skin and skin structure infections (ABSSIs) and CAP for children ages 2 months and older (Allergan, 2016
). Although ceftaroline was studied and approved for acute bacterial skin and skin structure infections caused by MRSA, its use in pneumonia was approved only for methicillin-susceptible S. aureus, Streptococcus pneumoniae, Haemophilus influenzae, Escherichia coli, and Klebsiella species (Allergan, 2016
, Cannavino et al., 2016b
, Korczowski et al., 2016
). Table 1 summarizes approved dosing specific to MRSA skin infections. Higher doses have been reported for both children and adults with invasive infections. Successful treatment of complicated MRSA bacteremia, including endocarditis with a dose of 600 mg every 8 hours instead of the FDA-approved 600 mg every 12 hours, has been reported in adult patients (- Korczowski B.
- Antadze T.
- Giorgobiani M.
- Stryjewski M.E.
- Jandourek A.
- Smith A.
- Bradley J.S.
A multicenter, randomized, observer-blinded, active-controlled study to evaluate the safety and efficacy of ceftaroline versus comparator in pediatric patients with acute bacterial skin and skin structure infection.
The Pediatric Infectious Diseases Journal. 2016; 35: e239-e247
Ho et al., 2012
). Additionally, off-label use of ceftaroline for MRSA respiratory infections has been described in children with cystic fibrosis (Cannavino et al., 2016a
, Molloy et al., 2014
, Zobell et al., 2015
), although resistance has been described, and optimal dosing remains unknown. In addition to MRSA and other Gram-positive organisms, ceftaroline is also active against a variety of Gram-negative pathogens including most Enterobacteriaceae as noted earlier (Allergan, 2016
). Although this may be advantageous for patients with concomitant MRSA and Gram-negative infections, good antimicrobial stewardship involves the use of the narrowest spectrum agents possible, and ceftaroline has a broader spectrum of Gram-negative activity than do most other MRSA treatment options.Table 1Recommended pediatric doses of anti-staphylococcal antibiotics
| Drug | Dose (mg/kg/day unless otherwise specified) | Common adverse effects | Monitoring parameters |
|---|---|---|---|
| Clindamycin, intravenous | 40 divided every 6 hours Maximum = dose of 600–900 mg | Diarrhea including Clostridium difficile colitis, hepatotoxicity | Stool output if warranted, LFTs |
| Clindamycin, oral | 30 divided every 8 hours Maximum = dose of 450–600 mg | ||
| Vancomycin, intravenous | 60 divided every 6–8 hours Adjust per targeted serum trough concentration Empiric dose may be altered based on severity of illness and baseline renal function | Nephrotoxicity, infusion-related reactions, ototoxicity, neutropenia | BUN, SCr, urine output, serum vancomycin concentrations, CBC |
| Linezolid, intravenous or oral | Under 12 years old: 30 divided every 8 hours; maximum = dose of 600 mg 12 years of age and older: 600 mg every 12 hours | Thrombocytopenia, hepatotoxicity, peripheral neuropathy, optic neuritis, serotonin syndrome with concomitant serotonergic agents | CBC, LFTs, interacting foods or medications |
| Daptomycin, intravenous | 6–10 once daily | Rhabdomyolysis, hepatotoxicity | CPK, BUN, SCr, LFTs |
| SMX-TMP, intravenous or oral | 8–12 (TMP component) divided every 12 hours Consider higher doses (10–20) for CNS infections | Elevated SCr, myelosuppression, hepatotoxicity | BUN, SCr CBC, LFTs |
| Ceftaroline, intravenous | 2 months to <2 years old: 24 divided every 8 hours 2 to <18 years weighing ≤33 kg: 36 divided every 8 hours 2 to <18 years weighing >33 kg: 400 mg every 8 hours or 600 mg every 12 hours | Seroconversion to positive direct Coombs test results, neutropenia | BUN, SCr CBC |
| Gentamicin, intravenous | 3–6 divided every 8 hours Adjust per targeted serum peak (3–4 mg/L) and trough (<1 mg/L) concentrations | Nephrotoxicity, ototoxicity | BUN, SCr, urine output, serum gentamicin concentrations |
| Rifampin, intravenous or oral | 20 divided every 8 hours | Red/orange discoloration of body fluids, hepatotoxicity | LFTs, CBC |
Note. BUN, blood urea nitrogen; CBC, complete blood count; CNS, central nervous system; CPK, creatine phosphokinase; LFTs, liver function tests; SCr, serum creatinine; SMX-TMP, sulfamethoxazole/trimethoprim; TMP, trimethoprim.
a Doses for U.S. Food and Drug Administration–approved indications only. Alternative doses have been reported for different infections; see text.
Adjunctive and Alternative Antibiotics
Gentamicin and rifampin have infrequent but important roles in the management of selected MRSA infections. Gentamicin is an aminoglycoside that inhibits bacterial protein synthesis by binding to bacterial ribosomes (
Leggett, 2015
). For the treatment of MRSA endocarditis in the setting of a prosthetic valve, gentamicin is routinely added with rifampin to the primary cell wall active agent, typically vancomycin, for the first 2 weeks of treatment only. The most recent consensus guideline for pediatric endocarditis also provides the option of adding gentamicin for the first 3 to 5 days of treatment for native valve endocarditis, a suggestion extrapolated from in vitro modeling (Baltimore et al., 2015
). The role of aminoglycosides in native valve endocarditis has been studied in adult patients and identified increased nephrotoxicity with no added clinical benefit (Cosgrove et al., 2009
). Although the use of additional gentamicin in native valve endocarditis has not been studied in children, similar results of increased kidney injury without improved clinical outcomes have been reported in the settings of both Gram-negative and enterococcal bacteremia (Ibrahim et al., 2015
, Tamma et al., 2013
). Traditional synergy dosing as recommended by consensus guidelines is presented in Table 1, but once-daily dosing has been recommended by others (Nichols et al., 2016
).In addition to prosthetic valve endocarditis, rifampin may also be considered for adjuvant therapy for CNS infections or potentially for selected bone and joint infections. Rifampin is a protein synthesis inhibitor, and its primary advantage for these selected infections is its excellent penetration through biofilms and also into the CNS. Resistance is known to develop rapidly when rifampin is used alone, so it must always be used in combination with another antibiotic (
Liu et al., 2011
).- Liu C.
- Bayer A.
- Cosgrove S.E.
- Daum R.S.
- Fridkin S.K.
- Gorwitz R.J.
- Chambers H.F.
Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
Clinical Infectious Diseases. 2011; 53: e18-e55
Dosing recommendations vary, but the typical treatment dose is 20 mg/kg/day divided in two or three doses. Rifampin is available for IV or oral administration and has good oral bioavailability, allowing for IV-to-oral conversion without any dose changes. Rifampin can cause hepatotoxicity, and patients and parents must be counseled about its benign, but potentially alarming, adverse effect of turning body fluids like urine and tears a red–orange color. Finally, rifampin is a potent inducer of cytochrome P450 enzymes, which results in enhanced metabolism, and subsequently reduced concentrations, of the many drugs dependent on these enzymes for metabolism. Some common examples of affected medications include tacrolimus, amiodarone, prednisone, and azole antifungals.
The tetracycline antibiotics (tetracycline, doxycycline, minocycline) are alternative agents for the outpatient management of SSTIs. These agents also interfere with bacterial protein synthesis and are bacteriostatic; they are typically reserved as alternative treatment options for MRSA SSTIs and are not used in invasive infections (
Liu et al., 2011
, - Liu C.
- Bayer A.
- Cosgrove S.E.
- Daum R.S.
- Fridkin S.K.
- Gorwitz R.J.
- Chambers H.F.
Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children.
Clinical Infectious Diseases. 2011; 53: e18-e55
Moffa and Brook, 2015
). Important adverse effects include photosensitivity and esophagitis, and these agents should be avoided for treating MRSA infections in patients younger than 8 years because they cause irreversible tooth discoloration when used during tooth development, although this is more common with long-term therapy and does not preclude use for rickettsial infections (Lexi-Comp, 2015
, Todd et al., 2015
).Mechanisms of Antimicrobial Resistance
Antimicrobial resistance of S. aureus to a variety of agents has been described. The most common mechanisms are summarized in Table 2 and described in detail below.
Table 2Common mechanisms of antibiotic resistance in S. aureus
| Mechanism of resistance | Drug class |
|---|---|
| β-lactamases | Natural penicillins |
| Aminopenicillins | |
| Penicillin-binding protein alterations | Penicillinase-resistant penicillins |
| Cephalosporins | |
| β-lactam–β-lactamase inhibitor combinations | |
| Peptidoglycan overproduction | Vancomycin |
| Daptomycin | |
| Altered glycopeptide precursors | Vancomycin |
| Ribosomal binding site methylation | Clindamycin |
| Macrolides |
a Except ceftaroline.
Resistance to Methicillin
The activity of β-lactams against S. aureus relies on their structural similarity to the d-alanyl–d-alanine portion of the peptidoglycan subunits of the bacterial cell wall. During cell wall formation, the bacterial enzyme transpeptidase crosslinks d-alanyl–d-alanine terminals together (
Berger-Bachi and Rohrer, 2002
, Doi and Chambers, 2015
). In the setting of methicillin-susceptible S. aureus, the bacterial transpeptidase is unable to discern between d-alanyl–d-alanine and the β-lactam ring, and it errantly binds to the β-lactam antibiotic, which halts bacterial cell wall production. Because it attaches to the β-lactam ring, the bacterial transpeptidase enzyme is also referred to as penicillin-binding protein (PBP).S. aureus infections were historically uniformly susceptible to penicillin until the identification of a penicillinase enzyme produced by S. aureus capable of hydrolyzing and thus inactivating penicillin, as well as the aminopenicillins amoxicillin and ampicillin. By the 1960s, this penicillinase was nearly uniformly present in all S. aureus strains (
Chambers and DeLeo, 2009
). Because the penicillinase enzyme is narrow in its ability to hydrolyze β-lactam rings, it cannot inactivate penicillinase-resistant penicillins like methicillin, β-lactam/β-lactamase inhibitor combinations like ampicillin/sulbactam, piperacillin/tazobactam, or cephalosporins. Thus, these agents remained active against S. aureus even in the presence of penicillinase.Although penicillinase results in destruction of certain antibiotics (natural and aminopenicillins), methicillin resistance is conferred by alteration of the drug target without destruction of antibiotics. In MRSA, the bacterial transpeptidase enzyme, or PBP, is mutated to PBP-2a, which has low affinity for the β-lactam ring and is therefore able to continue incorporating d-alanyl-d-alanine subunits into the bacterial cell wall without binding to the β-lactam antibiotic (
Berger-Bachi and Rohrer, 2002
; Chambers and DeLeo, 2009
). The PBP-2a mutation is encoded by the mecA gene, which is found within the mobile genetic element staphylococcal cassette chromosome mec, or SCCmec (Hiramatsu et al., 2001
). Importantly, as a mobile element, mecA can be acquired by horizontal gene transfer, promoting the spread of methicillin resistance (Chambers and DeLeo, 2009
).Resistance to Vancomycin
Vancomycin resistance among MRSA remains rare, but it can be difficult to detect and can lead to treatment failure. Vancomycin-intermediate S. aureus (VISA) can develop after prolonged, and particularly subtherapeutic, exposure to vancomycin (
Howden et al., 2004
). When vancomycin is present for long enough at inadequate serum concentrations, S. aureus can adapt to become less susceptible by developing a thickened cell wall, requiring a higher concentration of vancomycin to bind to the greater number of cell wall precursors (Ciu et al., 2003
). Additionally, VISA may have a slower rate of growth and reproduction, offering fewer opportunities for vancomycin to interrupt cell wall synthesis (Pfeltz et al., 2000
). Although VISA may be identified by MICs between 4 and 8 μg/ml, heterogeneous VISA (hVISA) is harder to detect and also presents the risk of vancomycin failure (Casapao et al., 2013
). Infections caused by hVISA consist of a small subpopulation of microorganisms with reduced vancomycin susceptibility among a much larger population of species fully susceptible to vancomycin (i.e., MIC ≤ 2 μg/ml). When the sample is tested for vancomycin susceptibility, the small subpopulation with reduced susceptibility is not detected, and the entire sample is interpreted as being fully susceptible to vancomycin. However, treatment with vancomycin in this scenario can lead to failure, persistence, and recurrence of infection (Casapao et al., 2013
, Gomes et al., 2015
). In contrast to VISA, wherein the cell wall is thicker but its components are otherwise unchanged, the cell wall subunits of vancomycin-resistant S. aureus terminate in a d-alanine–d-lactate sequence instead of d-alanyl–d-alanine (Gardete & Tomasz, 2014
). Vancomycin has substantially less affinity and subsequent ability to bind to d-alanine–d-lactate, and is thus no longer effective.Resistance to Other Antibiotics
Because clindamycin is widely used for the management of MRSA infections in children, understanding mechanisms and implications of resistance is important. Clindamycin resistance in S. aureus may be either constitutive or inducible, both of which involve the macrolide, lincosamide, streptogramin phenotype encoded by the erm gene. The macrolide, lincosamide, streptogramin phenotype promotes methylation of the bacterial ribosome, causing decreased antibiotic binding and ultimately resistance across the three classes of antibiotics (
Sasirekha et al., 2014
). Inducible resistance is identified by a positive double disk diffusion test result, confirmed by a blunted zone of bacterial clearance around a clindamycin disc in close proximity to an erythromycin disc (Gardiner et al., 2013
). Other mechanisms of resistance to a variety of antibiotics have been described. Reduced susceptibility to daptomycin is most widely observed among hVISA and VISA, likely because of the thickened cell wall hindering adequate penetration of daptomycin (Ciu et al., 2006
, Kelley et al., 2011
). Development of resistance to both linezolid and ceftaroline has been identified among patients with cystic fibrosis via the development of various mutations, attributed to subtherapeutic drug concentrations (Cannavino et al., 2016a
, Gales et al., 2006
, Hill et al., 2010
).Conclusion
Infections caused by MRSA are common both in the community and hospital settings and represent a significant health care burden. Management of these disease states in children is further complicated by unique dosage requirements, adverse drug effects, and pharmacokinetic profiles. Clinicians must maintain a current, working knowledge of pharmacotherapy of these common infections that vary widely in terms of presentation and severity.
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Biography
Leah Molloy, Clinical Pharmacist Specialist, Infectious Diseases, Department of Pharmacy, Children's Hospital of Michigan, Detroit Medical Center, Detroit, MI.
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Footnotes
Conflicts of interest: None to report.
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© 2016 by the National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.
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