is a major cause of both hospital- and community-acquired infections, ranging from minor skin infections to invasive diseases such as osteomyelitis, infective endocarditis, and septicemia.1
An enormous challenge in treating S aureus
bloodstream infections is the pathogen’s ability to simultaneously co-evolve resistance to both administered antibiotics and innate immune defense mechanisms.2,3
Consequently, serious infections are associated with high rates of treatment failure and mortality.4
In 2017, in the United States, there were an estimated 120,000 cases of Staphylococcus aureus bacteremia, resulting in 20,000 deaths. Although the mortality rate from methicillin-resistant S aureus
(MRSA) has been about double that of methicillin-susceptible S aureus
(MSSA), this article focuses on optimal antibiotic therapy for MSSA infections.5
The timely administration of appropriate antibiotic therapy is associated with improved clinical outcomes in serious systemic infections. Initial sepsis empiric regimens most often consist of vancomycin with either ceftriaxone, cefepime, or a carbapenem, depending on the site of infection and risk of health care–associated infection. Use of piperacillin/tazobactam with vancomycin carries a relative risk of acute kidney injury of approximately 3, so its use is discouraged.6,7
The decisions surrounding the transitioning of empiric appropriate therapy to optimal targeted therapy in S aureus
bacteremia involve the integration of patient risk stratification, assessing the rate of clinical response, and source control. Antimicrobial therapy for S aureus
bacteremia should be viewed as consisting of an intensive “induction” early phase to achieve clinical and microbiological stability followed by a less intensive “consolidative” stage for outpatient completion.
During the early targeted therapy phase of treatment, once blood cultures identify “gram-positive cocci in clusters,” regimens should be focused on S aureus
until cultures are processed by the clinical microbiology laboratory or, ideally, rapid diagnostic methods can discriminate MSSA from MRSA later that day. In cases of S aureus
bacteremia due to soft tissue infection or pneumonia, which are easily identified through initial physical exam and radiology, single-therapy regimens are likely adequate. However, great concern should arise with S aureus
bacteremia in the setting of an unclear source. Such patients usually present with protean symptoms, such as weakness, shortness of breath, and without fever. They may have nonspecific back and other joint pain, possibly as an acute exacerbation of previous long-standing chronic pain. Patients with end-stage renal disease and other immunocompromising comorbidities and bioprostheses, clinical instability, and a history of intravenous drug abuse should also be paid very close attention. We advocate early combination therapy with daptomycin plus ceftaroline until MRSA is ruled out microbiologically (either through rapid diagnostics or through standard susceptibility testing) based on a small but randomized prospective study showing reduced mortality in high-risk patients treated with this regimen compared with standard-of-care monotherapy.8
Vancomycin plus anti-staphylococcal β-lactam (ASBL) treatment has demonstrated more rapid S aureus bacteremia clearance but at the price of acute kidney injury, recapitulating the recommendation against vancomycin plus piperacillin/tazobactam.9
and vancomycin-plus-ceftaroline regimens may be considered, but improved outcomes with these regimens have not been demonstrated clinically. The combination of daptomycin plus fosfomycin has shown favorable data in Spain, but parental fosfomycin is not available in the United States.11
In cases where combination therapy for “gram-positive cocci in clusters” has not been adopted and the patient has remained on vancomycin, strong clinical evidence supports rapid transition from empiric vancomycin to β-lactam therapy as soon as MSSA is identified.12,13
The ability of rapid diagnostics to shorten the empiric window between the initial “gram-positive cocci in clusters” reported by the laboratory to either MSSA or MRSA has been associated with more timely β-lactam therapy, decreased length of stay, and decreased hospitalization costs, driven largely by prompt initiation of β-lactam therapy for MSSA.14 Beyond the generally accepted need to switch from vancomycin to a β-lactam, other antibiotic choices afford the opportunity for interpretation.
Optimal therapy for confirmed MSSA bacteremia has traditionally favored an ASBL (eg, nafcillin, oxacillin, flucloxacillin, cloxacillin) over cefazolin. One primary argument that favors ASBLs is that some MSSA strains exhibit a so-called cefazolin inoculum effect, whereby cefazolin is hydrolyzed when a dense inoculum of bacteria is present. Strains with an inoculum effect show cefazolin minimum inhibitory concentrations (MICs) that increase >3 dilutions when 107 cfu/mL of organisms is tested rather than the standard 105
cfu/mL recommended by susceptibility testing guidelines, frequently pushing MICs out of susceptible range.15-18
Like selection of susceptibility testing media itself, susceptibility testing inocula standards were not designed for simulation of in vivo conditions or bacterial counts seen in clinical infection, so the translation of susceptibility testing differences based on inocula to clinical response is unknown. However, several cases of clinical failure in cases of severe invasive S aureus
infections have been documented in the literature.15-18
One major limitation of ASBL therapy is the real-world concern of the tolerability for the weeks-long duration of therapy required for many invasive S aureus infections such as endocarditis, osteomyelitis, and other deep-space infections. Long-term administration of ASBLs has been associated with myelosuppression, hepatitis, phlebitis, and interstitial nephritis superimposed on an already cumbersome every-4-hour dosing regimen.19
These concerns have increased over the years due to the higher risk of complications among elderly patients and the increasing number of patients who are quickly discharged on outpatient parenteral antibiotic therapy (OPAT) with less supervision of adverse effects than would be available in a hospital setting. Recent retrospective data, while vulnerable to treatment selection bias, have shown similar outcomes in patients treated with cefazolin and ASBLs for MSSA bacteremia with better tolerability.19
Cefazolin also allows for placement of a midline rather than a peripherally inserted central catheter for treatments of 4 weeks or less, due to its reduced propensity to cause phlebitis. Midlines are less invasive, have reduced risk of thrombosis, and are less anxiety-provoking for some patients. Finally, in patients on hemodialysis, placement of a venous access can be avoided with cefazolin; the drug can be administered 3 times weekly after hemodialysis sessions. Some employ a regimen of 2 g, 2 g, 3 g, where the 3 g covers the longer 3-day gap between Friday–Monday or Saturday–Tuesday sessions, although data supporting that approach over standard 2 g dosing are lacking.
We believe that both concerns are valid and need to be incorporated into the decision-making process of prescribing antibiotics to treat MSSA bacteremia. In cases of MSSA, we favor ASBL therapy while the patient is in the hospital to bridge them through bacteremia clearance, source control, and clinical stability. Use of ASBL therapy early on reduces risk of the inoculum effect in cases with high organism burden infections. The inpatient period also allows for placement of a venous midline catheter for cefazolin OPAT (Table
). On occasion, we have encountered persistent MSSA bacteremia on cefazolin or ASBL monotherapy (frequently due to endocarditis) that we have successfully cleared with cefazolin plus ertapenem.20
Again, once stability is achieved, monotherapy is employed, with a preference for ASBL for OPAT in these more challenging circumstances, especially if the patient is being discharged to a skilled nursing facility where closer monitoring is enabled and the 4-hour dosing interval of ASBLs imposes less inconvenience than in the case of a more mobile patient being discharged to their home.
Although case reports describe successful use of ceftriaxone in MSSA bacteremia, a recent comparative study showed inferior outcomes of ceftriaxone compared with cefazolin.21
Given the pharmacokinetics (ie, protein binding) and MICs of MSSA to ceftriaxone, routine use of ceftriaxone in MSSA is not recommended. Finally, it is worth noting that discussions surrounding the use of combination therapy for the treatment of S aureus
infections, including MRSA, are sure to be controversial. We must consider the fact that combination therapy is employed in the treatment of many other infectious diseases, from mycobacterial and parasitic to viral (ie, HIV) and even fungal (ie, induction of cryptococcal meningitis therapy). The patients from initial case reports of penicillin use in the 1940s, which served as the foundation of current monotherapy paradigms, differed greatly from contemporary patients in terms of host innate immunity status and the complexity of their antecedent surgical interventions that led up to their infections, including the presence of bioprosthetic devices such as heart valves and pacemakers. To extrapolate antimicrobial monotherapy to all contemporary patients, some of whom are much more immunocompromised and with more complex infections, seems illogical. Considering that the net antimicrobial effect of a patient on antibiotic pharmacotherapy is the collective summation of exogenous pharmacotherapy and innate immunity points out that pure monotherapy does not actually exist; consequently, some patients may require exogenous pharmacotherapy to compensate for their attenuated innate immune-mediated killing or to overcome a large bacterial inoculum of infection.
In summary, the last 2 decades have increased therapy options in the treatment of MRSA and MSSA infections, yet there is a dearth of guidance on how to best utilize these new antibiotics and how to integrate them with older ones. We hope this review helps readers consider important differences between adequate and optimal therapy when treating these challenging infections.
Sakoulas is a clinical infectious disease physician at Sharp Rees-Stealy Medical Group in San Diego, California. He also is an associate adjunct professor at the University of California San Diego School of Medicine, where he participates in the Collaborative to Halt Antibiotic-Resistant Microbes.
- Stapleton PD, Taylor PW. Methicillin resistance in Staphylococcus aureus: mechanisms and modulation. Sci Prog. 2002;85(Pt 1):57-72. doi: 10.3184/003685002783238870.
- Schito GC. The importance of the development of antibiotic resistance in Staphylococcus aureus. Clin Microbiol Infect. 2006;12(Suppl 1):3-8. doi: 10.1111/j.1469-0691.2006.01343.x.
- Segal AW. How neutrophils kill microbes. Annu Rev Immunol. 2005;23:197-223. doi: 10.1146/annurev.imunol.23.021704.115653.
- Labreche MJ, Lee GC, Attridge RT, et al. Treatment failure and costs in patients with methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infections: a South Texas Ambulatory Research Network (STARNet) study. J Am Board Fam Med. 2013;26(5):508-517. doi: 10.3122/jabfm.2013.05.120247.
- Kourtis AP, Hatfield K, Baggs J, et al. Vital signs: epidemiology and recent trends in methicillin-resistant and in methicillin-susceptible Staphylococcus aureus bloodstream infections – United States. MMWR Morb Mortal Wkly Rep. 2019;68(9):214-219. doi: 10.15585/mmwr.mm6809e1.
- Watkins RR, Deresinski S. Increasing evidence of the nephrotoxicity of piperacillin/tazobactam and vancomcyin combination therapy—what is the clinician to do? Clin Infect Dis. 2017;65(12):2137-2143. doi: 10.1093/cid/cix675.
- Luther MK, Timbrook TT, Caffrey AR, Dosa D, Lodise TP, LaPlante KL. Vancomycin plus piperacillin-tazobactam and acute kidney injury in adults: a systematic review and meta-analysis. Crit Care Med. 2018;46(1):12-20. doi: 10.1097/CCM.0000000000002769.
- Geriak M, Haddad F, Rizvi K, et al. Clinical data on daptomycin plus ceftaroline versus standard of care monotherapy in the treatment of methicillin-resistant Staphylococcus aureus bacteremia [published online April 25, 2019]. Antimicrob Agents Chemother. doi: 10.1128/AAC.02483-18.
- Davis J, Foo H, Lye D, et al. Combination antibiotic therapy for methicillin-resistant Staphylococcus aureus bacteraemia: the CAMERA2 randomised controlled trial. Presented at: 29th European Congress on Clinical Microbiology and Infectious Diseases; April 13-16, 2019; Amsterdam, The Netherlands. Abstr L0014.
- Trinh TD, Zasowski EJ, Lagnf AM, et al. Combination vancomycin/cefazolin (VAN/CFZ) for methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI). Open Forum Infect Dis. 2017;4(Suppl 1):S281. doi: 10.1093/ofid/ofx163.631.
- Pujol M, Miro JM, Shaw E, et al. Daptomycin plus fosfomycin versus daptomycin monotherapy for methicillin-resistant Staphylococcus aureus bacteremia. a multicenter, randomized clinical trial. Presented at: ID Week 2019; October 4, 2018; San Francisco, CA. Abstract LB3. idsa.confex.com/idsa/2018/webprogram/Paper74232.html#.
- Holland TL, Arnold C, Fowler VG Jr. Clinical management of Staphylococcus aureus bacteremia: a review. JAMA. 2014;312(13):1330-1341. doi: 10.1001/jama.2014.9743.
- Schweizer ML, Furuno JP, Harris AD, et al. Comparative effectiveness of nafcillin or cefazolin versus vancomycin in methicillin-susceptible Staphylococcus aureus bacteremia. BMC Infect Dis. 2011;11:279. doi: 10.1186/1471-2334-11-279.
- Bauer KA, West JE, Balada-Llasat JM, Pancholi P, Stevenson KB, Goff DA. An antimicrobial stewardship program’s impact with rapid polymerase chain reaction methicillin-resistant Staphylococcus aureus/S. aureus blood culture test in patients with S. aureus bacteremia. Clin Infect Dis. 2010;51(9):1074-1080. doi: 10.1086/656623.
- Nannini EC, Singh KV, Murray BE. Relapse of type A beta-lactamase-producing Staphylococcus aureus native valve endocarditis during cefazolin therapy: revisiting the issue. Clin Infect Dis. 2003;37(9):1194-1198. doi: 10.1086/379021.
- Bryant RE, Alford RH. Unsuccessful treatment of staphylococcal endocarditis with cefazolin. JAMA. 1977;237(6):569-570.
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- Weis S, Kesselmeier M, Davis JS, et al. Cefazolin versus anti-staphylococcal penicillins for the treatment of patients with Staphylococcus aureus bacteraemia. Clin Microbiol Infect. 2019;25(7): 818-827. doi: 10.1016/j.cmi.2019.03.010.
- Ulloa ER, Singh KV, Geriak M, et al. Cefazolin and ertapenem salvage therapy rapidly clears persistent methicillin-susceptible Staphylococcus aureus bacteremia [published online November 27, 2019]. Clin Infect Dis. doi: 10.1093/cid/ciz995.
- Carr DR, Stiefel U, Bonomo RA, Burant CJ, Sims SV. A comparison of cefazolin versus ceftriaxone for the treatment of methicillin-susceptible Staphylococcus aureus bacteremia in a tertiary care VA medical center. Open Forum Infect Dis. 2018;5(5):ofyS89. doi: 10.1093/ofid/ofy089.
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