A #PharmToExamTable question about antibiotic resistance in S. aureus, answered by Feiyang Ding, PharmD, a Graduate of UNMC College of Pharmacy.
(Reviewed by Andrew Watkins, PharmD)
Background
Staphylococcus aureus has been recognized as an important cause of human diseases ranging from minor skin and soft tissue infections to fatal endocarditis, chronic osteomyelitis, or sepsis. Vancomycin has been the treatment of choice for serious infections caused by methicillin-resistant S. aureus (MRSA), and for many years, vancomycin resistance did not seem to be a problem in S. aureus. However, in 1997, a case of vancomycin-intermediate Staphylococcus aureus (VISA, MIC = 4-8) was reported in Japan. In that case, the MIC of vancomycin was 8 mcg/mL, and the patient was successfully treated with amoxicillin-clavulanate plus gentamicin. Subsequently, cases of VISA infections have been reported worldwide. Generally, the incidence of VISA is hard to estimate due to the rarity of infection and challenges related to laboratory detection.1 Shariati et al.2 performed a comprehensive systematic review of literature from 1997 to 2019 and found the overall prevalence rate was 1.7% among 22,227 S. aureus isolates. Incidence of vancomycin-resistant S. aureus (VRSA, MIC ≥ 12) was much lower, with 23 out of 5855 (0.39%) S. aureus isolates being reported as VRSA.2
Mechanism
Various studies, from morphological to molecular level studies, have been performed to determine the mechanism of S. aureus resistance to vancomycin.3 In morphological studies, VISA strains appeared to have a thickened cell wall compared to non-VISA strains, and it is believed that this could prevent the diffusion of vancomycin to its active site. Moreover, a fluorescence imaging study demonstrated that the vancomycin binding site D-Ala-D-Ala was also increased in resistant strains; however, these residues are maintained in the mature peptidoglycan due to the low carboxypeptidase activity and, therefore, they constitute potential nonlethal binding sites for vancomycin. By binding to theses inactive sites, access of vancomycin to the active sites are reduced. Another early phenotypic change observed in resistant isolates is reduced autolytic activity. Impaired acetate metabolism has also been described in very resistant strains, which could lead to altered antibiotic resistance and cell death. On the molecular level, a variety of experiments have identified mutations at genes, such as walkR, vraSR and rpoB in various resistant isolates4. In most cases, these mutations are involved with changes in the cell wall, leading to reduced vancomycin activity.
Treatment Options
Currently, there are no clinical trials on VISA/VRSA treatment, and few successfully treated cases are reported in the literature. As a result, the optimal regimen for treating infections due to VISA/VRSA remains uncertain. According to the 2011 IDSA MRSA treatment guidelines,5 for infections due to S. aureus with reduced susceptibility to vancomycin and daptomycin, options may include the following: quinupristin-dalfopristin, sulfamethoxazole-trimethoprim (TMP-SMX), linezolid, and/or telavancin (C-III). These options may be given as a single agent or in combination with other antibiotics. Kullar et al.6 performed a systematic review of literature examining salvage therapy for resistant/persistent MRSA bacteremia. Their findings are summarized below:
High-dose Daptomycin
Daptomycin is approved by the FDA for the treatment of S. aureus bacteremia and right-sided IE at 6 mg/kg/day. At this dose, however, non-susceptibility may occur. As a result, the IDSA MRSAB treatment guidelines recommend daptomycin to be dosed at 10 mg/kg/day when used as monotherapy. But currently there is no randomized trial comparing high- and standard-dose daptomycin in MRSA bacteremia treatment.
Ceftaroline
Ceftaroline is distinguished from other β-lactams by its uniquely high binding affinity for PBP-2a, thus conferring its activity against MRSA. In a retrospective evaluation of 527 patients treated with ceftaroline, most patients (80%) were initiated on ceftaroline after receipt of another antimicrobial, with 48% citing disease progression as a reason for switching. A total of 271 (51%) patients were culture positive for S. aureus. The median duration of ceftaroline treatment was 6 days, with an interquartile range of 4 to 9 days.7More clinical data is needed to analyze the effect of in patients with persistent MRSA bacteremia.
Linezolid
There are several successful case reports indicating the effectiveness of treating persistent MRSA bacteremia with linezolid alone. However, linezolid is bacteriostatic and its toxicities such as thrombocytopenia may limit its use clinically.8
Telavancin
Telavancin is a lipoglycopeptide which can inhibit cell wall synthesis as well as depolarize the cell membrane. With this additional mechanism of action, it has activity against VISA/VRSA. In vitro PK/PD data has demonstrated its activity against vancomycin and daptomycin non-susceptible S. aureus.9 In vivo studies for bacteremia treatment are needed for further evaluation.
Quinupristin/dalfopristin
In an observational study by Sander et al.10, Quinupristin/dalfopristin has been used in 9 patients with MRSA infections who failed vancomycin treatment initially. Of these patients, 7 out 9 achieved bacterial clearance with quinupristin/dalfopristin therapy.10 However, the use of this medication is limited due to its substantial adverse reactions such as hepatotoxicity, risk of superinfection and need for a central catheter for administration.
Vancomycin + β-lactam
In vitro studies have shown synergistic activity between vancomycin and several β-lactams like ceftaroline and oxacillin against S. aureus, and this synergy can be extended to VISA isolates.11 As salvage therapy, vancomycin combined with a β-lactam at or near the initiation of therapy seems to yield improved results compared with vancomycin monotherapy. In a retrospective study, MRSA bacteremia microbiological eradication was achieved in 48/50 patients (96%) who received vancomycin with a β-lactam (ampicillin, nafcillin, amoxicillin/clavulanate, piperacillin-tazobactam, cephalexin and meropenem and etc.) compared with 24/30 patients (80%) (P = 0.021) who received vancomycin monotherapy.12 Another open-label, multicenter trial conducted in Australia showed a shorter duration of MRSA bacteremia in patients receiving vancomycin plus flucloxacillin (n = 31, 1.94 days) compared to vancomycin alone (n = 29, 3 days).13However, CAMERA2 trial indicated that the combination of antistaphylococcal β-lactam to vancomycin or daptomycin were associated an increased risk of acute kidney injury without an significant improvement on mortality, bacteremia, relapse or treatment failure. 14
Daptomycin + β-lactam
The combination of daptomycin and β-lactam also shows synergistic activity in in vitro studies. β-Lactams with PBP-1 binding (e.g. meropenem, ampicillin, nafcillin, cefepime and piperacillin/tazobactam) appear to enhance daptomycin anti-MRSA activity the most.15 Sakoulas et.al16 reported the results of salvage therapy with daptomycin and ceftaroline combination therapy for persistent MRSA bacteremia in 22 patients. Of these, 2 patients had vancomycin intermediate S. aureus infections and 4 patients had daptomycin non-susceptible S. aureus infections. With the initiation of daptomycin plus ceftaroline, bacteremia cleared in a median of 2 days (range 1-6 days).
TMP-SMX + daptomycin/ceftaroline
Although guidelines suggest using TMP-SMX either alone or in combination with other recommended medications, a recent randomized controlled trial showed a greater bacteremia persistence with TMP-SMX monotherapy.17 Claeys et.al18 investigated the combination of TMP-SMX with daptomycin. For patients with persistent MRSA bacteremia, adding TMP-SMX to daptomycin could allow clearance of bacteremia in 2.5 days. Microbiological eradication was demonstrated in 24 out of 28 patients, and in vitro synergy was demonstrated in 17 of the 17 recovered isolates. For the combination of TMP-SMX with ceftaroline, a retrospective analysis studied 29 patients using ceftaroline alone, in which 23 switched to combination therapy. The median duration of bacteremia was 9.5 days (range 7-15 days) before the switch and 3 days (range 2-5 days) after the switch.19
Conclusions
Although various regimens have been suggested, trials have enrolled small numbers of patients and have yielded inconsistent results. Possible monotherapies for VISA/VRSA infection include telavancin, ceftaroline and linezolid. Possible combination therapies that have been investigated include daptomycin or vancomycin combined with a β-lactam and daptomycin or ceftaroline combined with TMP-SMX.
References
1 Lowy, F. D. UpToDate: Staphylococcus aureus bacteremia with reduced susceptibility to vancomycin, <https://www.uptodate.com/contents/staphylococcus-aureus-bacteremia-with-reduced-susceptibility-to-vancomycin?source=history_widget#H1509092719> (
2 Shariati, A. et al. Global prevalence and distribution of vancomycin resistant, vancomycin intermediate and heterogeneously vancomycin intermediate Staphylococcus aureus clinical isolates: a systematic review and meta-analysis. Sci Rep 10, 12689, doi:10.1038/s41598-020-69058-z (2020).
3 Howden, B. P., Davies, J. K., Johnson, P. D., Stinear, T. P. & Grayson, M. L. Reduced vancomycin susceptibility in Staphylococcus aureus, including vancomycin-intermediate and heterogeneous vancomycin-intermediate strains: resistance mechanisms, laboratory detection, and clinical implications. Clin Microbiol Rev 23, 99-139, doi:10.1128/CMR.00042-09 (2010).
4 Hafer, C., Lin, Y., Kornblum, J., Lowy, F. D. & Uhlemann, A. C. Contribution of selected gene mutations to resistance in clinical isolates of vancomycin-intermediate Staphylococcus aureus. Antimicrob Agents Chemother 56, 5845-5851, doi:10.1128/AAC.01139-12 (2012).
5 Liu, C. et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 52, e18-55, doi:10.1093/cid/ciq146 (2011).
6 Kullar, R., Sakoulas, G., Deresinski, S. & van Hal, S. J. When sepsis persists: a review of MRSA bacteraemia salvage therapy. J Antimicrob Chemother 71, 576-586, doi:10.1093/jac/dkv368 (2016).
7 Casapao, A. M. et al. Large retrospective evaluation of the effectiveness and safety of ceftaroline fosamil therapy. Antimicrob Agents Chemother 58, 2541-2546, doi:10.1128/AAC.02371-13 (2014).
8 Jang, H. C. et al. Salvage treatment for persistent methicillin-resistant Staphylococcus aureus bacteremia: efficacy of linezolid with or without carbapenem. Clin Infect Dis 49, 395-401, doi:10.1086/600295 (2009).
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10 Sander, A., Beiderlinden, M., Schmid, E. N. & Peters, J. Clinical experience with quinupristin-dalfopristin as rescue treatment of critically ill patients infected with methicillin-resistant staphylococci. Intensive Care Med28, 1157-1160, doi:10.1007/s00134-002-1358-7 (2002).
11 Werth, B. J. et al. Novel combinations of vancomycin plus ceftaroline or oxacillin against methicillin-resistant vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous VISA. Antimicrob Agents Chemother 57, 2376-2379, doi:10.1128/AAC.02354-12 (2013).
12 Dilworth, T. J. et al. beta-Lactams enhance vancomycin activity against methicillin-resistant Staphylococcus aureus bacteremia compared to vancomycin alone. Antimicrob Agents Chemother 58, 102-109, doi:10.1128/AAC.01204-13 (2014).
13 Davis, J. S. et al. Combination of Vancomycin and beta-Lactam Therapy for Methicillin-Resistant Staphylococcus aureus Bacteremia: A Pilot Multicenter Randomized Controlled Trial. Clin Infect Dis 62, 173-180, doi:10.1093/cid/civ808 (2016).
14 Tong, S. Y. C. et al. Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal beta-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: A Randomized Clinical Trial. JAMA 323, 527-537, doi:10.1001/jama.2020.0103 (2020).
15 Berti, A. D., Sakoulas, G., Nizet, V., Tewhey, R. & Rose, W. E. beta-Lactam antibiotics targeting PBP1 selectively enhance daptomycin activity against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 57, 5005-5012, doi:10.1128/AAC.00594-13 (2013).
16 Sakoulas, G. et al. Antimicrobial salvage therapy for persistent staphylococcal bacteremia using daptomycin plus ceftaroline. Clin Ther 36, 1317-1333, doi:10.1016/j.clinthera.2014.05.061 (2014).
17 Paul, M. et al. Trimethoprim-sulfamethoxazole versus vancomycin for severe infections caused by meticillin resistant Staphylococcus aureus: randomised controlled trial. BMJ 350, h2219, doi:10.1136/bmj.h2219 (2015).
18 Claeys, K. C. et al. Impact of the combination of daptomycin and trimethoprim-sulfamethoxazole on clinical outcomes in methicillin-resistant Staphylococcus aureus infections. Antimicrob Agents Chemother 59, 1969-1976, doi:10.1128/AAC.04141-14 (2015).
19 Fabre, V., Ferrada, M., Buckel, W. R., Avdic, E. & Cosgrove, S. E. Ceftaroline in Combination With Trimethoprim-Sulfamethoxazole for Salvage Therapy of Methicillin-Resistant Staphylococcus aureus Bacteremia and Endocarditis. Open Forum Infect Dis 1, ofu046, doi:10.1093/ofid/ofu046 (2014).