The potential role of daptomycin and quinupristindalfopristin as a bactericidal agent in the treatment of methicillin-resistant Staphylococcus aureus bacteremia

INTRODUCTION

Staphylococcus aureus significantly contributes to severe infections acquired in hospitals and communities, leading to considerable morbidity and mortality.^[1] In recent years, the rise of methicillin-resistant S. aureus (MRSA) strains, resistant to all β-lactam antibiotics and often to many other antimicrobial classes, has hampered the treatment of S. aureus infections. In comparison to patients infected with methicillin-susceptible S. aureus (MSSA), individuals infected with MRSA typically exhibit more severe comorbidities, extended previous hospitalizations, increased prior antimicrobial treatments, and additional unfavorable prognostic indicators, when these parameters are considered, MRSA infections continue to demonstrate markedly higher mortality, morbidity, duration of hospitalization, and treatment expenses compared to MSSA infections.^[2,3] Until recently, most MRSA infections were predominantly healthcare-associated MRSA, acquired either post-hospital admission or through recent contact with another hospital or healthcare facility, such as a nursing home for the elderly.^[4] The emergence of resistance to β-lactams and other medicines has led to the heightened utilization of glycopeptides, particularly vancomycin, as the primary treatment for severe MRSA. Multiple kinds of glycopeptide resistance have emerged in MRSA strains, encompassing rare high-level resistance, as well as homogenous, heterogeneous intermediate resistance, and glycopeptide tolerance.^[5] MRSA bacteremia remains a significant clinical concern due to its high morbidity, mortality, and treatment resistance rates. As the rise of vancomycin-intermediate S. aureus (VISA) and heterogeneous VISA strains hampers therapy, research into alternate bactericidal drugs such as daptomycin and quinupristin-dalfopristin has increased. Many innovative antimicrobials have been developed in response to this challenge, including oxazolidinones (linezolid), streptogramins (quinupristin/dalfopristin), and, more recently, cyclic lipopeptides (daptomycin).^[6] Quinupristin-dalfopristin is a streptogramin antibiotic with bactericidal efficacy against Gram-positive bacteria, including MRSA.^[7] The increased vulnerability of MRSA to quinupristin-dalfopristin may be ascribed to the unique resistance mechanisms present in MRSA relative to MSSA. MRSA often lacks efflux pumps and enzymes that can inactivate quinupristin-dalfopristin, making it more susceptible.^[8,9] Daptomycin is a member of the cyclic lipopeptides, a novel class of antimicrobial medicines, and has quick, concentration-dependent bactericidal action against a wide range of Gram-positive bacteria. Daptomycin is also effective against drug-resistant bacteria, including vancomycin-resistant enterococci and MRSA.^[10,11] This study intended to evaluate daptomycin and quinupristindalfopristin’s in vitro bactericidal efficacy against blood isolates of MRSA.

MATERIALS AND METHODS

This was a hospital-based observational study conducted at a tertiary care referral center in Northern India, from September 2017 to March 2018. The institutional ethics committee granted ethical clearance for this study. All the S. aureus isolates obtained from the automated blood cultures of patients admitted to various adult and pediatric wards were included in this study. The isolates were characterized using conventional biochemical methods. All the MRSA isolates were phenotypically confirmed by the cefoxitin disk diffusion method. MSSA isolates were used for the comparative study. Antibiograms of all S. aureus isolates were obtained by the Kirby–Bauer disc diffusion method using the following antibiotics: Amikacin, gentamicin, clindamycin, erythromycin, cotrimoxazole, levofloxacin, ciprofloxacin, tetracycline, penicillin, teicoplanin, and linezolid. Vancomycin and daptomycin were tested by the minimum inhibitory concentration (MIC) by the E strip method according to the Clinical and Laboratory Standards 2017 guidelines. Their spatial distribution within the hospital (wards from where they were isolated) was also studied under the hospital-associated infection surveillance program. We implement focused measures, assign resources, and assess efficacious corrective action.

RESULTS

During the study period, 75 S. aureus isolates were isolated from the automated blood culture, 53/77 (70.66%) of which were MRSA, and 22/75 (29.33%) were MSSA. Thus, the bacteremia caused by 70.66% MRSA was more than the MSSA 29.33%. All the MRSA isolates of S. aureus were more resistant to different groups of antimicrobials than MSSA [Table 1]. Aminoglycoside drugs such as amikacin (50.94%) and gentamicin (60.37%) showed significantly higher resistance in MRSA than in MSSA (22.7%), (31.8%), with P = 0.0244 and 0.0242, respectively. These findings underline the limited efficacy of these antibiotics against MRSA. It is important to note that levofloxacin exhibits stark resistance differences: MRSA shows a high resistance rate of 46/53 (86.79%) compared to 8/22 (36.3%) in MSSA, with a statistically significant P = 0.00001. This highlights MRSA’s pronounced resistance to fluoroquinolones, an essential class of antimicrobials. Erythromycin and clindamycin both demonstrate considerable resistance differences. Erythromycin 49/53 (92.45%) and clindamycin 31/53 (58.49%) exhibit significantly higher resistance rates in MRSA, whereas MSSA shows resistance 14/22 (63.63%) and 14/22 (31.8%), respectively, with P = 0.0019 and 0.0354. This shows how resistant MRSA is, which is an important trait for antimicrobials. Some antimicrobials, such as cotrimoxazole, show comparable resistance rates in MSSA (54.54%) and MRSA (58.49%), although with no statistical significance (P = 0.7531). Tetracycline has resistance rates of 9.0% in MSSA and 22.64% in MRSA, although the P-value (0.1703) suggests that this difference is not statistically significant. These findings indicate that certain antibiotics may still be useful in treating MSSA and MRSA. Daptomycin MIC was performed against the MRSA and MSSA; both S. aureus isolates were sensitive to daptomycin antimicrobials, and no resistance against daptomycin was observed. At the same time, the drugs quinupristin-dalfopristin showed more resistance in MRSA (37/53, 69.81%) as compared to MSSA (4/22, 18.18%), which was statistically significant with a P = 0.00004.

DISCUSSION

MRSA bacteremia continues to pose significant clinical challenges due to its associated high morbidity, mortality, and resistance to conventional treatments.^[12-14] This study underscores the escalating worry regarding MRSA as a predominant pathogen, exhibiting a prevalence of 70.66%, in contrast to MSSA, which accounted for 29.33% of isolates. The resistance profiles further underscore MRSA’s multidrug-resistant characteristics, highlighting the imperative for viable alternative treatment options. MRSA has significantly higher resistance to aminoglycosides such as amikacin and gentamicin than MSSA, highlighting a crucial problem in treating MRSA infections.^[15,16] The results of this study, with resistance rates of 50.94% for amikacin and 60.37% for gentamicin in MRSA versus 22.7% and 31.8% in MSSA, respectively, are consistent with global trends demonstrating rising resistance in MRSA strains. Aminoglycoside MRSA resistance is usually mediated by a combination of mechanisms, including the presence of aminoglycoside-modifying enzymes such as acetyltransferases, nucleotidyltransferases, and phosphotransferases. These enzymes change the antibiotic, rendering it ineffective.^[17,18] Efflux pumps like NorA help to lower aminoglycoside concentrations within cells. Mutations in ribosomal binding sites may diminish the affinity of aminoglycosides, resulting in resistance. The increased resistance reported in MRSA may also be attributed to its intrinsic multidrug-resistant phenotype, frequently coupled with the acquisition of the staphylococcal cassette chromosome mec, which contains additional resistance determinants.^[19-21] P = 0.0244 and 0.0242 for amikacin and gentamicin, respectively, demonstrate a statistically significant difference between MRSA and MSSA, underscoring the limited efficacy of aminoglycosides for MRSA infections. The limited efficacy of aminoglycosides against MRSA necessitates meticulous evaluation of therapeutic approaches.

These findings highlight the need for antibiotic susceptibility testing before starting medication. Furthermore, using aminoglycosides as monotherapy for MRSA infections is not recommended; instead, combination treatments or other drugs such as vancomycin, linezolid, or daptomycin should be explored. Fluoroquinolones, such as levofloxacin, are extensively used broad-spectrum antibiotics that limit DNA replication by targeting bacterial DNA gyrase and topoisomerase IV.^[22,23] However, the significant resistance disparities in this study between MRSA and MSSA highlight MRSA’s problems in clinical settings. The high resistance rate of 86.79% (46/53) in MRSA against 36.3% (8/22) in MSSA, with a statistically significant P = 0.00001, demonstrates MRSA’s strong resistance to fluoroquinolones. Mutations in the genes encoding DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE) diminish fluoroquinolone binding affinity, a common resistance mechanism in MRSA. MRSA obtains resistance genes through plasmids or transposons, contributing to its elevated resistance rates.^[24,25] MRSA exhibits significantly greater levofloxacin resistance compared to MSSA, which has critical implications for clinical infection management. Fluoroquinolones are frequently employed due to their superior bioavailability and tissue penetration; nevertheless, their diminished efficacy against MRSA necessitates alternative therapeutic strategies.^[26] MRSA exhibited significantly higher resistance to aminoglycosides (amikacin and gentamicin), fluoroquinolones (levofloxacin), macrolides (erythromycin), and lincosamides (clindamycin) than MSSA (P < 0.05). These resistance mechanisms illustrate MRSA’s genetic adaptations, encompassing efflux pumps and enzyme-mediated drug inactivation. Linezolid, vancomycin, daptomycin, and tigecycline exhibited no resistance in MSSA or MRSA, thereby affirming their effectiveness as first-line treatments. Daptomycin, a cyclic lipopeptide antibiotic, demonstrates fast bactericidal efficacy against Gram-positive bacteria, including MRSA. The distinctive method of action is calcium-dependent attachment to the bacterial membrane, resulting in depolarization, loss of membrane potential, and cell death without lysis, hence reducing inflammatory repercussions. Studies indicate that daptomycin is more effective than vancomycin in achieving fast eradication of bloodstream infections, particularly for isolates with elevated vancomycin MICs.^[27] Daptomycin effectively eradicates MRSA within biofilms, making it a promising agent for infections involving prosthetic devices or endocarditis. It is well-tolerated, with minimal nephrotoxicity compared to vancomycin, though creatine phosphokinase monitoring is required to mitigate the risk of myopathy. However, reduced susceptibility to daptomycin has been reported, often associated with mutations in the mprF gene and alterations in membrane charge, highlighting the need for combination therapy or alternative strategies in refractory cases.^[28-30] This study observed no daptomycin resistance in both S. aureus isolates. Quinupristindalfopristin, a streptogramin combination, offers an alternative mechanism of action by inhibiting bacterial protein synthesis. Its bactericidal activity against MRSA, including strains resistant to vancomycin and linezolid, highlights its potential role in salvage therapy. Despite its efficacy, higher resistance rates in MRSA compared to MSSA observed in this study (69.81% vs. 18.18%, P = 0.00004) indicate its limited standalone use and call for further optimization of its application, potentially in combination regimens. This study emphasizes the need to customize antimicrobial tactics to resistance patterns. Combination therapy, including daptomycin and β-lactams like ceftaroline, can improve bactericidal activity and prevent resistance.^[31] MRSA and MSSA isolates exhibit susceptibility to daptomycin and linezolid, demonstrating their therapeutic efficacy. Recent research emphasizes the optimization of dosing regimens, the elucidation of resistance mechanisms, and the investigation of innovative synergistic combinations to enhance outcomes in MRSA bacteremia.

CONCLUSIONS

Daptomycin and quinupristin-dalfopristin exhibit considerable bactericidal efficacy against MRSA. Daptomycin is favored for its superior safety and efficacy profile; however, quinupristindalfopristin continues to be a significant alternative in particular clinical situations. This study evaluated the efficacy of daptomycin and Quinupristin-dalfopristin against methicillin-resistant Staphylococcus aureus (MRSA) in vitro from 2017 to 2018. The results showed significant efficacy, but the study’s temporal relevance, sample size, and design limitations may limit generalizability. Future research should incorporate more recent data, larger populations, and longitudinal approaches to validate and extend these findings. Ongoing monitoring of resistance trends and developments in antimicrobial treatment is essential for enhancing outcomes in MRSA bacteremia. The markedly elevated resistance rates in MRSA relative to MSSA underscore the necessity for rigorous antibiotic management and the advancement of innovative therapeutic strategies to address resistant infections successfully.