Tackling Intrinsic Antibiotic Resistance in Serratia marcescens with a Combination of Ampicillin/Sulbactam and Phage SALSA

Abstract

<jats:p>During the antibiotic crisis, bacteriophages (briefly phages) are increasingly considered as potential antimicrobial pillars for the treatment of infectious diseases. Apart from acquired drug resistance, treatment options are additionally hampered by intrinsic, chromosomal-encoded resistance. For instance, the chromosomal ampC gene encoding for the AmpC-type β-lactamases is typically present in a number of nosocomial pathogens, including S. marcescens. In this study, phage SALSA (vB_SmaP-SALSA), with lytic activity against clinical isolates of S. marcescens, was isolated from effluent. Besides phage characterization, the aim of this study was to evaluate whether a synergistic effect between the antibiotic ampicillin/sulbactam (SAM) and phage can be achieved despite intrinsic drug resistance. Phage SALSA belongs to the Podoviridae family and genome-wide treeing analysis groups this phage within the phylogenetic radiation of T7-like viruses. The genome of Phage SALSA consists of 39,933 bp, which encode for 49 open reading frames. Phage SALSA was able to productively lyse 5 out of 20 clinical isolates (25%). A bacterial challenge with phage alone in liquid medium revealed that an initial strong bacterial decline was followed by bacterial re-growth, indicating the emergence of phage resistance. In contrast, the combination of SAM and phage, together at various concentrations, caused a complete bacterial eradication, confirmed by absorbance measurements and the absence of colony forming units after plating. The data show that it is principally possible to tackle the axiomatic condition of intrinsic drug resistance with a dual antimicrobial approach, which could be extended to other clinically relevant bacteria.</jats:p>

Synergy between Phage Sb-1 and Oxacillin against Methicillin-Resistant Staphylococcus aureus

“…The dynamics of phage-or antibiotic-based challenges on bacterial populations were determined via measurements of the changes in optical densities (OD 590 ), which is particularly suited for high throughput analysis [32][33][34]. According to our previous studies, the presence of a β-lactam antibiotic does not interfere with the optical density values, which correlated with the reduction of bacterial cells rather than with altered cell morphology [14,15].…”

“…A number of studies have already addressed the potential impact of a dual approach against S. aureus using a lytic phage in combination with MRSA-effective antibiotics, such as rifampicin, linezolid, fosfomycin, daptomycin, and vancomycin [7][8][9][10][11][12][13], as well as in combination with aminoglycosides, quinolone antibiotics, and β-lactam antibiotics [5,[11][12][13]. Interestingly, synergistic interactions between a phage and an antibiotic can also be observed in cases in which the pathogen is resistant against the antibiotic [14,15]. However, combining a phage with an antibiotic, which as a sole agent does not work against MRSA, has not been investigated thus far.…”

Benefits of Combined Phage–Antibiotic Therapy for the Control of Antibiotic-Resistant Bacteria: A Literature Review

“…In 2004, Huff et al assessed the therapeutic efficacy of using phages and enrofloxacin separately and in combination for the treatment of E. coli infections; they concluded that the phage–enrofloxacin combination was the most effective treatment [ 63 ]. In their 2020 study, Weber et al showed the utility of adding phage SALSA to ampicillin/sulbactam for the control of intrinsic Serratia marcescens resistance [ 59 ]. Other Gram-negative bacteria with intrinsic resistance to antibiotics, namely Burkholderia cepacia , Achromobacter spp.…”

Complete Genome Sequence of Serratia Phage 4S Isolated from Wastewater in Ukraine

“…Serratia marcescens is a Gram-negative bacterium of environmental origin like soil, water, and plant surfaces and known to be a plant as well as a human pathogen causing opportunistic infections in hospitals [1]. Serratia marcescens is still an underestimated bacterium that causes a range of infections in severely immunocompromised or critically ill patients with keratitis, conjunctivitis, urinary tract in-fections, pneumonia, surgical wound infections, sepsis, bloodstream infection, and menin gitis [2]. Considering that bacterial resistance to antibiotics increases, phages are one of the most promising alternatives that have to be applied [3].…”