A Narrative Review of Staphylococcus hominis Resistance Pattern: Multidrug-and Possible Extensively Drug-Resistance

ABSTRACT


INTRODUCTION
Coagulase-negative staphylococci (CoNS) are mainly associated with human and animal biota and are opportunistic pathogens that persist and multiply on a variety of environmental surfaces (Seng, et al., 2017).Among CoNS species, S. hominis is the third most frequent specie as an opportunistic pathogen in the blood of neonates and immunosuppressed patients.In recent years, reports of S. hominis infection-induced bacteremia, septicemia, endophthalmitis, and endocarditis have increased rapidly (Frickmann et al., 2018;Mendoza-Olazarán et al., 2013;Natsis & Cohen, 2018;Pereira et al., 2018).
S. hominis develops resistance to various antibacterial agents causing difficulties in treatment strategies.The emergence of MRSHo has been reported and is a growing concern.MRSHo occurs because of the acquisition of the mecA gene, which encodes an altered penicillinbinding protein with a low affinity for betalactam antibiotics such as penicillin (Oliveira et al., 2016;Pereira et al., 2018).A recent study reported S. hominis can produce a biofilm as an important factor of resistance.However, S. hominis is categorized as a weak biofilm producer when compared to other CoNS species (Mendoza-Olazarán et al., 2013, 2015).
Volume 34 Issue 3 (2023) The bacteria which produce biofilms can be up to 1000 times more resistant to antibiotic therapy than planktonic cells of the same microorganism.However, planktonic cells are still used in antibiotic susceptibility tests performed in routine clinical laboratory es.This fact impairs the assessment of the efficacy of the antibiotic tested.The bacteria are protected by the biofilm and the response will not be the same as that obtained in the tests (Oliveira et al., 2016).However, in areas where surveillance programs lack widespread access to large-scale sequencing and analyzed for their antibiotic susceptibility using minimum biofilm eradication (MBEC), phenotypic analysis using MIC and percentage of resistance provides important practical information on trends in antibacterial resistance (Michael et al., 2020;Mulla et al., 2016a).MIC data remains an important tool to allow for a better understanding of the bactericidal activity of antibiotics and how it relates to resistance using the MIC's breakpoint based on EUCAST (Committee et al., 2015;Falagas et al., 2012;Michael et al., 2020).
Until now, a recent study shows that five of ten CoNS isolates were multidrug-resistant (MDR) and two of ten CoNS isolates were extensively drugresistant (XDR) to antibiotic agents.According to Basak et al (2016), the CoNS antibiotic resistance profile does not specifically provide the phenotypic criteria of S. hominis (Basak et al., 2016).The effectiveness of antibiotic therapy against S. hominis infection depends on the resistance profile, phenotypic criteria of S. hominis, and pharmacokinetics/pharmacodynamics profile (Basak et al., 2016;Kowalska-krochmal & Dudekwicher, 2021).There have been limited studies on the S. hominis resistance profile.To that point, this review is intended to identify the susceptibility of S. hominis to antibiotic agents of different drug classes used to treat S. hominis infection based on the pharmacokinetics/pharmacodynamic approach.In addition, this review determined the phenotypic criteria (MDR and XDR) of S. hominis.

MATERIALS AND METHODS
This review adopted a systematic review method to eliminate potential bias and improve the quality of the narrative review (Ferrari, 2015;Greenhalgh et al., 2018;Satibi et al., 2022).This review was conducted in four steps; formulating the research question, searching the literature, selecting the relevant studies, and extracting data from selected articles.Data extracted were antibiotic resistance (MIC, percentage of resistance), phenotypic criteria, and mechanism of resistance to the antibiotic.

Formulating the research question
The questions include the susceptibility pattern of S. hominis to antibiotic agents, phenotypic criteria, antibiotic choice of S. hominis infection, pharmacokinetics and pharmacodynamics index related to antibiotic resistance, and the S. hominis mechanism of antibiotics resistance.

Searching the Literature
PubMed, PlosOne, ScienceDirect, and Google Scholar were used in searching for articles relevant to this topic.Keywords used for the search were "S.hominis" AND ("antibiotic resistance" OR antimicrobial resistance") AND (MIC OR "inhibition zone").The search of articles was done for articles published in English and published from 1 st January 2015 to 31 st March 2021.

Extracting the data
Antibiotic resistance was identified using MIC and the percentage of resistance.If the MIC is greater than breakpoint values, the bacteria are considered resistant to the antibiotic and vice versa.Breakpoint is a concentration (mg/L) of antibiotic, which defines whether the bacteria is sensitive or resistant to the antibiotic.In this study, the breakpoint values were based on EUCAST Breakpoint tables for interpretation of MICs and zone diameters Version 11.0 (Committee et al., 2015).The percentage of resistance is the percent of isolates that tested non-susceptible or resistant to certain antibiotics for each defined phenotype.Antibiotic resistance based on the percentage of resistance consists of three criteria: (1) recommended for therapy (if the percentage of resistance < 40%); ( 2) considered for therapy (if the percentage of resistance is between 40% -70%); and (3) Not recommended for therapy (if the percentage of resistance >70%) (Fadlilah et al., 2016).The percentage of resistance was presented in the median and interquartile range (IQR).
The antibiotics classification was based on the WHO Anatomical Therapeutic Chemical (ATC) classification system.The antibiotic resistance profile was categorized based on The Centers for Disease Control and Prevention (CDC) phenotypic criteria.The criteria are MDR (multidrugresistant), XDR (extensively drug-resistant), and PDR (pan-drug-resistant).According to the CDC, MDR is a phenotypic category for bacteria that has been resistant to at least one antibiotic from three antibiotic classes.XDR is a phenotypic category for bacteria that have been resistant to at least one antibiotic from all antibiotic classes except two or fewer antibiotic classes that are available for empirical treatment.PDR is defined as a category of bacteria that are resistant to all antibiotic classes available for empirical treatment (Basak et al., 2016;Magiorakos et al., 2012).This study also describes antibiotic resistance mechanisms and antibiotic resistance profiles with pharmacokinetics and pharmacodynamics approaches.

RESULTS AND DISCUSSION
The search for articles was done for articles published in English and published from 1 st January 2015 to 31 st March 2021 (Figure 1).In total, 876 articles were identified, and 35 duplications were removed.A total of 841 articles were screened and 820 articles were irrelevant.In this study, 21 articles were included, of which 11 articles were experimental studies and 10 articles were observational studies.More studies used clinical isolates (n=19) than non-clinical isolates (n=2) (Table I).Clinical isolates were collected from the patients' blood, urine, sputum, and other body fluid cultures at the hospital.Non-clinical isolates sourced from hospital and community environments.The findings of the 21 articles were summarized in (Table II S. hominis is the third most frequent species as an opportunistic pathogen that can cause septicemia, bacteremia, endocarditis, and endophthalmitis.This bacterium is found in the blood of neonates and immunosuppressed patients.S. hominis infections are difficult to treat because they are highly resistant to antibiotics, such as linezolid and vancomycin (Frickmann et al., 2018;Mendoza-Olazarán et al., 2013;Natsis & Cohen, 2018;Pereira et al., 2018).

Phenotypic Criteria and S. hominis resistance pattern
MIC provides an important tool for the surveillance of antibiotic resistance.MIC provides valuable and unique insights into resistance patterns, including adaptive resistance that can be paired with genomics data to provide more insight into acquired resistance (Michael et al., 2020).In this review, if the MIC is greater than breakpoint values based on EUCAST's MIC breakpoint, the antibiotic is not recommended for therapy because the bacteria is considered resistant to the antibiotic and vice versa (Kowalska-krochmal & Dudekwicher, 2021).
Volume 34 Issue 3 (2023) Interestingly, the isolate S. hominis was resistant to chloramphenicol (Table II) and vice versa (Table III) shows that the S. hominis is sensitive to tobramycin (Table III) vice versa (Alter et al., 2019;Mendoza-Olazarán et al., 2015;Rehman et al., 2016).The susceptibility of antibiotics to bacteria is not identical, and the regional reported drug resistance varies commonly due to differences in environment and antibiotic use (Tao et al., 2017).The local antibiotic resistance pattern is essential to confirm the choice of antibiotics against S. hominis (Luyt et al., 2014;Rezaie et al., 2016).The susceptibility of S. hominis to some antibiotic classes in the percentage of resistance (Table IV and V) some antibiotics with MICs greater than breakpoint values, and have a low percentage of resistance (percentage of resistance ≤ 60%).For instance, tetracycline, chloramphenicol, trimethoprim/sulfamethoxazole, clindamycin, amikacin, gentamicin, oxacillin, and fluoroquinolones (ofloxacin, ciprofloxacin, levofloxacin, and moxifloxacin) (Alter et al., 2019;Asai et al., 2020;Chiquet et al., 2015;Mendoza-Olazarán et al., 2015;Menezes et al., 2019;Morgenstern et al., 2016;Sader et al., 2016Sader et al., , 2021a;;Soroush et al., 2017).Performing antibiotic sensitivity evaluation is critical to combine MIC and other parameters such as the percentage of resistance.MIC data obtained at the sampling time may shift during storage including loss of resistance (Humphries et al., 2018).Furthermore, different results from MIC and the percentage of resistance will be clinically significant in relation to pharmacokinetic parameters (Kowalska-krochmal & Dudek-wicher, 2021).Pharmacokinetics/pharmacodynamics indices related to antibiotic efficacy and antibiotic resistance Successful treatments using antibiotics are affected by the complex triangle interactions between the patients (the hosts), the antibiotic used, and the bacteria.These interactions include the host pathophysiologic and immune system, the type of antibiotic (type, dose, pharmacokinetics, pharmacodynamics, and toxicity), and the resistant mechanism of the bacteria.MIC is the major indicator that provides information about antibiotic efficacy and antibiotic resistance (Kowalska-krochmal & Dudek-wicher, 2021).However, the clinical outcome is not only affected by the MIC value, it is also dependent on the interaction between the host and bacteria (Rodríguez-Gascón et al., 2021).The parameter which quantitatively describes antibiotic efficacy and antibiotic resistance is the pharmacokinetic and pharmacodynamics index (PK/PD index) (Asín-Prieto et al., 2015;Mouton et al., 2012).The PK/PD analysis integrates and analyzes simultaneously both the PK and PD information to optimize antibiotic use (Rodríguez-Gascón et al., 2021).
Several PK/PD indices related to antibiotic efficacy are T>MIC (the time during the concentration of the drug was above the MIC), Cmax/MIC (the peak concentration and MIC ratio), and AUC/MIC (the ratio of the 24-h area under the concentration-time and MIC).According to the PK/PD index, antibiotics are divided into three types.The first type is time-dependent antibiotics with no or very short persistent effects that include all β-lactam antibiotics such as cephalosporins, carbapenems, monobactams, and penicillin.The PK/PD parameter for the time-dependent antibiotic is T>MIC.The T>MIC is the percentage of time in which the antibiotic's concentration remains above the MIC.If the T>MIC is closer to 100% it means the antibiotic has great efficacy (Kowalska-krochmal & Dudek-wicher, 2021).The second type is concentration-independent antibiotics with prolonged persistent effects.The antibiotic classes included in this type are tetracyclines (Tetracycline and Tigecycline), macrolides (Azithromycin and Clindamycin), oxazolidinones (Linezolid), Chloramphenicol, Trimethoprim, Sulfonamides, and Vancomycin (Asín-Prieto et al., 2015).The PK/PD parameter for this type of antibiotic is AUC/MIC.The AUC/MIC (∫AUC/MIC) characterizes time and concentrationdependent antibiotics.The AUC value depends on several factors such as the patient's age, weight, and organ dysfunction.On the other hand, the MIC value influences the antibiotic effect (Kowalskakrochmal & Dudek-wicher, 2021).The third type of antibiotic is concentration-dependent with prolonged persistent effects, for instance, fluoroquinolones, aminoglycosides, daptomycin, metronidazole, and polymyxins.The PK/PD parameter for this type of antibiotic is Cmax/MIC and AUC/MIC.Cmax/MIC is a parameter that describes the antibiotic effectiveness depending on the maximum concentration, not the time above the MIC.The antibiotic which has a lower MIC value is more likely to meet the antibiotic efficacy while reducing the risk of toxic concentrationn (Kowalska-krochmal & Dudek-wicher, 2021) (Asín-Prieto et al., 2015;Rodríguez-Gascón et al., 2021).
To date, there is no study about antibiotic PK/PD indices in S. hominis infection.Further studies are needed to explore the PK/PD indices profile in S. hominis.Despite the MIC and PK/PD index, other parameters can be used to describe resistance profiles comprehensively such as MPC and MSW.MPC describes the lowest antibiotic concentration that prevents mutant growth in a large bacterial population (more than 10 10 CFU/mL bacteria).MSW is the range of antibiotic concentrations above the MIC and below the MPC.MPC parameters can be used to compare antibiotic susceptibility and to explore the relationships between PK/PD indices and resistance in several bacteria (Feng et al., 2019;Gianvecchio et al., 2019).
The mechanisms of S. hominis to counter antibiotics are shown in Figure 2. S. hominis possesses an inducible mecA gene, encoding PBP2a, a transpeptidase with a low affinity for beta-lactam antibiotics.In addition, S. hominis possesses an inducible MRS gene mediated antibiotic efflux; lnu(A) mediated enzymatic antibiotic inactivation; grlA, gyrA or ParC genes encode mechanism of resistance by biofilm formation; erm gene encodes the proteins that methylate adenine residue A2058 in peptidyl transferase region of 23S rRNA (domain V), the part of the large ribosomal subunit (50S) and prevents the binding of the antibiotic to the target site.Adhesins are proteins on the surface cell wall that help the bacteria to attach to the cell host, for instance, the Staphylococci surface protein (Ssp) and the autolysin protein (Aas) (Bui & Preuss, 2021;Chiang et al., 2020;Drago, 2019;Fishovitz et al., 2014;Jenner et al., 2013;Kapoor et al., 2017;Lahiri & Alm, 2016;Öztürk et al., 2015;Prescott, 2013;Ślusarczyk et al., 2018).
Penicillins and cephalosporins are extended-spectrum antibiotics that have a broad spectrum towards gram-positive, gram-negative, and anaerobic bacteria.Penicillins and cephalosporins are beta-lactam agents which have the beta-lactam ring.The primary targets for the actions of beta-lactam agents are the Penicillin Binding Proteins (PBPs).The antibacterial activity of beta-lactam agents is due to the inhibition of PBPs which are essential proteins involved in peptidoglycan synthesis in bacteria (Bui & Preuss, 2021;Kapoor et al., 2017;Prescott, 2013;Ślusarczyk et al., 2018).There are several types of PBPs inside the Penicillin Binding Domain, and every type of bacteria has a specific type of PBP (Fishovitz et al., 2014;Öztürk et al., 2015).Ceftaroline is the one of cephalosporins that inhibits several types of PBPs.It not only inhibits PBP1 to PBP4 but also has a high affinity in PBP2a that is responsible for the resistance to penicillin and the older generation of cephalosporin (Lahiri & Alm, 2016;Lee et al., 2018).Another mechanism related to the mechanism of ceftaroline eradicating S. hominis is ceftaroline not only binding to the active site but also in the allosteric site of PBPa2 that covalently inhibits the active site of the PBPa2 (Chiang et al., 2020).
Macrolides, lincosamides, and streptogramin B antibiotics are recommended as second-line drugs in the treatment of staphylococci infection.Moreover, erythromycin and clindamycin are the preferred alternative for patients with a βlactam allergy.Macrolides, lincosamides and streptogramin B antibiotics are functionally similar, whereas structurally distinct.They can inhibit protein synthesis by binding to the 50S subunit (23S rRNA) of the bacterial ribosome (Szczuka et al., 2016).
The other expanded broad-spectrum antibiotics that can be recommended to treat S. hominis are aminoglycosides, chloramphenicol, and tetracycline (Alter et al., 2019;Block & Blanchard, 2021;Perutelli et al., 2018).Similar to Macrolides, lincosamides, and streptogramin B antibiotics, the primary targets for the action are bound to the bacteria ribosomal (Abdollahi & Mostafalou, 2022;Block & Blanchard, 2021;Hutchings et al., 2019).Aminoglycosides bind to the bacterial ribosomal 30S subunit.Aminoglycosides bind to the A-site (aminoacyl) on the 16S rRNA, as a part of the ribosomal 30S subunit.This binding produces the genetic code that is received misread and the interpretation is disrupted, thus the bacteria is unable to complete protein synthesis (Block & Blanchard, 2021).Tobramycin is one of the aminoglycosides also effective in biofilm.Producing bacteria through a diffusion mechanism in a biofilm matrix leads to bacterial inhibition (Alzahrani et al., 2022;Bassenden et al., 2016;Zárate et al., 2018).
The mechanism of chloramphenicol is directly preventing the formation of bacterial protein by binding to the 50S ribosomal subunit.Chloramphenicol obstructs protein synthesis by interfering with the attachment of transfer RNA to the A site on the 50S ribosome (Abdollahi & Mostafalou, 2022;Diseases, 2017).

Chloramphenicol interferes with bacterial
Volume 34 Issue 3 (2023) adhesion before the biofilm formation, and also penetrates the biofilm matrix.Therefore, chloramphenicol can eradicate infection by combating biofilm-associated infections and improving patient outcomes (Drago, 2019).
Tetracyclines such as tigecycline are glycylcycline potent antibacterials that have an expanded broad spectrum of antimicrobial activity, ranging from gram-positive to gram-negative, from aerobic to anaerobic bacteria, multidrug-resistant pathogens, intracellular pathogens, and to atypical organisms (Perutelli et al., 2018).Inhibition of bacterial protein synthesis by tigecycline was 3fold more potent than inhibition by minocycline and 20-fold more potent than inhibition by tetracycline.Tigecycline affinity to the 30S and 70S ribosomes is 5-fold greater than minocycline.Tigecycline also has >100-fold greater affinity than tetracycline.Tigecycline dissociates more easily from the initial bimolecular interaction and rapidly binds to the 30S and 70S ribosomes (20-to 40-fold faster) than the other tetracyclines.Moreover, tigecycline blocks the efflux pump by the limited effect on the conformation of the repressor protein TetR (Barrenechea et al., 2021).Tigecycline shows increased antimicrobial activity compared to tetracycline, as well as overcoming the ribosome protection and efflux mechanism.Therefore, tigecycline is not affected by the classic tetracycline resistance mechanism (Jenner et al., 2013).
Moreover, tigecycline has the efficacy to combat MRCoNS like daptomycin, vancomycin, and minocycline.The efficacies of the antibiotics daptomycin, vancomycin, minocycline, and tigecycline against MRCoNS embedded in biofilm.The glycopeptides class, especially vancomycin, diffuses slowly into the deeper layers of bacterial biofilm and finally reduced the mass of pre-formed biofilms (Alter et al., 2019;Angelopoulou et al., 2020;Asai et al., 2020;Biedenbach et al., 2015;Chiquet et al., 2015;Decousser et al., 2015;Falcone et al., 2012;Morgenstern et al., 2016;Sader et al., 2016;Seng, Kitti, et al., 2017).Vancomycin reduces glycopeptide in bacterial biofilm since the biofilm is the virulence factor in CoNS infection.Furthermore, biofilm is an immune avoidance mechanism of CoNS.Moreover, metabolism and cell replication in the biofilm reduce the bactericidal activity of antibiotic agents leading to poor susceptibility to some antibiotic agents.Biofilm also plays an important role in facilitating the transfer of resistant genes (Rodriguezguerineau et al., 2013).Overall, CoNS, especially S. hominis is susceptible to the glycopeptide class, for example, vancomycin, dalbavancin, and teicoplanin.Vancomycin is the standard antibiotic to treat CoNS infections, especially a methicillinresistant staphylococci infection (Sader et al., 2021a).
In addition, linezolid was the most effective antibiotic in inhibiting staphylococci in the biofilm, without increasing the MIC.Linezolid affects the biofilm's structure and adhesion between the bacteria.Consequently, the biofilms grown were not well organized, as a result of low biofilms.Cell aggregation and cell-to-cell connections have been inhibited, resulting in loosely arranged cells that were easily disrupted (de Oliveira et al., 2016;Martinez et al., 2016).
Trimethoprim and fluoroquinolones have a unique mechanism of action that targets Deoxyribonucleic acid (DNA) synthesis.Trimethoprim is active against gram-positive bacteria and some gram-negative bacteria.This antibiotic inhibits bacterial DNA synthesis by binding to dihydrofolate reductase (DHFR) to prevent the conversion of dihydrofolic acid (DHF) to tetrahydrofolic acid (THF).Trimethoprim affinity to bacterial DHFR is 100,000 times stronger than human DHFR.The combination of trimethoprim with sulfamethoxazole has a synergistic effect to inhibit bacterial DNA synthesis through the folate pathway (Autmizguine et al., 2018).The addition of sulfamethoxazole provides an additional block in the folate biosynthesis pathway by inhibiting the synthesis of dihydrofolic acid (DHF).This combination improves the bactericidal effect of trimethoprimsulfamethoxazole (Cassir et al., 2014;Fernández-Villa et al., 2019;Wróbel et al., 2019).Moreover, fluoroquinolones act by blocking two enzymes, DNA gyrase and topoisomerase IV that are involved in DNS synthesis, and thereby block DNA replication and transcription.However, a study at Bascom Palmer Eye Institute, Miami, Florida, reported that fluoroquinolones for the treatment of infection caused by CoNS have a poorer clinical outcome (Bassetti & Righi, 2015;Stringham et al., 2017).

Limitation of study
This study provides information on the susceptibility of S. hominis antibiotic agents of different drug classes.Evaluation in this review was conducted based on the MIC and percentage of resistance values.MIC values describe the bactericidal activity of antibiotics and how it relates to resistance using the MIC's breakpoint based on EUCAST.However, Minimum Biofilm Eradication Concentration (MBEC) measures are more specific to assess the susceptibility of bacteria that produce biofilm (Mulla et al., 2016b).Further study is needed to determine S. hominis susceptibility using MBEC.Moreover, this review is a narrative review that has some weaknesses, for instance, the absence of an explicit determination to enlarge the scope or analyze data, and does not require any explanations of how the review process was conducted (Paré et al., 2015).

CONCLUSION
S. hominis is MDR and possible XDR bacteria that are resistant to some antibacterial.The choice of antibiotics against S. hominis should be based on local antibiotic resistance patterns.Obtaining appropriate cultures before antibiotic treatment is essential to confirm infection and susceptibility profiles.Antibiotic resistance profiles can be used as a reference in developing antibiotic use policies.Further study is needed to explore antibiotic resistance profile of S. hominis with PK/PD approach.

Figure 1 .
Figure 1.Diagram of The Article Selection Procedure.The search of articles was done for articles published in English and published from 1 st January 2015 to 31 st March 2021.

Figure 2 .
Figure2.Staphylococcus hominis resistance mechanism.Adhesins are proteins on the surface cell wall that help the bacteria to attach to the cell host for instance Staphylococci surface protein (Ssp) and autolysin protein (Aas); Staphylococcus hominis produce cytotoxic extracellular protein to invade the host cell; several genes encode difference resistance mechanism: mrs(A) mediated antibiotic efflux; lnu(A) mediated enzymatic antibiotic inactivation; mecA encodes PBP2a, a transpeptidase with a low affinity for beta-lactam antibiotics such as penicillin; grlA, gyrA or ParC genes encode mechanism of resistance by biofilm formation; erm gene encodes the proteins that methylate adenine residue A2058 in peptidyl transferase region of 23S rRNA (domain V), the part of the large ribosomal subunit (50S) and prevents the binding of the antibiotic to the target site.

Table I .
Study Characteristic

Table III .
The antibiotic resistance profile of CoNS which includes isolate Staphylococcus hominis based on MIC value

Table IV .
Percentage of resistance Staphylococcus hominis to some antibiotic classes

Table V .
CoNS Percentage of resistance which includes isolate Staphylococcus hominis