REVIEW ARTICLE

https://doi.org/10.5005/jp-journals-11003-0124
Journal of Medical Academics
Volume 6 | Issue 1 | Year 2023

Staphylococcus Infections and Emerging Drug Resistance: A Global Concern

Shivani Juneja¹ https://orcid.org/0000-0001-5324-7400, Rohit Kalia², Ratinder P Singh³ https://orcid.org/0000-0002-6173-9269, Vandana Roy⁴

^1,2Department of Clinical Pharmacology, Fortis Hospital, Mohali, Punjab, India

³Department of Cardiology, Healing Superspeciality Hospital, Chandigarh, India

⁴Department of Pharmacology, Maulana Azad Medical College, Delhi, India

Corresponding Author: Shivani Juneja, Department of Clinical Pharmacology, Fortis Hospital, Mohali, Punjab, India, Phone: +91 9915134000, e-mail: docshivani28@gmail.com

Received on: 22 March 2023; Accepted on: 03 May 2023; Published on: 28 June 2023

ABSTRACT

Staphylococcus aureus (S. aureus) infections are a global health concern resulting in morbidity and mortality worldwide. Numerous antimicrobial agents (AMAs) have been developed over the years to treat S. aureus infections and then followed by the rapid emergence of resistance to them. Methicillin-resistant S. aureus (MRSA) is one of the modern pathogens which poses a formidable clinical threat. Despite the ongoing development of new antibiotics, active surveillance, and advances in infection prevention, MRSA remains an eminent pathogen persevering with high mortality. The clinical impact can be achieved with some promising newer antibiotics which can deal with different types of infections caused by S. aureus. In this review, we provide an overview of clinical research on the treatment of MRSA infections and summarize the expansive body of literature on the clinical trials done to explore new drugs to counteract S. aureus infections.

How to cite this article: Juneja S, Kalia R, Singh RP, et al. Staphylococcus Infections and Emerging Drug Resistance: A Global Concern. J Med Acad 2023;6(1):20-27.

Source of support: Nil

Conflict of interest: None

Keywords: Bacterial infection, Drug resistance, Gram-positive, Methicillin-resistant Staphylococcus aureus, Staphylococcus aureus

BACKGROUND

Infections due to S. aureus are worldwide—a familiar cause of morbidity and mortality. Extended hospital stays, need for intensive care, and surgical intervention clubbed with an increased economic burden for patients/healthcare system can happen as a result of these infections. The mortality due to S. aureus infections may be due to the association of S. aureus with serious infections, along with the development of rapid antimicrobial resistance, which makes it difficult to treat.¹

STAPHYLOCOCCUS AUREUS (S. AUREUS)

Microbiology

Staphylococcus aureus (S. aureus) is a gram-positive cluster forming cocci, nonmotile, nonsporing, catalase, and coagulase-positive facultative anaerobe. It is a normal human commensal found in the anterior nares, oropharynx, skin, vagina, axilla, and perineum. This normal colonization acts as a trigger for future infections, especially for those at risk. These include the elderly, diabetics, immunocompromized, and those with prosthetic devices. Mild to life-threatening infections are attributed to this bacteremia. These include dermatological infections and serious systemic infections of the blood, skeletal, pulmonary, and cardiovascular systems. A number of reported outbreaks of community-based infections in the last decade have been attributed to poor hygiene, contamination, close contact, and damaged skin.¹^,²

A meta-analysis study by Patil et al. from India revealed a cumulative 37% MRSA prevalence in India (2015–2020). The study depicted that the east zone has shown a 43% prevalence of MRSA in the states of West Bengal and Odisha. In fact, the states of Northern India had the second-highest (41%) MRSA prevalence. On the contrary, the northeast zone—Assam, Tripura, and Sikkim, had shown the third-highest prevalence of MRSA (40%).³ The most common reasons attributable to antimicrobial resistance in literature are—lack of awareness and overuse of antimicrobials in humans/livestock. Inadequate/inappropriate sanitation and hygiene and lack of stringent rules and regulations for the use of antimicrobials are the other contributory factors.

Pharmacology

Various antimicrobial agents (AMAs) have been developed over the years to treat S. aureus infections. The primary mechanism of action includes inhibition of cell wall synthesis or protein synthesis. The bacteria show a propensity to develop antimicrobial resistance (AMR) rapidly; hence, a continuous endeavor to look for newer options and agents.

Development of Resistance

The rapid development of resistance to antimicrobials is attributed to continuing genomic variations involving horizontal transfer, spontaneous mutations, and positive selection. Elaboration of enzymes by bacteria that inactivate the antibiotic (β-lactamases and aminoglycoside modification enzymes), decreased affinity for AMAs following alteration of the bacterial target, trapping of the antibiotic, and efflux pumps expelling the antibiotic out of the bacterial cell are some of the mechanisms of resistance.⁴^,⁵

The mortality due to bloodstream infections caused by S. aureus was above 80% before antibiotics came into existence. Soon following the discovery of penicillin, the mortality dramatically reduced due to S. aureus infections.⁶ However, after the introduction of penicillin, bacteria-producing penicillinase came into existence in a short time, and these strains spread initially into hospitals and then into the community. To counteract this resistance due to the production of penicillinase by the bacteria, the first semisynthetic penicillinase-resistant penicillin, methicillin, was developed in 1959.⁷^,⁸ Subsequently, other penicillinase-resistant penicillins like oxacillin, flucloxacillin, dicloxacillin, and nafcillin were developed. Then very shortly (1960), S. aureus developed resistance to methicillin too. These bacteria came to be known as MRSA.⁹^,¹⁰

After methicillin, a number of drugs from different groups were developed and used against it, like vancomycin, fluoroquinolones, aminoglycosides (gentamicin), cotrimoxazole, linezolid, etc., but resistance developed rapidly against them too (Tables 1 and 2). The vancomycin intermediate-resistant S. aureus (VISA) came into existence in the year 1997, followed by vancomycin-resistant S. aureus (VRSA).¹¹^,¹² Over the years, it has evolved as a multidrug-resistant S. aureus (MDRSA). The emergence of resistance does not contribute to intrinsic virulence, but resistance does make treatment of MRSA infection challenging due to the limited therapeutic options.

**Table 1:** Mechanism of resistance in *S. aureus*⁴
Mechanism	Genetic factor	Antimicrobial agent
Reduced affinity for PBP. Elaboration of enzymes that hydrolyze β-lactam ring.	(PBP2a)/Mec A gene blaZ.	β-lactams (penicillin, oxacillin, and flucloxacillin) Methicillin
Synthesis of dipeptide with reduced affinity for vancomycin. Trapping of vancomycin in the cell wall.	D-Ala-D-Lac on transposon Tn1546 (Van).⁷⁷ Altered peptidoglycan.	Vancomycin
The reduced affinity of enzyme DNA complex for quinolones.	parC of topoisomerase IV, gyr A/B of gyrase	Quinolones (ciprofloxacin and moxifloxacin)
Modification of enzymes acetylating/phosphorylating	Aac, aph gene for acetyltransferase, phosphotransferase	Aminoglycosides (gentamicin)
P-aminobenzoic acid (PABA) overproduction. Reduced affinity for dihydrofolate reductase (DHFR).	Sulphonamide: sulA. TMP: dfrB.	TMP-SMX
Interferes with ribosomal binding	Domain V of 23s rRNA gene: rRNA gene	Oxazolidinone (Linezolid)
Reduced binding to 23s rRNA. Enzymatic modification of dalfopristin.	Ribosomal methylase Q: ermA/B/C. Acetyltransferase D: vat, vat B.	Quinupristin-dalfopristin (Q-D)
Reduced surface binding	Multipeptide resistance factor gene and yycFGHI operon⁷⁸	Daptomycin
Mutation in PBP2 and membrane protein	Transposon Tn1546	Teicoplanin

**Table 2:** Pharmacokinetic/pharmacodynamics property of AMA for treatment of *S. aureus* infections⁹⁰
Drug	Mechanism of action	Pharmacokinetics	Adverse drug reactions	Precautions
Penicillin	Acts by interfering with the synthesis of bacterial cell wall.	It is rapidly destroyed by gastric acidity. Only 1/3rd of the orally administered is absorbed. Both oral and parenteral preparations are available.	Hypersensitivity, anaphylactic shock, serum sickness, angioneurotic edema, seizures in patients with renal failure, and neutropenia.	Renal failure
Streptomycin (aminoglycoside)	Irreversibly inhibits protein synthesis and has bactericidal activity.	Absorption from the gastrointestinal (GI) tract is poor, but intramuscular injection is rapid. It is widely distributed in extracellular fluids. It can cross the placental barrier. It is excreted unchanged in the urine. Elimination half-life is 2–3 hours in normal renal function.	Nausea, vomiting, hypersensitivity, pain/irritation at the injection site, ototoxicity, nephrotoxicity, and neuromuscular blockade.	Hypomagnesemia, cross allergenicity, superinfection, and pregnancy/lactation.
TMP-SMX	Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid (DHF) by competing with PABA. Trimethoprim blocks the production of THF from DHF by inhibiting dihydrofolate reductase.	Rapid oral absorption. Administered as 800/160 mg combination twice daily. Wide distribution and can cross the placenta. Metabolized primarily by N4-acetylation. Excretion by kidneys through glomerular filtration and tubular secretion.	Gastrointestinal disturbances, hypersensitivity, agranulocytosis, QT prolongation, hyperkalemia, and hyponatremia	Cross-sensitivity with oral hypoglycemics and diuretics
Tetracyclines	Reversibly bind to the 30s subunit of the ribosome, inhibiting protein synthesis, and are thus bacteriostatic.	Incompletely absorbed by GI tract. Can cross the placenta. Absorption is interfered with by divalent or trivalent ions, milk, and food. Concentrated in the bile by the liver. Excreted both in urine and feces.	Anorexia, diarrhea, dyspepsia, alopecia, hyperpigmentation, fixed drug eruption, anemia, hepatic toxicity, Steven–Johnson syndrome, and toxic epidermolysis,	Cross-resistance within the group. Hypersensitivity, renal and hepatic impairment, pregnancy, lactation, and photosensitivity.
Clindamycin	Binds to the 50s subunit of the bacterial ribosome and suppresses protein synthesis.	Rapid GI absorption. Widely distributed in the body tissues and fluids. Excreted in the bile.	Hypersensitivity, pseudomembranous colitis, and superinfections.	Children, elderly, renal/hepatic impairment, pregnancy, and lactation.
Vancomycin	Tricyclic glycopeptide, bactericidal. Inhibits cell wall synthesis and alters cell membrane permeability and RNA synthesis.	Poor oral absorption.Eliminated by kidneys.	Abdominal pain, nausea, vomiting, diarrhea, hypersensitivity, nephrotoxicity, ototoxicity, and hypokalemia.	Renal impairment, elderly, children, anephric patient, pregnancy, and lactation.
Linezolid	It is an oxazolidinone and inhibits bacterial growth by inhibition of ribosomal protein synthesis and is bacteriostatic against Staphylococci.	Good oral absorption. Cmax reached within 1–2 hours after dosing. High-fat food interferes with its absorption. It is primarily metabolized by oxidation. Major excretion is nonrenal. It is available both in oral and injectable forms.	It is contraindicated in cases with known hypersensitivity to linezolid or its use with or within 14 days of monoamine oxidase inhibitors.	Thrombocytopenia, peripheral and optic neuropathy, serotonin syndrome with serotonergic agents, convulsions, lactic acidosis, and Clostridium difficile-associated diarrhea.

MRSA is widespread worldwide, with the highest rates (>50%) of MRSA prevalence reported in North and South America, Asia, and Malta. Some European countries like Netherlands and Scandinavia have reported low prevalence rates.¹³

Some studies from India reported an increasing prevalence of MRSA, where isolation rates steadily went up from 9.83% (1992) to 45.44% (1998). These strains are more commonly found in South India than in West or North India.¹⁴ Studies from Delhi reported a prevalence rate of 51.6% in 2001 and 38.44% in 2008.¹⁵^,¹⁶

TREATMENT OF S. AUREUS INFECTIONS

Penicillin

The discovery of penicillin in the 20th century is an outstanding contribution to medicine. It had been one of the landmark discoveries in marking the beginning of the AMA era. Previous agents had a limited spectrum of activity. The effectiveness of penicillin against Staphylococci and Streptococci was established. Within 2 decades of widespread use of penicillin G, 99% resistance was reported to most strains of S. aureus.⁶^,¹¹^,¹⁷^,¹⁸

Methicillin

Methicillin is semisynthetic penicillin which is also known as staphcillin, and acts by inhibiting bacterial cell wall synthesis. This penicillinase-resistant derivative of penicillin was developed in the 1950s because some S. aureus strains had acquired penicillinase-based resistance to penicillin.⁹^,¹⁷ The resistance to β-lactam antimicrobials (penicillin, oxacillin, dicloxacillin, and flucloxacillin) was attributed to penicillin-binding proteins (PBP) PBP2a or PBP2 of subclass B1, known as encoded by the mecA gene located on staphylococcal cassette chromosome mec.¹⁸ Likewise, resistance to methicillin was determined by the presence of mecA gene encoding altered PBP showing low affinity to β-lactam antibiotics.¹⁹

Streptomycin

The aminoglycoside group of drugs is mainly used for aerobic gram-negative bacteria, especially in drug-resistant cases. However, in some cases of staphylococcal endocarditis, streptomycin is given in combination with penicillins or sulphonamides.²⁰ In fact, S. aureus resistant strains were reported in some studies in the 1970s when streptomycin was used alone for the treatment of S. aureus infections. Another study demonstrated in vitro antimicrobial synergism of combinations of β-lactam-aminoglycoside (cefadroxil–streptomycin) against clinical isolates of S. aureus.²¹ Further studies may help in exploring in combination use of streptomycin in this direction.

Trimethoprim-sulfamethoxazole (TMP-SMX)

It is a synergistic combination of sulphonamides and trimethoprim. This combination was in use to treat both gram-negative as well as gram-positive infections, including S. aureus. Bacterial resistance to TMP-SMX is a rapidly increasing problem. Some studies in the past (1966–2003) have reported 8–100% worldwide resistance to TMP-SMX.²²^,²³

However, a recent study in Israel by Paul et al., in four hospitals, compared TMP-SMX vs vancomycin for MRSA-related severe infections. It was found in this study that for the treatment of severe MRSA infections, a high-dose TMP-SMX monotherapy did not achieve noninferiority as compared to vancomycin.²⁴ Hence, further studies in this direction of TMP-SMX use in MRSA may provide evidence if it can be used alone or in combination as an alternative to present therapy.

Tetracyclines

Tetracyclines are broad-spectrum bacteriostatic antimicrobials that act against many gram-positive and gram-negative infections.²⁵

According to retrospective cohort research, 95% of patients infected with MRSA strains were susceptible to tetracycline (minocycline, doxycycline) treatment. Long-acting tetracyclines (doxycycline and minocycline) may be an effective oral therapy option for individuals with particular strains of MRSA, according to some research.²⁶

Clindamycin

Clindamycin is derivative of lincomycin that acts by inhibiting protein synthesis, which has been in use for the treatment of skin and skin structure infections (SSSIs) caused by gram-positive cocci—Streptococci and Staphylococci.²⁷^,²⁸ A study in eastern India by Majhi et al. reported both clindamycin and erythromycin resistance in both MSSA and MRSA species causing SSSIs.²⁹^,³⁰

Vancomycin

It is a glycopeptide antibiotic that is used to treat severe gram-positive infections that are resistant to other antibiotics, such as in patients who are allergic to penicillin, MRSA, and ampicillin-resistant Enterococci.³¹

It was the antibiotic of choice for MRSA infections for >40 years. Some reports have shown ” minimum inhibitory concentration (MIC) creep,” which is known as an increase in the MIC for vancomycin.³²^,³³ The first VISA isolates were identified in 1996 as a result of extensive vancomycin use. The first vancomycin-resistant strain of S. aureus was isolated in June 2002, and subsequently, increased reports of vancomycin failure started to appear in the literature.³⁰^,³⁴^,³⁵

Teicoplanin

This is a glycopeptide used in the treatment of infections associated with MRSA and Enterococcus faecalis. Several studies have shown that teicoplanin is equally effective as vancomycin in the treatment of endocarditis, bacteremia, bone, and joint infections. It has a long half-life and has fewer adverse drug reactions, so better tolerated.³⁶^,³⁷

Tigecycline

Tigecycline is a glycylcycline antibiotic that is bacteriostatic in action and acts against gram-positive bacteria. Tigecycline was approved by United States Food and Drug Administration (FDA) for indications of complicated SSSIs and complicated IAIs, which includes infections due to MRSA and extended-spectrum β-lactamase (ESBL) producing enterobacteriaeceae.³⁸^-⁴¹

The Tigecycline Evaluation and Surveillance Trial between 2004 and 2012 done in France showed that tigecycline exhibits good in vitro activity against many resistant pathogens, including ESBL producers.⁴¹

Linezolid

The FDA approved linezolid in the year 2000 for the treatment of community-acquired pneumonia (CAP) and nosocomial pneumonia, as well as SSSTIs caused by MRSA, based on a number of studies comparing linezolid to conventional antibiotic therapy. It has a high oral bioavailability, so it can be administered both orally and intravenously (IV).⁴²^-⁴⁴

Some studies have reported resistance to linezolid and also some outbreaks of linezolid-resistant S. aureus in intensive care units.⁴⁵^,⁴⁷S. aureus resistant strains were developed via mutations in the 23S ribosomal ribonucleic acid (rRNA) gene’s domain V region.⁴⁸^,⁴⁹ Linezolid is associated with potentially serious adverse events. According to studies, it is well tolerated; however, reversible myelosuppression (thrombocytopenia) is documented on prolonged usage. Other adverse drug reactions seen are lactic acidosis, ocular and peripheral neuropathy, and serotonin-like syndrome.⁵⁰^-⁵² The majority of adverse events are partially or completely on discontinuation of treatment, but peripheral neuropathy may persist.⁵³

Daptomycin

It is a cyclic lipopeptide in structure having bactericidal activity against S. aureus. It has a similar spectrum of actions to vancomycin. A study found the noninferiority of daptomycin over the established standard therapy in the treatment of subacute bacteremia with or without infective endocarditis.⁵²^-⁵⁴ It is also associated with the elevation of creatine kinase, rhabdomyolysis, nephropathy, peripheral neuropathy, and hepatotoxicity. However, daptomycin is safe and well-tolerated AMA. It has the extra advantage of only once-daily dosing and hence, better compliance for outpatients.⁵⁵^,⁵⁶ The important concern with it is emerging resistance, as depicted in some studies involving clinical S. aureus isolates.⁵⁶^-⁵⁸

Telavancin

This is a semisynthetic lipoglycopeptide derived from vancomycin with a dual mechanism of action. It is also given once daily and is effective against MRSA, VISA, and VRSA strains. Telavancin is quite similar to vancomycin with respect to the treatment of MSSA and MRSA pneumonia.⁵²^,⁵⁹ It acts by inhibiting cell wall synthesis similar to vancomycin by binding to the D-Ala-D-Ala terminus of peptidoglycan in the growing cell wall. The researchers discovered that telavancin was just as effective as vancomycin for treating complex SSSIs caused by MRSA in a randomized, double-blind research, with clinical cure rates of 90.6 and 84.4%, respectively.⁵⁹

The FDA authorized (2009) telavancin for the treatment of SSSIs due to MRSA. The most common adverse effects seen are nausea, vomiting, metallic taste, headache, dizziness, rash, thrombocytopenia, and prolonged heart rate corrected QT interval on electrocardiogram intervals were also reported. Furthermore, animal studies raised concern about potential teratogenicity, therefore, to be avoided in pregnant women.⁵²^,⁵⁹^-⁶¹ Telavancin Observational Use Registry provided insights into clinicians’ use of telavancin to treat gram-positive associated bone and joint infections. This registry depicted good clinical response rates and proved it to be an effective therapy in bone and joint infections when other AMAs are ineffective.⁶¹

Ceftaroline Fosamil

This is a fifth-generation cephalosporin with broad-spectrum β-lactam activity against MRSA as well as resistant Streptococcus pneumoniae (S. pneumoniae). Basis two phase III studies in community acquired bacterial pneumonia (CABP) and in ABSSSIs, ceftaroline was granted approval from the FDA in the year 2010 for treating the CABP and complicated SSSIs due to S. pneumoniae.⁶²^,⁶³ The margin of safety and tolerability is comparable to other cephalosporins. The adverse effects seen in clinical trials were mild, and a few cases of swelling or tenderness at the infusion site were reported.⁶⁴

CANVAS-1 and 2 trials compared the efficacy of ceftaroline with vancomycin plus aztreonam in a sample size of 1378 adults having complicated SSSIs. The results demonstrated that ceftaroline was noninferior to vancomycin plus aztreonam, with a clinical response of 91.6% CANVAS-1 vs 92.7% in the CANVAS-2.⁶³^,⁶⁵ The FOCUS trials were phase III multicenter, randomized, and double-blind trials comparing ceftaroline to ceftriaxone in CBAP. In these trials, too, it was found that ceftaroline (84.3% achieving clinical cure) was noninferior to ceftriaxone (77.7% clinical cure).⁶⁴^-⁶⁶

Oritavancin

It is a bactericidal lipoglycopeptide AMA with activity against gram-positive microorganisms, including MRSA.⁵²^,⁵⁹ SOLO I was a phase III, multicenter, randomized, double-blind, parallel, comparative efficacy, and safety study of single-dose IV oritavancin vs vancomycin twice daily was done for ABSSSIs. The trial revealed that oritavancin was noninferior to vancomycin in the treatment of ABSSSIs caused by gram-positive organisms. The adverse effects profile reported was almost similar for both the drugs except for nausea which was more common with oritavancin.⁶⁷

Dalbavancin

Dalbavancin is a semisynthetic lipoglycopeptide which is a derivative of teicoplanin with a similar mechanism of action as vancomycin and teicoplanin. It differs from both of them, with better activity against gram-positive bacteria, including MRSA and VISA. DISCOVER 1 and DISCOVER 2 were similar in design noninferiority trials of dalbavancin for the treatment of ABSSSIs.⁶⁷^,⁶⁸ These trials were noninferior to each other, where Dalbavancin was administered once daily as compared with vancomycin–linezolid administered twice daily in seriously ill patients for the treatment of ABSSSIs.⁶⁸

Ceftobiprole

This is another fifth-generation cephalosporin with bactericidal activity against gram-positive pathogens like MRSA. Ceftobiprole is licensed in numerous European and other countries for the treatment of CABP and HAP.⁶⁹^,⁷⁰ It was tested in phase III studies which evaluated the efficacy of ceftobiprole in the treatment of CABP and hospital-acquired pneumonia (HAP) due to S. aureus, respectively.⁵²^,⁷⁰ In two other randomized, multicenter, and double-blind phase III trials (STRAUSS 1 and STRAUSS 2), ceftobiprole’s clinical effectiveness in hospitalized patients with complex SSSIs were investigated against ceftazidime and vancomycin. These trials showed the noninferiority of ceftobiprole—twice daily as compared with ceftazidime/vancomycin—twice daily administration for the treatment of ABSSSIs in seriously ill patients.⁷¹ Ceftobiprole was also tested in phase III studies evaluating the efficacy of ceftobiprole in the treatment of CABP and HAP due to S. aureus, respectively. Ceftobiprole was shown to be noninferior to ceftazidime/linezolid in the preliminary findings of a phase III study in patients with CABP and HAP.⁵²^,⁷¹

Tedizolid

Tedizolid phosphate is an oxazolidinone prodrug that is converted to the active form of tedizolid, which inhibits bacterial protein synthesis. It has been FDA-approved (June 2014) for the treatment of gram-positive ABSSSIs, including MRSA.⁶⁷ It differs from other oxazolidinones due to the presence of a modified side chain which confers activity against certain linezolid-resistant pathogens and, thus, improves its potency.⁷²^-⁷⁴

Arbekacin

Arbekacin sulfate is an aminoglycoside with broad antimicrobial activity. It has been used in Japan since 1990 to treat pneumonia and sepsis due to MRSA. It causes membrane damage and inhibits translation by binding to the ribosomal 50s and the 30s ribosomal subunits.⁷⁵^,⁷⁶ Some studies have reported that arbekacin was noninferior to vancomycin for treating MRSA infections.⁷⁷ However, more studies for the same would be required to confirm this finding.

Levonadifloxacin

Levonadifloxacin belongs to the subclass of quinolones—benzoquinolizine. Levonadifloxacin and its ester oral prodrug of alalevonadifloxacin have activity against MDR gram-positives, including MRSA, VISA, and VRSA.⁷⁸ It was approved by the FDA (2014), which gave it the status of a qualified infectious disease product for the treatment of ABSSSIs with concurrent bacteremia, diabetic foot, and respiratory tract infections. These infections are attributed to S. pneumoniae, Haemophilus influenzae (H. influenza), Moraxella catarrhalis, quinolone-susceptible gram-negative, and atypical bacteria.

It acts by inhibiting deoxyribonucleic acid (DNA) replication by introducing double-stranded breaks in the bacterial chromosome. The quinolones were otherwise seen to exhibit bactericidal activity by increasing the concentration of enzyme–DNA cleavage complexes.⁷⁹ Some studies revealed that levonadifloxacin therapy (IV and oral) was safe and well tolerated in the treatment of ABSSSIs. It was found to be noninferior to IV and oral linezolid therapy in the treatment of gram-positive ABSSSIs.⁷⁸^,⁷⁹

Omadacycline

This is a novel FDA-approved aminomethylcycline antibiotic for its action against ABSSSIs and CABP. A study depicted that omadacycline has in vitro activity against MSSA, MRSA, S. pneumoniae, hemolytic Streptococci, VRE, and Legionella pneumophila.⁸⁰^,⁸¹ OASIS-1 (ABSSSIs), OASIS-2 (ABSSSIs), and OPTIC (CABP) were phase III trials that established noninferiority of omadacycline to linezolid (OASIS-1 and OASIS-2) and moxifloxacin (OPTIC), respectively.⁸¹^,⁸²

Delafloxacin

This is also a new anionic fluoroquinolone that may be administered orally or with IV, which was authorized by the FDA in the year 2017 for the treatment of ABSSSIs. It is currently being investigated for CABP and complicated urinary tract infection (cUTI). It is found to have action against Neisseria gonorrhea, Legionella species, Chlamydia pneumoniae (C. pneumoniae), and Mycoplasma pneumoniae (M. pneumoniae).⁸³ Delafloxacin indicated noninferiority to existing antibiotic alternatives in the treatment of ABSSSIs caused by MDR–MRSA, P. aeruginosa based on a few phase III studies.⁸⁴ It was also found to be noninferior to vancomycin/aztreonam in a phase III study (large, multicentre, double-blind, and randomized) for the treatment of ABSSSIs. Delafloxacin monotherapy is effective against various gram-positive and negative infections and is supposed to exhibit similar efficacy when compared to vancomycin in the treatment of MRSA.⁸⁵ The most commonly reported adverse drug reactions were nausea, vomiting, diarrhea, headache, and elevated serum transaminases. Tendinitis and tendon rupture were not among the common adverse effects observed in clinical studies as compared to other fluoroquinolones.⁸⁴

Lefamulin

Lefamulin is another novel FDA-approved (2019) oral and IV antibiotic of class pleuromutilin for the treatment of CABP. Pleuromutilin’s ability to attach to the 50S ribosomal subunit in the peptidyl transferase center inhibits bacterial protein production. This interaction inhibits tRNA from properly positioning in the A and P (acceptor and donor) sites, preventing the formation of peptide bonds. It has antibacterial action against respiratory infections, which includes MRSP, MRSA, H. influenza, M. pneumoniae, C. pneumoniae, and Legionella pneumophila.⁸⁶

The phase III clinical trials of lefamulin in CBAP (LEAP 1–IV to oral lefamulin; LEAP 2–oral alone) have shown the efficacy and safety of oral and IV lefamulin for the treatment of CABP, noninferior to moxifloxacin. This prompted FDA, European Medical Agency, and Health Canada to approve lefamulin for CABP therapy in adults.⁸⁶^,⁸⁷ Prince et al. conducted a phase II clinical trial to see if lefamulin can be used to treat gram-positive ABSSSIs. It was found that clinical success rates with both IV and oral preparations of lefamulin in the clinically evaluable and modified intent to treat groups were high and equivalent to vancomycin. The most common adverse drug reactions seen were headache, nausea, diarrhea, hypokalemia, insomnia, and pain at the infusion site.⁸⁶

Eravacycline

Eravacycline is a novel, fully synthetic fluorocycline derivative of tetracycline approved by the FDA (August 2018) with a wide spectrum against pathogens that cause cUTIs and complicated intra-abdominal infections. It does not need any dose adjustment in patients with renal disorder, and this makes it a good treatment option for patients suffering from renal impairment. Two trials (IGNITE-2 and IGNITE3) compared eravacycline to levofloxacin in the treatment of cUTIs; the results indicated that eravacycline was not as effective as levofloxacin.⁸⁸^,⁹⁰

CONCLUSION

Staphylococcus aureus (S. aureus) is responsible for several difficult-to-treat infections in humans, and resistance is seen with most of the available treatment options. The continuous nature of genotypic variations in S. aureus thus poses serious clinical implications. Of concern are the few treatment options available and the rapidly emerging resistance resulting in treatment failure.

Some new AMAs are currently available for the treatment of serious MRSA infections. The current scenario of rapid antimicrobial resistance minimizes the availability of promising therapeutics against such infections and, thus, a growing global threat to human life. This review elaborates on the journey of AMAs used in the treatment of susceptible and resistant S. aureus infections, along with the resistance patterns.

ORCID

Shivani Juneja https://orcid.org/0000-0001-5324-7400

Ratinder P Singh https://orcid.org/0000-0002-6173-9269

REFERENCES

1. Gu F, He W, Xiao S, et al. Antimicrobial resistance and molecular epidemiology of staphylococcus aureus causing bloodstream infections at Ruijin Hospital in Shanghai from 2013 to 2018. Sci Rep 2020;10(1):6019. DOI: 10.1038/s41598-020-63248-5

2. Tong SY, Davis JS, Eichenberger E, et al. Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clin Microbiol Rev 2015;28(3):603–661. DOI: 10.1128/CMR.00134-14

3. Patil SS, Suresh KP, Shinduja R, et al. Prevalence of methicillin-resistant Staphylococcus aureus in India: a systematic review and meta-analysis. Oman Med J 2022;37(4):e440. DOI: 10.5001/omj.2022.22

4. Naber CK. Staphylococcus aureus bacteremia: epidemiology, pathophysiology, and management strategies. Clin Infect Dis 2009;48 Suppl 4:S231–SS237. DOI: 10.1086/598189

5. Peterson E, Kaur P. Antibiotic resistance mechanisms in bacteria: relationships between resistance determinants of antibiotic producers, environmental bacteria, and clinical pathogens. Front Microbiol 2018;9:2928. DOI: 10.3389/fmicb.2018.02928

6. van Hal SJ, Jensen SO, Vaska VL, et al. Predictors of mortality in Staphylococcus aureus bacteremia. Clin Microbiol Rev 2012;25(2):362–386. DOI: 10.1128/CMR.05022-11

7. Chambers HF, Deleo FR. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nat Rev Microbiol 2009;7(9):629–641. DOI: 10.1038/nrmicro2200

8. Karaman R, Jubeh B, Breijyeh Z. Resistance of gram-positive bacteria to current antibacterial agents and overcoming approaches. Molecules 2020;25(12). DOI: 10.3390/molecules25122888

9. Peacock SJ, Paterson GK. Mechanisms of methicillin resistance in Staphylococcus aureus. Annu Rev Biochem 2015;84:577–601. DOI: 10.1146/annurev-biochem-060614-034516

10. Stapleton PD, Taylor PW. Methicillin resistance in Staphylococcus aureus: mechanisms and modulation. Sci Prog 2002;85(Pt 1):57–72. DOI: 10.3184/003685002783238870

11. Al Johny. Characterization of methicillin-resistant staphylococcus aureus isolated from nearby hospitals from two different countries. J Pure Appl Microbiol 2019;13(3):1683–1688. DOI: 10.22207/JPAM.13.3.42

12. Gardete S, Tomasz A. Mechanisms of vancomycin resistance in Staphylococcus aureus. J Clin Invest 2014;124(7):2836–2840. DOI: 10.1172/JCI68834

13. Guo Y, Song G, Sun M, et al. Prevalence and therapies of antibiotic-resistance in Staphylococcus aureus. Front Cell Infect Microbiol 2020;10:107. DOI: 10.3389/fcimb.2020.00107

14. Craft KM, Nguyen JM, Berg LJ, et al. Methicillin-resistant Staphylococcus aureus (MRSA): antibiotic-resistance and the biofilm phenotype. Medchemcomm 2019;10(8):1231–1241. DOI: 10.1039/c9md00044e

15. Negi V. Staphylococcus aureus: an invincible bug. Curr Trends Biomed Eng Biosci 2017;5(5):99–102. DOI: 10.19080/CTBEB.2017.05.555672

16. Joshi S, Ray P, Manchanda V, et al. Methicillin resistant staphylococcus aureus (MRSA) in India: prevalence & susceptibility pattern. Indian J Med Res 2013;137(2):363–369. DOI: 10.18203/2320-6012.ijrms20172085

17. Gupta S, Dongre A, Pandey AC, et al. Antibiogram of methicillin resistant staphylococcus aureus (MRSA) in healthcare settings. J Chem Pharmaceut Res 2015;7(8):61–66.

18. da Costa TM, de Oliveira CR, Chambers HF, et al. PBP4: a new perspective on staphylococcus aureus β-lactam resistance. Microorganisms 2018;6(3): DOI: 10.3390/microorganisms6030057

19. Foster TJ. Antibiotic resistance in staphylococcus aureus. Current status and future prospects. FEMS Microbiol Rev 2017;41(3):430–449. DOI: 10.1093/femsre/fux007

20. Ubukata K, Nonoguchi R, Matsuhashi M, et al. Expression and inducibility in Staphylococcus aureus of the mecA gene, which encodes a methicillin-resistant S. aureus-specific penicillin-binding protein. J Bacteriol 1989;171(5):2882–2885. DOI: 10.1128/jb.171.5.2882-2885.1989

21. Simmons NA, Ball AP, Eykyn SJ, et al. Antibiotic treatment of streptococcal, enterococcal, and staphylococcal endocarditis. Heart 1998;79(2):207–210. DOI: 10.1136/hrt.79.2.207

22. Ahmed Z, Saeed Khan S, Khan M. In vitro trials of some antimicrobial combinations against Staphylococcus aureus and Pseudomonas aeruginosa. Saudi J Biol Sci 2013;20(1):79–83. DOI: 10.1016/j.sjbs.2012.10.005

23. Gibb J, Wong DW. Antimicrobial treatment strategies for stenotrophomonas maltophilia: a focus on novel therapies. Antibiotics (Basel) 2021;10(10): DOI: 10.3390/antibiotics10101226

24. Adra M, Lawrence KR. Trimethoprim/sulfamethoxazole for treatment of severe Staphylococcus aureus infections. Ann Pharmacother 2004;38(2):338–341. DOI: 10.1345/aph.1D156

25. Paul M, Bishara J, Yahav D, et al. Trimethoprim-sulfamethoxazole versus vancomycin for severe infections caused by meticillin resistant Staphylococcus aureus: randomised controlled trial. BMJ 2015;350:h2219. DOI: 10.1136/bmj.h2219

26. Chopra I, Roberts M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev 2001;65(2):232–260 ; second page, table of contents. DOI: 10.1128/MMBR.65.2.232-260.2001

27. Ruhe JJ, Menon A. Tetracyclines as an oral treatment option for patients with community onset skin and soft tissue infections caused by methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2007;51(9):3298–3303. DOI: 10.1128/AAC.00262-07

28. Guay DR. Treatment of bacterial skin and skin structure infections. Expert Opin Pharmacother 2003;4(8):1259–1275. DOI: 10.1517/14656566.4.8.1259

29. Khan A, Wilson B, Gould IM. Current and future treatment options for community-associated MRSA infection. Expert Opin Pharmacother 2018;19(5):457–470. DOI: 10.1080/14656566.2018.1442826

30. Adhikari RP, Shrestha S, Barakoti A, et al. Inducible clindamycin and methicillin resistant Staphylococcus aureus in a tertiary care hospital, Kathmandu, Nepal. BMC Infect Dis 2017;17(1):483. DOI: 10.1186/s12879-017-2584-5

31. Brook I, Wexler HM, Goldstein EJ. Antianaerobic antimicrobials: spectrum and susceptibility testing. Clin Microbiol Rev 2013;26(3):526–546. DOI: 10.1128/CMR.00086-12

32. Cong Y, Yang S, Rao X. Vancomycin resistant Staphylococcus aureus infections: a review of case updating and clinical features. J Adv Res 2020;21:169–176. DOI: 10.1016/j.jare.2019.10.005

33. Dhand A, Sakoulas G. Reduced vancomycin susceptibility among clinical Staphylococcus aureus isolates (’the MIC Creep’): implications for therapy. F1000 Med Rep 2012;4:4. DOI: 10.3410/M4-4

34. Kalil AC, Van Schooneveld TC, Fey PD, et al. Association between vancomycin minimum inhibitory concentration and mortality among patients with Staphylococcus aureus bloodstream infections: a systematic review and meta-analysis. JAMA 2014;312(15):1552–1564. DOI: 10.1001/jama.2014.6364

35. Shajari G, Khorshidi A, Moosavi G. Vancomycin resistance in Staphylococcus aureus strains. Arch Razi Inst 2017;90(54):107–110.

36. Disease I, Section E. Vancomycin-intermediate (VISA) vancomycin-resistant (VRSA). 2009;2748(504):1–7.

37. Bryson HM, Brogden RN. Piperacillin/tazobactam. A review of its antibacterial activity, pharmacokinetic properties and therapeutic potential. Drugs 1994;47(3):506–535. DOI: 10.2165/00003495-199447030-00008

38. Portolés A, Palau E, Puerro M, et al. Health economics assessment study of teicoplanin versus vancomycin in gram-positive infections. Rev Esp Quimioter 2006;19(1):65–75. PMID: 16688294.

39. Bassetti M, Nicolini L, Repetto E, et al. Tigecycline use in serious nosocomial infections: a drug use evaluation. BMC Infect Dis 2010;10:287. DOI: 10.1186/1471-2334-10-287

40. Townsend ML, Pound MW, Drew RH. Tigecycline in the treatment of complicated intra-abdominal and complicated skin and skin structure infections. Ther Clin Risk Manag 2007;3(6):1059–1070. PMID: 18516315.

41. Uzunović S, Bedenić B, Budimir A, et al. Emergency (clonal spread) of methicillin-resistant Staphylococcus aureus (MRSA), extended spectrum (ESBL)–and AmpC beta-lactamase-producing Gram-negative bacteria infections at Pediatric Department, Bosnia and Herzegovina. Wien Klin Wochenschr 2014;126(23-24):747–756. DOI: 10.1007/s00508-014-0597-2

42. Cattoir V, Dowzicky MJ. A longitudinal assessment of antimicrobial susceptibility among important pathogens collected as part of the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) in France between 2004 and 2012. Antimicrob Resist Infect Control 2014;3(1):36. DOI: 10.1186/2047-2994-3-36

43. Hashemian SMR, Farhadi T, Ganjparvar M. Linezolid: a review of its properties, function, and use in critical care. Drug Des Devel Ther 2018;12:1759–1767. DOI: 10.2147/dddt.s164515

44. Sazdanovic P, Jankovic SM, Kostic M, et al. Pharmacokinetics of linezolid in critically ill patients. Expert Opin Drug Metab Toxicol 2016;12(6):595–600. DOI: 10.1517/17425255.2016.1170807

45. Keel RA, Schaeftlein A, Kloft C, et al. Pharmacokinetics of intravenous and oral linezolid in adults with cystic fibrosis. Antimicrob Agents Chemother 2011;55(7):3393–3398. DOI: 10.1128/AAC.01797-10

46. Cai JC, Hu YY, Zhang R, et al. Linezolid-resistant clinical isolates of meticillin-resistant coagulase-negative staphylococci and Enterococcus faecium from China. J Med Microbiol 2012;61(Pt 11):1568–1573. DOI: 10.1099/jmm.0.043729-0

47. Gu B, Kelesidis T, Tsiodras S, et al. The emerging problem of linezolid-resistant Staphylococcus. J Antimicrob Chemother 2013;68(1):4–11. DOI: 10.1093/jac/dks354

48. Baos E, Candel FJ, Merino P, et al. Characterization and monitoring of linezolid-resistant clinical isolates of Staphylococcus epidermidis in an intensive care unit 4 years after an outbreak of infection by cfr-mediated linezolid-resistant Staphylococcus aureus. Diagn Microbiol Infect Dis 2013;76(3):325–329. DOI: 10.1016/j.diagmicrobio.2013.04.002

49. Pillai SK, Sakoulas G, Wennersten C, et al. Linezolid resistance in Staphylococcus aureus: characterization and stability of resistant phenotype. J Infect Dis 2002;186(11):1603–1607. DOI: 10.1086/345368

50. Musumeci R, Calaresu E, Gerosa J, et al. Resistance to Linezolid in Staphylococcus spp. clinical isolates associated with ribosomal binding site modifications: novel mutation in domain v of 23S rRNA. New Microbiol 2016;39(4):269–273. PMID: 27727405.

51. Falagas ME, Vardakas KZ. Benefit-risk assessment of linezolid for serious gram-positive bacterial infections. Drug Saf 2008;31(9):753–768. DOI: 10.2165/00002018-200831090-00004

52. Quinn DK, Stern TA. Linezolid and serotonin syndrome. Prim Care Companion J Clin Psychiatry 2009;11(6):353–356. DOI: 10.4088/PCC.09r00853

53. Rasmussen RV, Fowler VG Jr, Skov R, et al. Future challenges and treatment of Staphylococcus aureus bacteremia with emphasis on MRSA. Future Microbiol 2011;6(1):43–56. DOI: 10.2217/fmb.10.155

54. Silverman JA, Perlmutter NG, Shapiro HM. Correlation of daptomycin bactericidal activity and membrane depolarization in Staphylococcus aureus. Antimicrob Agents Chemother 2003;47(8):2538–2544. DOI: 10.1128/AAC.47.8.2538-2544.2003

55. Bradley J, Glasser C, Patino H, et al. Daptomycin for complicated skin infections: a randomized trial. Pediatrics 2017;139(3): DOI: 10.1542/peds.2016-2477

56. Anderson TP, Wong JSJ, Werno AM. Early-onset rhabdomyolysis related to daptomycin use. 2007;30:2006–2008.

57. Cui L, Tominaga E, Neoh HM, et al. Correlation between Reduced Daptomycin Susceptibility and Vancomycin Resistance in Vancomycin-Intermediate Staphylococcus aureus. Antimicrob Agents Chemother 2006;50(3):1079–1082. DOI: 10.1128/AAC.50.3.1079-1082.2006

58. Bonkowski J, Daniels AR, Peppard WJ. Role of telavancin in treatment of skin and skin structure infections. Clin Cosmet Investig Dermatol 2010;3:127–133. DOI: 10.2147/CCID.S9027

59. Stryjewski ME, Chu VH, O’Riordan WD, et al. Telavancin versus standard therapy for treatment of complicated skin and skin structure infections caused by gram-positive bacteria: FAST 2 study. Antimicrob Agents Chemother 2006;50(3):862–867. DOI: 10.1128/AAC.50.3.862-867.2006

60. Binda E, Marinelli F, Marcone GL. Old and new glycopeptide antibiotics: action and resistance. Antibiotics (Basel) 2014;3(4):572–594. DOI: 10.3390/antibiotics3040572

61. Koomanachai P, Crandon JL, Nicolau DP. Newer developments in the treatment of gram-positive infections. Expert Opin Pharmacother 2009;10(17):2829–2843. DOI: 10.1517/14656560903357491

62. Sims CR, Bressler AM, Graham DR, et al. Real-world clinical use and outcomes of telavancin for the treatment of bone and joint infections: results from the telavancin observational use registry (TOUR™). Drugs Real World Outcomes 2021;8(4):509–518. DOI: 10.1007/s40801-021-00255-6

63. Laudano JB. Ceftaroline fosamil: a new broad-spectrum cephalosporin. J Antimicrob Chemother 2011;66(Suppl 3):iii11–18. DOI: 10.1093/jac/dkr095

64. Frampton JE. Ceftaroline fosamil: a review of its use in the treatment of complicated skin and soft tissue infections and community-acquired pneumonia. Drugs 2013;73(10):1067–1094. DOI: 10.1007/s40265-013-0075-6

65. File TM Jr, Wilcox MH, Stein GE. Summary of ceftaroline fosamil clinical trial studies and clinical safety. Clin Infect Dis 2012;55(Suppl 3):S173–S180. DOI: 10.1093/cid/cis559

66. Merker A, Danziger LH, Rodvold KA, et al. Pharmacokinetic and pharmacodynamic evaluation of ceftaroline fosamil. Expert Opin Drug Metab Toxicol 2014;10(12):1741–1750. DOI: 10.1517/17425255.2014.972932

67. File TM Jr, Low DE, Eckburg PB, et al. FOCUS 1: a randomized, double-blinded, multicentre, Phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia. J Antimicrob Chemother 2011;66 Suppl 3:iii19–32. DOI: 10.1093/jac/dkr096

68. Koulenti D, Xu E, Mok IYS, et al. Novel antibiotics for multidrug-resistant gram-positive microorganisms. Microorganisms 2019;7(8): DOI: 10.3390/microorganisms7080270

69. Ramdeen S, Boucher HW. Dalbavancin for the treatment of acute bacterial skin and skin structure infections. Expert Opin Pharmacother 2015;16(13):2073–2081. DOI: 10.1517/14656566.2015.1075508

70. Chambers HF. Ceftobiprole: in-vivo profile of a bactericidal cephalosporin. Clin Microbiol Infect 2006;12(Suppl 2):17–22. DOI: 10.1111/j.1469-0691.2006.01404.x

71. Murthy B, Schmitt-Hoffmann A. Pharmacokinetics and pharmacodynamics of ceftobiprole, an anti-MRSA cephalosporin with broad-spectrum activity. Clin Pharmacokinet 2008;47(1):21–33. DOI: 10.2165/00003088-200847010-00003

72. Dauner DG, Nelson RE, Taketa DC. Ceftobiprole: a novel, broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus. Am J Health Syst Pharm 2010;67(12):983–993. DOI: 10.2146/ajhp090285

73. Hasannejad-Bibalan M, Mojtahedi A, Biglari H, et al. Antibacterial activity of tedizolid, a novel oxazolidinone against methicillin-resistant Staphylococcus aureus: a systematic review and meta-analysis. Microb Drug Resist 2019;25(9):1330–1337. DOI: 10.1089/mdr.2018.0457

74. Hall RG 2nd, Smith WJ, Putnam WC, et al. An evaluation of tedizolid for the treatment of MRSA infections. Expert Opin Pharmacother 2018;19(13):1489–1494. DOI: 10.1080/14656566.2018.1519021

75. Roch M, Varela MC, Taglialegna A, et al. Tedizolid is a promising antimicrobial option for the treatment of Staphylococcus aureus infections in cystic fibrosis patients. J Antimicrob Chemother 2020;75(1):126–134. DOI: 10.1093/jac/dkz418

76. Tanigawara Y, Sato R, Morita K, et al. Population pharmacokinetics of Arbekacin in patients infected with methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2006;50(11):3754–3762. DOI: 10.1128/AAC.00420-05

77. Matsumoto T. Arbekacin: another novel agent for treating infections due to methicillin-resistant Staphylococcus aureus and multidrug-resistant Gram-negative pathogens. Clin Pharmacol 2014;6:139–148. DOI: 10.2147/CPAA.S44377

78. Hwang JH, Lee JH, Moon MK, et al. The usefulness of arbekacin compared to vancomycin. Eur J Clin Microbiol Infect Dis 2012;31(7):1663–1666. DOI: 10.1007/s10096-011-1490-9

79. Bhagwat SS, Nandanwar M, Kansagara A, et al. Levonadifloxacin, a novel broad-spectrum anti-MRSA benzoquinolizine quinolone agent: review of current evidence. Drug Des Devel Ther 2019;13:4351–4365. DOI: 10.2147/DDDT.S229882

80. Koulenti D, Xu E, Song A, et al. Emerging treatment options for infections by multidrug-resistant gram-positive microorganisms. Microorganisms 2020;8(2):191. DOI: 10.3390/microorganisms802019

81. Watkins RR, Deresinski S. Omadacycline: a novel tetracycline derivative with oral and intravenous formulations. Clin Infect Dis 2019;69(5):890–896. DOI: 10.1093/cid/ciz242

82. Zhanel GG, Esquivel J, Zelenitsky S, et al. Omadacycline: a novel oral and intravenous aminomethylcycline antibiotic agent. Drugs 2020;80(3):285–313. DOI: 10.1007/s40265-020-01257-4

83. Abrahamian FM, Sakoulas G, Tzanis E, et al. Omadacycline for acute bacterial skin and skin structure infections. Clin Infect Dis 2019;69(Suppl 1):S23–S32. DOI: 10.1093/cid/ciz396

84. Saravolatz LD, Stein GE. Delafloxacin: a new anti-methicillin-resistant staphylococcus aureus fluoroquinolone. Clin Infect Dis 2019;68(6):1058–1062. DOI: 10.1093/cid/ciy600

85. Ocheretyaner ER, Park TE. Delafloxacin: a novel fluoroquinolone with activity against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. Expert Rev Anti Infect Ther 2018;16(7):523–530. DOI: 10.1080/14787210.2018.1489721

86. Pullman J, Gardovskis J, Farley B, et al. Efficacy and safety of delafloxacin compared with vancomycin plus aztreonam for acute bacterial skin and skin structure infections: a phase 3, double-blind, randomized study. J Antimicrob Chemother 2017;72(12):3471–3480. DOI: 10.1093/jac/dkx329

87. Zhanel GG, Deng C, Zelenitsky S, et al. Lefamulin: a novel oral and intravenous pleuromutilin for the treatment of community-acquired bacterial pneumonia. Drugs 2021;81(2):233–256. DOI: 10.1007/s40265-020-01443-4

88. Kollef MH, Betthauser KD. New antibiotics for community-acquired pneumonia. Curr Opin Infect Dis 2019;32(2):169–175. DOI: 10.1097/QCO.0000000000000526

89. Lee YR, Burton CE. Eravacycline, a newly approved fluorocyclinee. Eur J Clin Microbiol Infect Dis 2019;38(10):1787–1794. DOI: 10.1007/s10096-019-03590-3

90. Deck DH, Winston LG. Chemotherapeutic drugs. In:Katzung BG, Masters SB, Trevor AJ, editors. Basic and Clinical Pharmacology. 12th ed. New York: McGraw Hill; 2012. p. 790–831.

________________________
© The Author(s). 2023 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.