**6. Therapy**

Antibiotic strategy is considered the most potential therapeutic methods against staphylococ‐ cal infection and the resultant infertility. However, the emergence of antibiotic resistance has dramatically increased in the past two decades and becomes a serious threat to the worldwide public health. According to the National Healthcare Safety Network (NHSN) and Centers for Disease Control and Prevention, *S. aureus* and *Enterococcus* are the two most commonly reported pathogens, accounting for 15.6% and 13.9% of health care–associated infections, respectively. In particular, *S. aureus* is notorious for its ability to acquire the resistance to any antibiotic during the treatment of infection-associated infertility.

#### **6.1. Methicillin**

The introduction of penicillin in the early 1940s significantly reduced fatal invasive staphylo‐ coccal infection. However, the resistant strains, mostly *S. aureus* strains, emerged rapidly. These strains possess a plasmid-encoding enzyme, penicillinase, which can irreversibly hydrolyze the β-lactam, thus acquiring the drug resistance. Methicillin is a narrow-spectrum β-lactam antibiotic of the penicillin class. It can effectively block the synthesis of bacterial cell walls by inhibiting the peptidic cross-linkage between the linear peptidoglycan polymer chains. Therefore, the antibiotic destroys the integrity of the cell wall and selectively kills Grampositive bacteria. Compared with penicillin, methicillin harbors an orthodimethoxyphenyl group attached to the side chain of the β-lactam, which, in turn, forms a steric effect to prevent penicillinase from hydrolyzing the β-lactam. Even though, the first strain of MRSA, with an altered PBP2a to reduced affinity for the β-lactam, was reported two years later [59]. Now, MRSA refers to any strain of *S. aureus* that has developed resistance to β-lactam antibiotics such as the penicillins (methicillin, dicloxacillin, nafcillin, oxacillin, etc.) and the cephalospor‐ ins. Resistance is generally conferred by the acquisition of the mecA gene, which encodes a PBP2a. Due to the significantly decreased affinity for β-lactams, MRSA strains restore the ability of cell wall biosynthesis to continue even in the presence of typically inhibitory concentrations of antibiotic [11].

#### **6.2. Vancomycin**

Vancomycin belongs to the glycopeptide antibiotic class and is effective in treatment of serious infections caused by *Staphylococcus*. It is one of the main resources for combating infections caused by MRSA but is not recommended to treat the disease caused by methicillin-sensitive *S. aureus* (MSSA). Vancomycin is a complex compound consisting of a branched tricyclic glycosylated peptide and is a rare example of a halo-organic natural compound containing two covalently bonded chlorine atoms. The bactericidal activity of vancomycin is associated with its ability to bind at the D-Ala-D-Ala dipeptide terminus of the nascent peptidoglycan in Gram-positive bacteria and thereby to inhibit the peptidoglycan synthesis [60]. Common side effects associated this antibiotic involve pain in the area of injection and allergic reactions, and problems with hearing, low blood pressure, or bone marrow suppression occasionally occur. The strain with the reduced susceptibility to vancomycin (VISA) was first described in 1996, and the alteration of the D-Ala-D-Ala dipeptide was supposed to be the main reason under‐ lying this resistance.

#### **6.3. Linezolid**

Linezolid has been used for treatment of serious infections caused by Gram-positive bacteria that are resistant to other antibiotics such as MRSA. Its spectrum of activity is similar to that of vancomycin, a well-established antibiotic for MRSA infections. Either linezolid or vanco‐ mycin has been recommended by the US guidelines as the first-line treatment for hospitalacquired (nosocomial) MRSA pneumonia [61]. Mechanistically, linezolid binds to the 50s subunit of the bacterial ribosome through interaction with the central loop of the 23S rRNA and thus impedes the growth of bacteria by disrupting their production of proteins. Point mutation of 23S rRNA is the most common mechanism of linezolid resistance [62]. The common side effects of linezolid include diarrhea, headache, nausea, vomiting, rash, consti‐ pation, altered taste perception, and discoloration of the tongue, although they happen relatively rarely.

#### **6.4. Daptomycin**

public health. According to the National Healthcare Safety Network (NHSN) and Centers for Disease Control and Prevention, *S. aureus* and *Enterococcus* are the two most commonly reported pathogens, accounting for 15.6% and 13.9% of health care–associated infections, respectively. In particular, *S. aureus* is notorious for its ability to acquire the resistance to any

The introduction of penicillin in the early 1940s significantly reduced fatal invasive staphylo‐ coccal infection. However, the resistant strains, mostly *S. aureus* strains, emerged rapidly. These strains possess a plasmid-encoding enzyme, penicillinase, which can irreversibly hydrolyze the β-lactam, thus acquiring the drug resistance. Methicillin is a narrow-spectrum β-lactam antibiotic of the penicillin class. It can effectively block the synthesis of bacterial cell walls by inhibiting the peptidic cross-linkage between the linear peptidoglycan polymer chains. Therefore, the antibiotic destroys the integrity of the cell wall and selectively kills Grampositive bacteria. Compared with penicillin, methicillin harbors an orthodimethoxyphenyl group attached to the side chain of the β-lactam, which, in turn, forms a steric effect to prevent penicillinase from hydrolyzing the β-lactam. Even though, the first strain of MRSA, with an altered PBP2a to reduced affinity for the β-lactam, was reported two years later [59]. Now, MRSA refers to any strain of *S. aureus* that has developed resistance to β-lactam antibiotics such as the penicillins (methicillin, dicloxacillin, nafcillin, oxacillin, etc.) and the cephalospor‐ ins. Resistance is generally conferred by the acquisition of the mecA gene, which encodes a PBP2a. Due to the significantly decreased affinity for β-lactams, MRSA strains restore the ability of cell wall biosynthesis to continue even in the presence of typically inhibitory

Vancomycin belongs to the glycopeptide antibiotic class and is effective in treatment of serious infections caused by *Staphylococcus*. It is one of the main resources for combating infections caused by MRSA but is not recommended to treat the disease caused by methicillin-sensitive *S. aureus* (MSSA). Vancomycin is a complex compound consisting of a branched tricyclic glycosylated peptide and is a rare example of a halo-organic natural compound containing two covalently bonded chlorine atoms. The bactericidal activity of vancomycin is associated with its ability to bind at the D-Ala-D-Ala dipeptide terminus of the nascent peptidoglycan in Gram-positive bacteria and thereby to inhibit the peptidoglycan synthesis [60]. Common side effects associated this antibiotic involve pain in the area of injection and allergic reactions, and problems with hearing, low blood pressure, or bone marrow suppression occasionally occur. The strain with the reduced susceptibility to vancomycin (VISA) was first described in 1996, and the alteration of the D-Ala-D-Ala dipeptide was supposed to be the main reason under‐

Linezolid has been used for treatment of serious infections caused by Gram-positive bacteria that are resistant to other antibiotics such as MRSA. Its spectrum of activity is similar to that

antibiotic during the treatment of infection-associated infertility.

**6.1. Methicillin**

168 Genital Infections and Infertility

concentrations of antibiotic [11].

**6.2. Vancomycin**

lying this resistance.

**6.3. Linezolid**

Daptomycin is the first cyclic lipopeptide approved for clinical use in 2003. It is a calciumdependent antibiotic comprising a lipid molecule conjugated with anionic peptide. Daptomy‐ cin interacts with the cytoplasmic membrane in a calcium-dependent, leading to the cell membrane depolarization, ion loss, and cell death [63]. Many antibiotic-resistant strains, such as MRSA and VRSA, were found to be effectively inhibited by daptomycin. Till 2008, the first case of daptomycin resistance was reported, and the underlying mechanism is currently still not very clear [64]. However, the mutation of the mprF gene, which encodes lysyl-phospha‐ tidyl glycerol (LPG) synthetase, might be related to the occurrence of resistant strains. LPG can catalyze the coupling of lysine to PG and transfer the lysyl-PG to the outer leaflet of the membrane. In this way, LPG increases the positive charge and thus reduces the binding of Ca2+-bound daptomycin to bacterial membranes [65].

Besides the routinely used antibiotics mentioned above, numerous new antibiotics are developed to serve as the alternatives in treating staphylococcal infection and the associated infertility. For example, teicoplanin or quinupristin/dalfopristin has been widely used with daptomycin to treat Gram-positive bacterial infection. Some of the potential antibiotics, such as oritavancin and iclaprim, are currently in the early stages of clinical development, and other promising candidates, such as ceftobiprole, dalbavancin, and telavancin, are still being developed [66].
