Introduction {#S0001} ============ *Streptococcus* species are part of the normal flora of humans and can cause a variety of infections ranging from tonsillitis and skin infections to septic shock, meningitis, endocarditis, and deep wound infections. *S. pyogenes*, or group A streptococcus, is a leading cause of bacterial-associated neonatal mortality, respiratory tract infections, and systemic infections such as necrotizing fasciitis.[@CIT0001]--[@CIT0003] Historically, *S. pyogenes* was an important cause of morbidity and mortality from pneumonia until widespread use of antibiotics.[@CIT0001],[@CIT0003],[@CIT0004] Currently, the bacterium is listed as a reportable disease in certain states. The increasing numbers of reports indicate that in 2017, there were 3,010 cases of *S. pyogenes* from 1,017 distinct cases.[@CIT0005] According to the Centers for Disease Control and Prevention (CDC), streptococcal toxic shock syndrome (STSS) is an uncommon but devastating infection. The reported incidence has varied from 1.1 to 7.8 cases per million persons,[@CIT0006] with higher rates in southern China.[@CIT0007] The disease results from toxic shock syndrome toxin-1 (TSST-1) from *S. pyogenes*. In 2002, the US Food and Drug Administration (FDA) made the following comments on streptococcal toxic shock syndrome: (1) STSS is rarely associated with *S. pyogenes* isolation and appears to be associated with increased severity of STSS in the presence of the TSST-1 gene.[@CIT0008] (2) Infection with *S. pyogenes* is a predisposing condition for STSS, whether or not that organism is isolated. (3) Molecular methods such as PCR are rapid and reliable, and may be more sensitive than culture.[@CIT0008] The CDC provides further guidelines to reduce or eliminate non-compliance with the warning that suggests using antibiotic prophylaxis and screening at-risk patients for *S. pyogenes*.[@CIT0008] *S. pyogenes* is also one of the more frequent causes of scarlet fever. Scarlet fever can lead to secondary cases of invasive disease such as rheumatic fever and necrotizing fasciitis.[@CIT0009] In the 1930s, a major focus of antibiotic research was to develop drugs that would protect patients from *S. pyogenes*.[@CIT0010] However, the first antibiotic used to treat streptococcal infections was penicillin. A study that used penicillin as an antiparasitic agent in mice, discovered that the mouse was resistant to penicillin, but susceptible to the toxins secreted by *S. pyogenes*.[@CIT0011] Penicillin treatment of mice resulted in the production of antibodies that neutralized the toxin.[@CIT0011] The production of such antibodies suggested that it was possible to prevent toxic shock syndrome from *S. pyogenes* with the use of penicillin.[@CIT0012] Penicillin-resistant strains of *S. pyogenes* became prevalent in the 1940s, and researchers considered penicillin to be obsolete. It was only in the 1990s that penicillin began to be used again to treat *S. pyogenes* infections.[@CIT0013] Research on antimicrobial resistance increased as cases of *S. pyogenes* resistance to penicillin became more prevalent. From 1996 to 1997, 11 out of 22 isolates of *S. pyogenes* from Germany were found to have reduced susceptibility to penicillin. That same year, 8 out of 10 isolates from South Africa had reduced susceptibility to penicillin.[@CIT0014] Furthermore, studies in New Zealand reported similar findings, finding that 20% of invasive *S. pyogenes* strains were resistant to penicillin.[@CIT0015] *S. pyogenes* antibiotic resistance resulted in the development of alternative treatment strategies. New drugs were developed including the macrolides. Macrolides were initially developed as antibiotics to treat infections in a variety of pathogens.[@CIT0016] They have good activity against both Gram-positive and Gram-negative bacteria, and are active against both extracellular and intracellular organisms.[@CIT0017] Despite the new drug development, bacteria have been found to acquire mutations that make them resistant to macrolides. In 2006, Japan's national surveillance agency issued a warning that *S. pyogenes* was resistant to fluoroquinolones, macrolides, and tetracycline.[@CIT0018] Resistance to macrolides was also reported in China.[@CIT0019] In 2013, researchers reported cases of *S. pyogenes* resistance to macrolides, primarily erythromycin and azithromycin. These cases were reported to be more prevalent in Asia than previously reported.[@CIT0020] Antimicrobial resistance continues to be a worldwide problem. In 2010, the United Nations announced that drug-resistant bacteria will be the cause of 10 million deaths by 2050.[@CIT0021] The antimicrobial resistance causes 1.7 million annual deaths due to AIDS, tuberculosis, malaria, and diarrhea and is predicted to become one of the leading causes of death by 2020.[@CIT0021] One of the reasons for antimicrobial resistance is overuse and misuse. The drug resistance occurs naturally because a pathogen's genetic makeup is constantly changing. In the human body, there is also the constant mixing of genes to produce resistance to antibiotics. Additionally, in the environment, the bacteria do not die in a manner that will kill any more generations of the bacterial species. A study found that there were a few genes that gave resistance to antibiotics, but they were not selected in the bacterial genome as a selection marker.[@CIT0022] The development of antimicrobial resistance in *S. pyogenes* and the potential effects on clinical care call for a greater understanding of this bacterial species. However, research on streptococcal antibiotic resistance is still in its infancy. Therefore, we will review what we know about the incidence and transmission of antibiotic-resistant *S. pyogenes* as well as drug resistance profiles. Etiology {#S0001-S2001} -------- ### Virulence Factors and Antibiotic Resistance {#S0001-S2001-S3001} All streptococci have the ability to produce the enzyme staphylococcal chromosomal DNA (SEC) nuclease, which is encoded on a plasmid within the *S. pyogenes* genome.[@CIT0023] SEC nuclease is an exonuclease that is highly conserved and present in gram-positive bacteria that are not beta hemolytic (such as *S. pyogenes*, *S. equi*, and *S. dysgalactiae*). It has also been found in gram-negative bacteria such as *E. coli, Staphylococcus epidermidis, Staphylococcus haemolyticus*, and *Shigella dysenteriae*.[@CIT0024] The enzyme protects the DNA from degradation by bacterial restriction endonucleases.[@CIT0023] This allows the bacteria to survive better in the face of infection. Additionally, *S. pyogenes* has several virulence factors. One of the most important virulence factors is the M protein, which is encoded by the *emm* gene.[@CIT0025] This protein is important in protecting *S. pyogenes* from phagocytosis. It can also cross the M protein membrane, exposing it to the bacterial cell surface.[@CIT0026] These characteristics help *S. pyogenes* to escape the body's defense mechanism. The M protein also binds complement factor H, allowing the bacteria to resist lysis.[@CIT0027] The role of the M protein is to prevent the body's inflammatory response. These characteristics, in addition to the aforementioned nuclease, can allow for *S. pyogenes* to avoid immunological attack. However, when *S. pyogenes* begins to develop resistance against antibiotics, these characteristics may begin to lose their importance. The second mechanism of *S. pyogenes* resistance to the immune system is by the production of extracellular superoxide dismutase (SOD), which is a glycoprotein that is part of the cell wall. When the bacteria begin to produce it, it can be found in the cell wall.[@CIT0028] The extracellular SOD binds to catalase, inhibiting its function. The bacteria are then able to survive under conditions where there is limited amount of oxygen.[@CIT0029] ### Antibiotics {#S0001-S2001-S3002} *S. pyogenes* has several resistance mechanisms, including penicillin resistance, tetracycline resistance, macrolide resistance, and multidrug resistance. The penicillin resistance and tetracycline resistance in *S. pyogenes* is due to the activity of the Tn916-like transposon, or Tn1207. The resistance to penicillin is due to the penicillin binding protein (PBP) 2a.[@CIT0030] PBP2a can inhibit the first steps of peptidoglycan synthesis. A study found that *S. pyogenes* isolates from children with pharyngitis had a high prevalence of genes encoding Tn1207.[@CIT0031] The resistance to tetracycline is due to the fact that *S. pyogenes* has tetracycline resistant ribosomal proteins.[@CIT0032] Tetracycline interferes with the bacterial process of transcription. The macrolide resistance mechanism involves in the production of a protein called the MefA, which prevents ribosomal inhibition. This is common among beta-hemolytic streptococci and affects all macrolides except for erythromycin and clindamycin.[@CIT0033] Both penicillin-resistant *S. pyogenes* and *S. pyogenes* resistant to tetracycline and macrolides have been found to be emerging.[@CIT0034],[@CIT0035] In addition to these three forms of antibiotic resistance, more specific antibiotic resistance is becoming prevalent among *S. pyogenes*.[@CIT0036] The most common type of resistance among the *S. pyogenes