Emergency in Group A Streptococcal Infections: Single center data from Turkey.

Assessing the influence of the COVID-19 pandemic on the incidence, clinical presentation, and clindamycin resistance rates of Streptococcus pyogenes infections

Rising global incidence of invasive group A streptococcus infection and scarlet fever in the COVID-19 era – our knowledge thus far

Current scenario of recently rising up cases of invasive group A streptococcal (iGAS) infections in younger children in many European nations: clinical management and prospective counteracting measures – an update

Background In December 2022 the CDC issued an alert about possible increase of invasive group A Streptococcus infections (iGAS) among children in the United States. Colorado and Minnesota observed an increase in the number of cases in the Fall 2022. Similarly, the Pennsylvania Department of Health issued a health alert that was then lifted in February 2023. Preliminary CDC data showed that iGAS infections were higher in some areas of the country compared to pre-pandemic levels. Lehigh Valley Reilly Children’s Hospital is a community teaching hospital in Allentown, Pennsylvania. A rise in the number of children admitted with GAS infections was noted in the same period compared to previous years. The aim of our study was to determine the clinical characteristics of patients admitted with iGAS and non-iGAS infections during fall and winter 2022-2023. Methods Retrospective chart review of patients 18 years and younger admitted to Reilly Children’s Hospital between September 1st 2022 through March 31st 2023 and diagnosed with GAS infection plus those admitted with the same diagnosis between 2018 and 2022. Results There were 19 children admitted to the hospital with GAS infection: 6 (32%) with iGAS and 13 (68 %) with non-iGAS infections. The iGAS infections included bacteremia without source (2), myositis (1), pneumonia (2), and vascular infection (1). Non-iGAS infections included retropharyngeal abscess (3), peritonsillar abscess (2), parotid abscess (1), submandibular abscess (1), lymphadenitis (2), mastoiditis (1), cellulitis (1), pharyngitis (1), and erythema nodosum (1). Six children required intensive care and two were transferred to higher level care. Median age was 2.2 year for iGAS infections and 4.8 years for non-iGAS. All but one patient had no underlying medical conditions. There were no patient deaths. In 2018 there were zero cases of iGAS infection; in 2019: two cases; 2020: two cases; 2021: zero cases. There were no admissions between May 2020 and April 2022 for either iGAS or non-iGAS. Conclusion The number of children admitted for iGAS and non-iGAS infections in the fall and winter of 2022-2023 surpassed the preceding 4 years combined. This is reflective of what was happening in some other areas of the country as a result of reduced exposure and lack of immunity due to pandemic restrictions. Disclosures All Authors: No reported disclosures

Streptococcus is one of the common pathogens of suppurative infections. Invasive group A Streptococcus (iGAS) infections often develop from skin or soft tissue infections, and streptococcal toxic shock syndrome is considered the main cause of death in Chinese children with iGAS infectious disease. However, soft tissue infections caused by iGAS infections, especially the formation of abscesses, are relatively rare. A retrospective study was conducted, and pediatric in-patients who were diagnosed with an iGAS infection identified by cultures from normally sterile sites and treated in a tertiary hospital during 2016-2018 were included. A total of 14 patients were identified, which included 10 boys and four girls. The patients had an age range from 3 months to 10 years and were diagnosed with soft tissue infections and a formation of abscesses caused by iGAS infections. The most common sites of infections were the lower limbs. In five patients, the abscess was accompanied by fever, and the local soft tissue showed redness, swelling, tenderness, and an elevated skin temperature. Laboratory findings included an increased white blood cell (WBC) count in 12 patients, an increased C reactive protein (CRP) level in seven patients, and an increased erythrocyte sedimentation rate (ESR) in 10 patients. No patients had an elevated procalcitonin level. For all 14 patients, we performed puncture and drainage of abscesses, and cultured GAS from the drainage fluid. All children also received antibiotic treatment. During 2 months of follow-up, the patients' condition remained stable and no evidence of kidney or heart damage was observed. For pediatric patients with abscesses, early diagnosis, prompt treatment with incision and drainage, and immediate culture of the drainage fluid are important. Upon confirmation of an iGAS infection, β-lactam antibiotics should be given to provide effective treatment, and in some patients with poor therapeutic outcomes, the use of vancomycin as an alternative can achieve the desired results.

To the Editor: Group A streptococci (GAS) can cause severe invasive diseases, such as necrotizing fasciitis, streptococcal toxic shock syndrome, and sepsis. In 2012, ≈11,000 cases of invasive GAS (iGAS) disease and 1,100 associated deaths occurred in the United States (1,2). The risk for iGAS infection is 10 times higher among Native Americans than among the general population (3). Other predisposing factors for iGAS infection include skin wounds and underlying diseases, such as diabetes (1,3,4). Household risk factors include exposure to children with pharyngitis and crowding (4). Most iGAS infections occur sporadically within the community. Postpartum and postsurgical clusters arising from a common nosocomial source occur but are rare (5). During the winter of 2012–13, a 3-fold increase in necrotizing fasciitis was observed at an Arizona hospital (hospital X) that predominantly treats Native Americans. Tribal leadership initiated a collaborative investigation with state and federal officials to characterize the outbreak and implement appropriate control measures. A confirmed case of iGAS was defined as isolation of GAS from normally sterile sites (i.e., blood) or isolation of GAS from nonsterile sites (i.e., wound) in the presence of necrotizing fasciitis or streptococcal toxic shock syndrome among patients who sought care at hospital X during August 2012–March 2013. Hospital X serves ≈45,000 persons in a rural community. Eleven confirmed iGAS cases were identified (Figure), of which 8 (73%) occurred in women and 3 (27%) occurred in men. The case-patients had a mean age of 63 years (range 32–92 years). All cases were community-onset illnesses; none of the case-patients had recent exposures to health care settings, and all were of Native American ancestry. Of the 11 case-patients, 8 required critical care treatment and 3 died. Nine (82%) case-patients had open wounds or skin breakdown (e.g., skin abrasion, burns), and 9 had underlying medical conditions that are known risk factors for iGAS (e.g., obesity, diabetes, chronic kidney or heart disease, alcoholism). Figure Week of symptom onset and principal clinical syndrome of patients with confirmed invasive group A streptococcus infections at hospital X, Arizona, August 2012–March 2013. STSS, streptococcal toxic shock syndrome. Five GAS isolates were available. Two of the isolates were emm type 11; antimicrobial drug–susceptibility profiles for the 2 were identical (i.e., tetracycline resistant). The 2 patients reported no close contact with each other, but they had the same home health aide. The other 3 isolates had different emm types (1, 12, and 82) and were antimicrobial drug pansensitive. We interviewed 58 household contacts of the case-patients (35 adults, 23 children) regarding symptoms and risks for secondary GAS infection. Among these contacts, 2 adults reported a sore throat and 6 children reported fever (without sore throat), but no confirmed secondary GAS infections were identified. Because of the known increased risk for iGAS among Native Americans and the level of crowding (average of 2–3 persons/bedroom) and the high proportion of adult household contacts with predisposing underlying conditions (29%) in this population, azithromycin prophylaxis was offered to household contacts who spent >24 hours with a case-patient during the 7 days preceding the onset of illness. With the exception of the 2 case-patients with a common health aide, we found no common epidemiologic links or common behaviors among patients that suggested a single-source outbreak. This was further supported by the finding of multiple emm types among the isolates. These are not unusual findings in community outbreaks of iGAS; clusters of iGAS cases have often been observed without a common source (6–8). Localized and transient increases in sporadic GAS infections may occur because of an influx of a new emm type into a population with low levels of community immunity to that specific emm type; an increase in the detection and reporting of iGAS without a true increase in infection; or an increase in conditions that predispose persons to iGAS, such as GAS pharyngitis among children or concurrent influenza or other virus outbreaks in the community. Past studies have shown that the risk of secondary iGAS infection among household contacts of patients with iGAS disease is higher than that among the general population but still low (5). Although Centers for Disease Control and Prevention guidelines do not recommend routine chemoprophylaxis for household contacts of patients with iGAS infection, the guidelines state that providers may choose to offer antimicrobial drug prophylaxis to those household contacts at increased risk for iGAS infection (5). Because Native Americans have increased rates of iGAS disease, compared with those of the general population, and because households in this investigation were crowded and many contacts had predisposing underlying conditions, we recommended that household contacts receive prophylaxis if given within 30 days of the index case-patient’s illness (5). No additional cases were reported at least 3 months after the investigation and intervention.

After completing this article, readers should be able to: Staphylococci are hardy aerobic bacteria that are present in the environment and as normal flora of humans and animals. They are resistant to heat and drying and may be recovered from the environment months after contamination. These organisms are gram-positive cocci that grow in characteristic grapelike clusters. Staphylococci are distinguished from streptococci by a positive catalase (H2O2) test. Species are classified as Staphylococcus aureus if they are coagulase-positive or as one of many species of coagulase-negative staphylococci (eg, S epidermidis, S saprophyticus). S aureus is the most common cause of pyogenic infection of the skin; it also may cause osteomyelitis, septic arthritis, wound infection, abscess, pneumonia, empyema, endocarditis, pericarditis, meningitis, and toxin-mediated diseases, including food poisoning, staphylococcal scarlet fever, scalded skin syndrome, and toxic shock syndrome (TSS). Coagulase-negative staphylococci tend to be less pathogenic unless a foreign body (eg, intravascular catheter) is present.Many neonates are colonized with S aureus within the first postnatal week. Thereafter, up to 50% of healthy individuals carry at least one strain of S aureus in the anterior nares at any given time. The organisms may be transmitted from the nose to the skin, where colonization seems to be more transient. Persistent umbilical perianal and vaginal carriage has been described. S aureus generally is transmitted by direct contact, primarily on the hands. Autoinfection is common. Handwashing by caretakers between contacts with patients decreases the spread of staphylococci from patient to patient. Many different strains of S aureus are capable of causing a wide variety of diseases (Fig. 1); these strains, and the diseases they commonly cause, may change in a community over time.Strains of S aureus are identified best by the virulence factors they produce (Fig. 1). These factors have four different roles: protecting the organism from host defenses, localizing infection, causing local tissue damage, and acting as toxins affecting noninfected tissue sites.Many staphylococci produce a loose polysaccharide capsule, or slime layer, that may interfere with phagocytosis. Coagulase causes plasma to clot by interacting with fibrinogen, which may play an important role in localization of infection (ie, abscess formation) –a hallmark of S aureus infection. Clumping factor interacts with fibrinogen to cause the formation of large clumps of organism that interfere with effective phagocytosis. Production of coagulase and clumping factor differentiates S aureus from S epidermidis and other coagulase-negative staphylococci. Another important enzyme elaborated by staphylococci is penicillinase (or beta-lactamase), which inactivates penicillin.Many strains of S aureus produce substances that destroy local tissue. A number of immunologically distinct hemolysins have been identified. Alpha-toxin acts on cell membranes and causes tissue necrosis. Panton-Valentine leukocidin, which is produced by some virulent strains of S aureus, combines with the phospholipid of the phagocytic cell membrane, producing increased permeability, leakage of protein, and eventual death of the neutrophil and macrophage.Many strains of S aureus release exotoxins. Exfoliatin A and B are two serologically distinct proteins that produce skin separation by splitting the desmosome and altering the intracellular matrix in the stratum granulosum, resulting in localized (eg, bullous impetigo) or generalized (eg, scalded skin syndrome, staphylococcal scarlet fever) rashes (Fig. 2). One or more staphylococcal enterotoxins (types A, B, C1, C2, D, E) are elaborated by most strains of S aureus. Ingestion of preformed enterotoxin is associated with vomiting and diarrhea and is a principal cause of food poisoning. Toxic shock syndrome toxin-1 (TSST-1) is associated with TSS related to menstruation and focal staphylococcal infection. TSST-1 induces production of interleukin-1 and tumor necrosis factor, resulting in hypotension, fever, and multisystem involvement. Enterotoxin A and enterotoxin B also may be associated with nonmenstrual TSS. Epidemiologic and in vitro studies suggest that these toxins are produced selectively in the clinical environment commonly found in abscesses and in the vagina with tampon use during menstruation. The risk factors for symptomatic disease require a nonimmune host colonized with a toxin-producing organism that is exposed to focal growth conditions (eg, menstruation plus tampon use or abscess), which induce toxin production.The development of staphylococcal disease is related to resistance of the host to infection and to the virulence of the organism. The intact skin and mucous membranes serve as barriers to invasion by staphylococci. Defects in the mucocutaneous barriers produced by trauma, surgery, foreign surfaces (eg, sutures, shunts, intravascular catheters), and burns increase the risk of infection.Infants may acquire type-specific humoral immunity to staphylococci transplacentally. Antibody to the various S aureus toxins appears to protect against those specific toxin-mediated diseases but not necessarily focal or disseminated S aureus infection with the same organisms.Individuals who have congenital defects in chemotaxis (Job, Chédiak-Higashi, and Wiskott-Aldrich syndromes), defective phagocytosis, and defective humoral immunity (antibodies required for opsonization) are at increased risk of infection with staphylococci. Patients who have chronic granulomatous disease, in which phagocytosis proceeds normally but killing of ingested catalase-positive bacteria is severely impaired, are particularly susceptible to staphylococcal disease. Local host defense compromise (eg, surgical wound, cystic fibrosis) often is complicated by S aureus infection.S aureus is identified by its growth on blood agar and a positive catalase and coagulase test. Antibiotic susceptibility testing has become increasingly important. In the past, most strains were resistant to penicillin but susceptible to methicillin and the cephalosporins and termed methicillin-susceptible S aureus (MSSA). An increasing number have acquired the mecA gene that alters beta-lactam antibiotic binding to the staphylococcal cell wall, causing them to become methicillin (and cephalosporin)- resistant S aureus (MRSA). For many years, MRSA strains were seen primarily in hospitals and often were resistant to other antibiotics. Rare resistance to vancomycin also has been reported. In the past few years, community-associated methicillin-resistant S aureus (CA-MRSA) strains have become more common. In some locales, these strains remained susceptible to clindamycin and trimethoprim-sulfamethoxazole, but erythromycin-induced clindamycin resistance has become increasingly common. Most strains continue to be susceptible to trimethoprim-sulfamethoxazole.The signs and symptoms of S aureus infection vary with the specific strain and the location of the infection, which although located most commonly on the skin, may involve any tissue (Fig. 1). The classic manifestation of staphylococcal infection is a localized abscess. Disease states of various degrees of severity generally result from local tissue injury, systemic dissemination with metastatic infection, or systemic effects of toxin production. Although the nasopharynx may be colonized with S aureus, disease due to this organism is relatively uncommon. Lesions, especially those of the skin, are considerably more prevalent among persons living in low socioeconomic circumstances and particularly among those in tropical climates.Pyogenic skin infections may be primary or due to wound infection with S aureus. S aureus infection is the most common cause of both crusted impetigo and bullous impetigo. S aureus, group A streptococci, or both may cause crusted impetigo. Bullous impetigo commonly occurs in the diaper area and is due to exfoliatin-producing S aureus strains that cause bullae in locally infected lesions (see scalded skin syndrome). Folliculitis, hydradenitis, furuncles (boils), carbuncles, and wound infections are all different manifestations of localized infections caused by S aureus. Recently, necrotizing fasciitis has been described associated with CA-MRSA.Infections of the upper respiratory tract due to S aureus are uncommon, considering the frequency with which this area is colonized. Otitis media and sinusitis due to S aureus occasionally may occur. Staphylococcal tonsillopharyngitis is rare in otherwise healthy children. Unilateral cervical lymphadenitis is caused commonly by S aureus, especially in young children. A membranous tracheitis that complicates viral croup may be infected with S aureus but also by other organisms. Treatment requires antibiotics and careful airway management.Staphylococci may cause a necrotizing pneumonitis with empyema. Pneumatoceles, pyopneumothorax, and bronchopleural fistulas develop frequently. Hematogenous pneumonia may be due to septic emboli, right-sided endocarditis, or the presence of infected intravascular devices.A localized staphylococcal abscess in muscle associated with elevation of muscle enzyme concentrations but without septicemia has been called tropical pyomyositis. Although this disorder has been reported most frequently from tropical areas, it also has occurred in the United States in otherwise healthy children. Multiple abscesses occur in 30% to 40% of cases. Surgical drainage and appropriate antibiotic therapy are essential.Meningitis due to S aureus is not common; it is associated with cranial trauma and neurosurgical procedures (eg, craniotomy, cerebrospinal fluid shunt placement) and, less frequently, with endocarditis, parameningeal foci (eg, epidural or brain abscess), diabetes mellitus, or malignancy. Coagulase-negative Staphylococcus (CONS) is not ordinarily as virulent as S aureus, but it has a high affinity for attaching to foreign materials and is the most common cause of shunt-related infections.Acute bacterial endocarditis may follow staphylococcal bacteremia. S aureus is a common cause of acute endocarditis on native valves. Perforation of heart valves, myocardial abscesses, heart failure, conduction disturbances, acute hemopericardium, purulent pericarditis, and sudden death may ensue. CONS is a frequent cause of endocarditis affecting prosthetic heart valves.S aureus is a common cause of renal and perinephric abscess, usually of hematogenous origin. Urinary tract infection due to S aureus is unusual but more commonly may be caused in males by S saprophyticus.Staphylococcal bacteremia may be associated with any localized infection (Fig. 1). The onset may be acute and marked by nausea, vomiting, myalgia, fever, and chills. Organisms may localize subsequently at any site but are found especially in the lungs, heart, joints, bones, kidneys, and brain. S aureus is the most common cause of osteomyelitis and suppurative arthritis in children.In some instances, especially in young adolescent males, disseminated staphylococcal disease occurs, characterized by fever, persistent bacteremia despite antibiotics, and focal involvement of two or more separate tissue sites (eg, skin, bone, joint, kidney, lung, liver, heart). Endocarditis and septic thrombophlebitis must be ruled out.TSS is an acute multisystem disease characterized by high fever, hypotension, vomiting, diarrhea, myalgias, nonfocal neurologic abnormalities, conjunctival hyperemia, strawberry tongue, and an erythematous rash with subsequent desquamation on the hands and feet (TableT1). Many cases occur in menstruating women 15 to 25 years of age who use tampons or other vaginal devices (eg, diaphragm, contraceptive sponge) in the presence of vaginal colonization or infection with TSST-1-producing strains of S aureus. TSS, however, also occurs in children, nonmenstruating women, and men. Nonmenstrual TSS has been associated with wound infection, nasal packing, sinusitis, tracheitis, pneumonia, empyema, abscesses, burns, osteomyelitis, and primary bacteremia.Complications include acute respiratory distress syndrome, myocardial failure, and renal failure and are commensurate with the degree of shock. Recovery occurs within 7 to 10 days and is associated with desquamation, particularly of palms and soles. Hair and nail loss also have been observed after 1 to 2 months. Many cases of apparent scarlet fever without shock may be caused by TSST-1-producing S aureus strains.Group A Streptococcus can cause a similar TSS-like illness, termed streptococcal TSS, which often is associated with streptococcal bacteremia or a focal streptococcal infection such as necrotizing fasciitis or pneumonia.Staphylococcal scalded skin syndrome represents a spectrum of clinical entities mediated by exfoliatin-producing S aureus strains (Fig. 2). Patients who do not have antibody to the toxin develop generalized disease due to hematogenous dissemination of the toxin. The rash is characterized by a painful erythroderma with a positive Nikolsky sign, but signs are more severe in newborns (Ritter disease) and milder in older children (staphylococcal scarlet fever).Food poisoning may be caused by ingestion of enterotoxins that are preformed by staphylococci contaminating foods. Sudden, severe vomiting begins approximately 2 to 7 hours after ingestion of the toxin. Watery diarrhea may develop, but fever is absent or low. Symptoms rarely persist longer than 12 to 24 hours. Rarely, shock and death may occur.The diagnosis of staphylococcal infection depends on isolation of the organisms from normally noncolonized sites, such as skin lesions, abscess cavities, blood, or other sites of infection. Isolation from the nose or skin does not necessarily imply causation because these are normally colonized sites. The organisms can be grown readily on solid media. After isolation, identification is made on the basis of Gram stain and catalase, coagulase, or clumping factor reactivity. Patterns of susceptibility to antibiotics should be assessed in serious cases because resistance to penicillin is common and resistance to the penicillinase-resistant beta-lactam antibiotics is increasing (MRSA).The increasing resistance of S aureus to multiple antimicrobials both in the hospital and the community and another common cause of soft-tissue or toxin-mediated infection (group A Streptococcus) being resistant to trimethoprim-sulfamethoxazole make it imperative to initiate antimicrobial therapy likely to be effective for both organisms in serious infections (eg, sepsis, endocarditis, TSS, necrotizing fasciitis). The combination of vancomycin with the addition of clindamycin for toxin-mediated disease is a reasonable choice for such infections because clindamycin has been shown to reduce TSST-1 production by 90% in culture. Rare vancomycin-resistant strains of both S aureus and enterococci have been reported mostly in patients being treated with vancomycin. Vancomycin should be continued only in children who have proven MRSA infections. Linezolid and quinupristin-dalfopristin may be useful for serious S aureus infections highly resistant to other antibiotics. The combination of nafcillin (or vancomycin), gentamicin, and rifampin has been recommended for the initial treatment of S aureus endocarditis.The antibiotic used, as well as the dose, route, and duration of treatment, depend on the site of infection, the response of the patient to treatment, and the susceptibility of the organisms recovered from blood or local sites of infection. Appropriate cultures always should be obtained so the causative organism can be identified and susceptibility testing performed to optimize therapeutic decisions. Antibiotic therapy alone rarely is effective for individuals who have undrained abscesses or infected foreign bodies. Loculated collections of purulent material should be drained. Foreign bodies should be removed, if possible.Therapy for serious infection determined to be caused by MSSA usually is successful with a penicillinase-resistant antibiotic (eg, nafcillin, oxacillin, or a first- or second-generation cephalosporin).Intravenous treatment is recommended for most patients who have serious staphylococcal infection until the patient has been afebrile for 72 hours and other signs of infection have disappeared. Oral treatment may be provided in milder infections or to complete the course of treatment when parenteral therapy has been discontinued. Dicloxacillin is penicillinase-resistant, absorbed well orally, and clinically effective, although many children do not like its taste. The first-generation cephalosporins, amoxicillin combined with the beta-lactamase inhibitor clavulanic acid, clindamycin, or trimethoprim-sulfamethoxazole administered orally may be effective, depending on antimicrobial susceptibilities. Skin and soft-tissue infections and minor upper respiratory tract infections often may be managed by oral therapy alone, but in areas that have an increasing incidence of CA-MRSA, culture and susceptibility are necessary to optimize antimicrobial selection.For TSS, initial parenteral administration of a beta-lactamase-resistant antistaphylococcal antibiotic (eg, nafcillin or a first-generation cephalosporin) or vancomycin in locales where MRSA is increasingly prevalent is recommended after appropriate cultures have been obtained. The addition of clindamycin in severe or unresponsive cases may terminate toxin production. Drainage of the vagina, by removal of any retained tampons in menstrual TSS, and of focally infected sites in nonmenstrual TSS is important for successful treatment. Fluid replacement should be aggressive to prevent or treat hypotension, renal failure, and cardiovascular collapse. Inotropic agents may be needed to treat shock; corticosteroids and intravenous immune globulin may be helpful for severe cases.Untreated staphylococcal septicemia is associated with a high fatality rate. Fatality rates have been reduced dramatically by appropriate antibiotic treatment. Prognosis also may be influenced by numerous host factors, including nutrition, immunologic competence, and the presence or absence of other debilitating diseases. In most cases of abscess formation, surgical drainage is required.Staphylococcal infection is transmitted primarily by direct contact. Strict attention to handwashing techniques is the most effective measure for preventing the spread of staphylococci from one individual to another. Use of a soap containing an iodophor, chlorhexidine, or hexachlorophene is recommended. In hospitals or other institutional settings, all persons who have acute staphylococcal infections should be isolated until they have been treated adequately. Surveillance for nosocomial staphylococcal infections should be constant within hospitals. When MRSA is recovered, isolation of affected patients has been shown to be the most effective method for preventing nosocomial spread of infection. It also may be necessary to identify colonized hospital personnel and eradicate carriage in affected individuals. Strains of S aureus resistant to vancomycin that have limited treatment options have been reported, emphasizing the need for restricting the prescription of unnecessary antibiotics and the importance of isolating the causative organism and susceptibility testing in serious infections.The low risk of acquiring TSS (1 to 2 cases per 100,000 menstruating women per year) may be reduced by not using tampons or by using them intermittently during each menstrual period. If a fever, rash, or dizziness develops during menstruation, any tampon should be removed immediately and medical attention sought.

After completing this article, readers should be able to: Staphylococci are hardy aerobic bacteria that are present in the environment and as normal flora of humans and animals. They are resistant to heat and drying and may be recovered from the environment months after contamination. These organisms are gram-positive cocci that grow in characteristic grapelike clusters. Staphylococci are distinguished from streptococci by a positive catalase (H2O2) test. Species are classified as Staphylococcus aureus if they are coagulase-positive or as one of many species of coagulase-negative staphylococci (eg, S epidermidis, S saprophyticus). S aureus is the most common cause of pyogenic infection of the skin; it also may cause osteomyelitis, septic arthritis, wound infection, abscess, pneumonia, empyema, endocarditis, pericarditis, meningitis, and toxin-mediated diseases, including food poisoning, staphylococcal scarlet fever, scalded skin syndrome, and toxic shock syndrome (TSS). Coagulase-negative staphylococci tend to be less pathogenic unless a foreign body (eg, intravascular catheter) is present.Many neonates are colonized with S aureus within the first postnatal week. Thereafter, up to 50% of healthy individuals carry at least one strain of S aureus in the anterior nares at any given time. The organisms may be transmitted from the nose to the skin, where colonization seems to be more transient. Persistent umbilical perianal and vaginal carriage has been described. S aureus generally is transmitted by direct contact, primarily on the hands. Autoinfection is common. Handwashing by caretakers between contacts with patients decreases the spread of staphylococci from patient to patient. Many different strains of S aureus are capable of causing a wide variety of diseases (Fig. 1); these strains, and the diseases they commonly cause, may change in a community over time.Strains of S aureus are identified best by the virulence factors they produce (Fig. 1). These factors have four different roles: protecting the organism from host defenses, localizing infection, causing local tissue damage, and acting as toxins affecting noninfected tissue sites.Many staphylococci produce a loose polysaccharide capsule, or slime layer, that may interfere with phagocytosis. Coagulase causes plasma to clot by interacting with fibrinogen, which may play an important role in localization of infection (ie, abscess formation) –a hallmark of S aureus infection. Clumping factor interacts with fibrinogen to cause the formation of large clumps of organism that interfere with effective phagocytosis. Production of coagulase and clumping factor differentiates S aureus from S epidermidis and other coagulase-negative staphylococci. Another important enzyme elaborated by staphylococci is penicillinase (or beta-lactamase), which inactivates penicillin.Many strains of S aureus produce substances that destroy local tissue. A number of immunologically distinct hemolysins have been identified. Alpha-toxin acts on cell membranes and causes tissue necrosis. Panton-Valentine leukocidin, which is produced by some virulent strains of S aureus, combines with the phospholipid of the phagocytic cell membrane, producing increased permeability, leakage of protein, and eventual death of the neutrophil and macrophage.Many strains of S aureus release exotoxins. Exfoliatin A and B are two serologically distinct proteins that produce skin separation by splitting the desmosome and altering the intracellular matrix in the stratum granulosum, resulting in localized (eg, bullous impetigo) or generalized (eg, scalded skin syndrome, staphylococcal scarlet fever) rashes (Fig. 2). One or more staphylococcal enterotoxins (types A, B, C1, C2, D, E) are elaborated by most strains of S aureus. Ingestion of preformed enterotoxin is associated with vomiting and diarrhea and is a principal cause of food poisoning. Toxic shock syndrome toxin-1 (TSST-1) is associated with TSS related to menstruation and focal staphylococcal infection. TSST-1 induces production of interleukin-1 and tumor necrosis factor, resulting in hypotension, fever, and multisystem involvement. Enterotoxin A and enterotoxin B also may be associated with nonmenstrual TSS. Epidemiologic and in vitro studies suggest that these toxins are produced selectively in the clinical environment commonly found in abscesses and in the vagina with tampon use during menstruation. The risk factors for symptomatic disease require a nonimmune host colonized with a toxin-producing organism that is exposed to focal growth conditions (eg, menstruation plus tampon use or abscess), which induce toxin production.The development of staphylococcal disease is related to resistance of the host to infection and to the virulence of the organism. The intact skin and mucous membranes serve as barriers to invasion by staphylococci. Defects in the mucocutaneous barriers produced by trauma, surgery, foreign surfaces (eg, sutures, shunts, intravascular catheters), and burns increase the risk of infection.Infants may acquire type-specific humoral immunity to staphylococci transplacentally. Antibody to the various S aureus toxins appears to protect against those specific toxin-mediated diseases but not necessarily focal or disseminated S aureus infection with the same organisms.Individuals who have congenital defects in chemotaxis (Job, Chédiak-Higashi, and Wiskott-Aldrich syndromes), defective phagocytosis, and defective humoral immunity (antibodies required for opsonization) are at increased risk of infection with staphylococci. Patients who have chronic granulomatous disease, in which phagocytosis proceeds normally but killing of ingested catalase-positive bacteria is severely impaired, are particularly susceptible to staphylococcal disease. Local host defense compromise (eg, surgical wound, cystic fibrosis) often is complicated by S aureus infection.S aureus is identified by its growth on blood agar and a positive catalase and coagulase test. Antibiotic susceptibility testing has become increasingly important. In the past, most strains were resistant to penicillin but susceptible to methicillin and the cephalosporins and termed methicillin-susceptible S aureus (MSSA). An increasing number have acquired the mecA gene that alters beta-lactam antibiotic binding to the staphylococcal cell wall, causing them to become methicillin (and cephalosporin)- resistant S aureus (MRSA). For many years, MRSA strains were seen primarily in hospitals and often were resistant to other antibiotics. Rare resistance to vancomycin also has been reported. In the past few years, community-associated methicillin-resistant S aureus (CA-MRSA) strains have become more common. In some locales, these strains remained susceptible to clindamycin and trimethoprim-sulfamethoxazole, but erythromycin-induced clindamycin resistance has become increasingly common. Most strains continue to be susceptible to trimethoprim-sulfamethoxazole.The signs and symptoms of S aureus infection vary with the specific strain and the location of the infection, which although located most commonly on the skin, may involve any tissue (Fig. 1). The classic manifestation of staphylococcal infection is a localized abscess. Disease states of various degrees of severity generally result from local tissue injury, systemic dissemination with metastatic infection, or systemic effects of toxin production. Although the nasopharynx may be colonized with S aureus, disease due to this organism is relatively uncommon. Lesions, especially those of the skin, are considerably more prevalent among persons living in low socioeconomic circumstances and particularly among those in tropical climates.Pyogenic skin infections may be primary or due to wound infection with S aureus. S aureus infection is the most common cause of both crusted impetigo and bullous impetigo. S aureus, group A streptococci, or both may cause crusted impetigo. Bullous impetigo commonly occurs in the diaper area and is due to exfoliatin-producing S aureus strains that cause bullae in locally infected lesions (see scalded skin syndrome). Folliculitis, hydradenitis, furuncles (boils), carbuncles, and wound infections are all different manifestations of localized infections caused by S aureus. Recently, necrotizing fasciitis has been described associated with CA-MRSA.Infections of the upper respiratory tract due to S aureus are uncommon, considering the frequency with which this area is colonized. Otitis media and sinusitis due to S aureus occasionally may occur. Staphylococcal tonsillopharyngitis is rare in otherwise healthy children. Unilateral cervical lymphadenitis is caused commonly by S aureus, especially in young children. A membranous tracheitis that complicates viral croup may be infected with S aureus but also by other organisms. Treatment requires antibiotics and careful airway management.Staphylococci may cause a necrotizing pneumonitis with empyema. Pneumatoceles, pyopneumothorax, and bronchopleural fistulas develop frequently. Hematogenous pneumonia may be due to septic emboli, right-sided endocarditis, or the presence of infected intravascular devices.A localized staphylococcal abscess in muscle associated with elevation of muscle enzyme concentrations but without septicemia has been called tropical pyomyositis. Although this disorder has been reported most frequently from tropical areas, it also has occurred in the United States in otherwise healthy children. Multiple abscesses occur in 30% to 40% of cases. Surgical drainage and appropriate antibiotic therapy are essential.Meningitis due to S aureus is not common; it is associated with cranial trauma and neurosurgical procedures (eg, craniotomy, cerebrospinal fluid shunt placement) and, less frequently, with endocarditis, parameningeal foci (eg, epidural or brain abscess), diabetes mellitus, or malignancy. Coagulase-negative Staphylococcus (CONS) is not ordinarily as virulent as S aureus, but it has a high affinity for attaching to foreign materials and is the most common cause of shunt-related infections.Acute bacterial endocarditis may follow staphylococcal bacteremia. S aureus is a common cause of acute endocarditis on native valves. Perforation of heart valves, myocardial abscesses, heart failure, conduction disturbances, acute hemopericardium, purulent pericarditis, and sudden death may ensue. CONS is a frequent cause of endocarditis affecting prosthetic heart valves.S aureus is a common cause of renal and perinephric abscess, usually of hematogenous origin. Urinary tract infection due to S aureus is unusual but more commonly may be caused in males by S saprophyticus.Staphylococcal bacteremia may be associated with any localized infection (Fig. 1). The onset may be acute and marked by nausea, vomiting, myalgia, fever, and chills. Organisms may localize subsequently at any site but are found especially in the lungs, heart, joints, bones, kidneys, and brain. S aureus is the most common cause of osteomyelitis and suppurative arthritis in children.In some instances, especially in young adolescent males, disseminated staphylococcal disease occurs, characterized by fever, persistent bacteremia despite antibiotics, and focal involvement of two or more separate tissue sites (eg, skin, bone, joint, kidney, lung, liver, heart). Endocarditis and septic thrombophlebitis must be ruled out.TSS is an acute multisystem disease characterized by high fever, hypotension, vomiting, diarrhea, myalgias, nonfocal neurologic abnormalities, conjunctival hyperemia, strawberry tongue, and an erythematous rash with subsequent desquamation on the hands and feet (TableT1). Many cases occur in menstruating women 15 to 25 years of age who use tampons or other vaginal devices (eg, diaphragm, contraceptive sponge) in the presence of vaginal colonization or infection with TSST-1-producing strains of S aureus. TSS, however, also occurs in children, nonmenstruating women, and men. Nonmenstrual TSS has been associated with wound infection, nasal packing, sinusitis, tracheitis, pneumonia, empyema, abscesses, burns, osteomyelitis, and primary bacteremia.Complications include acute respiratory distress syndrome, myocardial failure, and renal failure and are commensurate with the degree of shock. Recovery occurs within 7 to 10 days and is associated with desquamation, particularly of palms and soles. Hair and nail loss also have been observed after 1 to 2 months. Many cases of apparent scarlet fever without shock may be caused by TSST-1-producing S aureus strains.Group A Streptococcus can cause a similar TSS-like illness, termed streptococcal TSS, which often is associated with streptococcal bacteremia or a focal streptococcal infection such as necrotizing fasciitis or pneumonia.Staphylococcal scalded skin syndrome represents a spectrum of clinical entities mediated by exfoliatin-producing S aureus strains (Fig. 2). Patients who do not have antibody to the toxin develop generalized disease due to hematogenous dissemination of the toxin. The rash is characterized by a painful erythroderma with a positive Nikolsky sign, but signs are more severe in newborns (Ritter disease) and milder in older children (staphylococcal scarlet fever).Food poisoning may be caused by ingestion of enterotoxins that are preformed by staphylococci contaminating foods. Sudden, severe vomiting begins approximately 2 to 7 hours after ingestion of the toxin. Watery diarrhea may develop, but fever is absent or low. Symptoms rarely persist longer than 12 to 24 hours. Rarely, shock and death may occur.The diagnosis of staphylococcal infection depends on isolation of the organisms from normally noncolonized sites, such as skin lesions, abscess cavities, blood, or other sites of infection. Isolation from the nose or skin does not necessarily imply causation because these are normally colonized sites. The organisms can be grown readily on solid media. After isolation, identification is made on the basis of Gram stain and catalase, coagulase, or clumping factor reactivity. Patterns of susceptibility to antibiotics should be assessed in serious cases because resistance to penicillin is common and resistance to the penicillinase-resistant beta-lactam antibiotics is increasing (MRSA).The increasing resistance of S aureus to multiple antimicrobials both in the hospital and the community and another common cause of soft-tissue or toxin-mediated infection (group A Streptococcus) being resistant to trimethoprim-sulfamethoxazole make it imperative to initiate antimicrobial therapy likely to be effective for both organisms in serious infections (eg, sepsis, endocarditis, TSS, necrotizing fasciitis). The combination of vancomycin with the addition of clindamycin for toxin-mediated disease is a reasonable choice for such infections because clindamycin has been shown to reduce TSST-1 production by 90% in culture. Rare vancomycin-resistant strains of both S aureus and enterococci have been reported mostly in patients being treated with vancomycin. Vancomycin should be continued only in children who have proven MRSA infections. Linezolid and quinupristin-dalfopristin may be useful for serious S aureus infections highly resistant to other antibiotics. The combination of nafcillin (or vancomycin), gentamicin, and rifampin has been recommended for the initial treatment of S aureus endocarditis.The antibiotic used, as well as the dose, route, and duration of treatment, depend on the site of infection, the response of the patient to treatment, and the susceptibility of the organisms recovered from blood or local sites of infection. Appropriate cultures always should be obtained so the causative organism can be identified and susceptibility testing performed to optimize therapeutic decisions. Antibiotic therapy alone rarely is effective for individuals who have undrained abscesses or infected foreign bodies. Loculated collections of purulent material should be drained. Foreign bodies should be removed, if possible.Therapy for serious infection determined to be caused by MSSA usually is successful with a penicillinase-resistant antibiotic (eg, nafcillin, oxacillin, or a first- or second-generation cephalosporin).Intravenous treatment is recommended for most patients who have serious staphylococcal infection until the patient has been afebrile for 72 hours and other signs of infection have disappeared. Oral treatment may be provided in milder infections or to complete the course of treatment when parenteral therapy has been discontinued. Dicloxacillin is penicillinase-resistant, absorbed well orally, and clinically effective, although many children do not like its taste. The first-generation cephalosporins, amoxicillin combined with the beta-lactamase inhibitor clavulanic acid, clindamycin, or trimethoprim-sulfamethoxazole administered orally may be effective, depending on antimicrobial susceptibilities. Skin and soft-tissue infections and minor upper respiratory tract infections often may be managed by oral therapy alone, but in areas that have an increasing incidence of CA-MRSA, culture and susceptibility are necessary to optimize antimicrobial selection.For TSS, initial parenteral administration of a beta-lactamase-resistant antistaphylococcal antibiotic (eg, nafcillin or a first-generation cephalosporin) or vancomycin in locales where MRSA is increasingly prevalent is recommended after appropriate cultures have been obtained. The addition of clindamycin in severe or unresponsive cases may terminate toxin production. Drainage of the vagina, by removal of any retained tampons in menstrual TSS, and of focally infected sites in nonmenstrual TSS is important for successful treatment. Fluid replacement should be aggressive to prevent or treat hypotension, renal failure, and cardiovascular collapse. Inotropic agents may be needed to treat shock; corticosteroids and intravenous immune globulin may be helpful for severe cases.Untreated staphylococcal septicemia is associated with a high fatality rate. Fatality rates have been reduced dramatically by appropriate antibiotic treatment. Prognosis also may be influenced by numerous host factors, including nutrition, immunologic competence, and the presence or absence of other debilitating diseases. In most cases of abscess formation, surgical drainage is required.Staphylococcal infection is transmitted primarily by direct contact. Strict attention to handwashing techniques is the most effective measure for preventing the spread of staphylococci from one individual to another. Use of a soap containing an iodophor, chlorhexidine, or hexachlorophene is recommended. In hospitals or other institutional settings, all persons who have acute staphylococcal infections should be isolated until they have been treated adequately. Surveillance for nosocomial staphylococcal infections should be constant within hospitals. When MRSA is recovered, isolation of affected patients has been shown to be the most effective method for preventing nosocomial spread of infection. It also may be necessary to identify colonized hospital personnel and eradicate carriage in affected individuals. Strains of S aureus resistant to vancomycin that have limited treatment options have been reported, emphasizing the need for restricting the prescription of unnecessary antibiotics and the importance of isolating the causative organism and susceptibility testing in serious infections.The low risk of acquiring TSS (1 to 2 cases per 100,000 menstruating women per year) may be reduced by not using tampons or by using them intermittently during each menstrual period. If a fever, rash, or dizziness develops during menstruation, any tampon should be removed immediately and medical attention sought.

Reported outbreaks of invasive group A Streptococcus (iGAS) infections among people who inject drugs (PWID) and people experiencing homelessness (PEH) have increased, concurrent with rising US iGAS rates. We describe epidemiology among iGAS patients with these risk factors. We analyzed iGAS infections from population-based Active Bacterial Core surveillance (ABCs) at 10 US sites from 2010 to 2017. Cases were defined as GAS isolated from a normally sterile site or from a wound in patients with necrotizing fasciitis or streptococcal toxic shock syndrome. GAS isolates were emm typed. We categorized iGAS patients into four categories: injection drug use (IDU) only, homelessness only, both, and neither. We calculated annual change in prevalence of these risk factors using log binomial regression models. We estimated national iGAS infection rates among PWID and PEH. We identified 12 386 iGAS cases; IDU, homelessness, or both were documented in ~13%. Skin infections and acute skin breakdown were common among iGAS patients with documented IDU or homelessness. Endocarditis was 10-fold more frequent among iGAS patients with documented IDU only versus those with neither risk factor. Average percentage yearly increase in prevalence of IDU and homelessness among iGAS patients was 17.5% and 20.0%, respectively. iGAS infection rates among people with documented IDU or homelessness were ~14-fold and 17- to 80-fold higher, respectively, than among people without those risks. IDU and homelessness likely contribute to increases in US incidence of iGAS infections. Improving management of skin breakdown and early recognition of skin infection could prevent iGAS infections in these patients.

Invasive group A streptococcal infections in children and adolescents in Denmark during 2022–23 compared with 2016–17 to 2021–22: a nationwide, multicentre, population-based cohort study

Methicillin-Resistant Staphylococcus aureus: A Pharmacotherapy Primer

Group A streptococcus and host metabolism: virulence influences and potential treatments.

BackgroundGroup A Streptococcus is responsible for severe and potentially lethal invasive conditions requiring intensive care unit (ICU) admission, such as streptococcal toxic shock-like syndrome (STSS). A rebound of invasive group A streptococcal (iGAS) infection after COVID-19-associated barrier measures has been observed in children. Several intensivists of French adult ICUs have reported similar bedside impressions without objective data. We aimed to compare the incidence of iGAS infection before and after the COVID-19 pandemic, describe iGAS patients’ characteristics, and determine ICU mortality associated factors.MethodsWe performed a retrospective multicenter cohort study in 37 French ICUs, including all patients admitted for iGAS infections for two periods: two years before period (October 2018 to March 2019 and October 2019 to March 2020) and a one-year after period (October 2022 to March 2023) COVID-19 pandemic. iGAS infection was defined by Group A Streptococcus isolation from a normally sterile site. iGAS infections were identified using the International Classification of Diseases and confirmed with each center's microbiology laboratory databases. The incidence of iGAS infections was expressed in case rate.ResultsTwo hundred and twenty-two patients were admitted to ICU for iGAS infections: 73 before and 149 after COVID-19 pandemic. Their case rate during the period before and after COVID-19 pandemic was 205 and 949/100,000 ICU admissions, respectively (p < 0.001), with more frequent STSS after the COVID-19 pandemic (61% vs. 45%, p = 0.015). iGAS patients (n = 222) had a median SOFA score of 8 (5–13), invasive mechanical ventilation and norepinephrine in 61% and 74% of patients. ICU mortality in iGAS patients was 19% (14% before and 22% after COVID-19 pandemic; p = 0.135). In multivariate analysis, invasive mechanical ventilation (OR = 6.08 (1.71–21.60), p = 0.005), STSS (OR = 5.75 (1.71–19.22), p = 0.005), acute kidney injury (OR = 4.85 (1.05–22.42), p = 0.043), immunosuppression (OR = 4.02 (1.03–15.59), p = 0.044), and diabetes (OR = 3.92 (1.42–10.79), p = 0.008) were significantly associated with ICU mortality.ConclusionThe incidence of iGAS infections requiring ICU admission increased by 4 to 5 after the COVID-19 pandemic. After the COVID-19 pandemic, the rate of STSS was higher, with no significant increase in ICU mortality rate.

To the Editors: During the second and third year of the COVID pandemic, an increased number of serious cases due to different microorganisms have been reported. In the second half of 2022, it has been reported that there has been an increase in invasive group A streptococcal (iGAS) infections in many countries including England, the Netherlands and others.1–3 iGAS is defined as a life-threatening invasive infection characterized by the isolation of Streptococcus pyogenes from normally sterile body fluids with culture or by pathogen-specific polymerase chain reaction (PCR). If GAS has grown from a probable carrier location, such as the throat, and the clinical course is compatible with GAS disease and no other causing organism has been found, these patients need to be handled as iGAS.4 Before the pandemic, GAS was the most common pathogen among children in Europe who had to be hospitalized for a community-acquired bacterial infection. Patients with GAS infection had a 12% impairment at discharge and a 2% fatality rate. Increases in toxic shock syndrome, necrotizing fasciitis and pleural empyema have all been linked to increased mortality.4 In UK, during the last couple of months, the rate per 100,000 population of iGAS is higher among children.1 Between December 2022 and January 2023, in our tertiary care facility, we followed up 7 consecutive cases of iGAS infection—3 boys and 4 girls, ages 37–96 months—without any relation to one another (Table 1). All children were previously healthy. Five children were admitted to the pediatric intensive care unit, including 1 with toxic shock syndrome and 4 with pleural effusion/empyema. In 6 out of 7 children, the diagnosis of iGAS infection was made based on a positive culture and/or PCR from a typically sterile place, with the pleural fluid being the most frequent site. iGAS infection was defined in a child with toxic shock syndrome based on positive throat culture. In Table 1, antibiotic therapy is displayed. Each patient received clindamycin and 1 patient received intravenous immunoglobulin (IVIG). Due to empyema, thoracic tubes had to be inserted in 5 patients. In 2 of the pleural empyema cases, tube thoracostomy was carried out; in the third video assisted thoracostomy and in the fourth, thoracotomy and decortication were carried out. One child with GAS bacteremia required surgery for mastoiditis, and throughout the course of the investigation, sinus venous thrombosis was detected. Five children required pediatric intensive care unit stay. The length of hospital stay ranged from 7 to 21 days. TABLE 1. - Clinical Characteristics of 7 Children with Invasive Group A Streptococcal Infection Patient Age (month) Gender Diagnosis Culture Multiplex PCR Treatment PICU Stay Length of hospital stay (day) 1 37 Girl Pleural Empyema - Pleural fluid Streptococcus pyogenes Meropenem + vancomycin + clindamycin IVIG Thoracotomy and decortication + 14 2 40 Girl Pleural Empyema Throat Streptococcus pyogenes Pleural fluid Streptococcus pyogenes Tube thoracostomy Ceftriaxone + clindamycin + 9 3 96 Girl Pleural Empyema - Pleural fluid Streptococcus pyogenes Meropenem + vancomycin + clindamycin Tube thoracostomy Video assisted thoracostomy + 15 4 62 Boy Bacteremia, Mastoiditis, Sinus vein thrombosis Blood Streptococcus pyogenes - Meropenem + vancomycin + clindamycin Mastoidectomy - 21 5 48 Boy Pleural Empyema - Pleural fluid Streptococcus pyogenes Ceftriaxone + vancomycin + clindamycin Tube thoracostomy + 10 6 59 Boy Toxic Shock Syndrome Throat Streptococcus pyogenes - Ceftriaxone + vancomycin + clindamycin + 7 7 42 Girl Bacteremia, Pleural Empyema Blood Streptococcus pyogenes - Ceftriaxone + clindamycin - 10 IVIG, intravenous immune globulin; PICU, pediatric intensive care unit. Both the frequency and morbidity of iGAS infections increased after the COVID-19 pandemic as before. While there was only one iGAS case during the previous 3 years, 7 patients in a row were hospitalized during a 2-month period in our setting. Clindamycin would be efficient to deactivate M-protein and these exotoxins because S. pyogenes has the cell wall M-protein that prevents complement activation and reduces phagocytosis. This would produce a positive outcome similar to our case series.4,5 Although culture is the gold standard method for diagnosis, molecular methods such as multiplex PCR are important in identifying the causative agent. Despite treatment, we have seen serious complications in our case series, such as pleural decortication, mastoiditis, sinus venous thrombosis and toxic shock syndrome. Early diagnosis of patients (using molecular techniques included) and the initiation of appropriate treatment including clindamycin, are crucial. To comprehend the postpandemic condition, it is essential to monitor the clinical findings and prognosis of iGAS cases from various countries.

Trimethoprim-Sulfamethoxazole for Skin and Soft Tissue Infections—Let Us Not Forget the Risks