Bacterial Infectious Diseases

### **Chapter 1**

## Pneumococcal Carriage in Jordanian Children and the Importance of Vaccination

*Adnan Al-Lahham*

### **Abstract**

Pneumococcal carriage is a prerequisite for invasive and non-invasive infections, where children and elderly are the most vulnerable groups. Aims: Determine rates of carriage, resistance, and coverage of the pneumococcal conjugate vaccines (PCVs) in children attending day care centers (DCC) in north Jordan. Methods: Nasopharyngeal swabs (NP) were taken from healthy Jordanian children from north Jordan with ages ranging from 1 month to 14 years in the period from 2008 to 2019. Classical methods were used for cultivation, identification, resistance testing, and serotyping. Results: 1866 NP swabs were tested with carriage rate 39.3% (733 isolates). Resistance was variable; however, it showed highest rates for penicillin (89.3%) and trimethoprimsulfamethoxazole (73.0%). Serotype 19F predominates with 17.6% of all serotypes. Coverage of the future PCV20 was 73.1% compared to the old PCV7 (41.7%). About 493 cases had a previous 1–3 PCV7 injections, among which 256 (51.9%) cases were pneumococcal carriers, distributed as non-PCV vaccine serotypes (31.6%), and with PCV types (68.4%). Conclusions: The potential inclusion of the PCV vaccination in the national immunization program of the country is necessary.

**Keywords:** *Streptococcus pneumoniae*, PCVs, coverage, nasopharyngeal carriage, resistance

### **1. Introduction**

### **1.1 Describing the Jordanian situation**

Jordan is an upper middle-income country with a total population of 10,806,000 inhabitants, where 44.3% of them are under the age of 19 years, and quite youthful with almost 75% under the age of 30. However, risk groups are the children below 15 years of age (34.4%), among which 11.1% are under the age of 5 years, and 3.67% are over 65 years of age. These age groups (children and elderly) are considered to be at risk from pneumococcal infections globally [1–3]. The prevalence of pneumococcal carriage was the only way in Jordan to detect the serotypes rotating in the Jordanian community, which reflects the clones of infections that might take place. The carriage rates in these areas were relatively high compared to other countries in the region. However, different serotypes were found in different areas. All of these isolates have

high resistance rates and are covered to a high percentage with the PCV13 or PCV20. This implies the necessity for a "strategic plan for vaccination in Jordan". *Streptococcus pneumoniae* is considered a leading causative agent of death because of pneumonia globally, especially in the developing countries or in Africa and Asia. In the case and history of Jordan, there is no data available on the pneumococcal infections or serotypes of invasive pneumococcal diseases (IPD), although parts of some publications have described infections with the pneumococci. However, to-date, the PCVs are not available in the National Immunization Program (NIP) of the country, but they are available in the private sector since the year 2000, followed by PCV13 in the year 2010. In Jordan, an average of 400–500 meningitis infections of different causative agents were reported annually, and many infections of otitis media and pneumonia with no identified causative agents, therefore surveillance of the carriage due to *Streptococcus pneumoniae* is essential. Another serious problem for Jordan is the antibiotic consumption, where no reported data are available. Although Jordan is one of the best countries in the region for medical tourism, but there is no numbers stating the antibiotic consumption of the country, where high resistance rates in antibiotics were found [4]. Causes for the high antibiotic resistance in the country are the misuse and abuse of the antibiotics [5, 6]. Furthermore, there are no statistics from the Ministry of Health (MOH) of Jordan regarding the statistics of IPD taking place in hospitals. However, only non-meningococcal meningitis is registered from the statistical department of the MOH, which includes a variety of causative agents including *Streptococcus pneumoniae* (i.e., pneumococcus). This fact is shown in **Figure 1** from the year 1990–2018. By checking these data in the figure, it appears that more than 50% of all cases are from Irbid (North Jordan), 1% from Madaba and 10% from Amman. However, almost 20% of the causative agents of non-meningococcal meningitis are due to the pneumococcus [7]. Another crucial point about Jordan is the absence of national centers working separately on different types of bacteria. These centers in the developed countries and other countries work together with the epidemiological national centers to develop statistics about the rate of invasive diseases caused by infectious agents and their resistance development. Such data are important for setting recommendations to develop new anti-infectious products or to set new treatment strategies. Furthermore, collection

**Figure 1.**

*Number of cases and incidence/100,000 of non-meningococcal meningitis in Jordan.*

of invasive samples isolated at the hospitals is almost impossible, because the patients have consumed antibiotics prior to the microbiological sample testing. Therefore, shifting the surveillance to study the carriage of the pneumococci in children was the solution to find out all the possible serotypes rotating with their resistance data.

### **1.2 Global importance of** *Streptococcus pneumoniae* **(i.e., the pneumococcus)**

*S. pneumoniae*, or the pneumococcus, is a lancet shape, Gram-positive diplococci, bile soluble, mainly optochin sensitive, and encapsulated. The diversity of capsular types is large, with more than 100 serotypes recognized to date based on the composition of the capsular polysaccharide. Many *S. pneumoniae* serotypes are capable of causing invasive diseases, including meningitis, septicemia, bacteremia, and non-invasive diseases like pneumonia, sinusitis and others; however, most of these diseases globally are caused by a small number of common serotypes [8]. The relative contribution of each serotype to the local burden of disease varies globally, with serotypes 1, 5, 23F, 19A, 19F, 6B and 6A more prominent in developing countries. *S. pneumoniae* infections may vary seasonally and large outbreaks exists but rarely found [8–10]. Meningitis due to *S. pneumoniae* occurs most commonly in early ages of children and in patients over 65 years of age, with an estimated incidence rate of 17 cases per 100,000 population in children less than five years of age [11]. This bacterium is widely spread and can also be found in pets [12]. As a comparison, the incidence of non-meningococcal meningitis for Jordan is estimated to be 4.5/100,000 cases in the year 2016 as shown in the figure. The case fatality rate for meningitis due to *S. pneumoniae* in children less than five years of age exceeds 73% in some parts of the world.

An important study done by the GBD 2016 Lower Respiratory Infections Collaborators in 2016 showed that the lower respiratory infections are the leading cause of morbidity and mortality around the world [13]. This study provides an up-to-date analysis of the burden of lower respiratory infections in 195 countries for the past 26 years, and shows how the burden of lower respiratory infection has changed in people of all ages. Their Findings In 2016 indicate that lower respiratory infections caused 652,572 deaths in children younger than 5 years, 1,080,958 deaths in adults older than 70 years, and 2,377,697 deaths globally in people of all ages. In this regard, *Streptococcus pneumoniae* was the leading cause of lower respiratory infection morbidity and mortality globally, contributing to more deaths than all other etiologies combined in 2016 [13].

*S. pneumoniae* was given the name as the forgotten killer in children in 2006 by the WHO in 2006 [14]. Furthermore, according to the WHO, 142 countries have introduced the PCV in the National Immunization Program. Jordan as one of the upper middle-income countries has not included this vaccine to the National Immunization Program (NIP) to-date.

The aim of this chapter is to show results of investigations of continuous surveillance on the carriage of *Streptococcus pneumoniae* from 2008 to 2019 in Jordanian children and to show the need of the inclusion of the PCVs in the NIP of the country.

### **2. Material and methods**

Research studies on the carriage of Streptococcus pneumoniae were approved by the Independent Ethical Committee (IEC) of the Ministry of Health (MOH) of Jordan, followed by approval of the Ministry of Health (MOH) with approval number 8/75/2/2257, and other approvals of the directorates of each day care center (DCC). Informed written consent for the participants and the use of NP swabs was obtained from parents prior to collecting the swabs. Parents were educated on the benefits of future vaccination with the available PCVs. Nasopharyngeal swabs were taken from children attending the governmental Day Care Centers (DCCs) from the governorates of Ajlun (n = 415) [15], Madaba (n = 761) [1, 16], private clinic in Amman (n = 149) [16], Irbid (n = 423) [1], Wadi Alseer (n = 118) [17], with total number of samples 1866. Only one NP-swab was obtained from each child with exception to the research project from Ajlun, where 3 consequent samples were taken at 2 months at the time of the first vaccination, then at 4 months of age at the time of the second vaccination and finally a third sample was taken 2–3 months after the third vaccination with PCV7. NP-samples were collected in the period from 2008–2019. Processing, culturing and identification were done by classical methods [1, 18]. Resistance testing was performed according to the latest CLSI standards using *S. pneumoniae* ATCC 49,619 as a control strain [19]. The Neufeld's Quellung reaction method was used for Serotyping using type and factor sera provided by the Statens Serum Institute (SSI), Copenhagen, Denmark.

### **3. Results and discussion**

Four governorates and the capital of Jordan were tested during the whole period of carriage surveillance in Jordan. The total carriage rate for the whole period and for the whole population tested was 39.3% as presented in **Table 1**. The highest carriage rate was in the governorate of Ajlun with 58.1%, because three samples were obtained from the same child over one year period. Nevertheless, this carriage rate of Ajlun was not significantly different (p > 0.05) from the carriage rate obtained from Wadi Al Seer, even with only one NP-swab obtained from each child. Wadi Al Seer and Ajlun were tested almost at the same period. The most interesting finding of all cities is the findings in the capital of Amman, where only 13.4% of the children involved in the study were carriers and that the coverage of the PCVs was minimal as found in **Table 1**. This was due to the reason that 69 cases from 149 (46.3%) were vaccinated with PCV7. Only 11 cases from the vaccinated children of Amman were carriers, but none of them was carrier of PCV7 serotype. The second highest carriage was shown in Madaba with 37.1% carriage rate, followed by Irbid with carriage rate of 29.6%. Coverage rates of the PCVs were highest (76.0%) for Irbid with PCV20, and this coverage was not significantly different from the PCV20 coverage for Irbid city (p < 0.05). To-date, there are at least 220 publications all over the world investigating carriage or nasopharyngeal carriers of Streptococcus pneumoniae. Our findings are comparable with other studies all over the world; in the region as an example, a study done in Palestine in 2013 has found carriage rates in 11 cities of Palestine to be from 34.1% in Ramallah up to 66.7% in Tubas [20]. In the kingdom of Saudi Arabia, carriage rate was found in 2014 to be 6% [21]. Another study done in 11 countries of Asia and the Middle East on 4963 children below 5 years of age found nasal carriage rate of 22.3% of antibiotic-resistant pneumococci isolates [22]. In Israel, carriage rates tested on ages between 2 and 24 months was shown to increase with age from 2 months with 26% carriage rate to 62% at age of 24 months [23]. In a recent study about carriage of the pneumococcus in Indonesia showed high carriage rate of 73% in school children with acute otitis media (AOM) [24]. Dominant serotypes of the school children were 23A (11 %), 6A/6B (10 %), 3 (8 %), 14 (7 %), 6C/6D (7 %), 11A/11D (6 %), 15B/15C

*Pneumococcal Carriage in Jordanian Children and the Importance of Vaccination DOI: http://dx.doi.org/10.5772/intechopen.104999*


### **Table 1.**

*Carriage rate of* S. pneumoniae *in 5 cities of Jordan with the coverage rate of PCVs including the future PCV20.*

(4 %) and 35 B (4 %). Coverage of the PCV13 in the Indonesian study was 41%. Other study in south Italy on healthy children aged 1–7 years attending day-care centers and schools showed nasopharyngeal colonization rate of Streptococcus pneumoniae to be 18.29%. PCV13 serotypes of this study covered 60.34% of the isolates with serotypes 19A, 19F, 14, 6B, or 23F; and that 8.62% of the strains were intermediately resistant to penicillin, 65.5% were erythromycin-resistant, and 17.2% were resistant to Co-trimoxazole [25]. To date, there is no data describing the invasive Streptococcus pneumoniae infections in Jordan, but this bacterium was identified as the causative agent in 30% of meningitis cases in Yemen, 16% in the UAE, 19–21% in Kuwait, 13% in Qatar, 23–31% in Saudi Arabia, and 21–30% in Egypt [26].

Resistance rates to antibiotics are increasing worldwide. The main reasons for this global threat of resistance are the misuse and abuse of the antibiotics [27]. Streptococcus pneumoniae is one of the major pathogens of community-acquired respiratory tract infections, where Alexander Project in 1997 for resistance showed the variation of antibiotic resistance in Europe [28]. In our studied 5 regions in Jordan as found in **Table 2**, resistance rates to penicillin varied from 80% to 95.4%, and for erythromycin from 55% to 73.6%, for clindamycin from 20%–44.4%, and for Co-trimoxazole (SXT) from 30%–78.5%. Extreme differences in antibiotic resistance were observed in this surveillance in the last 13 years. This resistance is increasing in Europe and in the United states [29, 30]. More than 80% of the resistance is covered by the new PCV20 [27].

In **Table 3**, an uneven distribution of the serotypes in each city was found. Certain clones of the serotypes were found only in one city or two, but not in others. As an example, Serotype 5 was only found in Madaba. This serotype 5 is prevalent in many countries [31–35]. Serotype 4 was only found in Ajlun, but it is also prevalent in many countries as causative agent of an outbreak in a home for aged people [36, 37]. Serotype 13 was also only found in Ajlun, which was found as multidrug resistant in Russia [38]. Serotypes 19A and 19F were mainly found in Ajlun and Madaba.

**Table 4** gives an insight about the differences and comparisons of the Jordanian carriage rate, resistance and coverage of PCVs with other countries worldwide. In literature, pneumococcal nasopharyngeal carriage was studied in different directions,


*Abbreviations: PEN (Penicillin), ERY (Erythromycin), CLI (Clindamycin), TET (Tetracycline), SXT (Sulfamethoxazole-Trimethoprim), CHA (Chloramphenicol), R (Resistance).*

### **Table 2.**

*Resistance rate of S. pneumoniae in 5 cities of Jordan.*



### *Pneumococcal Carriage in Jordanian Children and the Importance of Vaccination DOI: http://dx.doi.org/10.5772/intechopen.104999*

### **Table 3.**

*Serotypes detected in the surveillance studies with numbers isolated in each city.*

either to find out the carriage rate, to check the impact of the PCVs on colonization, or to check the rate of carriage before and after vaccination strategies, or the carriage rates after certain infection, and many other issues related. The data available in **Table 4** are from the region, from Africa, from Europe, and Latin America. As an example, in Palestine 11 cities were tested for pneumococcal carriage with rates ranging from 34.1% in Ramallah to 77.7% in Salfeet [20].


*Abbreviations: nd = not defined; PEN (Penicillin), ERY (Erythromycin), CLI (Clindamycin), SXT (Sulfamethoxazole-Trimethoprim), R (Resistance), PCV7 (7-Valent Pneumococcal Conjugate Vaccine), PCV13 (13-valent Pneumococcal Conjugate Vaccine).*

### **Table 4.**

*Comparison of carriage rate, resistance and coverage of PCV7 and PCV13 in other locations (regional and international).*

### **4. Conclusions**

The prevalence of pneumococcal carriage was the only way in Jordan to detect the serotypes rotating in the Jordanian community, which reflects the clones of infections that might take place. The carriage rates in these areas were relatively high compared to other countries in the region. However, different serotypes were found in different areas. All of these isolates have high resistance rates and are covered to a high percentage with the PCV13 or PCV20. This implies the necessity for a strategic plan for vaccination in Jordan.

### **Acknowledgements**

The author would like to thank the supporting institutions for this prevalence including the German Jordanian University, Wyeth (Now Pfizer), and Pfizer. Special thanks for the participating children with their parents, and for the MOH for the approvals to make this study successful.

### **Conflict of interest**

The author declares no conflict of interest.

*Pneumococcal Carriage in Jordanian Children and the Importance of Vaccination DOI: http://dx.doi.org/10.5772/intechopen.104999*

## **Author details**

Adnan Al-Lahham Department of Biomedical Engineering, School of Applied Medical Sciences, German Jordanian University, Amman, Jordan

\*Address all correspondence to: adnan.lahham@gju.edu.jo

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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### **Chapter 2**

## Streptococcal Skin and Skin-Structure Infections

*Alwyn Rapose* 

### **Abstract**

Infections attributable to *Streptococcus* are protean. These range from mild skin and soft tissue infections to life-threatening conditions like meningitis, endocarditis and toxic shock syndrome. In addition, streptococcal infection can be associated with noninfectious sequelae like rheumatic fever and post-streptococcal glomerulonephritis. There is a wide range of *Streptococcus* s*pp.* causing human infections and different classifications of these organisms have been described, the most quoted being the Lancefield classification based on cell-wall antigens. *Streptococci* can be studied based on their species: *S. pyogenes, S. pneumoniae, S. anginosus* etc. or by the Lancefield classification group A, B, C, D etc. or by the clinical syndromes associated with these bacteria. This chapter will describe clinical syndromes associated with streptococcal skin and soft tissue infections ranging from mild: cellulitis and lymphangitis which can be treated in the out-patient setting, to more aggressive manifestations that require hospitalization (sepsis and toxic shock syndrome) and even surgery (necrotizing fasciitis, myositis and gangrene), It will also provide clues to clinical diagnosis as well as suggest recommendations for optimized management of these conditions.

**Keywords:** *Streptococcus*, Skin and Skin-Structure Infections (SSTI), Necrotizing Fasciitis (NF), Toxic Shock syndrome (TSS)

### **1. Introduction**

Streptococcal skin and skin-structure infection (SSTI) is associated with significant morbidity all over the world and the impact is felt predominantly in resource-poor areas with inadequate personal hygiene and over-crowded living conditions. While exact numbers are difficult to estimate on account of the lack of systematic reporting, a literature search conducted by Sims and colleagues [1] reported an estimated prevalence of 18 million cases, with an incidence rate of around 1.78 million cases per year of invasive *S. pyogenes* (*S. pyogenes*) infection in 2005, and more than 140 million cases of impetigo globally each year as reported in the 2010 Global Burden of Disease study. Rising numbers of cases of infectious diseases of the skin is also seen in Western nations, probably driven by drug abuse and homelessness [2, 3]. Increased cases result in increased costs from emergency room visits and hospital care, hence outpatient parenteral antibiotic therapy (OPAT) has proven to be a valuable alternative to hospitalization [4], and when patients are chosen appropriately, OPAT results

in very significant cost-savings without compromising outcomes [5]. Advances in pharmaceutical research has contributed to development of longer acting antibiotics that can be dosed once a day and in some cases once a week. There is ongoing research to determine the optimum duration of antibiotic therapy for these conditions.

Skin infections have been variously classified based on different criteria like depth of infection or the bacterial agents causing the infections or as primary infection in contrast to infection of pre-existing wounds or skin conditions. A very practical classification of patients hospitalized with skin infections (cellulitis versus abscess versus skin infections with additional complicating factors) has been described by Jenkins et al. [6]. The authors found in their study that cutaneous abscesses were primarily caused by *Staphylococcus aureus* and less often by the *Streptococcus spp*, in contrast with cellulitis which was caused primarily by *β-hemolytic streptococci* and less commonly by *Staphylococcus spp*. This differentiation is especially helpful when choosing the appropriate narrow spectrum antibiotic therapy for individual patients with these diagnoses. In contrast, "skin infections with additional complications" require more broad antibiotic coverage on account of mixed bacterial infection or infection with unusual organisms.

The clinical features of common streptococcal SSTIs and the antibiotics used in the management of these conditions will be further elaborated in this chapter.

### **2. Streptococcal pyoderma**

Superficial skin infection has been described as **impetigo or pyoderma**. This is in contrast to more invasive diseases cellulitis and erysipelas. Impetigo (and the less precise term pyoderma) refers to superficial infection that begins in the form of a papule that progresses to a vesicle and pustule, ultimately forming crusted lesions (**Figure 1**). They resolve with hyper or hypopigmentation. These infections are caused either by *Staphylococcus* or *Streptococcus*, and one cannot clinically differentiate between the two causative organisms. They occur as a complication of underlying skin diseases

**Figure 1.** *Impetigo secondary to infected contact dermatitis.*

like scabies [1] or contact dermatitis. The streptococci associated with these infections are most often group A (*S. pyogenes*). However other serotypes can also be isolated on cultures from these infections. Although considered benign, these infections could progress to more locally invasive cutaneous diseases (see below) and are associated with post-streptococcal complications like glomerulonephritis and acute rheumatic fever in resource limited populations (as reviewed in other chapters of this textbook).

### **3. Treatment of impetigo**

Antiseptic soaks and antibacterial creams are the mainstay of therapy for impetigo. A wide variety of topical antimicrobial agents are available including silver-based products, iodides, hydrogen peroxide, zinc, chlorhexidine and potassium permanganate. There is very little data in the literature comparing benefits of one product versus the other [7, 8]. Antibacterial creams: mupirocin, Na-fusidate and bacitracin are also available for use in localized superficial skin infections [9]. Drawbacks of topical therapy include development of resistance, risk of irritant or allergic dermatitis (sensitization), and if used in high concentrations, these could cause burn injuries.

### **4. Invasive streptococcal infections: erysipelas and cellulitis**

When skin infection results in erythematous (red in color), edematous (raised above the surface) and well demarcated (sharp boundary between involved and uninvolved skin) areas of involvement, it is referred to as **Erysipelas** (**Figure 2**). Erysipelas is characterized by marked edema in the skin, sometimes severe enough to cause skin blisters. While it could be seen at any age, it is more common in the very young and in older individuals. Classically described as occurring on the face, it can be seen in other parts of the body including the trunk and extremities. It is commonly associated with systemic symptoms like fever, chills and body ache, and blood cultures could be positive. Erysipelas is most commonly caused by *S. pyogenes* but could also be caused by other streptococci and less commonly by *S. aureus* [10]. Superficial skin culture should not be obtained, and causative organism can be established if blood cultures return positive. The diagnosis is usually clinical and it responds well to antibiotic therapy. However, in patients with uncontrolled diabetes or other immunocompromising conditions, the infection can spread deeper and the patient could develop sepsis and shock. Recurrences—especially on the extremities—are common in patients with underlying chronic lymphedema [11].

When streptococcal infection involves the skin as well as the subcutaneous tissue, it results in ill-defined areas of erythema that are rapidly spreading and this is called **Cellulitis.** The skin appears red with irregular spreading borders (**Figure 3**). The entry point for the infection is a break in the skin like a surgical wound or other skin trauma, underlying dermatoses like eczema and psoriasis or a fungal infection of the intertriginous areas like web spaces of the toes: "athlete's foot" (**Figure 4**). The area of the skin involved is tender to touch, and cellulitis is associated with systemic symptoms like fever, chills and body ache. Sometimes infection spreads along a lymphatic channel rather than the entire skin and this is called **streptococcal lymphangitis**

**Figure 2.** *Erysipelas with sharply-defined edematous red skin lesions.*

**Figure 3.** *Cellulitis with irregular and ill-defined borders.*

*Streptococcal Skin and Skin-Structure Infections DOI: http://dx.doi.org/10.5772/intechopen.102894*

**Figure 4.** *Fungal infection in the webspace of the toes, also called "athlete's foot."*

**Figure 5.** *Lymphangitic streaking of the upper extremity.*

(**Figures 5** and **6**). Blood cultures are positive in around 10% of cases [12, 13] which include patients with more severe disease, older patients, patients with underlying liver cirrhosis [12] and diabetes [13]. The yield of blood cultures is higher if cultures are obtained at the time when the patient is experiencing fever and chills. Cellulitis responds very quickly to appropriate antibiotic therapy. As with erysipelas, recurrences are common in those with underlying risk factors, and left untreated, the infection can spread to deeper tissues and result in sepsis and shock.

**Figure 6.** *Lymphangitic streaking (double) of the lower extremity.*

In some patients there is an overlap between erysipelas and cellulitis and the clinical differences are not so clear. Importantly, management of both conditions is similar.

### **5. Treatment of cellulitis and erysipelas**

Mild localized infections are treated with oral antibiotics, while more extensive infections or infections with systemic symptoms are treated with parenteral (intravenous) antibiotic therapy [14]. Patients with signs of sepsis: fever or hypothermia, tachycardia and hypotension, and patients with underlying conditions like uncontrolled diabetes, liver cirrhosis, severe peripheral vascular disease or severe lymphedema and patients with immunocompromising conditions like HIV, or patients on chemotherapy should be admitted to the hospital for antibiotics as well as aggressive management of the underlying conditions. Penicillins and β-lactams are considered the antibiotics of choice for treatment of streptococcal cellulitis. The addition of a second antibiotic like trimethoprim/sulfamethoxazole (TMP/SMX) or clindamycin has been shown to provide no additional benefit [6, 15–18]. Penicillins are available in the form of oral as well as intravenous preparations (**Table 1**). Extended spectrum penicillins: dicloxacillin, amoxicillin, ampicillin, oxacillin and nafcillin can be used if there is associated methicillin susceptible *S. aureus* (MSSA) infection. Cephalosporins are among the most commonly used β-lactams for the treatment of cellulitis. Different preparations are available both in the oral as well as the intravenous forms (**Table 2**). Physician preference and dosing convenience often define the choice of the antibiotic prescribed. Ceftaroline—one of the newest cephalosporins has excellent skin penetration and has activity against methicillin resistant *S. aureus* (MRSA) [19]. Patients who have an allergy to penicillin will require alternate agents. It should be noted here that there is increasing evidence in the literature

*Streptococcal Skin and Skin-Structure Infections DOI: http://dx.doi.org/10.5772/intechopen.102894*


### **Table 1.**

*Penicilins.*


*Effective also against MSSA. Ceftaroline is also effective against MRSA. All (except ceftriaxone) require dose adjustment in patients with kidney disease.*

### **Table 2.**

*β-Lactam antibiotics used for streptococcal skin infections.*

indicating patients who claim penicillin allergy may not have a true allergy and are able to tolerate β-lactams [20, 21]. TMP-SMX [22], doxycycline, linezolid, clindamycin and fluoroquinolones (**Table 3**) all have excellent skin penetration and may be used as alternate oral agents in patients with allergies to penicillin and β-lactams. Severe cellulitis in patients who have a true allergy to both penicillin and β-lactams is


### **Table 3.**

*Non β-lactam antibiotics used for streptococcal skin infections.*

treated with intravenous (IV) vancomycin. IV vancomycin requires close monitoring of levels to achieve optimized benefits while avoiding nephrotoxicity [23, 24], and often therapeutic levels are difficult to achieve in obese individuals [25]. Other alternatives to β-lactams are listed in **Table 3**. Daptomycin is a lipopeptide antibiotic that has excellent skin penetration [26, 27]. It has the advantage of once- a- day

*Streptococcal Skin and Skin-Structure Infections DOI: http://dx.doi.org/10.5772/intechopen.102894*


### **Table 4.**

*Newer antibiotics approved for treatment of skin infections.*

dosing, making daptomycin a convenient agent for outpatient antibiotic therapy (OPAT). Other antibiotics with excellent skin penetration include linezolid [28, 29] and tigecycline [27, 30]. Both these antibiotics are dosed twice a day and hence less convenient for use as OPAT. Tigecycline is only available in the parenteral form and is recommended for patients hospitalized with severe infections. Linezolid is available in both parenteral as well as oral formulations. IV linezolid is used when a patient is hospitalized with severe cellulitis, and treatment can be completed with oral formulation once the patient improves. There are a number of newer agents approved for the management of SSTIs including long acting lipo-glycopeptide agents oritavancin and dalbavancin, extended-spectrum fluoroquinolone delafloxacin, and the new tetracycline derivative omadacycline [28, 29]. Important comments regarding the advantages as well as the potential side effects of these antibiotics are listed in **Tables 3** and **4**.

### **6. Streptococcal infection of deeper tissues**

When streptococcal infection spreads deep beyond the subcutaneous tissue, it can result in extensive necrosis (gangrene) of the overlying skin and inflammation and necrosis of underlying fascia **(Streptococcal Necrotizing Fasciitis)** and even muscle (**Streptococcal Myositis).** These infections are considered surgical emergencies.

**Necrotizing Fasciitis (NF)** is characterized by rapidly (within hours) spreading infection of the skin, subcutaneous tissue and fascia with associated symptoms of fever, prostration, hypotension and shock. It carries a high mortality [31]. It could start as a benign appearing skin wound that rapidly spreads both on the surface as well as into deeper tissues and the entire limb or body-part could be involved in a matter of a few hours. Skin changes include a rapid progression from mild erythema to a dusky appearance followed by ecchymosis, purpura, blisters and tissue

**Figure 7.** *Necrotizing fasciitis of the lower extremity.*

necrosis—resulting in open wounds often discharging purulent or hemorrhagic fluid (**Figures 7** and **8**). "Pain out of proportion to physical findings" is a characteristic sign of NF. In other words, there may be pain when palpating areas beyond the visible area of redness or in other cases even gentle palpation of involved area elicits excruciating pain. Some authorities divide NF into type I and type II. Type I is characterized by poly-microbial infection (involving both aerobic as well as anaerobic bacteria), while type II is characterized by mono-microbial infection of which

**Figure 9.** *Necrotic areas with skip lesions on leg of patient who is abusing self with injection drugs.*

*group A streptococcus* is the most commonly implicated organism [32]. Mortality was found to be lower in *group A streptococcus*—associated NF (type II) compared to type I: 10% versus 20% in one large study [31]. NF may also be seen in persons who inject drugs. In these cases, multiple skip lesions are seen (**Figure 9**) and infection is usually poly-microbial. In addition to the skin lesions, the patient usually has systemic symptoms of sepsis including high fever, tachycardia, hypotension and may progress to have multi-organ failure. Streptococcal pyrogenic exotoxins

**Figure 10.** *Necrosis of skin, soft tissue and muscle with exposure of tendon.*

(Spe) A, B and C are responsible for causing stimulation of a severe inflammatory cascade resulting in injury not only at the area of infection (local necrosis) but also to distant sites (lungs, kidneys, liver, central nervous system). Blood cultures are universally positive, and imaging of involved body-part (CT scan or MRI) will demonstrate edema and/or gas in the soft tissue planes and other changes consistent with this diagnosis [33].

When infection spreads beyond the fascial planes into the underlying muscles it is called myositis. **Streptococcal myositis** is often a complication of the overlying skin infection. Sometimes a deep tissue hematoma caused by blunt trauma [34] could get inoculated by the organism in a patient with bacteremia. This too is an emergency and requires rapid surgical intervention to relieve the pressure created by the severe inflammation in the muscle planes (**Figure 10**). Patients will also have systemic symptoms and signs of sepsis as seen in NF. There is often overlap of these two conditions in many patients.

### **7. Management of necrotizing fasciitis and streptococcal myositis**

Patients need admission to the hospital often to the intensive care unit. They require management by a team of experts involving medical, surgical, infectious diseases and critical care specialties. They often present with septic shock and require pressors like epinephrine, norepinephrine and vasopressin to maintain adequate blood pressure in order to perfuse critical organs. Patients require broad spectrum antibiotic coverage, aggressive fluid resuscitation, as well as emergent aggressive debridement of the infected areas. Surgical removal of infected/ necrotic tissue is essential in order to reduce bacterial burden and hence remove the source of toxins. Often patients require a second or even third visit to the operating room because of extensive tissue necrosis not amenable to removal in a single operation [14]. Operative tissue is sent for microbiology (cultures) to help determine the infectious agent and obtain an antibiotic sensitivity profile to help guide appropriate antibiotic choices. While awaiting the results of cultures, the antibiotics chosen should cover Gram-positive bacteria including *Streptococcus* and *S. aureus*, Gram-negative bacteria including drug-resistant bacteria like *Pseudomonas*, as well as anaerobic bacteria. Different combinations of antibiotics from **Tables 1–3** can be used. IV vancomycin (or IV daptomycin) plus cefepime (or fluoroquinolone) plus metronidazole, or IV vancomycin (or IV daptomycin) plus meropenem (or imipenem), or IV daptomycin plus piperacillin- tazobactam are some potential options for empiric therapy. Linezolid could be used in place of vancomycin and daptomycin in the above combinations. Vancomycin, daptomycin and linezolid provide Gram-positive coverage, cefepime and fluoroquinolones provide Gram-negative coverage. While metronidazole provides only anaerobic coverage, imipenem, meropenem and piperacillin-tazobactam provide Gramnegative as well as anaerobic coverage. Clindamycin is added in the initial critical stages of the infection on account of its antitoxin effect [14, 33]. If linezolid is used, additional clindamycin is not required because linezolid itself also has an antitoxin effect [33]. When culture results become available, antibiotics should be deescalated to target the organisms identified. Intravenous immunoglobulins (IVIG) is used at some centers as part of management of NF, however large studies have not shown a statistically significant benefit compared to those patients who did not receive IVIG [14, 33].

## **8. Toxic shock syndrome (TSS)**

TSS is associated with a dramatic widespread skin rash and severe systemic symptoms. This condition is not due to direct inoculation of the skin with *Streptococcus,* but rather it is secondary to exotoxin [35] released by *Streptococcus* infection at a

**Figure 11.** *Clinical photograph of sheet of erythema seen in acute phase of toxic shock syndrome.*

**Figure 12.** *Toxic shock syndrome with desquamation in the recovery phase.*

distant site. Originally described in children with *S. aureus* infection, TSS is seen with *Streptococcus* and Clostridial infection in children as well as adults [36]. Patients present with widespread rash associated with fever, hypotension and multi-organ system involvement as a result of circulating streptococcal exotoxins A, B and C. The rash is described as sheets of erythema (**Figure 11**) involving the face, trunk as well as extremities, and it subsides with characteristic desquamation (**Figure 12**) when the patient recovers. A detailed examination is important to determine the source of infection: either retained foreign body like menstrual tampon or surgical sponge/ dressing material, necrotizing infection in a deep space, post-operative wound infection or peritonitis. Rarely, streptococcal pharyngitis is the primary event. The circulating toxins (super-antigens) are responsible for injury to internal organs—lungs, kidneys, liver [35] and the disease can be fatal in 40 to 60% cases of streptococcal TSS especially when there is delay in the diagnosis and hence delayed initiation of appropriate antibiotics. Blood cultures may be positive, as are cultures from an identified focus of infection.

## **9. Management of TSS**

As with other severe streptococcal infection, patients with TSS require admission to the hospital. If they are hypotensive or experience multi-organ failure, management is in the intensive care unit where patients are treated with aggressive fluid resuscitation, broad antibiotic therapy (choices similar to that as described for management of necrotizing fasciitis) and pressor support. Surgery may be required if a deep focus of infection is identified. Rarely patients do not respond to standard therapy and may require intravenous immunoglobulins (IVIG) [36].

## **10. Discussion on general principles of systemic antibiotic therapy**

Streptococcal SSTIs respond very well to antibiotic therapy. A wide range of antibiotics with excellent skin penetration are now available as noted in **Tables 1**–**4**. All antibiotics carry the potential for side effects like allergic reactions and gastrointestinal disturbances. There are some side effects that are unique to certain antibiotics and patients need to be monitored for these toxicities. For example: β-lactam antibiotics have the potential for hepatotoxicity, vancomycin is associated with nephrotoxicity, daptomycin can cause rhabdomyolysis and eosinophilic pneumonitis and clindamycin is one of the most common antibiotics associated with *Clostridioides difficile* (*C. Diff*) infection. In addition, inappropriate use of broad-spectrum antibiotics—and even prolonged use of narrow spectrum antibiotics—can result in collateral damage (destruction of protective normal bacterial flora of the skin and the gastrointestinal tract) and cause antibiotic-associated diarrhea and *C. Diff* infection [37, 38]. Indiscriminate use of broad-spectrum antibiotics has also contributed to the development of multidrug-resistant pathogens [39]. Therefore, judicious use of antibiotics is very important to reduce the risk of these complications. Streptococcal infections should be treated with narrow spectrum antibiotics like penicillin and β-lactams. When streptococcal cellulitis or erysipelas does not seem to be responding adequately within the first 2–3 days of β-lactam therapy, antibiotics with additional coverage against MRSA will need to be used.

## **11. Specific points regarding treatment of SSTIs**


### **12. Conclusions**

Streptococcal skin infections cause significant morbidity all over the world, and severe infections like necrotizing fasciitis and toxic shock syndrome can be fatal. There is a wide spectrum of manifestations of skin infections ranging from mild superficial disease to deep necrotic and life-threatening infections. Skin infection is one of the most common reasons for prescriptions of antibiotics in the community as well as in hospitalized patients. Some of the most commonly used antibiotics have excellent skin penetration and hence the armamentarium to treat skin infections is quite large. Over the last few years there have been multiple new antibiotics approved for the treatment of skin infections and these should be reserved for treatment of severe infections not responding to the common antibiotics and for infections with multi-drug-resistant organisms. A thorough understanding of the different types of skin infections, as well as a detailed knowledge of the different antibiotics are essential for the early diagnosis and selection of the most appropriate antibiotic for the management of simple as well as complex skin infections.

## **Author details**

Alwyn Rapose University of Massachusetts Medical School, Reliant Medical Group, Worcester, Massachusetts, USA

\*Address all correspondence to: Alwyn.rapose@reliantmedicalgroup.org

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Streptococcal Skin and Skin-Structure Infections DOI: http://dx.doi.org/10.5772/intechopen.102894*

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Section 2
