SEM image of S. aureus

Staphylococcal Infections (adapted from Microbiology Profile Assignment) and Scenario: A Diver Gets a Staph Infection

Staphylococcus aureus is a Gram-positive bacterium that is cocci-shaped, despite the genus belonging to class Bacilli, which are typically rod-shaped bacteria. These bacteria tend to arrange in clusters – the name Staphylococcus comes from the Greek word meaning “bunches of grapes”. This can be observed using a scanning electron microscope (see Figure 1). As a facultative anaerobe, Staphylococcus species grow better in the presence of oxygen but can also grow without it. These bacteria are halophilic, salt-loving organisms that thrive in saline environments such as on the surface of human skin (Parker et al., 2016).

SEM image of S. aureus
Figure 1: This color-enhanced Scanning Electron Microscope image of Staphylococcus aureus illustrates the clustering arrangement of these bacteria. Reprinted from Centers for Disease Control and Prevention. (2016). Retrieved from https://www.cdc.gov/mrsa/community/photos/index.html

Staphylococcus species are commonly found in the normal microbiota of the skin and in the nasal passages. They exist in commensalism with a healthy human host; that is, the human is not affected while the bacteria benefit. However, Staphylococcus aureus is an opportunistic pathogen. It may harm the host if it enters a break in the physical barriers of the innate immune system, such as the skin and mucous membranes. Infections occur when there is a breach in one of these barriers, such as in an open wound or during the use of invasive medical devices. S. aureus can cause local skin infections or travel to other body systems, causing systemic infections (Parker et al., 2016).

The term virulence can be defined as “the degree to which an organism can cause disease” (Parker et al., 2016). The virulence factors of Staphylococcus aureus include exoproteins such as exoenzymes and exotoxins, endotoxins, and antigens. These factors enable it to adhere to the surfaces of cells, evade the immune system, or harm the host (Thomer, Schneewind, & Missiakas, 2016).

Many strains of S. aureus secrete a variety of exoenzymes. These extracellular enzymes have a range of targets and they help support the pathogen’s growth and immune system defense. They also provide the means for the invasion of host cells and deeper tissues. For example, the exoenzyme coagulase exploits the body’s blood clotting mechanism. Coagulase triggers the production of fibrin, a protein normally produced in response to a damaged blood vessel. S. aureus becomes coated in the host’s own fibrin and is shielded from the immune system cells in the blood. The bacterium can then secrete kinases to digest the fibrin clots and allow it to spread to other areas. S. aureus can produce another enzyme called hyaluronidase, which degrades the hyaluronic acid that cements cells together. This also allows the pathogen to travel through tissues and disperse throughout the body (Parker et al., 2016).

Exotoxins are damaging proteins secreted outside of the bacterial cell. One type of exotoxin produced by Staphylococcus aureus is a group called membrane-disrupting toxins. These toxins destroy a host cell such as a phagocyte by disrupting the plasma membrane. Phagocytes are a type of cell in the body that ingests and sometimes digests foreign bodies. Exotoxins such as leukocidins and hemolysins enable bacteria to escape from within these cells once ingested by forming pores in the cell membrane, leading to the leakage of cellular contents and cell lysis (Parker et al., 2016).

When physical barriers fail, the body may rely on chemical defenses such as cytokines. Cytokines are soluble proteins that can be released during an innate immune response and contribute to fever and inflammation. Increasing the body temperature with a fever stimulates white blood cells to attack pathogens. While a low-level fever may aid in recovery from an illness, Staphylococcus aureus has the ability to cause an excessive immune response using cytokines and superantigens, another class of exotoxins. This response has the propensity to induce toxic shock syndrome (Parker et al., 2016).

Humans possess both innate and adaptive immunity. Innate immunity is nonspecific, responding to a wide range of pathogens instead of targeting specific pathogens. Innate immunity provides the first and second lines of defense. The first line of defense includes the physical and chemical defenses previously discussed. The second line of defense is cellular defense, comprised of white blood cells, also called leukocytes (Parker et al., 2016). In humans, neutrophils are our primary cellular defense (Thomer, Schneewind, & Missiakas, 2016). Neutrophils are highly motile and phagocytic leukocytes that are very active in the initial stages of infection (Parker et al., 2016).

Another type of white blood cell is the monocyte, which differentiates into macrophages and dendritic cells, both highly phagocytic. Dendritic cells are one of the first cells that invading bacteria will encounter. These are called antigen-presenting cells (APCs). An antigen is something that is not ordinarily found in the body. Once the dendritic cell is activated, it will process the pathogen and present the antigens on its surface, priming the specific adaptive immune response. The body responds to the antigens by making specific antibodies for that antigen. Antibodies are recognized by phagocytic cells, which will then attack the invading pathogen. Staphylococcus aureus uses a virulence mechanism called antigenic variation, changing its appearance so that the host’s immune system no longer recognizes it. It does this by altering its surface protein antigens. Antibody generation takes seven to fourteen days. During this time, S. aureus can change its antigenic properties so the newly made antibodies will not bind to the surface of the pathogen. When Staphylococcus aureus evades the humoral immune response, which is responsible for attacking extracellular pathogens, it is able to enter a host cell via endocytosis. S. aureus relies on surface proteins called invasins in order to adhere to the host cell and establish an infection while capitalizing on the cell’s nutrients (Parker et al., 2016).

Staphylococcus aureus has evolved to find a way around the innate immune system. The immune response induced by this pathogen is a vigorous inflammatory response. Infection symptoms can include fever, hypotension, persistent skin rash, and the involvement of several organ systems. S. aureus is responsible for many bacterial infections of human skin and soft tissue, but can also cause food poisoning, toxic shock syndrome, and serious system infections that can lead to life-threatening conditions (Thomer, Schneewind, & Missiakas, 2016). It is an opportunistic pathogen that can exist as a free-swimming cell or as part of a biofilm. S. aureus can cause different types of infections depending on its lifestyle. Independent cells typically cause acute infections while biofilm communities can promote chronic infections (García-Betancur, et al., 2017).

Staphylococcus aureus is a contagious pathogen that is easily spread by physical contact of the skin. Because S. aureus is often found in the nasal cavities of asymptomatic individuals, it can be spread from the nose to the hands, other surfaces, or to other individuals. Purulent skin infections, or those having pus, are commonly caused by S. aureus. Pus forms because many strains of this bacterium produce leukocidins, which kill leukocytes. One example of a skin infection caused by Staphylococcus aureus is a superficial infection called impetigo. Impetigo is highly contagious and is characterized by the presence of blisters, especially around the mouth, and itchy red bumps or pimples. If left untreated, this condition can cause deep abscesses and boils, requiring a topical antibiotic for treatment. If fever and chills manifest, boils may require draining as well as antibiotic therapy. Another example is Staphylococcal scalded skin syndrome, common in young children and infants, which causes the skin to redden and then peel severely. Treatment requires intravenous antibiotics (Parker et al., 2016).

Staphylococcus aureus can cause a local infection in the skin and then spread. In rare instances, the thin layer of connective tissue between the skin and muscle, called the fascia, can become infected and lead to necrotizing fasciitis, also called flesh-eating bacteria syndrome. Infection can spread quickly, and large areas of skin will detach and die. If left untreated, this condition can be fatal. Treatment requires the surgical removal of infected tissue or amputation, in conjunction with intravenous antibiotic therapy (Parker et al., 2016).

Staphylococcus aureus can readily infect body systems beyond the skin. Toxic shock syndrome (TSS) may develop from the colonization of S. aureus in the vagina, particularly in women who leave tampons or other devices in the vagina for longer than is recommended. Staphylococcal TSS induces vomiting, diarrhea, myalgia, high fever, a rapid drop in blood pressure, and a rash. It can affect several organ systems at a time. Medical attention is required and includes antibiotic therapy (Parker et al., 2016).

If it comes in contact with the surface of the eye, Staphylococcus aureus can cause bacterial conjunctivitis, or pink eye. This condition is highly contagious, can affect one or both eyes, and usually requires medical attention to control symptoms such as pain, blurred vision, and light sensitivity. Bacterial infections of the eyes and skin are particularly susceptible to the formation of biofilms. Biofilms are of particular concern regarding S. aureus because of its prevalence in chronic surface wounds and may be problematic in the diagnosis, treatment, and healing process of the infection (Parker et al., 2016).

Staphylococcus aureus can also affect the joints and is the most common cause of acute septic arthritis. Septic arthritis, or infectious arthritis, causes pain in the joints and swelling that limits range of motion. It can be acute or chronic. S. aureus is also the most common causative agent of osteomyelitis, or inflammation of bone tissue. These infections can be acute or chronic and are often caused by trauma or prosthetic surgical procedures (Parker et al., 2016).

If Staphylococcus aureus is transmitted to food items, it can cause staphylococcal food poisoning. Infection is usually associated with undercooked or raw foods and dairy products. Gastric juice produced by glands in the stomach is a highly acidic mixture of enzymes, mucus, and hydrochloric acid. This chemical barrier is one of the first lines of defense in the innate immune system and is usually enough to kill microbes and deactivate toxins. However, S. aureus produces a toxin that targets the digestive system and can quickly lead to symptoms such as nausea, diarrhea, cramps, and vomiting. While signs and symptoms may become more severe, they typically resolve within 48 hours (Parker et al., 2016).

In the tissue surrounding the heart, heart valves, and heart muscles, a Staphylococcus aureus infection can lead to pericarditis or endocarditis. Pericarditis symptoms include chest pain, breathing difficulty, and a dry cough. Medical attention is usually not required. Endocarditis, or inflammation of the cardiac valves and muscles, is more serious and can be fatal if left untreated. Wounds and catheterization are common portals of entry. Infected individuals will present with a fever. Treatment includes intravenous antibiotics. It is important to note that patients with prosthetic valves are susceptible to biofilms that can form on these devices, and specific antibiotics, such as Rifampin, are required (Parker et al., 2016).

Staphylococcus aureus pneumonia is one of the most prevalent staphylococcal infections in the United States, largely due to increasing numbers of the elderly population requiring intensive care therapy. S. aureus is a leading cause of ventilator-associated pneumonia, and was once primarily associated with the health care environment but has since been identified as a prominent cause of community-acquired pneumonia, affecting otherwise healthy individuals. While S. aureus resides in the normal upper respiratory flora of up to 30% of individuals, lower respiratory infections are less common but are associated with a high fatality rate. Individuals with pulmonary infections of this pathogen present with pleural effusions (a buildup of fluid in the lungs and chest), empyema (a gathering of pus in the pleural space), abscesses, and cysts. Treatment currently relies on the use of antibiotics; however, this method is met with a high degree of difficulty due to this pathogen’s tendency toward antimicrobial resistance (Cowley, Ritchie, Hampton, Kollef, & Micek, 2019), as will be further discussed later.

Currently, there is no vaccine to prevent the infection of Staphylococcus aureus in humans (Montgomery, Daniels, Alegre, Chong, & Dam, 2014). The first step to prevent infection transmission is proper hygiene (Parker et al., 2016). Hands should be kept clean by using soap and water. Further, open wounds, scrapes, and cuts should be cleaned and covered until they are healed, and coming into contact with another individual’s bandages or open wounds should be avoided. If shared gym equipment is used, always wipe it down with an antiseptic before use. Shower after exercising, and do not enter a pool or a sauna if another individual with an open wound or sore has used it. Finally, personal care products, clothing, towels, and cosmetics should not be shared in order to limit or prevent the spread of S. aureus (Chambers, 2016).

Some Staphylococcus aureus infections may be treated with wound drainage or device removal, depending on the type of infection. Typically, all staphylococcal infections are treated with antibiotic therapy. Antibiotics work by inhibiting the syntheses of protein or cell walls, destroying cell membranes, destroying nucleic acid structure or function, or by blocking essential metabolic pathways (Etebu & Arikekpar, 2016).

There are several classes of antibiotics, frequently identified based on their molecular structure. A common class of antibiotics is the beta-lactams. These molecules contain a 3-carbon ring and a highly reactive 1-nitrogen ring. Beta-lactams work by interfering with proteins required for synthesis of the bacterial cell wall. This will either kill the bacterium or inhibit bacterial growth. Certain bacterial enzymes called penicillin-binding proteins (PBPs) are involved in the synthesis of peptidoglycan. A layer of peptidoglycan that protects the cell from the environment surrounds most bacterial cells. Beta-lactam antibiotics bind to these enzymes, interfering with peptidoglycan synthesis, which leads to cell lysis and death. One common example of a beta-lactam antibiotic is penicillin (Etebu & Arikekpar, 2016).

One of the most well-known virulence factors of Staphylococcus aureus is its antibiotic resistance. A popular example of an antibiotic-resistant strain is methicillin-resistant S. aureus, or MRSA. Methicillin is semisynthetic penicillin. When penicillin was mass-produced in the 1940s, pathogenic resistance quickly developed and spread. Now, more than 90% of Staphylococcus aureus species are resistant to penicillin. Some strains of Staphylococcus aureus are even resistant to Vancomycin, an antibiotic used to combat gram-positive microorganisms. MRSA is a ubiquitous strain of S. aureus that has historically been associated with the healthcare setting. However, it is now widespread in the general population. S. aureus is present in the normal microbiota in approximately one-third of the population, with about 6% being methicillin-resistant. While most carriers are not affected, MRSA can raise concern for susceptible individuals (Parker et al., 2016).

Methicillin was created to resist the inactivation caused by beta-lactamases. These are bacterial enzymes that provide resistance to multiple beta-lactam antibiotics, such as penicillin. Staphylococcus aureus produces large amounts of beta-lactamase. Because of its antibiotic resistance, the choice of medication is important when treating a staphylococcal infection. Typically a suspected infection is treated with trimethoprim-sulfamethoxazole (Bactrim), clindamycin, a tetracycline (doxycycline or minocycline), or linezolid, as these medications have been known to successfully treat MRSA infections. In treating serious staphylococcal infections, Vancomycin has become the standard antibiotic. Vancomycin, a glycopeptide antibiotic, inhibits peptidoglycan synthesis by binding to peptidoglycan units. It is usually administered intravenously; oral Vancomycin is only effective for the treatment of intestinal infections (Parker et al., 2016).

Because Vancomycin has been used for over 70 years to combat MRSA and other antibiotic-resistant pathogens, cases of Vancomycin resistance are now quite common (Etebu & Arikekpar, 2016). Vancomycin-resistant and Vancomycin-intermediate Staphylococcus aureus strains have surfaced (VRSA and VISA, respectively) (Parker et al., 2016). It is now often combined with a second antibiotic, such as rifampin or gentamicin. Combining these antibiotics helps to facilitate tissue and intracellular penetration as well as increase speed of bactericidal effects. It also encourages activity against biofilms and interference of toxin production (Cázares-Domínguez et al., 2015).

Multidrug-resistant strains of Staphylococcus aureus such as MRSA, VRSA, and VISA, are known healthcare-associated pathogens and are highly contagious. These strains are often carried into healthcare facilities on hospitalized patients where they are transferred to other patients, healthcare workers, surfaces, and medical equipment. Immunocompromised patients are particularly susceptible to infection, as well as those with open wounds, catheters, and indwelling medical devices (Parker et al., 2016).

The following is a hypothetical scenario about a scuba diver who cut her leg on a barnacle while diving. After the dive, she visited a local emergency clinic and was prescribed doxycycline, a tetracycline antibiotic, and ciprofloxacin, a quinolone antibiotic (Etebu & Arikekpar, 2016). A week later the infection was still progressing. The patient came back with a fever. The wound in her leg was red and filled with pus, which had to be opened and drained. At this time, a culture was taken from the incision and given to the lab for analysis. The results identified Staphylococcus aureus as the causative agent. Because this organism is resistant to many antibiotics, including the ones prescribed, a more aggressive antibiotic therapy was employed. The diver was started on Bactrim and Rifampin. Within ten days, the infection had subsided and no residual bacteria were found in the culture taken at a follow-up appointment.

In this scenario, the reservoir, or source of infection (Parker et al., 2016), was the barnacle. A barnacle is an aquatic filter feeder (Power et al., 2019). Contaminated water had been circulating through its body and on its surface, which acted as the portal of exit. Direct contact was the mode of transmission. This occurred when the diver scraped her leg, creating an open wound that would act as the portal of entry, or the anatomical site where the pathogen enters into the susceptible host, the diver. For a visual representation of the mode of transmission, see Figure 2 below.

mode of transmission - s. aureus
Figure 2: This diagram provides a visual representation of how Staphylococcus aureus could be transmitted from a contaminated barnacle in the water to a susceptible SCUBA diver who had direct contact with the barnacle, procured an open wound, and created a portal of entry for the infectious bacteria.

 

References

Cázares-Domínguez, V., Cruz-Córdova, A., Ochoa, S. A., Escalona, G., Arellano-Galindo, J., Rodríguez-Leviz, A., … & Xicohtencatl-Cortes, J. (2015). Vancomycin tolerant, methicillin-resistant Staphylococcus aureus reveals the effects of vancomycin on cell wall thickening. PLoS One10(3), e0118791.

Chambers, H. (2016). Staphylococcal infections. Goldman L, Schafer AI, eds. Goldman-Cecil Medicine. 25. Philadelphia, PA: Elsevier Saunders

Cowley, M. C., Ritchie, D. J., Hampton, N., Kollef, M. H., & Micek, S. T. (2019). Outcomes Associated With De-escalating Therapy for Methicillin-Resistant Staphylococcus aureus in Culture-Negative Nosocomial Pneumonia. Chest155(1), 53-59.

Etebu, E., & Arikekpar, I. (2016). Antibiotics: Classification and mechanisms of action with emphasis on molecular perspectives. Int. J. Appl. Microbiol. Biotechnol. Res4, 90-101.

García-Betancur, J. C., Goñi-Moreno, A., Horger, T., Schott, M., Sharan, M., Eikmeier, J., Wohlmuth, B., Zernecke, A., Ohlsen, K., Kuttler, C., … Lopez, D. (2017). Cell differentiation defines acute and chronic infection cell types in Staphylococcus aureus. eLife, 6, e28023. doi:10.7554/eLife.28023

Montgomery, C., Daniels, M., Alegre, M., Chong, A., & Dam, R. (2014). Protective Immunity against Recurrent Staphylococcus aureus Skin Infection Requires Antibody and Interleukin-17A. American Society for Microbiology. 82 (5) 2125-2134 doi:10.1128/IAI.01491-14

Parker, N., Schneegurt, M., Thi Tu, A., Forster, B. M., Lister, P., Allen, S., Franklund, C. (2016). Microbiology. OpenStax at Rice University. Retrieved from https://openstax.org/details/books/microbiology

Power, C., Balli-Garza, J., Evans, D., Nowak, B. F., Bridle, A. R., & Bott, N. J. (2019). Detection of Miamiensis avidus (Ciliophora: Scuticociliatia) and Cardicola spp.(Trematoda: Aporocotylidae) DNA in biofouling from Southern Bluefin Tuna, Thunnus maccoyii pontoons off Port Lincoln, South Australia. Aquaculture502, 128-133.

Thomer, L., Schneewind, O., & Missiakas, D. (2016). Pathogenesis of Staphylococcus aureus bloodstream infections. Annual Review of Pathology: Mechanisms of Disease11, 343-364.

 

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