Skin Infections Due to Panton-Valentine Leukocidin–Producing S. Aureus

Background: Panton-Valentine leukocidin (PVL)–producing Staphylococcus aureus (PVL-SA) strains are frequently associated with large, recurring abscesses in otherwise healthy young individuals. The typical clinical presentation and the recommended diagnostic evaluation and treatment are not widely known.

Methods: This review is based on pertinent publications retrieved by a selective search in PubMed, with special attention to international recommendations.

Results: PVL-SA can cause leukocytolysis and dermatonecrosis through specific cell-wall pore formation. Unlike other types of pyoderma, such conditions caused by PVL-SA have no particular site of predilection. In Germany, the PVL gene can be detected in 61.3% (252/411) of skin and soft tissue infections with S. aureus. Skin and soft tissue infections with PVL-SA recur three times as frequently as those due to PVL-negative S. aureus. They are diagnosed by S. aureus culture from wound swabs and combined nasal/pharyngeal swabs, along with PCR for gene detection. The acute treatment of the skin abscesses consists of drainage, followed by antimicrobial therapy if needed. Important secondary preventive measures include topical cleansing with mupirocin nasal ointment and whole-body washing with chlorhexidine or octenidine. The limited evidence (level IIb) concerning PVL-SA is mainly derived from nonrandomized cohort studies and experimental analyses.

Conclusion: PVL-SA skin infections are easily distinguished from other skin diseases with targeted history-taking and diagnostic evaluation.

Bacterial skin and soft tissue infections are among the more common infections worldwide (1). Some of them arise from wounds or trauma, and others from small, superficial lesions. Their clinical presentation is characterized by the depth of penetration and virulence of the bacterial species involved, among other features (1, 2, 3). Infections arising from skin lesions are usually caused by pathogens that belong to the local flora, including Staphylococcus aureus, hemolytic streptococci, and Enterobacterales.

Among these pathogens, S. aureus often causes abscesses. The processes of encapsulation and immune evasion are aided by various surface proteins and virulence factors, including secreted ones (4). One particular virulence factor, Panton-Valentine leukocidin (PVL), is associated with recurrent, often large skin abscesses, which are its most common clinical sign (5, 6) (Figure 1b). PVL is named after the British pathologists Philip N. Panton and Francis C.O. Valentine, who first described the association between PVL and severe S. aureus-associated disease in 1932. Skin and soft-tissue infections due to PVL-producing S. aureus recur more frequently than those due to PVL-negative S. aureus (20% versus 45%, OR 3.2 (95-% CI: [1.7; 6.3]), p = 0.001) (7). In accordance with this finding, a study from Germany detected the PVL gene in 61.3% (252/411) of skin and soft tissue infections with S. aureus (8). Recurrences of PVL-SA skin infection are remarkably frequent (often multiple times per month) and can be anywhere on the body. Patients are markedly stigmatized, with impairment of their quality of life and mental health (9). Half of all cases are not correctly diagnosed until at least five months after the onset of disease (10); once the proper treatment and preventive measures have been started, it may still be weeks or months until the patient is permanently free of infection. In a survey conducted as part of an observational study, the main concerns expressed by patients were about transmitting the infection to their personal contacts and suffering from recurrences themselves (27/34 [79%] and 17/34 [38%], respectively) (9). Approximately two-thirds of the respondents could not work for at least one month. Patients suffer further distress because physicians are not well versed in the diagnosis and treatment of this disease (9).

Figure 1

clinical presentations

Learning goals

PVL-SA skin infections are a common problem in family medicine and general practice. This article is intended to enable readers to:

• acquire basic knowledge of this clinical entity,
• become familiar with the elements of its clinical presentation and pathogenesis,
• and gain an overview of its epidemiology, prevention, diagnosis, and treatment.

Clinical features

The most common presentation of PVL-SA is the new, sudden onset of skin infections, which go on to recur, in young adults or children who are otherwise in good health and with otherwise healthy skin (5) (Figure 2). The abscesses usually arise on previously normal skin, but can also arise at the site of a minimal lesion, e.g., a mosquito bite or a cut from shaving; they can be found anywhere on body (8, 9, 10). The infection often spreads to others through close physical contact, e.g., sexual intercourse, team sports or martial arts that can lead to skin abrasions (such as football or wrestling), or sharing of occupational equipment (such as firefighters‘ gear). These characteristics usually make PVL-SA skin infections easy to distinguish from other types of skin infection. The most important competing element in the differential diagnosis of recurrent cutaneous abscesses, if they occur in the axillary or inguinal regions, is hidradenitis suppurativa.

Figure 2

The clinical pyramid of infections with Panton-Valentine-leukocidin-producing S. aureus

In all patients with severe or recurrent cutaneous infections, particularly infants and preschool children, an immunodeficient state should be ruled out.

Infections due to PVL-SA generally take a more severe course than those due to PVL-negative S. aureus: they recur more often (higher frequency of infections per patient), and the abscesses are larger than those due to other typical cutaneous pathogens (6, 11). PVL-SA infections of bones, joints, and muscles have been described, as well as PVL-SA bacteremia, particularly in children (12, 13). Necrotizing pneumonia due to PVL-SA is, fortunately, rare (14, 15); it is very severe, carries a high mortality, and may arise in the aftermath of certain viral respiratory infections, including influenza (6, 14) and SARS-CoV-2 (16) (Figure 1a).

Pathogenesis

PVL is a pore-forming exotoxin consisting of two subunits, LukS-PV and LukF-PV. The PVL-encoding genes, which consist of two co-transcribed open reading frames (lukS and lukF), are located on lysogenic bacteriophages that can be integrated at a specific site on the S. aureus chromosome. Together, these subunits form a biologically active heptamer causing lysis in human leukocytes (e.g., granulocytes, monocytes, and macrophages) via pore formation and membrane injury. Leukocyte apoptosis leads to the release of inflammatory mediators, including reactive oxygen species (ROS) and cytokines, which can damage epithelial cells and the surrounding tissue (Figure 3) (6).

Figure 3

Molecular pathogenesis of PVL-SA infection, PVL pore formation on cell membrane, leukocytes and epithelial cells

Epidemiology

PVL formation is independent of methicillin resistance: both methicillin-resistant and methicillin-sensitive strains of Staphylococcus aureus [MRSA and MSSA] can produce PVL. The prominence of PVL producing MRSA in the literature is owing to the dissemination of PVL-positive MRSA clones (so-called USA300 MRSA strain) across the United States (5, 6).

In Germany, however, most PVL-SA isolated from cutaneous infections is methicillin-sensitive (MSSA in 76–81%) (8, 17). The overall prevalence of PVL among clinical S. aureus strains in Germany is not known with precision; it is estimated at 2–5% for MSSA and less than 3% for MRSA (18, 19). Retrospective analyses of S. aureus isolates from skin infections yielded a much higher proportion of PVL-SA (50%-60%) (8, 10). In some parts of the world, such as Latin America and Africa, the frequency of PVL production among S. aureus isolates is much higher than in Germany; a number of studies have shown that PVL-SA is a frequent cause of skin infections after travel to tropical and subtropical countries (7, 20, 21). A history of travel to, or migration from, such countries is an important risk factor for PVL-SA skin infection (22). The population of S. aureus is largely clonal, and, therefore, parts of the genome are only rarely exchanged between different strains. This is why the geographic origin of a particular sample of S. aureus can be determined by molecular biologic analysis (21, 23).

Diagnostic evaluation

Testing for PVL is not a component of routine microbiologic testing, but is performed in case of clinical suspicion and upon specific request to the microbiology laboratory. The polymerase chain reaction (PCR) is used to detect the PVL-encoding genes, lukS-PV and lukF-PV. A thorough history is important, as the clinical suspicion of PVL-SA infection is aroused by its typical presentation. Any prior skin infections and the patient’s travel history (especially to tropical or subtropical countries) should be asked about specifically. If PVL-SA infection is suspected, native material (for example, abscess material, tissue samples, pus if obtainable) and/or swabs from the wound and/or from the probable colonization site (e.g., the nose, throat, groin, and perineum) should preferably be sent for microbiologic analysis (17, 24). In view of the fact that PVL-SA infections in Germany are often associated with travel and manifest atypical antibiotic resistance patterns, microbiological material must be collected for antibiotic susceptibility testing before the prompt initiation of empirical antimicrobial therapy. The antibiotic therapy can then be adjusted as needed according to the antibiogram.

Management and therapy

The available evidence on PVL-SA management and treatment is limited and mainly derived from non-randomized cohort studies and experimental analyses (class IIb evidence). The management of patients with PVL-SA infections depends on the severity of the disease and the likelihood of spread to persons in the patient’s familial, social, and professional environment. The treatment must be addressed toward the existing infection as well as the prevention of further PVL-SA infections (secondary prevention) (1, 2, 25). Purulent lesions, particularly smaller boils or carbuncles, often drain spontaneously; the affected area should be left alone as far as possible, with the avoidance of manipulations that might promote further infection. This holds particularly for lesions on the face, where there is an increased risk of meningitis, cavernous sinus thrombosis, and phlegmon formation (1, 2). It is recommended that superficial PVL-SA infections be treated with a local antiseptic (e.g., octenidine, chlorhexidine, polyhexanide, or polyvidone) or antibiotic (fusidic acid) (1, 2). To minimize the spread of PVL-SA, special care should be taken to disinfect the hands thoroughly with an alcohol-based hand disinfectant after contact with a skin lesion (and in general) (26). Topical antimicrobial agents play a supportive role at best in the treatment of acute infection and are not recommended as the primary form of treatment (1).

The surgical eradication of lesions is of great importance in skin and soft tissue infections with abscess formation (1, 2). Uncomplicated abscesses are treated with local incision and drainage, with no need for systemic treatment. If there is evidence of systemic infection, systemic antibiotic therapy is indicated in addition (1, 2, 27). Systemic therapy can also be considered if the lesion is in an unfavorable site (face/neck, hands, genital area), if it is very large (> 5 cm in diameter, or multiple abscesses), or if other risk factors are present (e.g., comorbidities such as diabetes mellitus, hepatic cirrhosis, severe neutropenia, alcoholism, malnutrition, immunosuppression, a history of radio- or chemotherapy, or very advanced age). As the infection may be due MRSA, risk assessment and microbiological testing should always be performed initially. The available information and risks profile can then serve as the basis for targeted antimicrobial therapy. The choice of oral antibiotic therapy should be based primarily on the resistance profile of the detected pathogen. Until the resistance profile is known, empirical monotherapy may be given, based on local pathogen statistics. First-line antibiotics include the oral anti-staphylococcal agents trimethoprim-sulfamethoxazole, clindamycin, and doxycycline (1, 2). The predicted efficacy of these agents depends on the locally predominant S. aureus strains and the likelihood of methicillin-resistant PVL-SA. A positive travel history must be considered in the selection of empirical antibiotic therapy, because of wide geographic variation in resistance patterns. High rates of resistance to trimethoprim-sulfamethoxazole have been described in travelers returning from Africa (30%) and South Asia (44%); to clindamycin, in those returning from Southeast Asia (16%); to methicillin, in those returning from Latin America (31%); and to doxycycline, in those returning from Africa (34%) and Southeast Asia (19%) (7). Potential oral antimicrobial agents are listed in the Table. The antibiotic treatment can be discontinued upon normalization of the patient’s clinical findings, temperature, and CRP and reversion of the leukocyte count to less than 8 000/μL. Treatment for five days often suffices but may need to be longer in severe cases (1, 2).

Table

Selected oral antibiotics for the treatment of PVL-SA skin and soft tissue infections in adult patients

Oral treatment with cefuroxime is explicitly not recommended because of the low oral bioavailability of this agent, and monotherapy with rifampicin is contraindicated because of the rapid development of resistance. Oral flucloxacillin was recommended in some of the older guidelines, but its low bioavailability implies that it may only be effective in higher doses, with a resulting higher potential for undesired effects.

Pathogen eradication (secondary prevention)

There is only sparse evidence concerning the eradication and secondary prevention of PVL-SA, derived mainly from non-randomized cohort studies and extrapolated findings from high-quality studies (RCTs) on MRSA decolonization (class IIb evidence or worse). Patients with confirmed, symptomatic PVL-SA should undergo pathogen eradication (decolonization) to prevent further infections. This consists of 5 days of topical antibiotic therapy of the nasal mucosa, antiseptic skin and mouth rinses, and extensive hygienic and disinfective measures in the home (30, 31). High-quality studies on MRSA have documented the infection-preventing and MRSA-decolonizing efficacy of topical pathogen eradication (31, 32, 33, 34, 35). Although evidence at such a high level is still lacking with respect to PVL-SA, the efficacy of pathogen-eradicating measures has frequently been observed in practice and has thus already been established internationally as the main treatment strategy (1, 2, 5, 6, 35). Patients must be advised that repeated pathogen eradication may be needed. For decolonization, mupirocin nasal ointment is used in combination with chlorhexidine-based (e.g., 2%) or octenidine-based wash lotions for whole-body application (30, 36). Antiseptic resistance has reportedly developed in extremely rare cases, but this is not a relevant problem in current clinical practice (30).

Person-to-person transmission of PVL-SA occurs mainly within the household (close physical contact), and less often in other realms of the patient’s social life (37). Simultaneous pathogen-eradicating measures in close contacts have, therefore, become an important strategy in clinical practice, for the avoidance of “ping-pong” transmission. Successful eradication can be verified by nasopharyngeal swabbing, which, however, is only 60–80% sensitive (frequent false-negative findings). Alternately, it can simply be judged from the non-occurrence of further infection. There can be no substitute for the periodic screening over time of health-care workers who are colonized with PVL-SA and work in high-risk areas for infection (intensive care, neonatology, stem cell transplant and oncology wards). In the hospital, patients with symptomatic PVL-SA infection and those with PVL-SA colonization should be placed in single-room isolation. The most important standard measure to prevent PVL-SA transmission is hand disinfection. In the outpatient setting, no hygienic measures beyond the standard ones need to be observed.

Patients who have not yet received decolonization treatment suffer from an average of ca. one abscess per month; after such treatment, approximately half of all patients report a recurrence within six months (10). In case of recurrence, further topical pathogen-eradicating measures are carried out, along with treatment of the acute infection. These measures are repeatedly applied until the infections cease. In a study of 115 symptomatic patients, the probability of symptomatic recurrences decreased with each repetition (10). Long-term freedom from abscesses was achieved in 50% of patients with a single decolonization and in 90% after five decolonizations (Figure 4). When pathogen-eradicating treatment fails, it is recommended that diagnostic evaluation for PVL be extended to the patient’s close contacts and, where applicable, even to pets (on a trial basis). This may enable the identification and targeted treatment of potential reservoirs; if necessary, antimicrobial therapy can be tried along with pathogen-eradicating measures, in special cases (28).

Figure 4

Repeated decolonization is associated with increasing success of decolonization

The cleansing of inanimate surfaces is another component of PVL-SA eradication because of the persistence of S. aureus in the environment, and it may be needed. The disinfection, cleaning, or disposal of items used close to the body (e.g., personal care products such as combs, razors, and open creams; used towels, toys) is therefore recommended, albeit on the evidence level of individual expert opinion. Detailed information can be found on the homepage of our working group: www.pvl-abszess.de.

Topical eradication is costly for the individual patient. A five-day course costs 50–110 euros per person (17); the average hospitalization for a PVL-SA skin infection costs some 20 times as much. With the exception of mupirocin nasal ointment, the costs of pathogen eradication are not covered by health insurance, but their reimbursement can be requested from health insurance carriers in individual cases. The implementation of topical eradication measures is a very complex matter for some patients. The individual steps should be discussed and planned one at a time, and in detail. If skin infections keep recurring despite repeated eradicative treatments that have been carried out appropriately, the remaining potential obstacles to decolonization must be discussed with the patient. The efficacy of antimicrobial therapy in addition to eradicative measures is questionable; this option should only be considered in exceptional cases.

In-hospital PVL-SA clusters have been reported, particularly in neonatology wards (38, 39). The approach to these outbreaks should always be discussed with the hospital hygiene department and varies depending on the individual circumstances of the outbreak. Nosocomial outbreaks must be reported to the public health authorities, according to German law. Outbreaks in public facilities such as schools, kindergartens, accommodations for asylum-seekers, etc., can be especially complex. In principle, any relevant, uncontrolled outbreak should also be reported the public health authorities. here. The relevant law in Germany is IfSG § 6 para. 1 pt. 5 a/b: “Notification by name of the occurrence of a (not further specified) dangerous communicable disease.”

PVL-SA in children

Eradication measures differ in some ways in premature and newborn infants. Chlorhexidine should not be used in premature infants because of its potential local and systemic side effects. As infants and young children cannot gargle, antiseptic throat rinses are contraindicated. Brushing the oral cavity with octenidine or chlorhexidine solution is inadvisable, as it may lead to injury (39). As for antiseptic wash solutions, a special octenidine 0.1% preparation should be used in premature infants. Mupirocin has not been approved for use by children less than 1 year old, but it is recommended for PVL-SA eradication even in preterm infants (40); the parents must be informed that this application is off label. With regard to the attendance of PVL-SA-colonized or infected children at day-care centers, schools, clubs, and so forth, decisions must be made on a case-by-case basis, after consultation with physicians, public health officials, and other caregivers.

Open questions

Many open questions regarding PVL-SA need to be addressed by further research. The efficacy of topical PVL-SA eradication measures for preventing skin infections is only supported by moderate-level evidence (1). The acuity of the infections and the fact that they are generally managed on an outpatient basis makes it very difficult to conduct randomized trials with appropriate control groups, both as an ethical matter and as an organizational challenge. The significance of the virulence factor PVL has only recently become known to infectious-disease epidemiology (8, 14), and thus only a few targeted research projects have been funded to date to provide answers to the important clinical and epidemiological questions. A further open question is that of immunity to PVL-SA. In outbreaks involving large numbers of infected people, individuals and even families have been repeatedly identified who were colonized over the long term, but never infected (23). PVL-SA immunity is poorly understood; presumably, genetic factors influence both the risk of colonization and the risk of infection by PVL-SA.

Overview

Recurrent skin infections, especially abscesses, are largely caused by Panton-Valentine (PVL-SA) strains of Staphylococcus aureus. This disease is diagnosed on the basis of the clinical history, the physical examination, and the findings of specific microbiological testing. The acute outpatient treatment of the skin infection focuses on the incision and drainage of the abscesses and, if necessary, oral antimicrobial therapy. To prevent recurrent infection, topical pathogen eradication is required, with mupirocin nasal ointment, antiseptic skin cleansing, and antiseptic mouth rinsing if necessary. Pathogen eradication should be carried out at the same time in all of the patient’s close contacts, regardless of the swab findings. In case of recurrence, this procedure must be repeated there are no further symptoms over the long term. Whenever there is an outbreak, e.g., in community facilities, day-care centers, and elsewhere, screening for PVL-SA with smear tests can be helpful, and the public health authorities must be notified. Early diagnosis, proper treatment, and close involvement of patients in preventive measures can help lessen the burden of disease, the risk of transmission, and the adverse psychosocial effects of this disease.

Acknowledgments

The authors thank Dr. rer. nat. Franziska Layer-Nicolaou (NRZ for Staphylococci and Enterococci at the Robert Koch Institute, Wernigerode Division) and Dr. med. Daniel Humme (Clinic for Dermatology, Venereology and Allergology, Charité – Universitätsmedizin Berlin) for their many years of active support and expert advice. Special thanks are due, in particular, for the preparation and provision of Figure1b (Dr. Humme) and Figure 2 (Dr. Layer-Nicolaou). We also thank Dr. Henning Kolarikal (Praxis an der Kulturbrauerei, Berlin-Prenzlauerberg, Germany; practice for general medicine, infectiology, and internal medicine), for his kind advice regarding the practical orientation of this article.

Conflict of interest statement
The authors state that no conflict of interest exists.

Manuscript received on 15 March 2022, revised version accepted on 16 August 2022.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
PD Dr. med. Rasmus Leistner

Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie

Charité – Universitätsmedizin Berlin

Freie Universität Berlin und Humboldt-Universität zu Berlin

Hindenburgdamm 30

D-12203 Berlin, Germany

Cite this as:
Leistner R, Hanitsch LG, Krüger R, Lindner AK, Stegemann MS, Nurjadi D: Skin infections due to Panton-Valentine leucocidin–producing S. aureus. Dtsch Arztebl Int 2022; 119: 775–84. DOI: 10.3238/arztebl.m2022.0308

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