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Muhammad Musthafa Poyil^*

^*Correspondence: Muhammad Musthafa Poyil, Department of Microbiology, Vivekanandha College of Arts and Sciences for Women, Namakkal, Tamil Nadu, India, Email: pmusthu@gmail.com

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Abstract

Skin infections are considered as a group of various conditions that affecting the skin layers and soft tissues resulting superficial uncomplicated to complicated systemic infections which are caused by both gram positive as well as gram negative organisms. Mostly, the complicated skin infections were caused by gram negative bacilli such as Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii gained much attention owing to its multidrug resistance to existing antibiotics which further complicated the skin infection by prolonged hospitalization, cost for health care and mortality. In this review, we mainly focused the risk factor which predominantly complicates the skin infection, current treatment challenges as well as future direction for skin infection treatment and management.

Keywords

Multidrug resistance, Skin infection, Gram negative bacilli

Introduction

Skin infections are manifested by microbial invasion into the different skin layers as well as underlying soft tissues resulting mild to severe life-threatening infections [1]. The infections are commonly encountered in both ambulatory and hospital settings [2-4]. The severity and its complexity are extensive which is ensuing in bacteraemia, hospitalization, surgery and in some times death [2]. This skin infection includes an extensive clinical range of frequent infectious diseases that are repeatedly required a treatment as well as admission for patients [5]. This infection has a diverse appearance and microbial involvement in the various regions of the skin such as epidermis, dermis etc., Skin infections are very severe in complicated cases which involving deeper tissues which including cellulitis, infection in the wound tissues [6]. Previously, Staphylococcus aureus and β- haemolytic Streptococci have been reported as main reason behind the skin infections [7] which accounted for 6.8 to 17.39 % and 3.3 to 8.1% cases respectively [8] but in recent times, gram negative pathogens and mixed pathogens which includes both gram positive as well as gram negative bacteria’s, have become a significant cause for acute skin infections [9,10] which leads to health care associated problematical skin infection like diabetic foot infections [11]. The earlier study reported that gram negative bacteria have become an emerging pathogen, including E. coli and K. pneumoniae related for 28 and 17 % respectively, which affecting the mortality rate of skin infection [8].

The prevalence and the dissemination of skin infections are increased due to antibiotic resistance, particularly, occurrence of multidrug resistant as well as the appearance of the carbapenem resistant Enterobacteriaceae was causing a serious obstacle to the treatment of skin infections which is caused by gram negative pathogens [12]. Many factors were considered while classifying the skin infections such as the infection occurrence place, Rate of infection, causative agent, depth of infection and severity [13,14]. The food and drug administration has announced the new classification category named acute bacterial skin and skin structure infections in 2013, which were defined as wound infection, cellulitis, abscess, skin redness and oedema. This classification was developed for the regulation of the drug of choice for the treatment of skin infections. Most importantly, the complicated skin infection has different microbial community along with gram negative pathogens particularly, the patient who have diabetes, neutropenia patient and malignant patient [15]. However, in this review mainly focused on the multiple antibiotic resistant gram-negative pathogens which cause skin infection and their treatment challenges (Figure 1).

Figure 1: Summary of challenges and hopes for gram negative bacilli causing skin infection.

Microbiology of skin infection

The skin is most important organ which visibly spread out the whole human body as well as it has several layers (epidermis, dermis, subcutaneous and cutaneous) to protect the body from the external sources like microbes and other elements and it provided numerous prospects for infections. Though, the skin and soft tissue infection (SST) has occurred owing to microbial invasion into different skin layers that determines the severity. The largest organ in the body harbour millions of microbes including bacteria, fungi and virus which have played a major role in evading pathogen, immune response and to breakdown the natural products [16]. The skin is niche for many beneficial microorganisms like our gut has which are acting as barrier to prevent the entry of invasive pathogens. In certain conditions when the barrier is breakdown or stability between the commensal and the pathogen gets disturbed, the result will be the complicated and uncomplicated skin diseases. The entry of microbes into the skin and soft tissue through interruption of skin structures are the basis for skin infection but many other risk factors are increasing the susceptibility of the skin infection [17]. In general, skin infections are monomicrobial or polymicrobial in nature. P. aeruginosa, Klebsiella spp, E. coli, Enterococcus spp, A. baumannii, Citrobacter are the mainly isolated gram-negative bacilli in patient hospitalized with skin infections [7]. Therefore, the treatment for skin infection caused by polymicrobial or mixed microbes required a multidrug effect that will be effective against all the microbes [18,19]. Apart from gram positive microbe, P. aeruginosa played a major role in skin infection among other gram-negative bacilli [20].

Clinical characteristic features of skin infection

The bacteria can enter the skin through many ways such as bite wounds, existing skin wounds, scratches, and burns wounds to rupture the skin barrier cause skin. The bacteria can develop skin infection after entering the skin by means of adhering to host cell, spreading to tissues and toxin elaboration [21]. Virulence factors possessed by the organism played a major role in the skin infection development. Skin infections produced a wide variety of clinical symptoms like oedema, pain, erythema, warmth, necrosis and ischemia [22].

Treatment options for skin infections

Clinical examination is the primary diagnostic method for skin infection. Identification of skin infection provided the information about the causative agent as well as the choice for antibiotic therapy which helps to start the prognosis of the skin infection. Initially, the skin infection treatment relies on prescription of various β-lactam antibiotics, aminoglycosides, polymyxins, tigecycline, Carbapenems, Fosfomycin, imipenem, ceftazidime, meropenem, Ceftolozane and cephalosporins. Unfortunately, the organisms were developed resistance to any of these antibiotics which makes antibiotic resistant organism leading treatment failure. The skin infections caused by gram negative bacilli (P. aeruginosa, Klebsiella sp., E. coli and A. baumannii) are the most challenging concern for physicians due to antibiotic resistant.

Current challenges for skin infection

Multi drug resistance

Though the skin infections are able to treat by empirical antimicrobial therapy, every physician faced a most important challenge while treating skin infection caused by gram negative pathogens. The increases of drug resistant organism resulting treatment failure due to the multidrug resistance strains to existing antibiotics have complicated the skin infections. The gramnegative bacilli were developed antibiotic resistance through the antibiotic inactivating enzymatic and nonenzymatic pathways expression resulting increase in the intrinsic resistance by chromosomal gene mutation (target modification) or through the mobile genetic elements which carries the resistant genes like plasmid encoding beta lactamases transfer, enzyme modification in aminoglycosides plasmid borne quinolone resistant gene. Report says 25% of K. Pneumonia, 20-40 % of P. aeruginosa and 40-70% of A. baumannii showed resistance to carbapenem [23].

P. aeruginosa is the one of the most important pathogens causing skin infection which acquired antibiotic resistance via many mechanisms like innate resistance by efflux pumps over expression, outer membrane permeability decreases and also gaining the resistance genes, mutation in genes which code for porin channel and alteration in important proteins are makes the P. aeruginosa treatment difficult. The β- lactam antibiotics (penicillin and carbapenem) as well as third and fourth generation of cephalosporin such as cefepime and ceftazidime were the most important β- lactams which inhibit the cell wall synthesis used for the treatment of P. aeruginosa causing skin infection. The development of resistant to these antibiotics was mediated by the enzyme β- lactamases via cleavage of β- lactam ring which makes antibiotic ineffective. It is also gained resistance to aminoglycosides through the transferable aminoglycoside modifying enzymes which inactivate the antibiotic by the attachment of phosphate to antibiotics resulting decrease in binding affinity to target organism [24].

A. baumannii is the most important organism in multidrug resistance to skin infection. It showed a variety of resistant mechanism such as β- lactams inactivation by β- lactamases, hydrolysis of ESBL makes carbapenem resistance, over expression of multidrug efflux pumps makes resistance in A. baumannii to tigecycline as well as resistance to aminoglycosides by transferees, target site alteration, decrease in membrane permeability [25]. K. pneumonia and E. coli showed resistance to carbapenems.

Risk factors for skin infection

Skin infections are most common in all the competent populations but it was frequently identified in certain populations those who are increased risk for associated co morbidities (Figure 2). The previous report says that, the highest rate of skin infection was observed in children were aged above five years and adults were aged below sixty five when compared to other age groups [7]. The other reports says various co morbid situations like critical illness, obesity, diabetes, kidney disease, vascular insufficiency, liver, immune deficiency as well as immune compromise has affected not only the skin infections development but their outcomes as well [26]. Some co morbid condition like obesity was reported as risk factor for infection in surgical site but also for recurrent infection owing to multidrug resistance resulting treatment failure in patients were admitted in hospitals for prolong period with abscess or cellulitis [20]. Many studies have reported that diabetic condition is the most important risk factor for skin infection among the other co morbid conditions [27].

Figure 2:Various risk factors and their causative agents.

Diabetes

Skin infections like abscesses, cellulitis was more frequent in diabetic patient when compared to nondiabetic patient. Besides that, it has nearly fourfold risk of complicated skin infection compared to non-diabetic patients [28]. A study reported the patient with diabetes who has admitted in intensive care unit has a risk for skin infections as well as the diabetic patient who undergo for bypass surgery those are more prevalent for surgical site infection [29]. The diabetic patient those who are hospitalized with other risk conditions like surgical site infection, major abscesses and necrotizing fasciitis resulting an increasing and worrying gram negative bacilli detection. Unfortunately, a recent study reported that, the majority of diabetic patients those who had blood stream infections through skin infection but no history of foot infection, among this, one third of the infections were caused by gram negative bacilli particularly, P. aeruginosa, K. pneumoniae and E. coli [30]. Most importantly, gram negative bacilli causing skin infection is the main factor which individually connected with mortality [30]. The prevalence and multidrug resistance among the organism in the hospital settings signifies an important threat to public health along with increasing morbidity and mortality rate mainly in patients with a greater number of co-morbidities [31- 33]. Consequently, the patient with no history diabetes but had foot infection was detected with carbapenem-resistance organism including A. baumannii, Citrobacter [34].

Diagnosis and management

The rapid diagnostic techniques have been developed for enhancement of the better outcome for the skin infected patients those are affected with other critical conditions, incomplete data and strategies. However, a greater number of studies is immediately required for the establishment of the actual function of the different new diagnostic technologies for the skin infection [35]. Even this highly developed diagnostic is available, the treatment for skin infections were highly challenging because elevated rate of culture negative skin infection in patients with higher menace for infection caused by both gram negative and mixed organisms. Therefore, this is the time for a swift, from intravenous to oral antibiotic therapy but the duration of the treatment was unknown. These swift from IV to oral antibiotic is possible, when the clinical advancement is evident. Along with, an intensive course therapy played a role for some skin infected population but there is a lack for clinical evidence on this particular thing.

Future directions for skin infection

Antibiotic resistance is an emerging and huge concern which causes more than seven hundred thousand deaths annually. Therefore, the development of novel or newer drug is required urgently. Here, we discussed about the novel treatment option for gram negative bacilli which causing skin infection that was emerged from research.

Antibiotic adjuvants

Antibiotic adjuvants are compound which has no antibiotic activity but when it is administered along with the antibiotics and forms the complex. This complex enhances the drug activity or blocks the resistance of the organism to that drug. So, the adjuvants are called as antibiotic resistance breakers [36]. Still, three types of antibiotic adjuvants such as β-lactamase inhibitors, inhibitors for efflux pump system and outer membrane permeabilizers were developed to assist the bacteria to overcome the drug resistant. β-lactamase inhibitors are most widely used antibiotic adjuvant which is used for β-lactam antibiotic against A. baumannii, P. aeruginosa and K. pneumonia to overcome drug resistance. Clavulanic acid, Sulbactam, tazobactam, Avibactam, Zidebactam, LN-1-255 which is penicillanic acid sulfone substituted 6-alkylidene and diaz bicyclooctane are the potent β-lactamase inhibitors used in clinical practice against multidrug resistant P. aeruginosa and A. baumannii [37- 39]. The other antibiotic adjuvant is vaborbactam a boric acid agent act as serine protease inhibitors against E. coli [40] (Figure 3).

Figure 3:Structures of some important antibiotic adjuvants.

Alternative to antibiotics

The abrupt increases of resistance prompted to find an alternative way to fight against multidrug resistance microbes. In this way, bacteriophage and its products played a same role as antibiotics does. The first clinical trial Biophage-PA was attempted against P. aeruginosa in 2017 [41,42]. Another compound called dichloro carbazol propane and peptic benzimidazole were showed a broadspectrum antibacterial activity against P. aeruginosa and E. coli [43,44]. In addition, quorum sensing inhibitors like auto inducer 2 and some metal based antibacterial agents such as gold, silver, ruthenium, gallium, bismuth and copper were used against multidrug resistant E. coli, P. aeruginosa, A. baumannii and K. pnemoniae [45-49].

Combinational therapy

Though, many antibiotics are available to treat skin infections, newer antibiotic will be discovered or is being developed for the treatment of skin infections owing to its high prevalence of multiple resistant strains. Still, the newer antibiotics has some advantage like expensive as well as least accessible but it may lack the evidence on clinical data for top to bottom comparison among the discovered antibiotics. Consequently, inadequate data for their usage in patient who has high risk factor such as diabetes etc., To achieve the cost effective and synergistic efficacy for treatment for skin infection the rising information is needed on their combination with existing antibiotics.

Conclusion

Gram negative multidrug resistant organisms such as P. aeruginosa, K. pneumonia, E. coli and A. baumannii causing skin infection in patients with risk factors were more challenging to treat. These organisms were getting resistant to antibiotics by over expression of efflux pump, target site alteration, decrease permeability and gene mutation. This resistant property prompted the researcher to find the alternate way like bacteriophage; some metal based antibacterial agents to treat skin infection efficiently. The current data revealed that most of the alternative agents were under trial as well as most of the novel compounds are being developed. It is giving the hope that the compounds under clinical trials will be considered for the treatment skin infection caused by gram negative multidrug resistant organisms.

Acknowledgement

The authors are grateful to the Deanship of Scientific Research, Prince Sattam bin Abdulaziz University, Al- Kharj, Saudi Arabia, for its support and encouragement in conducting the research and publishing this report.

Conflict of Interest

Authors declare no conflict of interest.

References

Esposito S, Noviello S, Leone S. Epidemiology and microbiology of skin and soft tissue infections. Curr Opin Infect Dis 2016; 29:109–115.

Challenges and future perspectives of gram negative multidrug resistant bacilli causing skin infections