Management of Inflammation and Infection

 

Acute and Chronic Wounds

Acute wounds are caused by external trauma and usually heal within a predictable time frame by progressing through a natural series of phases including inflammation and granulation to repithelialization and re-modeling. During acute wound healing, the inflammatory response is initiated by the release of cytokines and growth factors that induce vasodilatation and an increase in blood flow to the site of injury. Increased vascular permeability and an influx of phagocytic cells also occur. Antibodies trap and remove micro-organisms, foreign debris, and bacterial toxins and enzymes. The symptoms and signs of the inflammatory response are pain, erythema,swelling, and increased temperature. By contrast, chronic wounds do not heal in a predictable fashion and are usually the result of endogenous mechanisms associated with underlying conditions. In a chronic wound infected with a persistent microbial population, the inflammatory response produces a chronic influx of neutrophils that release cytolytic enzymes, free oxygen radicals, and inflammatory mediators that injure host tissue. Localized thrombosis and vasoconstriction lead to tissue hypoxia, a condition that promotes bacterial proliferation, especially of anaerobic organisms.

Chronic wounds frequently appear to be “stuck” in the inflammatory stage of healing. Inflammation is a part of the normal healing process but prolonged inflammation and contact with chronic wound fluid may be harmful.Persistent inflammation or systemic diseases that cause inflammatory local wound beds (eg, vasculitis and pyoderma gangrenosum) can be confused with infection.

The inflammatory response consists of a cellular response and a humoral (fluid or antibody) response. The humoral response involves B-cells, which develop into plasma cells that secrete antibodies. The cellular response involves T-cells (named for their maturation in the thymus), macrophages (activated monocytes), and granulocytes (neutrophils, eosinophils, and basophils). Two main subpopulations of T-cells include the T-helper cells (TH) and cytotoxic T-cells (TC). Cytokines are small polypeptides that regulate both the cellular and humoral immune responses. They exert powerful effects on chemotaxis, proliferation, and differentiation of inflammatory cells and also have important actions on non-inflammatory wound cells such as fibroblasts, epithelial cells, and vascular endothelial cells. Persistent inflammation occurs in a chronic wound because the levels of key pro-inflammatory cytokines, such as TNF- ß and IL-1, are elevated, probably due to the presence of bacteria, fungi, and viruses in the open wound

 

Inflammation and Infection

 

The diagnosis and management of infection and inflammation in chronic wounds is beset with difficulties for the wound care practitioner. A clinically infected wound can have serious consequences for the patient and can add to the overall cost of care. Treatment of infected surgical wounds can add up to 10 days of hospital care to the length of treatment.

However, the role of micro-organisms in chronic wounds, the definition of infection, the role of quantitative and qualitative culture of wounds, the sampling methods that should be used, and the most appropriate course of treatment for infected wounds and for non- infected wounds that fail to heal are subjects for debate and disagreement.

 

Interaction of Wounds with Bacteria

 

All wounds contain bacteria at levels ranging from contamination, through colonization, critical colonization (also known as increased bacterial burden or occult infection) to infection. The increased bacterial burden may be confined to the superficial wound bed or may be present in the deep compartment and surrounding tissue of the wound margin. Several systemic and local factors increase the risk of  infection . Great emphasis is frequently placed on bacterial burden; whereas, host resistance is often the critical factor in determining whether infection will take place. Host resistance is lowered by poor tissue perfusion as outlined above, poor nutritional status, local edema, and other behavioral factors such as smoking and drug and alcohol abuse. Other systemic factors that impair healing include comorbidities and medication that the patient may be taking for other conditions. Local characteristics of the wound also affect healing and the risk of infection. The presence of foreign material such as necrotic debris, retained packing materials, or small fragments of gauze dressing will significantly decrease host resistance and decrease the number or virulence of bacteria necessary to cause bacterial infection

RISK FACTORS FOR INFECTION IN CHRONIC WOUNDS

Local factors

 

Systemic factors

 

Large wound area

Deep wound

High degree of chronicity

Anatomic location (eg anal

region)

Presence of foreign bodies

Presence of necrotic tissue

Mechanism of injury

(eg, contaminated

penetrating objects)

High degree of contamination

Reduced tissue perfusion

Vascular disease

Edema

Malnutrition

Diabetes mellitus

Alcoholism

Prior surgery or radiotherapy

Corticosteroids and other

immunosuppressants

Inherited neutrophil defects

Immune deficient conditions

Rheumatoid arthritis

 

 

Contamination and colonization.

 

Contamination is the presence of non-replicating organisms in a wound. Once a wound has been created, whether through surgery, trauma, or endogenous mechanisms, the probability for contamination is 100%. Contaminating micro-organisms arise from the external environment, surrounding skin, and endogenous sources such as the gastrointestinal (GI) and oral tracts. The normal flora of the oral and GI mucosae are diverse and present in large numbers. They will have little impact on a minor wound that is healing rapidly but may establish large colonies on slowly healing chronic wounds. Most chronic wounds become contaminated from endogenous secretions, healthcare providers, or the environment.

It is widely believed that aerobic or facultative pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa and the beta-hemolytic streptococci are primarily responsible for delayed healing and infection in all types of wounds, but this has largely been based on studies in which the culture and isolation of anaerobic bacteria was minimal or omitted. When wound colonization is investigated using microbiological techniques appropriate to anaerobic species, anaerobes form a significant proportion of the colonizers in acute and chronic wounds. The under-reporting of anaerobes in wounds may be due to the fact that culturing, isolating, and identifying anaerobes are more demanding than practices required for aerobic species. Also, some clinicians hold the view that anaerobes are not detrimental to wound healing.However, anaerobes can be highly virulent and may be the cause of postoperative infections when routine culture fails to yield bacterial growth.

 

Critical colonization, increased bacterial burden, or covert infection.While the signs of frank infection are generally easy to identify, making a judgment about wounds that display persistent inflammation can be difficult.Wounds may display signs of covert infection where the host is harmed enough to impede healing but not enough to cause typical inflammatory symptoms. Covert infection is difficult to diagnose, as many of the  usual clinical signs are absent, but the most obvious sign is failure of the wound to heal or stalling after making signs of progress. Atrophy or deterioration of previously healthy granulation tissue, discoloration of granulation tissue to pale gray or deep red, and increased friability are less serious signs, along with excess exudate that is watery and serous rather than purulent.

 

Another confounding factor in diagnosis is the presence of biofilms, which may give the wound a healthy pink appearance while harboring large colonies of bacteria. Proliferating bacteria attach to the wound bed and secrete a glycocalyx coating that helps protect the micro-organisms from antimicrobial agents. These protected colonies can undergo genetic mutation to alter their sensitivity to antimicrobials. Biofilms intermittently release single viable bacterial cells that lead to local infections or weakening of the collagen matrix in recently healed wounds, causing breakdown and reulceration.

Infected wounds less than 1 month in duration usually have a high percentage of Gram-positive organ-

isms. In infected wounds of longer than 1-month’s duration, the wound is likely to acquire multiple organisms including Gram-negatives and anaerobes in addition to the Gram-positive bacterial flora. Infected diabetic foot ulcers. People with diabetes have compromised immunity that leads to a reduced resistance to infection. This is further exacerbated if blood sugars are poorly controlled: patients with a Hb A1C (glycosylated hemoglobin) of greater than 6% will have impaired neutrophil chemotaxis. Diabetes may suppress the classical inflammatory signs of infection.

  1. aureus is a common aerobic isolate in diabetic foot ulcers along with Staphylococcus epidermidis,

Streptococcus spp, P. aeruginosa, Enterococcus spp, and coliform bacteria. When appropriate microbiological techniques are used, anaerobes are also isolated from  up to 95% of diabetic wounds,the most common isolates being Peptostreptococcus, Bacteroides and prevotella species.

Infected leg ulcers and pressure ulcers (decubitus).

The flora in chronic venous leg ulcers is often polymicrobial, with anaerobes constituting approximately 30% of the total number of isolates in non-infected wounds. S. aureus is the most common pathogen found in leg ulcers but the incidence of anaerobes increases in clinically infected leg ulcers to approximately 49%.  The flora of infected pressure ulcers is also polymicrobial and is often similar to that seen in some acute necrotizing soft tissue infections.

 

Most chronic wounds contain more than three species of micro-organisms, which increases the risk of infection because they may develop synergies with each other. The combined effects of aerobes and anaerobes in wounds may be synergistic, producing effects that are not seen with just one type of micro-organism. Oxygen consumption by aerobic bacteria brings about tissue hypoxia, which favors the growth of anaerobic bacteria; one bacterium may produce specific nutrients that are required by other micro-organisms; and some anaerobes are able to impair the host immune cell functions, providing a competitive advantage to themselves and other micro-organisms

 

Diagnosing Infection

 

Diagnosis is primarily a clinical skill, and microbiological data should be used to supplement the clinical diagnosis, not the other way around. The progress of a wound along the continuum to an infected state cannot be predicted by the presence of a specific type of bacterium. Neither bacterial load nor type can be used in isolation to provide a definitive diagnosis of infection because the immune response of the host is critical in determining whether a wound will become infected. A healthy host will be able to tolerate a higher bacterial load and to resist infection from otherwise highly virulent pathogens better than a compromised host. The classical signs of infection in acute wounds include pain, erythema, edema, purulent discharge, and increased heat. These are related to the inflammatory process occurring in the wound. Increased blood flow produces the rise in temperature, and fluid leaking from intravascular spaces accumulates in the tissue, causing visible swelling. Vasoactive mediators such as histamine produce the characteristic erythema, and pain is caused through activation of plasma-derived mediators near unmyelinated nerve fiber endings. For chronic wounds, it has been suggested that other signs should be added: delayed healing, increased exudate, bright red discoloration of granulation  issue, friable and exuberant granulation, new areas of slough or breakdown on the wound surface, undermining, foul odor, and new areas of wound breakdown. Purulent exudate, usually white and creamy, is common in infections produced by bacteria such as S. aureus. By contrast, serous exudate is thin and clear in color. Serous exudate may be increased in a chronic wound with increased bacterial burden before purulence is noted.

It has been suggested that chronic wounds should show some evidence of healing within 4 weeks to progress to healing within 12 weeks. If this time limit is exceeded, increased bacterial burden or infection should be suspected as one of the causes of delayed healing.Discolored granulation tissue arises from excessive angiogenetic responses caused by pathogens, while friable granulation tissue bleeds easily with light pressure. Healthy granulation tissue is pink-red and firm with a moist translucent appearance.When infected, it will appear dull and may have patches of greenish or yellow discoloration. Certain anaerobic species such as Bacteroides fragilis and streptococci can produce a dullish, dark-red hue, while Pseudomonas will produce green or blue patches which may fluoresce with a black or Woods light. Undermining is probably caused by a lack of granulation tissue that has been inhibited or digested by bacteria along some areas of the wound bed. Foul odor is usually caused by Gram-negative bacilli, Pseudomonas species, or anaerobic bacteria.

Faulty collagen formation arises from increased bacterial burden and results in over-vascularized friable loose granulation tissue that usually leads to wound breakdown. Deep infection will often cause erythema and warmth extending 2 cm or more beyond the wound margin. This increased inflammatory response is painful and will cause the wound to increase in size or lead to satellite areas of tissue breakdown that cause adjacent ulceration. Deep infections, especially in ulcers of long duration, can often lead to osteomyelitis.Probing to bone is a simple clinical test that carries a high probability of osteomyelitis, especially in peoplewith diabetic foot ulcers

 

CLINICAL SIGNS AND SYMPTOMS OF WOUND INFECTION

 

Superficial increased bacterial

burden (critically colonized)

 

Deep wound infection

 

Systemic infection
Non-healing

Bright red granulation tissue

Friable and exuberant granulation

New areas of breakdown or

necrosis on the wound surface

(slough)

Increased exudate that may be

translucent or clear before

becoming purulent

Foul odor

 

Pain

Swelling, induration

Erythema

Increased temperature

Wound breakdown

Increased size or satellite areas

Undermining

Probing to bone

 

Fever

Rigours

Chills

Hypotension

Multiple organ failure

 

 

BIOFILMS AND WOUND INFECTION

 

Biofilms are complex polymicrobial communities that develop on or near wound surfaces. Biofilms may not present with clinical signs of infection , but their presence has been implicated in chronicity .

They are invisible to the naked eye, cannot be detected by routine cultures and are extremely difficult to eradicate. Not all biofilms are harmful, but some communities can be tantamount to wound infection, delaying healing as a result. The host’s attempt to rid the wound of a biofilm stimulates a chronic infammatory response, which releases high levels of reactive oxygen species (ROS) and proteases (MMPs and elastase). Although these substances help break down the attachments between the tissue and the biofilms, the ROS and proteases also damage normal and healing extracellular matrix tissues, potentially delaying healing .

DEVELOPMENT OF BIOFILMS

Te extracellular polymeric substance that contributes to the structure of the biofilm lets microbial species exist in close proximity to one another. This matrix — which can be largely impermeable to antibiotics — acts as a thick, slimy protective barrier and attaches the biofilm firmly to a living or non-living surface.

Bioflms are dynamic and heterogeneous communities. They form quickly — within two to four hours — and evolve into a fully mature biofilm community within two to four days . They rapidly recover from mechanical disruption and reform mature biofilm within 24 hours. Communities can consist of a single bacterial or fungal species or, more commonly, can be polymicrobial .

PREVALENCE OF BIOFILMS

Using electron microscopy and confocal scanning laser microscopy, biofilms have been found in 60% of biopsy specimens from chronic wounds, compared with only 6% of biopsies from acute wounds. Because biofilms are thought to signifcantly contribute to multiple infammatory diseases, it is likely that almost all chronic wounds have biofilm communities on at least part of the wound bed. Although biofilms might be an important contributor to wound chronicity, not all wounds with delayed healing can be assumed to contain bioflm. Further, the distribution of bioflms when they do exist in wounds seems to depend on the species, with P. aeruginosa found in deeper wound areas than S. aureus. In addition, it is not known whether the presence of a biofilm in a wound will always lead to problems.

WHEN TO SUSPECT A BIOFILM

Chronic skin wounds often lack overt clinical signs of infection and might have low bacterial burdens as measured by standard clinical microbiology laboratory assays . The term ‘biofilm’ was developed in an attempt to acknowledge that bacteria play a critical role in the failure to heal of wounds that do not have obvious signs of infection.

MANAGING BIOFILMS

Evidence to date suggests that debridement or vigorous physical cleansing, are the best methods for reducing biofilm burden . Before commencing debridement, however, the patient should be assessed to determine the wound’s healing potential. Wound irrigation using sterile saline or tap water can be used to clean chronic wounds to allow assessment and debridement. It is important to remember to not use gauze or cotton wool during cleaning, to avoid leaving debris in the wound bed, which might in turn cause infection. Topical antiseptic agents are considered unnecessary for general wound cleansing, but might be of value when irrigating an infected cavity wound or chronic wounds at risk of infection

Active debridement is contraindicated in cases of severe vascular compromise. When indicated, remove non-viable tissue as quickly and effciently as possible using an appropriate debridement method to assist with assessment, reduce bioburden/biofilm and accelerate healing . Clinicians can use autolytic, mechanical, sharp, larval therapy (biosurgical), ultrasonic, hydrosurgical and surgical debridement.

The debridement method chosen should be determined by the patient’s clinical need and choices, and not limited by the skills of the clinician. Keep in mind that no form of debridement or cleansing is likely to remove all bioflm, so remaining bacteria/biofilm could reform into mature biofilm in a matter of days. Topical antimicrobial interventions are potentially more effective at this post-cleansing/post-debridement stage, and should be considered for application to the wound, either as an antiseptic wound-cleansing agent with a surfactant component and/or antimicrobial dressing.

Use of topical antimicrobial agents in the presence of biofilms should occur only after biofilm disruption. These key steps summarise the management of bioflms in practice :

■  Seek to prevent biofilm development whenever possible.

■  Prepare the wound bed, considering the use of cleansing, debridement and topical antimicrobials where appropriate.

■ Vigorously clean the wound with products designed to disrupt biofilm.

■  Select debridement method based on wound type, best practice and patient preference.

■ After debridement, consider topical antimicrobial treatment, as the biofilm is more vulnerable at this stage and can be managed with topical antimicrobial application more efectively than it could have been pre-debridement.

 

The Role of Microbiology in Diagnosis

Culturing a chronic wound that is healing at an expected rate and does not display any signs or symptoms of infection is unnecessary. Because all wounds are contaminated and colonized, a culture simply confirms the presence of micro-organisms without providing any information as to whether they are having a detrimental effect on the host. However, bacterial swabs can provide information on the predominant flora within a non-progressing, deteriorating, or heavily exudating wound.Microbiological tests also can screen for multi-resistan bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE). The degree of inflammatory response is measured by the presence and quantity of neutrophils per high power field in the Gram stain of the swab contents before inoculating the specimen on growth media. If a wound has progressed beyond the stage of increased bacterial burden or covert infection, systemic antimicrobial therapy would be required to supplement local treatment, and the microbial analysis would assist in targeting therapy. However, quantifying the bacterial load through invasive tissue biopsy is not always necessary in clinical practice. A number of alternative non invasive techniques have been assessed and provide similar information with far less trauma to the patient.

Which culture technique should be used?

Quantitative sampling (tissue biopsy) has merits, and a strong association exists between the number of orgaisms in a wound and the ability of the wound to heal. Once bacterial load reaches 106 CFU/g of tissue, wound healing is usually impaired. However, these findings need to be viewed in perspective. At least 20% of wounds colonized with more than 105 CFU/g of tissue will still heal, and normal skin flora present in high quantities appear to enhance wound healing.

On the other hand, some micro-organisms (eg, beta-hemolytic Streptococci, Mycobacterium tuberculosis, Treponema pallidum, Corynebacteria diphtheriae, Bacillus anthracis, Francisella spp and Brucella spp) can be detrimental in small numbers. Thus, quantitative microbiology does not necessarily provide an unambiguous diagnosis of infection. Quantitative biopsy also may have poor sensitivity and reliability.

Procedure for Taking a Swab

In most cases, wounds should not be cultured if no evidence of infection or impaired healing is noted unless screening is being performed for colonization of multi-resistant organisms. The wound bed must first be cleaned with saline and superficially debrided so the cultures from the superficial wound compartment more closely resemble those in the deep wound compartment. Some clinicians have recommended alginate or rayon-tipped swabs in the belief that the fatty acids contained in cotton swabs might inhibit growth in certain bacteria. However, the organisms commonly encountered in infection are likely to withstand the environment of a cotton swab. Pre-moistening a swab in the transport media is useful if the surface of the wound is dry (it can improve the yield) but is not necessary if the wound is already moist. The swab should be taken from the granulation tissue surface of the wound, avoiding debris and frank collections of pus. The tip of the swab should be rolled on its side for one full rotation over the part of the wound granulation tissue with the most obvious signs of infection, avoiding slough and surface purulent discharge. A zigzag pattern can be used for wounds larger than 5cm2 . This technique is likely to increase the yield of non-significant colonizers; a preferred alternative is to take more than one regional swab from the upper and lower areas of the wound. If pus or discrete abscesses are collected locally, the fluid should be aspirated into a syringe using a needle. The fluid is an ideal specimen for culture. Likewise, deep curettings from the debridement process should be sent for analysis; these closely correlate to biopsy samples.

 

Treating Infected and Inflamed Ulcers

Local wound care. If all systemic factors have been identified and corrected and the wound still fails to heal, the prime objective of treatment will be to reduce bacterial burden using debridement, moisture balance, and topical antimicrobial agents. If inflammation due to active vasculitis or pyoderma gangrenosum is suspected, sharp debridement is not recommended, although other aspects of management are similar to those for infected wounds.

 

Antiseptics 

Antiseptics can be toxic both to microbial cells and host cells, although this appears to be concentration-dependent and can be modified by altering the form in which the agent is delivered. Concern over the use of antiseptics, especially hydrogen peroxide and aniline dyes (crystal violet, neutral red, mercurochrome), has largely centered on their potential for cytotoxicity toward important components of wound healing such as fibroblasts, keratinocytes, and leukocytes. However, the cytotoxic effects were observed in vitro where concentrations were high and have not been observed in lower in vivo concentrations where they may retain their antimicrobial activity without damaging host cells. These agents are generally reserved for those patients with non-healable wounds (those with inadequate blood supply or lowered host resistance) and may be used for short periods in patients with increased bacterial burden in the superficial compartment if the bacteria are of more concern than potential cellular toxicity. This may be the case if the wound surface shows significant necrotic debris that has not been debrided. A deep infection or sinus beneath a moist wound surface will facilitate bacterial proliferation and hinders host response. Preferred local antiseptic agents that have a  combination of acceptable cellular toxicity, broad-spectrum antibacterial coverage, residual effect, and low sensitization potential include povidone iodine and chlorhexidine.

CONSIDERATIONS WHEN SELECTING TOPICAL ANTIMICROBIALS

Products vary according to the concentration and availability of the active ingredients, mode and duration of action, and ability to handle exudate, odour or pain, and should be selected specific to the needs of each wound, weighing the advantages and drawbacks of use To avoid serious consequences of infection, clinicians must also identify high-risk patients, such as those with poor vascularity or compromised immune systems, for whom the systemic antibiotic use might be indicated. For spreading infection, systemic antibiotics are normally selected empirically.

TWO-WEEK REVIEW

Once started, the effect of the antimicrobial on the wound must be closely monitored. The wound should be reviewed at each dressing change and fully at two weeks. Take the following actions in the follwing situations:

■  If there are signs of progression and a reduction in the signs and symptoms of infection or critical colonisation, discontinue the antimicrobial dressing.

■  If the wound shows signs of progression and of infection, continue with the antimicrobial dressing for a further two weeks, unless the wound deteriorates earlier.

■  If the wound deteriorates, fully reassess to exclude contributing causes (other than infection) that might indicate an alternative approach or the addition of systemic therapy.

 

Microbiological control

 

Principles of antibiotic treatment

  • The microbiology of the diabetic foot is unique.Infection can be caused by Gram-positive aerobic, and

Gram-negative aerobic and anaerobic bacteria, singly or in combination

  • As there may be a poor immune response from the diabetic patient, even bacteria normally regarded as skin commensals may cause severe tissue damage. This includes Gram-negative organisms such as Citrobacter, Serratia, Pseudomonas and Acinetobacter. When Gram-negative bacteria are isolated from a deep ulcer swab or curettings they should not, therefore, be regarded as automatically insignificant
  • When a positive culture is found, it is then possible to focus antibiotic therapy according to sensitivities of the bacteria cultured
  • However, at initial presentation it is important to prescribe a wide spectrum of antibiotics for three reasons:

(a) it is impossible to predict the number and type of organisms from the clinical presentation

(b) there is no way of predicting who will develop a rapidly ascending infection which becomes limb-

threatening and even life-threatening

(c) diabetic patients are immunosuppressed. The neuropathy and ischaemia of the diabetic foot reduces the local resistance to invading bacteria.

Duration of antibiotic therapy will depend on the clinical progress of the foot and ulcer, tissues involved, severity of the initial infection and also on individual factors relating to the patient.

The route by which therapy is given will depend on the severity of the infection. Use oral therapy for localized infections, intramuscular or intravenous therapy for spreading infections and intravenous therapy for severe infections. Intestinal absorption is unreliable in these  circumstances.

It is important to have a working knowledge of the principal bacteria and their local antibiotic sensitivities including awareness of the prevalence of resistant organisms. However, in every patient, individual sensitivities of each organism isolated on culture should be sought to guide rational antibiotic therapy.

Staphylococcus aureus

This is the commonest pathogen in the diabetic foot and flucloxacillin is the ideal treatment. Clindamycin can also be used but beware of antibiotic-induced colitis especially in the elderly and postoperative patients. Erythromycin may increase the risk of myositis from statin therapy. When taking erythromycin, patients should be advised to stop their statin therapy temporarily.

Methicillin-resistant Staphylococcus aureus (MRSA)

MRSA is associated with the whole spectrum of clinical presentations of diabetic foot infections and commonly occurs in patients who have been in hospital. It can be simply a commensal with no signs of invasive infection but it can also cause severe infections, osteomyelitis and bacteraemia. The frequency of MRSA infections is increasing in the diabetic foot. However, MRSA infections are not necessarily more pathogenic than conventional Staphylococcus aureus  infections. They do frequently cause more extensive tissue destruction because they are often not diagnosed until late These MRSA do not have the multi-resistance of the hospital-acquired MRSA but nevertheless can rapidly progress to severe infections. Approximately two-thirds possess the Panton-Valentine leukocidin (PVL) toxin, which acts to form pores in the cell membrane of mononuclear cells and polymorphonuclear cells and can lead to severe tissue necrosis. Also beware that one-third of hospital-acquired MRSA can express the PVL toxin. MRSA can lead to invasive infection and in these circumstances it is best to give vancomycin intravenously with dosage to be adjusted according to serum levels, or teicoplanin. These antibiotics may need to be accompanied by either sodium fusidate or rifampicin orally. Linezolid is also active against MRSA and has good soft tissue and bony penetration. It is well absorbed. It is necessary, however, to check the platelet count regularly as there may be some marrow suppression with this antibiotic. Courses should not exceed 28 days. The combination of antibiotics quinupristin and dalfopristin can be used when an MRSA infection has not responded to other antibacterials. Daptomycin and tigecycline may also be used in MRSA infections. MRSA can also be treated with clindamycin but sensitivity needs to be confirmed as MRSA resistance to clindamycin has emerged. If MRSA is isolated in localized infections, oral therapy can be given with two of the following: sodium fusidate 500 mg tds, rifampicin 300 mg tds, trimethoprim 200 mg bd or doxycycline 100 mg daily, according to sensitivities.

Streptococcus group A, B, C, E, F and G

Streptococcus group B is the commonest and can cause severe infection in the diabetic foot although C, E, F and G can infect the foot.  Streptococcus group A rarely causes infection but when it does it causes a severe blistering  cellulitis and tissue destruction. The Streptococcus milleri group of organisms are beta haemolytic streptococci that can cause abcesses in the foot. Streptococci can be treated with amoxicillin. Clindamycin, rifampicin and erythromycin may also be also active against streptococci.

Enterococcus

Enterococcus faecalis is rarely pathogenic. It may be selected out by cephalosporin treatment. If it is causing definite infection then it may be treated with amoxicillin. Enterococcus faeciummay need vancomycin.

Anaerobes

These are commonly found in deep infections but anaerobes are also a feature of many chronic wounds even when they are superficial. They are associated with necrotic wounds. Anaerobes can act synergistically with Gram-positive and Gram-negative aerobes to cause severe tissue destruction.

Metronidazole is the treatment of choice. Clindamycin and co-amoxiclav (amoxicillin/clavulanic acid) also have anti-anaerobic activity. Meropenem, piperacillin/ tazobactam and ertapenem are also active against anaerobes.

Gram-negative organisms

Klebsiella, Escherichia coli, Proteus, Enterobacter, Citrobacter, Serratia and other Gram-negative bacteria can be definitely pathogenic in the diabetic foot especially when they are in a pure growth or as part of a polymicrobial deep infection. Oral agents that are available to treat Gram-negatives are ciprofloxacin and trimethoprim. Parenteral agents include ceftazidime, aminoglycosides, meropenem, piperacillin/tazobactam, ticarcillin/clavulanate, tigecycline and ertapenem. It is crucial to obtain sensitivity patterns with Gram-negative organisms and not depend on empirical therapy alone. Recently, Gram-negative bacteria have acquired various resistance patterns through the development of certain enzymes and this is relevant to the choice of antibiotic therapy.

Organisms have developed extended-spectrum beta lactamases which are known as ESBLs. By this means, they have developed resistance to extended-spectrum (third generation) cephalosporins (e.g. ceftazidime, cefotaxime, and ceftriaxone) but not to carbapenems (e.g. mero- penem or imipenem). ESBL enzymes are most commonly produced by two bacteria: Escherichia coli and Klebsiella pneumoniae. Another group of lactamases are AmpC  β-lactamases, which are typically encoded on the chromosomes of many Gram-negative bacteria including Citrobacter, Serratia and Enterobacter species where expression is usually inducible.

Pseudomonas

There are many members of the genus  Pseudomonas.Pseudomonas aeruginosa is an important human opporunist bacterium in the diabetic foot. It can be responsible for a spectrum of presentations from superficial colonization of ulcers to extensive tissue damage, including osteomyelitis, septic arthritis and bacteraemia. It may be  sensitive to ciprofloxacin as an oral agent. Otherwise parenteral therapy is necessary and includes ceftazidime, aminoglycosides, meropenem, piperacillin/tazobactam, and ticarcillin/clavulanate.

Antibiotics used mainly against Gram-positive organisms

Amoxicillin

This antibiotic is active against streptococci but is inactivated by penicillinases that are produced by  Staphylococcus aureus and by Gram-negative bacteria such asEscherichia coli.

Co-amoxiclav

This is a combination of amoxicillin and clavulanic acid.The latter is a beta lactamase inhibitor, thus widening thespectrum of activity of co-amoxiclav against beta lactamase producing bacteria that are resistant to amoxicillin including staphylococci, anaerobes and Gram-negative bacteria. The risk of liver toxicity is six times greater with amoxiclav compared with amoxicillin.

Flucloxacillin

This antibiotic is not destroyed by pencillinases and thus it is effective against penicillin-resistant staphylococci. When given intravenously, its dosage may be increased to 2 g qds in staphylococcal bacteraemia or osteomyelitis.

Erythromycin and clarithromycin

They have a similar spectrum to penicillin and are thus useful against staphylococci and streptococci in patientswho are allergic to penicillin. There is an increased risk of myositis and rhabdomyolysis if the patient is on  statin therapy. Thus, statin therapy should be stopped for the duration of erythromycin therapy. If the patient develops intolerance to erythromycin, particularly gastrointestinal side-effects, then clarithromycin may be used.

Fucidin

This is active against penicillin-resistant staphylococci. It has good bone penetration and is useful in osteomyelitis. Resistance to it develops quickly if it is given alone and therefore it should be given with another antistaphylococcal agent. It is useful in combination therapy to treat MRSA infections. Liver function should be monitored if therapy is prolonged and it should be given with caution in patients with liver disease.

Doxycycline

This antibiotic can be used in treating MRSA infections. It should be used with caution in patients with hepatic impairment.

Rifampicin

This is active against staphylococci and streptococci and has good soft tissue and bone penetration. Patients should be warned that if they develop nausea, vomiting or malaise they should report this immediately as it may reflect liver dysfunction, which is a well described but rare side-effect of rifampicin therapy. It should be given with caution in patients with existing liver disease. Patients should be warned that their body secretions will turn red. Rifampicin should not be given alone because resistance can develop rapidly.

Clindamycin

This has very good soft tissue and bone penetration and is active against staphylococci, streptococci and anaerobes including Bacteroides fragilis. However, historically it has been linked with antibiotic-associated colitis caused by Clostridium difficile infections although this can occur with many antibiotics.

Vancomycin

This is usually given intravenously. It is active against Gram-positive organisms and is usually used for MRSA infections. Blood levels should be monitored and trough levels should be less than 15 mg/L.

Teicoplanin

This is a glycopeptide antibiotic which is active againstGram-positive organisms including MRSA. It can be given intravenously but also intramuscularly. This is a convenient therapy to be given at home.

Linezolid

Linezolid is active against Gram-positive organisms, including MRSA and vancomycin-resistant enterococci. It can be given orally or intravenously. It may cause marrow suppression and regular platelet counts are advisable. It should not be given for more than 28 days.

Daptomycin

This is a lipopeptide antibacterial active against Gram-positive organisms including MRSA. It is given intravenously and has good soft tissue penetration. Weekly creatine phosphokinase levels should be monitored.

Quinupristin/dalfopristin

This is a combination of two antibiotics, quinupristin and dalfopristin, which work synergistically against Gram-positive organisms including MRSA.

Trimethoprim

It has reasonable soft tissue penetration and is active against Gram-positive and -negative bacteria. It is also useful in combination therapy against MRSA.

Antibiotics used mainly against Gram-negative organisms

Ciprofloxacin

This is useful against Gram-negative organisms and  has good soft tissue and bone penetration. It has only moderate activity against Gram-positive organisms. It is relatively well tolerated but occasionally can give neurological side-effects and can rarely predispose to hypoglycaemia in certain patients.

Septrin

This is a combination of trimethoprim and sulphmethoxazole. This is occasionally used to treat resistant Gram-negative organisms such as  Stenotrophomonas  maltophilia but should only be used if other antibiotics against Gram-negative organisms are not appropriate.

Ceftriaxone

This is a useful antibiotic that can be given either intravenously or intramuscularly when it is administered as 1 g in 3.5 mL of 1% lidocaine. It needs to be given only once a day. This can be given in the community on a once daily basis. It has a wide spectrum of activity but is not active against MRSA or Pseudomonas.

Ceftazidime

This is useful as an initial agent to cover Gram-negative infections as it is usually active against  Pseudomonas.  If the dosage is not reduced in renal impairment, then  the patient may develop muscular twitching and even  fits.

Piperacillin/tazobactam

This antibiotic is given intravenously. It has a wide spectrum of activity including Gram-positive and Gram- negative organisms such as Pseudomonas and anaerobes. It may be useful against bacteria with extended-spectrum beta lactamases.

Ticarcillin/clavulanic acid

This is given intravenously and is active against Pseudomonas, and other Gram-negative bacteria including Proteus spp. and Bacteroides fragilis. Imipenem with Cilastin It is a carbapenem with broad-spectrum activity against Gram-positive and Gram-negative organisms including anaerobes. Imipenem is partly inactivated in the kidney and this is blocked by cilastin. It should be used with caution in renal failure as it may cause fits.

Meropenem

This also has a wide spectrum of activity including usually Pseudomonas. Meropenem is given intravenously and has less frequently caused central nervous system side-effects including fits compared with imipenem. It is also useful against bacteria with ESBLs.

Ertapenem

This is given once daily and is useful against Gram-positive and Gram-negative organisms and also anaerobes. In a recent study it was shown to be equivalent in action with piperacillin/tazobactam in treating infected diabetic feet. It is not active against Pseudomonas or against Acinetobacter. It is useful against bacteria with ESBLs and AmpC-producing Gram-negative bacteria. It may be given intramuscularly as 1 g diluted with 3.2 mL of 1% lidocaine.

Tigecycline

This is a broad-spectrum glycylcycline antibiotic that is structurally similar to tetracycline antibiotics. It is useful in infections caused by Gram-positive organisms, including MRSA, Staphylococcus aureus, vancomycin-resistant enterococci, streptococci, Gram-negative organisms including those with ESBLs and anaerobes including Bacteroides fragilis. Strains of Proteus spp. and Pseudomonas aeruginosamay be resistant.

Aminoglycosides.

These include amikacin, gentamicin, netilmicin and tobramycin. Gentamicin is the aminoglycoside of choice in the UK. It is active against some Gram-positive organisms and many Gram-negative organisms. Important  side-effects are ototoxicity and nephrotoxicity. These side effects are dose-related and thus extreme care should be taken with dosage. Gentamicin should be administered with strict blood level monitoring and the trough level should be less than 1 mg/L. Antibiotics used against anaerobic organisms

Metronidazole

This is useful against anaerobic bacteria. Patients must be warned not to take alcohol.