Systemic Antimicrobial Therapies for Pressure Ulcers

Marco Romanelli, MD, PhD; Antonio Magliaro, MD; Diego Mastronicola, MD; and Salvatore Siani, MD

I n chronic wounds, an altered balance among the number of organisms present, their virulence, and host resistance leads to bacterial infection. Infected chronic wounds may manifest with a friable bright red granulating wound bed, localized pain, increased wound size, perilesional warmth and tenderness, erythema on the surrounding skin, malodorous base, and increased wound exudate. The final outcome of infected wounds depends on a balance between factors that promote further complications or lead to their resolution. Wound infection in the geriatric population merits especially assiduous control and rapid intervention because it adversely affects patients' psychological, functional, and medical status. Patients may fear that infection will progress, causing severe psychological distress due to pain or altered appearance; they may experience a rapid decline of their already compromised functional status.
Simple bacterial wound infections often are treated according to their morphological appearance and to clinical experience because only a few pathogens are involved (see Figure 1). Treatment of critical lesions such as infected pressure ulcers or foot ulcers in a person with diabetes once involved administering oral or parenteral antibiotics among normal hosts. Usually, patients with deeper infections are sicker and require more vigorous intervention. Intravenous antibiotics are often prescribed after hospital admission in these cases; surgical drainage and rapid debridement are necessary when the infectious process is deep, extending down to fascia or muscle (see Figure 2). In recent decades, with a dramatic development of several groups of antimicrobial agents, the clinician has been faced with a long list of new antibiotics1 that may be lacking meaningful comparative information. Because of the large number of new agents in clinical practice, terms such as "new generation" antibiotics are commonly used.

Pressure ulcers are commonly colonized by several organisms in the absence of clinical signs of infection (see Table 1). When infection is present, the significance of laboratory tests must be critically evaluated and drug susceptibility tests must be considered according to the clinician's experience and the evidence base from the literature.2 On the other hand, some organisms that once had predictable antibiotic susceptibility characteristics now have become resistant.3 The rapid emergence of antibiotic-resistant bacteria has been highlighted by Colsky et al4 in an ongoing surveillance of patients with complicated skin infections that required hospitalization. In this study, 50% of Staphylococcus aureus isolates from chronic wounds was resistant to oxacillin, with 36% of Pseudomonas isolates resistant to ciprofloxacin. A comparison between these data and previous data obtained by the same authors for the same group of patients5 demonstrated an increasing trend in antibiotic resistance for different species of bacteria involved in soft and deep skin infections.

Clinical Response
A favorable clinical outcome is achieved in infected pressure ulcers when the patient is in stable condition and systemic treatment is established together with good local care (ie, a combination of surgical debridement and exudate control). The antimicrobial drug regimen must be adjusted according to the clinical response of the patient. If marked discrepancies are evident between drug susceptibility tests and clinical response, the following possibilities must be considered: inappropriate selection of drug dosage or route of administration, the emergence of drug-resistant bacteria, and the additional participation of micro-organisms not previously detected. Because patients who develop pressure ulcers often are critically ill and already have received several courses of antibiotic therapy in addition to wound management, host defenses must be maximized to include maintaining adequate nutrition and correcting electrolyte imbalances.6
Osteomyelitis is a common complication in infected pressure ulcers; S. aureus is the cause of approximately 60% of all cases.7 The diagnosis of osteomyelitis is obtained by blood culture and bone biopsy and should be the second step in the event of sterile blood culture. A prolonged parenteral therapeutic regimen of 4 to 6 weeks is often required.8
Preventing infection in pressure ulcers is a difficult task and no uniformly accepted approach has been adopted. Nosocomial-acquired infections account for up to 5% of hospitalized patients in the US. Invasive devices such as intravenous catheters, Foley catheters, and nasogastric tubes must be used only when absolutely necessary and follow sterile procedures as much as possible. The implementation of simple measures to prevent wound infection such as hand washing should be done routinely even when gloves are utilized.9

Duration of Treatment
A targeted antimicrobial treatment is usually efficacious in reversing the clinical and laboratory parameters of active infection. Using systemic antibiotics in infected chronic wounds may require different periods of treatment. The optimal duration of the antimicrobial therapy depends on several factors, including: a) the type of infecting organism, b) the location and depth of the wound, and c) the immunocompetence of the patient. Current practice calls for oral antibiotics for 2 to 4 weeks after initial treatment of symptomatic infected wounds with topical antimicrobials.10 This practice is based on several trials11 showing that failure to provide adequate antibiotic treatment for several weeks results in an unacceptably high rate of recurrences. Although the optimum duration of therapy is unresolved, several studies12-14 have shown that prolonging the administration of oral antibiotics is associated with a significant increase in the risk of microbial resistance. Therefore, at present, long-term oral antibiotic therapy remains a matter of clinical judgment where the benefits outweigh the risk in the individual patient.

Route of Administration
Superficial wound infections of mild to moderate severity can be treated with local antimicrobials, oral antibiotics, or a combination of these methods. Deep wound infections, with or without systemic manifestations, should be vigorously treated with parenteral antibiotics in adequate dosage. A number of factors must be considered in administering antibiotics (see Table 2). Food does not significantly influence the bioavailability of most oral antimicrobial agents with the exception of the tetracyclines and quinolones.
Caution must be exercised in administering intramuscular medications to avoid sterile or infected abscesses. A major complication of intravenous antibiotic therapy is catheter infections. When the intravenous route is used, a needle or heparin-lock is preferred.15 Percutaneous catheters should be changed frequently (every 48 to 72 hours) and all line-skin sites kept clean with a topical antibiotic ointment and sterile dressing. Most catheter-related infections present with local signs of infections at the insertion site. The excretory pattern of a given antibiotic should always be considered in order to avoid toxic accumulation in critically ill patients. In patients with altered renal or hepatic clearance of drugs, the dosage and frequency of administration must be carefully monitored.

Systemic Antimicrobial Agents
Beta-lactams. Amoxicillin-potassium clavulanate is a naturally occurring beta-lactam structurally similar to the penicillin nucleus. This antibiotic group of beta-lactam/beta-lactamase combination has demonstrated a broad-spectrum activity; therefore, it is frequently used for the treatment of infected pressure ulcers. The carbapenems (imipenem/cilastatin, meropenem) have the broadest spectrum of activity of any available antibiotics but they are costly and need to be administered parenterally. They are active against most aerobic and anaerobic Gram-positive and Gram-negative bacteria, making these compounds a good alternative in combination regimens in severe infections, even in immunocompromised patients. The carbapenems have to be administered parenterally because the are not absorbed after oral ingestion. Dosing for imipenem depends on the type of infection. Usually, 500 mg every 6 hours is recommended. Because of its broad spectrum of activity, imipenem is most useful in treating infections of mixed flora, such as those found in pressure ulcers or diabetic foot ulcers. It is also used to treat soft-tissue infections, where it has achieved clinical efficacy rates of 95%.16 The most serious toxicity is increased seizure potential. Nausea and vomiting also occur frequently.17
Aztreonam is a member of the monobactams, a new class of beta-lactam antibiotics synthesized by bacteria. Its antibacterial activity is most effective against Gram-negative aerobic bacteria. Aztreonam is administered to patients with a proven allergy to penicillin and cephalosporins. Because it is not well absorbed by the oral route, aztreonam is usually administered parenterally. Aztreonam can be used alone to treat Gram-negative infections such as postoperative wounds, chronic ulcers, burns, and ecthyma gangrenosum.18-20
Cephalosporins. Cephalosporins have been divided into four major groups or "generations" based mainly on their antimicrobial activity.21 All the oral cephalosporins are rapidly absorbed from the gastrointestinal tract, achieving peak serum levels in 1 to 2 hours. The presence of food in the stomach delays, but does not affect the extent of, absorption. The oral cephalosporins are distributed widely in body fluids and tissues, except for spinal fluid and the aqueous humor.22 The oral cephalosporins, with the exception of cefixime, are FDA-approved for the treatment of skin infections caused by S. aureus and group A beta-hemolytic Streptococci.23-25 The usual adult dosage of cephalexin and cephradine is 250 mg every 6 hours or 500 mg every 12 hours. The parenteral agent ceftriaxone is FDA-approved for the treatment of skin and soft-tissue infections caused by susceptible strains of S. aureus, Staphylococcus epidermidis, Streptococccus species (excluding enterococci), Enterobacter cloacae, Klebsiella species, Proteus mirabilis, and Pseudomonas aeruginosa.26 Cephalosporins are contraindicated for patients with either a history of allergy to these drugs or a history of anaphylaxis or severe immediate reactions to penicillin.27
The cephalosporins have an excellent safety profile. The most common adverse systemic effects are hypersensitivity reactions, such as maculo-papular rash, eosinophilia, and drug fever. Immediate hypersensitivity reactions such as anaphylaxis, urticaria, and bronchospasm occur less commonly.28 Gastrointestinal disturbances may occur but are usually mild and transient.29
Fluoroquinolones. The newer fluorinated derivatives (ciprofloxacin and ofloxacin) have been successfully used to treat complicated skin and soft tissue infections such as abscesses, cellulitis, and infected pressure ulcers caused by multiresistant Gram-negative bacteria.30,31 Ciprofloxacin is rapidly absorbed after oral administration. Peak serum concentrations of 1 to 3 mcg/mL are obtained within 1 to 3 hours after a standard oral dose of 500 mg. Concomitant food intake or administration of aluminum- and magnesium-containing antacids reduces absorption.32
Glycopeptides. Vancomycin is bactericidal for most Gram-positive organisms. It is the drug of choice for methicillin-resistant S. aureus (MRSA) and S. epidermidis, but the drug must be administered intravenously for systemic effect. Today, vancomycin-resistant strains of Enterococci have become an increasing problem, accounting for 15% to 25% of isolates; because this is one of the last available therapeutic options for patients with MRSA, the drug must not be overused.33,34
Teicoplanin has been found safe and effective for the treatment of Gram-positive infections, offering advantages (eg, the single daily dose either via IV or IM and without the problems of toxicity) over vancomycin.35,36
Metronidazole. An antiprotozoal drug, metronidazole is also active against most anaerobic Gram-negative organisms. Despite the increasing use of topical application in chronic wound management, metronidazole is widely distributed in tissues after oral administration. A dosage of 500 mg orally three times daily is recommended. Patients receiving this drug should avoid the ingestion of ethanol because of the potential enhancement of Disulfiram-like reactions. Metronidazole should be added as part of the first-line therapy when vancomycin-resistant enterococci are present.

The use of systemic antibiotics in infected pressure ulcers should be based on culture results. Therapy should be specific to isolated pathogens to avoid the widespread use of antimicrobial drugs that contribute to the proliferation of drug-resistant organisms. Combinations of drugs are often required to provide synergy, prevent resistance, and offer broad-spectrum coverage of multiple pathogens. Despite the developments observed in the last few years, newer, safer, and more efficacious antimicrobial agents are needed.


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