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Antimicrobial therapy in diabetic foot infections
(Portuguese PDF version)

Hélio S. Sader¹, Anaí Durazzo²

1. Associate Professor, Universidade Federal de São Paulo. Director of International Surveillance Programs, Jones Microbiology Institute, North Liberty, Iowa, EUA.
2. PhD in Medicine, School of Medicine, Universidade de São Paulo.

Correspondence:
Dr. Hélio S. Sader
LEMC - Laboratório Especial de Microbiologia Clínica
Rua Leandro Dupret, 188
CEP 04025-010 - São Paulo - Brasil
E-mail: lemcdipa@terra.com.br

J Vasc Br 2003;2(1):61-66

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Diabetic patients are more prone to developing ulcers in lower extremities, especially on the feet. The presence of peripheral neuropathy predisposes to lesions that heal more slowly due to peripheral vascularization disorders and metabolic disorders caused by diabetes. As in any type of ulcer, the ones that form on the diabetic foot will be colonized by bacteria that colonize the skin. However, disorders of peripheral vascular circulation and peripheral neuropathy that affect diabetic patients increase the frequency of infection and compromise its control by the immune system.¹

All these factors should also be considered for the selection of antimicrobial therapy, since the transport of the antimicrobial up to the infection site is also hindered. Another important factor concerns the type of bacterial colonization that occurs in the diabetic foot ulcer. In general, skin ulcers are colonized by bacteria of the normal skin microbiota, which include gram-positive, aerobic and occasionally anaerobic cocci. Therefore, the most frequently isolated pathogens in skin infections, including infected ulcers, are streptococci, followed by staphylococci and peptostreptococci, the latter of which are anaerobic gram-positive cocci. However, due to frequent contact with health professionals and with medical centers (hospitals, outpatient clinics and private clinics, etc), diabetic patients often have a different microbiota from that of nondiabetics. The pathogens mentioned above are also found in diabetic patients, but the prevalence of bacteria that are more resistant to antimicrobial agents is higher. In addition, other pathogens, usually more resistant to antimicrobials, are also frequently found in diabetic patients.^1-5

These changes to the skin microbiota and, consequently, to the microbiota that colonizes and infects the ulcer, vary considerably from patient to patient and are related to the level of contact with medical centers. Therefore, patients with frequent hospitalizations and visits to outpatient clinics have relevant changes to the microbiota that colonizes and infects the ulcer.^3-5

The etiology of infection in diabetics is directly related to the time of evolution and severity of the ulcer. This way, infections are classified into two major groups: (1) mild infections or non-limb-threatening infections and (2) limb-threatening infections (Table 1). Mild infections are superficial, without major systemic toxicity, with a low level of ulceration and/or cellulitis (less than 2 cm) or nonexistent, and very low level of ischemia. On the other hand, in limb-threatening infections, cellulitis is usually extensive, and the ulcer affects the subcutaneous cellular tissue, resulting in lymphangitis and important ischemia. The selection of the empirical antimicrobial therapy depends on the characteristics mentioned above.^1-2

Table 1 - Staging of infection

Mild or non-limb-threatening infections

Superficial

Without systemic toxicity

Mild superficial cellulitis (less than 2 cm)

Mild ulceration (whenever present)

Slight ischemia

Limb-threatening infections

Extensive cellulitis

Ulcer in the subcutaneous cellular tissue

Lymphangitis

Important ischemia

 

Milder infections or non-limb-threatening infections are often caused by streptococci, staphylococci resistant to oxacillin and to most beta-lactam antibiotics (except penicillin, aminopenicillins and some oral cephalosporins) and, occasionally, anaerobic gram-positive cocci (peptostreptococci) (Table 2).^1-5

Table 2 -Bacterial etiology according to the severity of infection

Non-limb-threatening	Limb-threatening
	Polymicrobial
Mild	Moderate	Severe
- Staphylococcus aureus	Gram-positive, aerobic cocci (staphylococci, streptococci and enterococci)	Gram-positive, aerobic cocci (staphylococci, streptococci and enterococci)
- Streptococci	Gram-negative, aerobic bacilli (E. coli, Enterobacter, etc.)	Gram-negative, aerobic bacilli (E. coli, Enterobacter, etc.)
		Gram-positive anaerobic cocci and Bacteroides
		Gram-negative non-fermenting bacilli (Pseudomonas, Acinetobacter)

 

For teaching purposes, we can divide limb-threatening infections into moderate and severe. Although no significant difference exists as to the etiology of the latter types of infection, the selection of empirical therapy must be different. More powerful antibiotics, with a broader spectrum, should be reserved for severe infections, since the delayed use of the appropriate antibiotic may bring serious consequences. In addition, if broad-spectrum antibiotics are used in moderate infections, there might be no other therapeutic option if the infection does not respond properly. Moderate infections can also be divided into two other types: those that only require the administration of oral antibiotics at an outpatient clinic and those that require hospitalization.^1-5

For both types of infection, a sample should always be collected for culture and antibiogram examination. Although the implementation of antimicrobial therapy is empirical, the identification of the pathogen is essential if the patient does not show a favorable clinical outcome after two or three days of treatment. Anyway, empirical therapy should be targeted at gram-positive cocci, staphylococci and streptococci, which represent the most frequent causes; however, we should expect bacterial strains that are more resistant to the antimicrobials used in mild infections. On top of that, enterococci, which are intrinsically more resistant gram-positive cocci, may be related to these types of infection, especially in hospitalized patients.^1-5

The frequency of gram-negative bacilli is much higher in moderate and severe infections. In moderate infections, it is necessary to cover enterobacteria such as Escherichia coli, K. pneumoniae and Enterobacter spp. In more severe infections, it is necessary to cover glucose non-fermenting gram-negative bacilli, such as Pseudomonas aeruginosa and Acinetobacter spp., and of anaerobic gram-negative bacilli such as Bacteroides fragilis.^6-8

The major therapeutic options for diabetic foot infections are shown in Table 3 according to the severity of the infection. The pathogens involved in mild infections (oxacillin-resistant streptococci and staphylococci) are often sensitive to a large number of oral antimicrobials, among which second-generation cephalosporin, such as oral cefuroxime (Zinat®) or doxycycline (Vibramycin®) are the best choice. Other therapeutic options for mild infections include amoxicillin combined with a beta-lactamase inhibitor, such as clavulanic acid (Clavulin®) and clindamycin (Dalacin®); however, the latter two drugs could be reserved for moderate infections treated at outpatient clinics, or for mild infections that are already at a more advanced stage or which do not have a good clinical response to the initially used antimicrobial.^1-5

Table 3 - Therapeutic options according to the severity of infection

Mild	Cefuroxime (Zinat®); Doxycycline (Vibramycin®); Amoxicillin/clavulanate (Clavulin®); Clindamycin (Dalacin®).
Moderate (oral)	Amoxicillin/clavulanate (Clavulin®); Ampicillin/sulbactam (sultamycin - Oral unasyn ®); Gatifloxacina + metronidazole (Tequin® + Flagyl®); Clindamycin + ciprofloxacin (Dalacin® + Cipro®).
Moderate (IV)	Clindamycin + ciprofloxacin (Dalacin® + Cipro®); Clindamycin + ceftriaxone (Dalacin® + Rocephin®); Gatifloxacina + metronidazole (Tequin® + Flagyl®).
Severe	Levofloxacin + Metronidazole +/- vancomycinb (Levaquin® + Flagyl® +/- Vancocin®); Piperacillin/tazobactam +/- vancomycinb (Tazocin® +/- Vancocin®); Meropenem +/- vancomycinb (Meronem® +/- Vancocin®).

For moderate infections, it is necessary to cover gram-negative bacilli, especially enterobacteria. Aminopenicillins combined with beta-lactamase inhibitors (amoxicillin/clavulanate or ampicillin/sulbactam) are a good therapeutic choice for this type of infection, due to the fact that they have an appropriate spectrum for most non-hospital enterobacteria, have a good coverage of gram-positive skin cocci and of the most common anaerobic cocci. Fluoroquinolones are an excellent therapeutic option for moderate and severe infections that can be treated at outpatient clinics. These drugs are quite powerful against most gram-positive cocci and gram-negative bacilli. Nevertheless, fluoroquinolones should be combined with oral metronidazole (Flagyl®) or clindamycin (Dalacin®), due to their limited effect on anaerobic pathogens. Most recent fluoroquinolones, known as respiratory quinolones, (gatifloxacin [Tequin®], levofloxacin [Levaquin® or Tavanique®] and moxifloxacin [Avalox®]) have a greater power and spectrum against gram-positive cocci and are therefore the most appropriate fluoroquinolones against moderate infections, when combined with metronidazole (Table 3). Another advantage of this combination is that these compounds are available for intravenous and oral administration. If other fluoroquinolone, such as ciprofloxacin (Cipro®) or ofloxacin (Floxstat®), is chosen, it is necessary to combine it with a drug against streptococci (which will not be properly covered by these quinolones) and against anaerobic cocci; in this case, clindamycin (Dalacin®) is an excellent option.^8-10

The therapeutic options for moderate infections that require hospitalization are very similar to the ones previously mentioned, because these antibiotics can be used either orally or intravenously. Another alternative is the combined use of a third-generation or fourth-generation cephalosporin (ceftriaxone [Rocephin®] or cefepime [Maxcef®]) with a drug against anaerobic cocci.¹¹ We should not forget that if oxacillin-resistant Staphylococcus aureus is suspected, vancomycin (Vancocin®) should be included, even if the infection is not considered to be severe.

Severe infections will probably require hospitalization, and the local microbiota should be considered when selecting empirical therapy. As the infection is severe and the introduction of an inappropriate therapy could have serious consequences to the patient, the use of powerful broad-spectrum antimicrobials may be necessary, especially in hospitals with high resistance rates. Two major pathogens are of great importance: oxacillin-resistant S. Aureus (ORSA) and Pseudomonas aeruginosa. These pathogens are usually quite resistant and present few therapeutic choices.^7-8

A fluoroquinolone combined with a drug that has an excellent spectrum against anaerobic organisms, such as metronidazole (flagyl®), plus a drug that is efficient against ORSA, is a quite appropriate treatment scheme.^9-10 In this case, the most suitable fluoroquinolone may be levofloxacin (Levaquin® or Tavanique®), since it is highly efficient against gram-positive cocci and its action is very similar to that of ciprofloxacin against P. aeruginosa. Other options are gatifloxacin (Tequin®)¹¹ or moxifloxacin (Avalox®). Ciprofloxacin (Cipro®) should be avoided since it does not properly cover streptococci. The resistance rates of P. aeruginosa to fluoroquinolones are quite high at some centers.^7-10,12

Another adequate therapeutic option is the combination of piperacillin/tazobactam (Tazocin®) with vancomycin (Vancocin®). This scheme provides good coverage against gram-negative bacilli (including P. aeruginosa), gram-positive cocci, and gram-negative and gram-positive anaerobic organisms. However, two aspects should not be forgotten: (1) the rates of resistance to piperacillin/tazobactam may be high in some species of enterobacteria, such as Enterobacter spp., and (2) the infusion of piperacillin/tazobactam requires a large amount of fluid and NaCl, which is a serious problem in diabetic patients with abnormal renal function.^2-6

A scheme that is widely used in case of severe infections of unknown etiology, which may also be used in severe cases of diabetic foot infections, is the combination of carbapenem with vancomycin (Vancocin®). This scheme offers excellent coverage against gram-negative bacilli (including P. aeruginosa and Acinetobacter spp.), gram-positive and anaerobic cocci. As for carbapenems, the best choice would be meropenem (Veronem®), because of its greater power and spectrum against P. aeruginosa. Resistance to carbapenems among strains of P. aeruginosa and Acinetobacter spp. has increased in some Brazilian hospitals. These beta-lactam antibiotics, available in most medical centers, are still the antimicrobials with the broadest spectrum against gram-negative bacilli.^7,8,13

In case of carbapenem-resistant strains of P. aeruginosa and Acinetobacter spp. the only therapeutic option is to use a polymyxin (polymyxin B or colistin). These drugs are not available in many medical centers and their use may cause some toxicity, especially to the kidneys. Nevertheless, in some situations, they may be the only effective therapeutic option. Notably, some rare glucose non-fermenting gram-negative bacilli, such as Stenotrophomonas maltophilia and Burkholderia cepacia, are intrinsically quite resistant to most antimicrobials. In addition, these pathogens may present a quite uncommon sensitivity profile. S. maltophilia, for instance, is resistant to carbapenem and to most beta-lactamic drugs, quinolones and even to aminoglycosides, but it is usually sensitive to sulfamethoxazole/trimetoprim (Bactrim®). Moreover, the laboratory of microbiology will have problems to perform the sensitivity test for these bacteria. Thus, in case of isolation of less frequent species, an infectologist should be consulted.^1-7

With regard to coverage for ORSA, there are today other therapeutic options besides vancomycin. Another glycopeptide that may be used is teicoplanin (Targocid®). This glucopeptide has a longer half-life and can be given once a day. However, teicoplanin is less powerful against staphylococci and there have been reports of therapeutic failure. The combined use of streptogramins, quinupristin and dalfopristin (Synercid®) is quite effective against gram-positive cocci, except against Enterococcus faecalis, but it produces a considerable amount of side effects and toxicity. An excellent option for the treatment of infections caused by gram-positive cocci, especially oxacillin-resistant staphylococci and enterococci, is oxazolidone linezolid (Zyvox®). This new antimicrobial is available for both oral and intravenous administration, and due to its long half-life, it may be given once a day.¹⁴

If osteomyelitis is present, some precautions should be taken: (1) a quite aggressive surgical debridement should be made; (2) coverage for S. aureus should be implemented; and (3) a quite long antimicrobial therapy should be used. In case of osteomyelitis caused by oxacillin-sensitive S. aureus, a fluoroquinolone with higher power against gram-positive cocci, such as gatifloxacin (Tequin® or moxifloxacin (Avalox®) may be used. Ciprofloxacin (Cipro®) or older fluoroquinolones should not be used due to the easier development of resistant mutants during the treatment. In case of osteomyelitis caused by ORSA, aside from conventional therapy with vancomycin, we can use linezolid. However, there have been reports of blood toxicity when this drug is used for long periods (for more than 15 days). Therefore, hematological monitoring is recommended in this situation.14 Another recommendation, which still has to be validated by more comprehensive clinical studies, is the combination of rifampicin in the first five or seven days of treatment against osteomyelitis. Since this drug is highly powerful against staphylococci, we believe its use can improve clinical outcome. On the other hand, the development of resistant mutants is quick and for this reason this drug is only used within the first days of treatment.

Our conclusion is that antimicrobial therapy for diabetic foot infections, and for other types of infection as well, must take into account the local epidemiology, the interaction with other medications used by the patient, clinical conditions, and local experience. However, the selection should be mainly based on clinical and microbiological studies and should always be reviewed depending on culture results obtained.

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