The choice of antibiotic therapy in patients with complicated diabetic foot syndrome

B.S. Briskin, A.V. Proshin, V.V. Lebedev, Ya.I. Yakobishvili, L.V. Tokareva

Moscow State University of Medicine and Dentistry, City Clinical Hospital No. 81, Moscow

Treatment of angiopathy in complicated diabetic foot syndrome remains a challenge [1-4]. Acute purulent-inflammatory processes of the skin and soft tissues, especially of the lower extremities, are frequent companions of diabetes mellitus (DM), which significantly aggravates the course of the disease and poses a threat of infection generalization with the expansion of the zone of purulent-necrotic changes. The appearance of purulent foci leads to a catastrophic increase in hyperglycemia, glucosuria, and ketoacidosis [5, 6]. Currently, problems associated with diabetic foot remain the most common cause of non-traumatic amputation of the lower extremities, disability, which requires large material costs for the treatment and rehabilitation of this group of patients [7–9]. The main cause of morbidity, hospitalization and mortality in patients with diabetes is an infectious lesion of the lower extremities. Infection is a common complication of developing ulcers or wounds on the foot [10–11]. In conditions of impaired blood flow, infection significantly worsens the prognosis of the probability of saving a limb or even life itself [12–14]. The infectious process contributes to thrombosis of already altered arteries due to atherosclerosis, which leads to the progression of ischemia and the development of gangrene [15, 16]. Antibacterial therapy is one of the important links in the complex treatment of patients with this pathology. In this regard, one of the most difficult tasks of the surgeon in the treatment of patients with complicated diabetic foot syndrome is to provide adequate antibiotic therapy against the background of complex conservative and surgical treatment [17–19].

Bacteriology of complicated forms of diabetic foot
Infection plays a special role in the pathogenesis of diabetic foot [20–22]. The microbial landscape of purulent-necrotic foci in patients with DM is polyvalent in nature, and it is necessary to take into account the probability of the presence of various strains of microorganisms on the surface and in the depth of the ulcer [23–24]. At present, the position on the polymicrobial nature of the purulent focus on the feet in patients with DM with an association of aerobes and anaerobes has become generally recognized [25, 26]. The results of bacteriological studies show that in purulent foci on the foot in patients with DM, there is a mixed aerobic-anaerobic infection in 90% of cases, aerobic – in 10% [27]. According to N.Tentolouris, E.Jude et al. (1999), the microflora causing diabetic foot infections is predominantly anaerobic, with approximately 75% associated with staphylococci and 25% with facultative anaerobic Gram-negative rods. The number of bacterial species isolated from purulent-necrotic foci in patients with complicated diabetic foot syndrome varies from study to study [28, 29]. Associations of microorganisms in the purulent focus are polyvalent in nature and include from 2 to 14 types of aerobic, facultative anaerobic and obligate anaerobic non-spore-forming bacteria. Of the aerobic microorganisms in associations, Pseudomonas aeruginosa is the most common, of the facultative anaerobic – Staphylococcus aureus , Staphylococcus epidermidis , Streptococcus haemoliticus , Enterococcus spp . , PeptoStreptococcus spp. , Fusobacterium spp. In addition, in associations there are: Proteus mirabilis , Proteus vulgaris , Acinetobacter spp. , Citrobacter spp. , Klebsiella spp. [21, 30, 32].
According to our data, in the study of cultures from purulent foci in 246 patients, microbial associations included from 2 to 10 types of microorganisms, and mixed (anaerobic-aerobic) infection was diagnosed in 224 (91.1%) patients, only aerobic – in 22 (8, nine%). The most common facultative anaerobic microorganisms in associations were Staphylococcus aureus (59%), Staphylococcus epidermidis (19%); from non-sporogenic anaerobes – Bacteroides fragilis (21%), Peptococcus spp. (19%) and Fusobacterium spp. (12%). The nature of the microflora sown from purulent foci in complicated diabetic foot syndrome is presented in Table. one.
The presence of multiple associations in the purulent-necrotic focus was combined with a high microbial contamination of the wound tissues – 10 7 -10 12 microorganisms per 1 g of tissue, which correlated with the general reaction of the body to the source of intoxication, as well as a pronounced inflammatory reaction of the surrounding soft tissues. A clear correlation between the types of pathogens in various forms of diabetic foot syndrome (neuroischemic or neuropathic) could not be established in the course of our study.
It should be emphasized that it is difficult to stop the infectious process caused by anaerobic-aerobic associations, which is associated with the synergism of associates [33]. Often, due to the duration of the course of the wound process in patients with DM, an open postoperative wound remains, which determines the constant risk of reinfection with hospital highly resistant strains. Literature data [34] on the sensitivity of microorganisms sown most often from purulent foci in complicated diabetic foot syndrome are presented in Table. 2.
Along with surgical interventions aimed at draining purulent foci and removing necrotic tissues, one of the important links in the complex conservative treatment of this category of patients is timely, adequate antibiotic therapy [18, 35, 36]. However, it should be noted that the rationality and adequacy of prescribing antibacterial drugs can only be judged along with the restoration of disturbed regional blood flow in the lower extremities, especially in neuroischemic form of foot injury [7].

Antibacterial therapy
According to a number of researchers [25, 37-39], indications for antibiotic therapy are:

  • general manifestations of infection (temperature, leukocytosis, etc.),
  • local signs of a progressive purulent-necrotic process (perifocal edema, formation of secondary necrosis, purulent discharge, characteristic odor, etc.);
  • the presence of cellulite in the depth of the wound defect;
  • the presence of trophic ulcers penetrating the entire depth of soft tissues to the bone with signs of an infectious process;
  • the presence of osteomyelitis or arthritis with signs of progression of the infection;
  • performing early reconstructive operations on the foot.

The effectiveness of antibiotic therapy in patients with complicated diabetic foot syndrome largely depends on the correct choice of the drug and should provide the maximum therapeutic effect with minimal impact on the body of a patient who usually suffers from severe concomitant diseases. In the treatment of infection in patients with complicated diabetic foot syndrome, two types of antibiotic therapy are performed – empirical and targeted. Schemes of various options for the use of antibiotics, according to the literature [30, 31, 34] are presented in Table. 3.

Empiric Therapy
Empirical therapy is carried out until the result of a microbiological study from a purulent focus is obtained and plays one of the main roles in complex therapy in patients with purulent-necrotic lesions of the feet in diabetes. According to a number of researchers [33, 36, 37, 40], adequate empirical therapy is based on the following principles:
1. The antimicrobial spectrum of the drug should cover all potential pathogens in this pathology.
2. The regimen of antibiotic therapy takes into account current trends in antibiotic resistance and the likelihood of the presence of multidrug-resistant pathogens.
3. The regimen of antibiotic therapy should not contribute to the selection of resistant strains of pathogens.
For successful treatment, antibacterial drugs used for empiric therapy must have a wide spectrum of action, including both aerobes and anaerobes, have a high ability to penetrate into infection zones, creating bactericidal concentrations in them, which is especially important when macro- and microcirculation is disturbed in this categories of patients [10, 42]. We fully share this point of view and adhere to the same positions. The presence of non-clostridial anaerobes in the purulent lesion of the feet in patients with DM requires the immediate initiation of antibiotic therapy from the moment the clinical diagnosis is established.

Table 1. The most frequently isolated microorganisms from purulent foci in patients with complicated diabetic foot syndrome

Facultative anaerobes obligate anaerobes Aerobes
Staphylococcus aureus Bacteroides fragilis Pseudomonas aeruginosa
Staphylococcus epidermidis PeptoStreptococcus spp.
Streptococcus haemolyticus Peptococcus spp.
Enterococcus spp. P. melaninogenica Fusobacterium spp.

Table 2. Microorganism susceptibility to antibiotics

S. aureus; hemolytic Streptococci Enterococcus faecalis G bacilli Pseudomonas Anaerobes
Fusidic acid Metronidazole
Fluclox
Cephalosporins* Cephalosporins Ceftazidime Cefoxitin
Clindamycin Clindamycin
Gentamicin*+ Gentamicin Gentamicin
Co-amoxiclav Co-amoxiclav Co-amoxiclav Co-amoxiclav
Ciprofloxacin Ciprofloxacin Ciprofloxacin Ciprofloxacin
Imipenem* Imipenem Imipenem Imipenem Imipenem
Note: * parenterally only, + except for Streptococci .

Table 3. Schemes of various options for the use of antibiotics

The use of tablet forms of antibiotics in a superficial local process The choice of antibiotics for parenteral administration
Flucloxacillin + ampicillin + metronidazole Co-amoxiclav (amoxicillin + clavulanic acid) Co-trimoxazole + Metronidazole Ciprofloxacin + Metronidazole Ciprofloxacin + Clindamycin Ampicillin + Flucloxacillin + Metronidazole Cefuroxime or (cefatoxime) + Metronidazole Ampicillin + Gentamicin + Metronidazole Second-line antibiotics III-IV generation cephalosporins Fluoroquinolones (levofloxacin, moxifloxacin) MRSA – glycopeptides (vancomycin, teicoplanin), lincosamine
Choice of antibiotics during sequential therapy Levofloxacin: for 3–5 days parenterally, followed by switching to the tablet form Moxifloxacin: within 3–5 days, parenterally, followed by switching to the tablet form

Table 4. The effectiveness of empirical therapy in the treatment of patients with complicated forms of DFS

Antibiotic Number of patients Dosing regimen per day Course of treatment, days Microorganism susceptibility to antibiotics
abs. %
Amikacin 500 mg 3 times 88.1
Gentamicin 240 mg 1 time 75.5
Levofloxacin 500 mg 2 times 7–14 97.7
Moxifloxacin 400 mg 1 time 7–14
Cefotaxime 1 g 2 times 89.6
Ceftazidime 1 g 2 times 88.9
Ceftriaxone 1 g 2 times 88.6
cefepime 1 g 2 times 92.9
Vancomycin 1 g 2 times 90.9
Co-moxiclav 1.2 g 3 times 94.5
Clindamycin 600 mg 3 times 85.7
Lincomycin 1.2 g 2 times 66.7
Metronidazole 300 g 3 times 96.4
Imipenem 1 g 2 times 7–10

Rice. 1. The choice of antibacterial drugs for complicated diabetic foot syndrome.

Rice. 2. Type of cytogram depending on the timing of the use of antibacterial drugs, in%.

As drugs of choice, it is advisable to use fluoroquinolones of III-IV generations (levofloxacin, moxifloxacin), cephalosporins of III-IV generation (cefotaxime, ceftazidime, cefoperazone, cefepime), glycopeptides (vancomycin), inhibitor-protected penicillins (co-amoxiclav) [31, 43, 44 ]. A number of empirical therapy drugs that do not have a spectrum of action on the anaerobic microflora are prescribed in combination with metronidazole [45, 46]. In especially severe cases (with a septic condition), we consider it justified to prescribe a group of carbapenems (imipenem, meropenem) as empirical therapy. The drugs of these groups are characterized by low toxicity, good tolerance by patients, long-term preservation of high concentrations in the blood and tissues of the purulent focus, which makes it possible to prevent the development of microorganism resistance to them. An analysis of the study of the sensitivity of pathogens from isolated purulent foci showed that most microbes were sensitive to empirically prescribed antibiotics. According to our data, out of 246 patients who were prescribed empirical therapy, sensitivity to prescribed antibiotics after receiving analyzes of bacteriological examination was noted in 228 (92.7%) patients, 18 (7.3%) patients needed a change in antibacterial drugs, taking into account the sensitivity of the inoculated microflora to the antibiotic (Table 4.).
In our clinic, the most commonly used as monotherapy were: penicillins with an extended spectrum – co-amoxiclav; fluoroquinolones III, IV generations (levofloxacin, moxifloxacin); imipenem/cilastatin. Of the combinations of antibacterial drugs, the following were mainly used: levofloxacin + lincomycin (clindamycin); levofloxacin + metronidazole; cephalosporins III, IV generation (cefotaxime, ceftazidime, cefepime) + amikacin (gentamicin) + metronidazole; vancomycin + metronidazole. The scheme for choosing antibacterial drugs is shown in fig. one.
After receiving the results of a bacteriological study, a correction of antibiotic therapy is carried out, taking into account the isolated microorganisms and their sensitivity to antimicrobial drugs.
Thus, timely and adequate empirical antibiotic therapy allows stopping the progression of the purulent-necrotic process on the affected foot, giving time, especially in the neuroischemic form of foot damage, to restore disturbed macro- and microhemodynamics in the lower limb and perform adequate surgical treatment of the purulent focus, and when neuropathic form of the lesion after early surgical debridement of the purulent focus to prevent the spread of infection and thereby avoid repeated surgical interventions, and preserve the supporting function of the foot.

Etiotropic antibiotic therapy
Targeted antibiotic therapy is carried out only after receiving the results of a microbiological study (crops taken from a purulent-necrotic focus). After obtaining data from microbiological studies, if necessary, antibiotic therapy is corrected taking into account the isolated microflora and its sensitivity to antibacterial drugs [18, 19, 30]. The need to replace antibacterial drugs arose:
1. In the absence of a clinical effect from antibiotic therapy for 5 days, provided that the phenomena of critical ischemia on the foot are stopped and the purulent-necrotic focus is surgically sanitized.
2. When new strains of microflora appear in the purulent focus (reinfection of the wound), which are not sensitive to ongoing antibiotic therapy.
3. With the development of complications or adverse reactions associated with the use of this antibiotic.
The choice of antibacterial drugs and the correction of their dosage (taking into account sensitivity to inoculated microorganisms) was carried out in accordance with the functional state of the excretory organs – renal elimination, liver metabolism [47]. The choice of antibacterial drugs used in complicated diabetic foot syndrome is shown in Fig. 1. The duration of antibiotic therapy in patients with complicated diabetic foot syndrome was carried out on average 10–14 days, until a clear clinical effect appeared and the level of microbial contamination in the wound decreased to 103 microbial bodies per 1 g of tissue. To assess the effectiveness of ongoing antibiotic therapy, data from studies of cytological prints from wounds and microbial contamination of the tissues of the purulent focus were used. Cytological examination of wound imprints makes it possible to judge the nature and phases of the course of the wound process, the effectiveness of the complex treatment, as well as determine the indications or contraindications for various conservative and surgical measures. The cytological study was based on determining the quantitative and qualitative composition of neutrophils, lymphocytes, macrophages, fibroblasts, and the presence of microflora. For a more accurate understanding of the dynamics of the cellular composition, it was expressed as a percentage when counting 100 cells in different parts of the preparation, depending on the homogeneity of the cellular composition of wound prints in patients with various forms of complicated diabetic foot syndrome (neuropathic, neuroischemic). Analysis of the obtained data shows that upon admission to the hospital in 23% of patients, the cytology of the wound process was of a degenerative-inflammatory nature. The cellular composition of the wound in this type of cytogram was characterized by the presence of neutrophils in a state of varying degrees of destruction, as well as a large number of microorganisms. In 39% of patients, a purulent-necrotic type of cytogram was noted. This was evidenced by a large number of neutrophils in a state of degeneration and destruction. In all patients, cytograms showed the presence of microorganisms among the destroyed neutrophils. In 38% of patients, the cytology of the wound process corresponded to the purulent-inflammatory type. In this group of patients, the cellular composition was characterized by the predominance of neutrophils, most of which were in the decay stage. Other cellular elements in the wound imprint had dystrophic changes. The cytological dynamics of the wound process was assessed from the moment the patient arrived, on the 5th, 10th, 15th, and 20th days of treatment. It should be noted that antibiotic therapy was carried out in the complex treatment of this pathology, including conservative therapy and surgical correction.
Conservative treatment:
1) SD compensation;
2) antibiotic therapy;
3) relief of the phenomena of critical ischemia (according to indications);
4) local treatment of purulent-necrotic focus with the use of modern dressings;
5) symptomatic therapy, taking into account existing comorbidities and late complications of diabetes (polyneuropathy, retinopathy, nephropathy, encephalopathy).
Surgery:
1) reconstructive operations on the arteries of the lower extremities;
2) palliative operations aimed at improving regional blood flow in the affected limb – sympathectomy;
3) surgical treatment of a purulent focus and early recovery operations.
On the 10-14th day of adequate antibiotic therapy, the cytological characteristics of the wound process changed – in 42% for the inflammatory type, in 38% for the inflammatory-regenerative type, which was characterized by the predominance of a neutrophilic reaction in combination with a high level of lymphocytes and macrophages, as well as the presence of smears-imprints of single fibroblasts. Continuation of the course of antibiotic therapy in patients with an inflammatory type of cytogram for 10 days made it possible to change in 69% of patients to the regenerative type (Fig. 2). At the same time, it was possible to achieve a decrease in the level of microbial contamination in the purulent focus to 103–104 microbial bodies in 87% of patients. A complex of clinical, microbiological and cytological studies made it possible to resolve the issue of the abolition of antibacterial drugs. Further treatment of the open wound was carried out under dressings with drugs that provide a high antimicrobial effect directly in the wound.
In the event of a recurrence of the infectious process or the absence of a positive course of the wound process, it is necessary to conduct repeated courses of antibiotic therapy with mandatory control of the sensitivity of the seeded microflora. It is also advisable to resume antibiotic therapy in case of decompensation of diabetes or worsening of the patient’s condition with the possible formation of new purulent foci. Properly conducted complex conservative therapy, along with surgical treatment, can reduce the indications for prescribing antibacterial drugs and the timing of their use, thereby providing breaks between antibiotic courses. According to our data, in 115 patients with neuroischemic foot lesions after restoration of macro- and (or) microhemodynamic disorders on the affected limb and after radical surgical debridement, antibiotic therapy was stopped on days 22+2.73 of treatment, which was argued by the achievement of a stable clinical course of wound healing. process, data of bacteriological and cytological examinations. In 131 patients with neuropathic foot lesions, antibiotic therapy was discontinued on days 11±1.24. Further treatment of the open wound was carried out under dressings that provide a high antimicrobial effect directly in the wound (antiseptics: dioxidine, chlorhexidine, povidone-iodine, iodopyrone, iodovidone), which in a short time made it possible to achieve the elimination of pathogenic microorganisms from the wound.
Of particular interest at the present time is the so-called stepwise therapy. A number of new antibacterial drugs are being produced in dosage forms intended for both parenteral administration and oral administration, which allows them to be used sequentially (first parenterally, then orally). Given the good assimilation of modern tableted antibacterial drugs and focusing on the dynamics of the course of the wound process, it is possible to reduce the time for the introduction of parenteral drugs to 3-5 days, with the subsequent transfer of the patient to the tablet form of the antibiotic. This tactic significantly reduces the overall cost of treatment without affecting its quality. We carried out stepwise monotherapy of 20 (8.1%) patients with levofloxacin and 12 (4.9%) patients with moxifloxacin, for a period of 10 to 15 days. In all cases, the full sensitivity of the microflora to these antibacterial drugs was noted with the achievement of a distinct clinical effect by the end of treatment.
Thus, modern antibiotic therapy in patients with complicated diabetic foot syndrome is based on the need for an integrated approach to this problem, namely, adequate surgical treatment of a purulent focus, relief of critical ischemia (if necessary), rational prescription of antibacterial drugs, taking into account the sensitivity of the microflora to them, sown from a purulent focus. Antibacterial therapy is indicated for any type of foot injury – neuroischemic, neuropathic. The best results can be achieved only with the complex treatment of this pathology, one of the links of which is antibiotic therapy.

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