64053

2015

IJLXXX10.1177/1534734614564053The International Journal of Lower Extremity WoundsCervantes-García et al

Clinical and Translational Research

Infections of Diabetic Foot Ulcers With Methicillin-Resistant Staphylococcus aureus

The International Journal of Lower Extremity Wounds 2015, Vol. 14(1) 44­–49 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1534734614564053 ijl.sagepub.com

Estrella Cervantes-García, MS1,2, Rafael García-González, MS1, Aldo Reséndiz-Albor, PhD2, and Paz Maria Salazar-Schettino, PhD1

Abstract Infected diabetic foot is the most common reason for hospitalization and complications in patients with type 2 diabetes mellitus (DM2). Methicillin-resistant Staphylococcus aureus (MRSA) is frequently isolated from such lesions, and its presence is growing, seriously deteriorating the infected patient’s quality of life. The aim of this study was to assess the prevalence of MRSA as well as other microbiota in 100 patients diagnosed with (DM2) and with infected foot ulcers at the Hospital General de Mexico. The main results obtained show a prevalence of Staphylococcus aureus (42%), followed by Escherichia coli (36%) and, in lower percentages, other bacteria. MRSA was predominant (34%), and we conclude that the use of cefoxitin instead of oxacillin as the first-choice antibiotic has an advantage because it is a better inducer of methicillin-resistance expression. Keywords diabetic foot, Staphylococcus aureus, MRSA, microbiota, infection, type 2 diabetes mellitus, methicillin-resistance Type 2 diabetes mellitus (DM2) is a widespread public health problem. Its occurrence has increased worldwide, especially affecting developing countries and the underprivileged sectors of society. In the year 2000, its prevalence was estimated to be 2.8%, which will increase to 4.4% by 2030. It has been considered that by then, the total number of individuals suffering from DM2 will rise from 111 million to 366 million.1,2 Foot ulcers are among the most severe complications associated with DM2. They are the first cause of morbidity in patients with diabetes, and they are the core reason for amputations of the lower limbs. In fact, DM2 patients require amputation of lower extremities in 15% to 30% of the cases, and this leads to hospitalization. Foot lesions frequently get infected because deep tissues are exposed to bacterial colonization once the skin is damaged.3,4 Infected diabetic foot ulcers satisfy 3 aspects that have been linked to a proliferation of multiresistant microorganisms: (a) chronicity, (b) inappropriate antibiotic therapy, and (c) hospitalization. The widespread use of antimicrobial agents fails to eradicate the infection caused by these pathogens despite its benefits. Thus, inadequate treatment has contributed to the emergence of multiresistant bacteria that have increased the therapeutic problem.5-8 Diabetic foot infections are classified as monomicrobial or polymicrobial depending on the number of pathogens present. Some of the most common organisms found are Gram-positive cocci like Staphylococcus aureus, coagulase-negative staphylococci, Streptococcus pyogenes, and

Enterococcus. Also, polymicrobial infections frequently involve Gram-negative bacteria like Pseudomonas aeruginosa and Enterobacteriaceae such as Escherichia coli and Klebsiella pneumoniae.9,10 Among Gram-positive bacteria, Staphylococcus aureus is the most common. In particular, outcomes in different trials indicate that the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in individuals with infected diabetic foot ulcers is 15% to 40%. Hence, MRSA is currently one of the main hospitalacquired resistant microorganisms found in these lesions.10-12 Also, there are reports recognizing new strains of MRSA in diabetic foot ulcers that are also resistant to vancomycin (VA).13,14 Furthermore, there has been an increase in the incidence of Gram-negative bacteria that produce extended-spectrum β-lactamase, such as Enterobacteriaceae,15,16 thus becoming another menace for infection treatment in both hospitalized and nonhospitalized patients. The aim of this research was to assess the prevalence of MRSA and the microbiota in infected diabetic foot ulcers in patients diagnosed with DM2. We consider diabetic foot ulcers of grades 3, 4, and 5, according to Wagner’s classification,17 1

Facultad de Medicina, UNAM, Mexico Laboratorio de Mucosas, Escuela Superior de Medicina, IPN, Mexico

2

Corresponding Author: E. Cervantes-Garcia, Facultad de Medicina, Universidad Nacional Autónoma de México, Avenida Universidad 3000, Mexico. Email: [email protected]

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Cervantes-García et al as infected. Obtaining information concerning the prevalence and incidence of these pathogens in clinical settings is extremely necessary and important, for it can help select the appropriate empirical treatment in a specific environment.

Participants and Methods A prospective study in 100 patients diagnosed with DM2 and with infected foot ulcers was carried out from July 2012 to December 2013 in the Emergency Room and the Diabetic Foot Clinic of the Hospital General de México. Inclusion criteria were patients presenting with (a) extensive cellulitis, greater than 2 cm; (b) deep ulcers grades 2 to 3, according to Wagner’s classification, and with or without associated ischemia; or (c) gangrene in toes or in the rest of the foot.17 Cellulitis was used as part of the inclusion criteria because it indicates infection,18 and it may lead to osteomyelitis, gangrene, necrotizing fasciitis, sepsis, and even death. Moreover, cellulitis allows the infection to spread and makes the treatment more difficult. Diabetic foot ulcers of grades 4 and 5 according to Wagner’s classification exhibit localized and generalized gangrene, respectively. Even if amputations take place, the infection persists. Therefore, we took samples from these types of ulcers, and some were found to have MRSA. After obtaining informed consent from the patient, we applied a 15-item questionnaire to each patient. It included social-demographic characteristics such as age, sex, origin, and schooling and medical issues such as diabetes onset, treatment, ulcer evolution, and previous treatment if any. The 15-item questionnaire is part of the history and physical record of the patient and was answered by each patient.

Microbiological Methods The foot lesions were washed vigorously with sterile saline solution and were debrided afterward. Then, the samples were obtained from the foot ulcer base with a sterile swab and were placed in a Stuart transport medium to be sent to be analyzed at the Laboratorio de Bacteriología de la Facultad de Medicina de la Universidad Nacional Autónoma de México. The samples were cultured in blood agar, MacConkey agar, and mannitol salt agar and were then incubated at 37°C for 24 to 48 hours under aerobic conditions. The colony morphology was determined, and Gram staining was performed. Identification of bacteria was done using conventional biochemical procedures. The antibiotic susceptibility test was carried out by the Kirby Bauer disk diffusion method in a Müller-Hinton agar. The antibiotics used for Gram-negative bacilli were the following: ampicillin, amoxicillin, cefoxitin (CEX), imipenem, gentamicin, amikacin, ciprofloxacin, aztreonam, cefuroxime, cefotaxime, ceftriaxone, polymyxin B, and

colistin. The antibiotics used for Staphylococcus aureus were the following: oxacillin (OXA), CEX, and VA. In all cases, the antibiotic susceptibility was detected following the guidelines of the Clinical Laboratory Standard Institute (CLSI 2011).19 In particular, all Staphylococcus aureus isolates were tested with a CEX 30 µg disk and with a OXA 1 µg disk according to the CLSI guidelines (CEX: susceptibility ≥22 mm, resistance ≤21 mm; OXA: susceptibility ≤2 µg/mL, resistance ≥4 µg/mL).

Statistical Analyses Statistical analyses were performed to determine if sociodemographic characteristics (age and sex) and properties of the disease (degree of ulcer and time the patient has had DM2) influence the resistance or sensitivity of Staphylococcus aureus to the antibiotics used in patients with DM2 and infected foot ulcers. We used Student’s t test for quantitative variables (age and time with DM2) and the χ2 test for categorical variables (sex, degree of ulcer). We used Fisher’s exact test with 2 nominal variables (Staphylococcus aureus resistant or sensitive to OXA or CEX), with 2 × 2 cross-tabs and with at least 1 cell with ≤5 cases. For all these tests, we used the program SPSS v20, and P < .05 was considered statistically significant.

Ethical Approval The study was approved by the ethics committee of the Hospital General de México.

Results Table 1 shows the total amount of monomicrobial and polymicrobial isolates of the bacteria present in the diabetic foot ulcers of the patients studied (n = 100). Table 2 shows the number of patients with monomicrobial and polymicrobial diabetic foot infections, diabetic foot ulcers grades 2 to 5 (according to Wagner’s classification), and the time they have had DM2, according to sex and age. Finally, Table 3 presents the number of patients infected with Staphylococcus aureus who are resistant or sensitive to both OXA and CEX. Among all 100 patients, 12% showed no microorganisms, 32% were monomicrobial, and 56% were polymicrobial; see Figure 1 and Table 2. Likewise, 22% had deep ulcers (grade 2), 30% deep ulcers with cellulitis and/or abscess (grade 3), 31% localized gangrene (grade 4), and 17% extensive gangrene with possibility of amputation (grade 5); see Figure 2 and Table 2. These results indicate that polymicrobial infection and foot ulcers of grades 3 and 4 (according to Wagner’s classification) are the most common in DM2 patients. We note that the number of patients with recurrent cellulitis was 25.

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The International Journal of Lower Extremity Wounds 14(1)

Table 1.  Frequency of Microorganisms Isolated in Monomicrobial and Polymicrobial Cultures. Microorganism

Number of Isolates

Gram positive Staphylococcus aureus CoNS Gram negative Escherichia coli Klebsiella pneumoniae Enterobacter cloacae Enterobacter hafnie Enterobacter agglomerans Enterobacter aerogenes Proteus mirabilis Proteus vulgaris Morganella morganii Citrobacter freundii Serratia marcescens Pseudomonas aeruginosa NFGNB

Monomicrobial

Polymicrobial

42 25

 5  5

37 20

36 10 8 6 4 5 5 6 4 5 3 3 4

23 — — — — — — — — — — — —

13 10 8 6 4 5 5 6 4 5 3 3 4

Abbreviations: CoNS, coagulase-negative Staphylococcus; NFGNB, nonfermentative Gram-negative bacillus.

Table 2.  Differences by Age Between Men and Women in the Variables Studied (n = 100).a Age Groups

  Variables Studied

20-40 Years Old (n = 26)

54-65 Years Old (n = 25)

66-82 Years Old (n = 25)

Women (n = 17)

Men (n = 14)

Women (n = 10)

4 1 4

2 7 8

1 5 8

1 2 7

3 3 8

0 2 9

0 8 10

1 4 2

2 2 0 5

4 8 4 1

3 6 4 1

2 5 3 0

4 3 5 2

4 2 2 3

2 2 11 3

1 2 2 2

4 3 1 1

11 4 1 1

2 7 3 2

4 2 1 3

2 3 6 3

1 4 3 3

3 3 3 9

2 1 2 2

Men (n = 9)

Type of infection Absence Monomicrobial Polymicrobial Grade of ulcer Grade 2 Grade 3 Grade 4 Grade 5 Diabetes duration (years) 2-7 8-10 11-15 16-30

41-53 Years Old (n = 24)

Total

Women Women Men (n = 14) (n = 11) Men (n = 18) (n = 7)

n = 100 n = 100   12 32 56   22 30 31 17   29 27 20 24

a

Data reported in this table show frequencies.

It was observed that 29% of patients had had the disease (DM2) for 2 to 7 years, 27% for 8 to 10 years, 20% for 11 to 15 years, and 24% for 16 to 30 years (see Table 2). As for age, the 20- to 40-year-old age group showed a greater trend toward having grade 3 foot ulcers and manifesting the disease (DM2) for a short time (2-7 years). In the 41- to 53-year-old age group, just as in the previous group, the

most common kind of foot ulcer was grade 3, although the majority of patients had had DM2 for 8 to 10 years. The 54to 65-year-old age group had grades 2 and 4 foot ulcers most frequently, and the majority of the patients had had DM2 for 11 to 15 years. Finally, the 66- to 82-year-old age group commonly had grade 4 foot ulcers, and they were also the ones who had had DM2 for the longest period

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Cervantes-García et al Table 3.  Differences in Resistance Tests by Antibiotic (n = 42).a CEX

OXA*  Resistant  Sensitive  Total

Resistant

Sensitive

Total

34 3 37

0 5 5

 34 8 42

Abbreviations: CEX, cefoxitin; OXA, oxacillin. a Data reported in this table show frequencies.

Figure 3.  Types of ulcers (Wagner’s classification) in patients with lesions infected with Staphylococcus aureus.

Figure 1.  Type of infection.

Figure 2.  Type of ulcer (Wagner’s classification).

(16-30 years). Also, in this age group, we found the same amount of monomicrobial and polymicrobial foot lesions, whereas the rest of the age groups had a majority of polymicrobial foot lesions (see Table 2). As for sex-related differences, it was found that the majority of men (55%) and women (58%) showed polymicrobial lesions. Also, the majority of men (36%) showed localized gangrene (grade 4 ulcers), whereas the majority of women (38%) had deep ulcers with cellulitis and/or abscess in the skin (grade 3 ulcers). Finally, the great majority of women (40%) had had the disease for 2 to 7 years, whereas the sample of men was more uniform (the percentage of male patients in each age group varied from 20% to 29%; see Table 2). With regard to age differences, the youngest men commonly presented with grade 5 foot ulcers, whereas the oldest men had a higher frequency of localized gangrene (grade 4). In contrast, the youngest women commonly presented with grade 3 foot ulcers, whereas the rest of the age groups showed a more homogeneous incidence in types of foot ulcers (Table 2). Of the n = 100 patients, 42 had foot ulcers infected with Staphylococcus aureus (Table 1). We performed tests to determine the resistance of Staphylococcus aureus to methicillin using OXA, CEX, and VA in the 42 patients—20 men (48%) and 22 women (52%)—between 20 and 82 years of age. The patients had an average age of 51.6 years, with a standard deviation of 50 years. Of the 42 patients, 10 exhibited deep foot ulcers (grade 2 according to Wagner’s classification), 11 presented with deep foot ulcers with cellulitis and/or abscess in the skin (grade 3), 11 had localized gangrene (grade 4), and 10 presented with extensive gangrene with possibility of amputation (grade 5); see Figure 3. Statistical analyses carried out using the χ2 test (sex, degree of ulcer) and Student’s t test (age, time with DM2) showed that factors such as sex, degree of ulcer, age, and time with DM2 do not influence the resistance or sensitivity

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The International Journal of Lower Extremity Wounds 14(1)

to an antibiotic of Staphylococcus aureus (there were no statistically significant results). Hence, the methicillinresistance trials carried out indicate a homogeneous distribution among diverse groups, thus concluding the validity of the methicillin-resistance test. In other words, this implies that the sensitivity or resistance to an antibiotic is not affected by these other factors. The results reveal that only 10% of the cases (n = 4 of a total of n = 42) showed resistance to VA, whereas 81% (n = 34) presented resistance to OXA and 88% (n = 37) showed resistance to CEX (see Table 3). Also, 5 cases were sensitive to both OXA and CEX, whereas 3 were sensitive to OXA but resistant to CEX (see Table 3). Therefore, these 3 cases behave genotypically as MRSA, although they must be considered methicillin-sensitive Staphylococcus aureus (MSSA) populations from an epidemiological point of view. Because these 3 cases were more resistant to CEX and more sensitive to OXA, it suggested that CEX is a better inductor of methicillin-resistance expression in Staphylococcus aureus. To determine if this was a statistically significant result, Fisher’s exact test was performed to determine the differences between the different antibiotics according to the degree of resistance and sensitivity. The results show that CEX is a better inductor of methicillin resistance expression in Staphylococcus aureus because the samples were more resistant to CEX and more sensitive to OXA (Fisher’s exact test(1) = 20.077; P = .000). Furthermore, the magnitude of this effect is high according to Gravetter and Wallnau20 because the values of the ϕ coefficient (ϕ = 0.758; P = .000), Cramer’s V (V = 0.758; P = .000), and C of contingency (C = 0.604; P = .000) are high and significant.

Discussion This is the first transverse prospective study carried out in Mexico to determine the microbiological profile of infections by MRSA and the commonly associated microbiota in diabetic foot ulcers. We found that the majority of patients exhibited ulcers of different grades, according to Wagner’s classification, although grades 3 and 4 were the most common. These data are related to the duration of disease because the longer the time with the condition, the greater the risk of presenting complicated ulcers, as it has been noticed in patients from underdeveloped countries. We found that the majority of infected diabetic foot ulcers are polymicrobial in nature, which is consistent with other reports.21,22 The most predominant microorganism found was Staphylococcus aureus (42%), followed by E coli (36%), and coagulase-negative Staphylococcus (25%); see Table 1. Other Gram-negative bacteria were less frequently found (eg, Proteus vulgaris 6%, Pseudomonas

aeruginosa 3%, and Streptococcus pyogenes 0%); see Table 1. Also, MRSA was found in 34% of the cases. These results contrast with data recently obtained in India and other parts of Asia,23,24 where there is a prevalence of Gram-negative multiresistant microorganisms (such as K pneumoniae and Pseudomonas aeruginosa). However, our results are consistent with reports by other authors21,22 in which MRSA has been usually observed in isolates because of uncontrolled use of antibiotics in both hospitalized and nonhospitalized patients. We also note that the outcomes from this study revealed that some patients did not develop infected ulcers (12%), perhaps because the patient was under antimicrobial therapy such as trimetrophin-sulfamethoxazole, amoxicillin-clavulanic acid, clindamycin, ciprofloxacin, tetracycline, or VA. OXA, CEX, and VA disks were used to determine the prevalence of MRSA and VA-resistant Staphylococcus aureus. The great majority of our Staphylococcus aureus isolates were MRSA: 34 were MRSA and 8 were MSSA, of a total of 42 cases (see Table 3). In the present research, CEX-resistant Staphylococcus aureus strains sensitive to OXA were observed (3 of a total of 42 cases); see Table 3. Although these last strains genotypically behave as MRSA, they must be considered MSSA from an epidemiological point of view. We concluded that the use of CEX rather than OXA as the first-choice antibiotic has an advantage because the former is a better inducer of methicillin-resistance expression. Statistical analysis carried out showed that factors such as sex, degree of ulcer, age, and time with DM2 do not influence the resistance or sensitivity to an antibiotic of Staphylococcus aureus. We also observed that ulcers infected by MRSA showed a prolonged healing time when compared with those infected by strains of MSSA. During the time of the study (July 2012 to December 2013), we observed that lesions infected with MRSA took 1 to 3 months or even longer to heal, whereas the lesions infected with MSSA took 15 days to 1 month to heal. This is a result of the fact that the antibiotic therapy is much more effective in the case of lesions infected by MSSA. Other authors have reported similar findings.21,22,25 Our work emphasizes the fact that to make the best choice of antibiotic therapy, it is necessary to have detailed knowledge about antimicrobial susceptibility of the main agents infecting the foot because mortality rates associated with multiresistant microorganisms are higher than those for antibiotic-sensitive pathogens. Furthermore, early identification can help in the development of effective strategies to avoid the growth of multiple-antibiotic-resistant microorganisms, especially MRSA and ESBL (extended spectrum beta-lactamases) strains, which should be taken into account when

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Cervantes-García et al prescribing antibiotics. An effective antibiotic therapy combined with a decrease in ulcer pressure, timely debridement, and adequate leg perfusion are necessary for successful treatment of infected diabetic foot ulcers and would improve the patient’s overall well-being (eg, decrease hospital stay, improve the individual’s biopsychosocial health). Finally, given the size of our sample, we highly recommend CEX over OXA as a better inducer of methicillin-resistance expression in Staphylococcus aureus. Acknowledgments We gratefully acknowledge the assistance of QFB Angélica Reyes-Torres, Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México. The authors also thank Dr Silvia Martínez Jiménez and Dr César Rivera Benítez for assistance and support at the Hospital General de México. We also are also grateful for the support of the Escuela Superior de Medicina, Instituto Politécnico Nacional de México.

Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Infections of diabetic foot ulcers with methicillin-resistant Staphylococcus aureus.

Infected diabetic foot is the most common reason for hospitalization and complications in patients with type 2 diabetes mellitus (DM2). Methicillin-re...
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