Extended-Spectrum Beta-Lactamase Diabetic Foot Osteomyelitis Causing Sausage Toe Deformity: Successful Therapy with Ertapenem in the Outpatient Setting

Background

Diabetic foot ulcers (DFUs) are high-morbidity and debilitating complications that carry increased rates of associated major amputations, and they have been associated with higher cost of healthcare services [1]. The main risk factors that have been strongly related to the development of DFUs are: (i) trauma; (ii) insufficient glycemic control; (iii) peripheral arterial disease of the lower extremities; (iv) peripheral neuropathy and subsequent reduction of protective sensation; (v) foot deformities; (vi) diabetes-related suppression of immune function; and (vii) inadequate foot care [2,3].

Diabetic foot osteomyelitis (DFO) is a high-morbidity and debilitating complication of DFUs that contributes to significantly worse quality of life in the affected population [1,3,4]. It is a frequent complication of DFUs, since bacteria can contiguously penetrate from soft tissues into the bones, involving the cortex first and then the bone marrow [1,3,4]. Staphylococcus aureus (approximately 50% of DFO cases), Streptococcus spp., Enterobacterales genera (Escherichia coli, Proteus spp., and Klebsiella spp.), Pseudomonas aeruginosa, and Enterococcus spp. are the most common pathogens isolated from patients with DFO [2,4]. One of the clinical presentations of DFO, the ‘sausage’ toe deformity, affects the phalanges (local soft tissue infection and underlying bony changes) and is highly suggestive of DFO [5]. We report a case of a 74-year-old woman with long-standing insulin-treated type 2 diabetes (T2D), who experienced infection with extended-spectrum beta-lactamase (ESBL)-producing E. coli, causing DFO with ‘sausage’ deformity in her second right toe. She was successfully treated with surgical debridement combined with the administration of ertapenem in the outpatient setting, completing, in total, a 6-week course of antibiotic therapy.

Case Report

A 74-year-old woman presented to our clinic with fever and tenderness in her right lower foot. Her past medical history was significant for long-standing T2D diagnosed 15 years previously and treated with metformin 1000 mg daily, empagliflozin 10 mg daily, and insulin glargine administered subcutaneously in a daily dose of 30 units. She also experienced diabetic neuropathy of the lower limbs (abnormal 10 g monofilament and biothesiometer), hypertension treated with ramipril 10 mg daily, dyslipidemia treated with simvastatin 20 mg daily, and obesity. Her body mass index (BMI) was 31 kg/m2.

Her daughter reported a 9-month history of redness, swelling, and tenderness of the second right toe, suggesting a ‘sausage’ toe deformity. During this time, she received several courses of antibiotic combinations (including amoxicillin/clavulanic acid, cefixime, levofloxacin, and clindamycin), experiencing intervals of remissions and recurrences. Three weeks before her presentation in our clinic, she was hospitalized, and she underwent surgical sharp debridement and stitching of a DFU arising from her second right toe. She was then treated with oral ciprofloxacin 500 mg every 12 hours and metronidazole 500 mg every 8 hours until her presentation to our clinic. She did not report any recent trauma.

During her physical examination she was in excellent mental condition. Her body temperature was 37.7°C and she was hemodynamically stable. Clinical examination was normal except for bilateral toenail onychomycosis. Results of her laboratory investigations showed anemia (hemoglobulin: 10 g/dL) and white blood cell count of 12.15 cells/mm3 (neutrophils: 80%). The erythrocyte sedimentation rate (ESR) was 65 mm/h, and the C-reactive protein (CRP) level was 8.2 mg/dL. Her glycated hemoglobin (A1C) was 7.6%. All other laboratory values were within normal limits. The purified protein derivative skin test was also negative. Magnetic resonance imaging (MRI) of her right foot was performed and disclosed contrast-enhancing osteolysis of the proximal and the middle phalanx of the second right toe (Figure 1, blue arrows), with associated pathological contrast enhancement of the bone marrow and diffuse surrounding soft tissue edema, suggesting DFO (Figure 1).

The DFU was unstitched and drained. Surgical removal of all devitalized and necrotic soft tissues was performed. Metformin and empagliflozin were stopped and she was treated with insulin therapy alone, which was adjusted as needed targeting a glucose range of 140-180 mg/dL. Two sets of blood cultures for bacteria (aerobic and anaerobic) and fungi were obtained. Cultures were obtained from deep tissues that were removed from the area closest to the bone, as well as from a small bone specimen. Imipenem/cilastatin 1 g intravenously every 8 h was started. An ESBL-producing E. coli strain was isolated from all the investigated specimens, which was resistant to amoxicillin/clavulanic acid, trimethoprim-sulfamethoxazole, fluoroquinolones, piperacillin/tazobactam, and third-generation cephalosporins. Sensitivity was found to carbapenems, aminoglycosides, and tigecycline. Blood cultures did not disclose the presence of any pathogen.

The patient’s condition gradually improved and she became afebrile 3 days after the initiation of therapy. Her treatment was changed to ertapenem 1 g per day intravenously, which was continued in the outpatient setting. She was advised to restart metformin and empagliflozin as before and to change her lifestyle habits. She experienced regular cautious sharp debridement of the DFU to remove slough and nonviable necrotic tissues. She was advised to use offloading footwear, to reduce her weight-bearing activity, and to increase her non-weight-bearing activity. After 3 weeks of treatment, her CRP declined to normal levels, while her ESR (a marker that has been associated with remission or cure of DFO) was normalized after 5 weeks of therapy [6]. She eventually completed, in total, a 6-week course of antibiotic therapy, resulting in complete healing of the DFU and full resolution of the ‘sausage’ toe deformity (Figure 2). The onychomycosis was also treated aggressively with terbinafine. She was also advised to avoid nail polish until the end of her treatment. The patient performed good medication adherence and self- management practices [7]. No recurrence was found 30 months after the end of her antimicrobial therapy.

Discussion

DFO is a serious complication of DFUs that is very frequently clinically unsuspected [6,8,9]. ‘Sausage’ toe deformity is highly suggestive of DFO and should be an alarming sign in everyday clinical practice [10,11]. As was the case with our patient, DFO has been related to suboptimal and inappropriate antibiotic therapy, as well as with infections from highly resistant pathogens [4,6,8]. Toenail onychomycosis has been also associated with increased risk of ulceration in patients with diabetic foot disease, although a recent systematic review did not find any association [12,13]. The surgical closure of the ulcer promoted inadequate wound drainage and exacerbated the underlying infection.

Unfortunately, during recent years, the emergence of antibiotic-resistant pathogens has created great difficulties in choosing appropriate empirical antibiotics for the treatment of diabetic foot infections (DFIs) [6,8,14]. The most common multidrug-resistant (MDR) organisms isolated in DFUs are ESBL-producing gram-negative bacteria, carbapenem-resistant Enterobacteriaceae, methicillin-resistant coagulase-negative staphylococci (MR-CoNS), and methicillin-resistant S. aureus (MRSA) [4,6,7,11]. MDR pathogens have been strongly related to higher morbidity and mortality compared with their susceptible counterparts [15].

The rates of ESBL-producing gram-negative bacteria in patients with DFIs have been rising steadily over the last decade, especially in patients who experience long-standing infections and those with prior antibiotic exposure [16,17]. These microorganisms can delay clinical and microbiological cure as they confer resistance to third-generation cephalosporins and monobactams, apart from decreasing sensitivities to β-lactams with β-lactamase inhibitors, aminoglycosides, fluoroquinolones, and trimethoprim-sulfamethoxazole [18]. Several studies have shown that ESBL E. coli has been isolated from 20–78% of all isolated E. coli strains in patients with DFIs [17,19–24]. One of the largest prospective series exploring DFIs showed that ESBL-producing Enterobacterales genera were significantly associated with DFO (OR: 6.351; 95% CI: 1.609–25.068) and previous use of cephalosporins (3 months before, OR: 5.824; 95% CI: 1.517–22.361) [17]. Indeed, ESBL-producing Enterobacterales genera were found to be more prevalent than ESBL-producing P. aeruginosa, limiting treatment options considerably and causing great concern regarding the lack of adequate treatment and the spread of ESBL-carrying isolates in the community [17,22].

Outpatient parenteral antibiotic therapy (OPAT) has several advantages, including earlier hospital discharge/shorter length of hospital stays, lower cost, and better overall patient satisfaction [25]. Early discharge also helps to prevent the evolution of secondary nosocomial infections [6,25]. Ertapenem has demonstrated encouraging results in patients with bone infections, both as monotherapy and in combination with other antibiotics, making it an excellent option for OPAT [26,27]. Its administration can also significantly reduce overall treatment costs, when compared with inpatient care [28,29]. Unfortunately, OPAT is not covered by the national health system of Cyprus [6]. Since the daily cost of ertapenem is 58 euros, the total cost of ertapenem administration for our patient was approximately 2000 euros, and was chosen due to the absence of other therapeutic options with lower cost.

Conclusions

‘Sausage’ toe deformity is one of the clinical presentations of DFO and should be an alarming sign in everyday clinical practice. Ertapenem is an excellent option for the treatment of ESBL E. coli DFIs in the OPAT setting. Tigecycline also could have been used as it has excellent activity in soft-tissue infections. Early diagnosis and proper therapeutic approach are of great importance to reduce the risk of amputations, overall mortality, total cost, and the rise of antimicrobial resistance in the community.