Feature Article

Update on the Antimicrobial Management of Foot in Patients With Diabetes

Gregory T. Matsuura, PharmD, and Neil Barg, MD

electing appropriate antibiot- involve only the skin or subcutane- kocytosis, fever, hypotension, or ics for the treatment of diabetic ous tissue, and erythema, if present, tachycardia). Empiric treatment for Sfoot infections (DFIs) is crucial. is within 2 cm of an ulcer. Most moderate to severe DFIs includes Identifying the optimal mild infections and many moderate an expansive assortment of options choice requires careful consideration infections can be treated by narrow- (Table 2). of three major criteria: severity of spectrum focused against The differing pharmacologi- , duration of wounds, and staphylococcal and streptococcal cal properties of these agents must previous antibiotic exposure. .3 Suggested treatment of be thoughtfully considered when Chronic wounds can be colo- mild DFIs consists of oral agents selecting antimicrobial therapy. For nized on the surface by a varied with activity against Staphylococcus infections of greater severity, empiric group of organisms, including aureus (Table 1). therapy usually includes activity aerobic gram-positive cocci (e.g., Moderate infections refer to those against both aerobic gram-positive staphylococci, streptococci, and with surrounding erythema > 2 cm and gram-negative organisms. enterococci), enterobacteriaceae or deeper infections that extend Longstanding infections or infec- (e.g., Escherichia coli, Klebsiella beyond the subcutaneous structures tions with necrotic tissue often spp., Enterobacter spp., and Proteus (e.g., deep abscesses, septic arthritis, harbor anaerobic bacteria in addi- spp.), nonfermentive gram-negative or osteomyelitis). Severe infections tion to those listed above. Generally, rods (e.g., ), are defined as cases with both local these infections require the use of and anaerobic bacteria. Isolates signs of infection and a systemic broad-spectrum antibiotics with from superficial swab cultures may inflammatory response (e.g., leu- additional activity against anaerobes not represent the underlying infect- such as Bacteroides fragilis. ing pathogen.1 Therefore, cultures In Brief Patient-specific factors also obtained after the debridement of influence optimal antibiotic choice. superficial debris, eschar, or calluses Foot infections are common prob- Patients with diabetes are at a high are best to guide targeted antibi- lems in patients with diabetes and risk of compromised skin integrity otic therapy.2 Once the probable can lead to devastating complica- and impaired wound healing because pathogen(s) are isolated, de- tions and long-term morbidity. of complications such as peripheral escalation of empiric therapy can be Although these infections invari- neuropathy, vascular insufficiency, guided by relevant culture results. ably start in superficial soft tissues, and hyperglycemia. The severity of infection affects they can involve deeper structures, DFIs without open skin wounds including bone. Complications several treatment decisions. These or with ulcers of limited duration are may include necrotizing fasci- include the route and choice of typically caused by gram-positive itis, soft tissue gangrene, septic antibiotic, the need for hospital organisms, including S. aureus and arthritis, and osteomyelitis. This admission, consideration of surgi- β-hemolytic streptococci (Groups A, article reviews the factors involved cal intervention, and overall length B, C, and G). In a study of 653 post- in appropriate antibiotic selec- of therapy. debridement samples from diabetic tion and describes antimicrobial DFIs are characterized by the foot wounds,4 aerobic gram-positive agents included in recently presence of at least two of the organisms accounted for 77% of all updated treatment guidelines from following clinical symptoms: local- bacterial isolates, with staphylo- the Infectious Diseases Society ized edema, erythema, pain, and cocci (43%) and streptococci (13%) of America. purulent discharge. Mild infections representing the largest proportion

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Table 1. Spectrum of Activity of Suggested Oral Antibiotics for the Treatment of Mild DFIs Activity Against MSSA Activity Against MRSA Activity Against Enterobacteriaceae Yes No No Clindamycin Yes Yes for community-acquired No strains, inducible resistance reported (detected by D-test) Cephalexin Yes No Limited, but covers some strains of E. coli Amoxacillin-clavulanate Yes No Yes, but high rates of E. coli resistance Minocycline Yes Yes Limited Trimethoprim- Yes Yes Limited sulfamethoxazole Only variable activity No Yes, broad-spectrum activity against MSSA MRSA, -resistant S. aureus; MSSA, methicillin-sensitive S. aureus of these organisms. Wounds of < 6 results.5–7 For example, clinical bials.12,13 To minimize antibiotic weeks’ duration coincided with the response did not differ in a study exposure, chronic wounds without greatest number of gram-positive that compared , an agent clinical signs of infection should not infections. In contrast, gram-nega- lacking anti-pseudomonal activity, be cultured.3 Unwarranted microbio- tive infections were more prevalent to - in 586 logical samples may encourage the in patients with wounds present for patients with moderate to severe use of antibiotic therapy and thereby ≥ 6 weeks. DFIs.5 Some caution is advised in increase the risk of harboring multi– The inclusion of anti-pseudo- interpreting this finding because drug-resistant organisms. monal spectrum in the treatment only 28 cultures in this study isolated of DFIs is common but contro- P. aeruginosa. Expanded-Spectrum versial. Empiric antibiotic therapy Patients with DFIs have numer- –Based Therapy with activity against P. aeruginosa ous hospitalizations and are often Expanded-spectrum penicillin–based (i.e., , , piper- exposed to multiple courses of regimens include dicloxacillin and acillin-tazobactam, , or antibiotics.8 Previous antibiotic β-lactam/β-lactamase inhibitor ) is advised for patients exposure can have a substantial combinations. Dicloxacillin, an oral with risk factors for this organism, influence on anticipated antimicro- penicillinase-resistant penicillin, is those who have undergone recently bial resistance. Kaye et al.9 reported a recommended treatment for mild failed nonpseudomonal therapy, and that patients with previous treatment DFIs. This agent has excellent activity in cases of severe infection. Risk with penicillin-based therapy had against methicillin-sensitive S. aureus factors for P. aeruginosa infection higher rates of E. coli resistance to (MSSA) and β-hemolytic strepto- include warm climate, open wounds the β-lactam/β-lactamase inhibitor cocci but has no activity against that have been soaked in water, and combination -. gram-negative pathogens. Although a high local rate of pseudomonal Fluoroquinolone use has been inexpensive, dicloxacillin has variable infections.3 associated with an increase in the oral absorption and requires dosing Surprisingly, clinical improve- acquisition of methicillin-resistant S. four times daily. ment in severe infections has been aureus (MRSA).10,11 A common risk Other penicillin-based therapies observed with regimens devoid of factor for the development of highly consist of β-lactam/β-lactamase meaningful P. aeruginosa activity resistant bacteria is the previous inhibitor combinations such as regardless of microbiological culture use of broad-spectrum antimicro- -clavulanate, ampicillin-

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Table 2. Characteristics of Suggested Antibiotic Regimens for Moderate to Severe DFIs

Available Once-Daily Activity Against Activity Against Activity Against formulations Dosing MRSA P. aeruginosa B. fragilis Ampicillin- IV No No No Yes sulbactam Levofloxacin IV and oral Yes No Variable resistance No rates Ciprofloxacin IV and oral No Yes for clindamycin, Yes for ciprofloxacin, Yes for clindamycin, plus clindamycin but variable but variable but variable resistance rates resistance rates resistance rates Moxifloxacin IV and oral Yes No No Yes, but rare resistance IV No No No Yes, but some resistance IV Yes No No No Ertapenem IV Yes No No Yes Piperacillin- IV No No Yes Yes tazobactam Imipenem IV No No Yes Yes Linezolid IV and oral No Yes No No IV Yes Yes No No IV, intravenous; MRSA, methicillin-resistant S. aureus subactam, -clavulanate, inhibitor combination with broad- respectively). Although ticarcillin- and piperacillin-tazobactam. The spectrum coverage of aerobic clavulanate has been studied in the addition of a β-lactamase inhibitor gram-positives, obligate anaerobes, treatment of DFIs, it has mainly increases the spectrum of penicillin- and aerobic gram-negatives. In been supplanted by piperacillin- based antibiotics to include MSSA, comparison to ampicillin-sulbactam, tazobactam and is infrequently used. certain β-lactamase–producing gram- piperacillin-tazobactam has simi- negatives, and anaerobes such as lar activity against gram-positive B. fragilis. Amoxacillin-clavulanate and anaerobic bacteria but has an Cephalosporins are semisynthetic and ampicillin-sulbactam are almost increased spectrum against non- β-lactams classified by generations. identical with regard to spectrum, fermentive gram-negative rods Generally, cephalosporins in higher with activity against gram-positive including P. aeruginosa. This dif- generations have enhanced activity organisms, enterobacteriaceae, and ference in gram-negative activity against gram-negative organisms obligate anaerobes. Of note, isolates may not translate into a clinical but have varying degrees of activity of E. coli can be resistant to these advantage for all cases of DFIs. against gram-positive cocci. agents, particularly in patients with An open-label, randomized study15 The spectrum of first-generation previous antibiotic exposure.9 A compared these two agents in 314 cephalosporins is focused against recent study of E. coli bloodstream adult patients with moderate to gram-positive bacteria. Cephalexin infections14 observed an increase in severe infections of diabetic foot is an oral first-generation cephalo- ampicillin-sulbactam resistance over ulcers. The clinical efficacy rate for sporin with activity against MSSA, a 10-year period. ampicillin-sulbactam was found to streptococcus spp., and some strains Piperacillin-tazobactam is a par- be statistically equivalent to piper- of enteric gram-negative bacilli enteral /β-lactamase acillin-tazobactam (83.1 vs. 81%, such as E. coli. This agent has been

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studied in the treatment of uncom- carbepenems—imipenem, merope- within larger studies of skin and plicated lower-extremity infections nem, and —have similar skin structure infections. Graham in diabetic patients.16 Cephalexin spectrums of activity that include et al.27 compared levofloxacin in the usually requires dosing four times ESBL-producing gram-negatives and treatment of complicated soft tissue daily but offers a cost-effective P. aeruginosa. infections to ticarcillin-clavulanate option for mild DFIs. Although also parenterally followed by oral amoxicillin-clavu- Cefoxitin is a parenteral second- administered, ertapenem is the lanate. For the subset of 54 patients generation with only with once-daily with DFIs, a clinical success rate of activity against gram-positive, dosing. With regard to therapeutic 69.2% for levofloxacin and 57.1% for gram-negative, and anaerobic bac- spectrum, ertapenem lacks clini- ticarcillin-clavulanate/amoxicillin- teria. This antimicrobial is usually cal activity against enterococcus clavulanate was observed. In two given every 6 hours and, although spp. and P. aeruginosa.21 A differ- trials,6,7 moxifloxacin monotherapy active against obligate anaerobes, an ence in clinical outcomes was not was shown to be clinically non- increasing rate of B. fragilis resis- observed in trials5,22 comparing inferior to a regimen consisting tance has been observed.17 piperacillin-tazobactam to carbape- of initial piperacillin-tazobactam Ceftriaxone is an injectable nem-based therapy. therapy with a sequential switch to third-generation cephalosporin that Carbapenem use has been oral amoxicillin-clavulanate. Both provides broad-spectrum gram- associated with the emergence of studies included patients with DFIs, positive and gram-negative activity. multi-drug–resistant P. aerugi- but these were smaller subsets within Ceftriaxone lacks clinically useful nosa and K. pneumonia. Therefore, larger groups with skin and skin activity against bacteroides spp. and these antimicrobials must be used structure infections. For example, should be combined with an agent judiciously.23–25 Involvement of an one study using moxifloxacin6 such as metronidazole if anaerobic infectious diseases specialist should included only 78 DFIs from among pathogens are also suspected.18 An be considered for patients who 617 patients enrolled in the original open-label study19 compared metroni- require the use of these agents. study. Because it has no demon- dazole plus ceftriaxone to ticarcillin/ strated clinical superiority over other clavulanate as empiric treatment for Fluoroquinolones well-established treatment choices, diabetic lower-extremity infections Ciprofloxacin, levofloxacin, and empiric fluoroquinolone therapy in older men. Both regimens had moxifloxacin are potential options for should be reserved for β-lactam– similar treatment success rates (72 the empiric treatment of DFIs.3 These allergic patients. and 76%, respectively). Convenient fluoroquinolones are available in both once-daily dosing makes ceftriaxone oral and intravenous formulations, Agents Active Against MRSA an attractive parenteral option for but differ with regard to antibacterial The prevalence of MRSA in DFIs outpatient therapy. spectrum. Ciprofloxacin should be has increased compared to historic used in combination with clindamy- rates and has been reported to be as cin because of its relatively poor high as 30%.28 Risk factors for MRSA Carbapenems are broad-spectrum gram-positive activity. In contrast isolation from DFIs include chronic parenteral antimicrobials that have to ciprofloxacin, levofloxacin has ulcers of > 6 weeks’ duration, previous activity against gram-positive, improved gram-positive activity but hospitalization, long-term antibiotic gram-negative, and anaerobic is less potent against P. aeruginosa. use, osteomyelitis, previous history of bacteria. Carbapenems should be Moxifloxacin possesses activity MRSA infection, and MRSA nasal reserved for treatment of infections against obligate anaerobes, including colonization.4,28–30 Empiric coverage likely to be caused by multi-antibiotic– B. fragilis, but lacks clinical utility for of MRSA should be considered for resistant gram-negatives (e.g., when pseudomonal infections. Although patients with previous isolation of extended-spectrum β-lactamase levofloxacin and moxifloxacin can MRSA within the past year, high [ESBL]–producing organisms are of be used as empiric monotherapies, local MRSA rates (prevalence rates particular concern). Both imipenem they may not provide reliable activity of 50% for mild infections and 30% and meropenem have been studied for against S. aureus, particularly when for moderate infections), or severe the treatment of diabetic foot infec- MRSA is suspected.26 infections while awaiting definitive tions in subsets of patients with Most of the published fluoroqui- culture results.3 complicated skin and skin structure nolone DFI data have been derived For mild infections, oral agents infections.20 The three available from smaller subsets of patients with MRSA activity include

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minocycline, trimethoprim-sul- patients with diabetes receiving The superiority of alternative agents famethoxazole (TMP-SMX), and either linezolid or for such as linezolid or daptomycin in clindamycin. Although TMP-SMX complicated skin and skin structure the treatment of DFIs has not been and minocycline have in vitro activ- infections observed comparable demonstrated. ity against many isolates of MRSA, rates of clinical success (74 and 71%, their activity against streptococcal respectively). Linezolid is available Conclusion species is not uniform. For example, in both intravenous and oral formu- Identifying the appropriate antimicro- group B streptococci are intrinsically lations and is active against aerobic bial treatment of DFIs is a complex resistant to TMP-SMX, and tetracy- gram-positive organisms, including process with many patient-specific cline–resistant group A streptococci MRSA and vancomycin-resistant considerations. Proper selection of are widely prevalent. An additional enterococcus. This agent is well antimicrobial therapy is imperative agent such as amoxicillin should be absorbed orally but considerably but often difficult because of poly- added if β-hemolytic streptococci more expensive than the older oral microbial colonization of chronic coverage is required.30 antibiotics previously mentioned. diabetic ulcers. Therapy must have Clindamycin, a lincosamide, is Because of frequent myelosuppres- activity against gram-positive organ- available in both intravenous and sion, complete blood counts should isms and, if risk factors are present, oral formulations. This agent has be monitored for treatment courses include coverage of MRSA. The activity against community acquired > 14 days. One study35 reported role of P. aeruginosa therapy is less strains of MRSA, β-hemolytic anemia (17.6%), thrombocytopenia clear, and empiric antimicrobial streptococci, and anaerobic bacte- (12.8%), and neutropenia (2.0%) coverage is not always necessary for ria. However, MRSA isolates should associated with linezolid use. this organism. be tested for inducible clindamycin Furthermore, linezolid interacts Regimens studied have not dem- resistance because treatment failures with medications that increase con- onstrated meaningful superiority have been reported.31 centrations of serotonin, resulting in of any particular agent. The major- Treatment options for moderate rare but sometimes severe cases of ity of published data pertain to the to severe DFIs with MRSA include serotonin syndrome.36 use of β-lactam–based regimens. vancomycin, daptomycin, and line- Daptomycin is a parenteral cyclic Newer agents such as ertapenem and zolid. Vancomycin, a glycopeptide lipopeptide similar in spectrum to moxifloxacin are possible choices antimicrobial, has been the tradi- vancomycin with activity against in the treatment of DFIs but should tional agent used to cover MRSA in gram-positive organisms. Once- be considered only as alternative more severe DFIs. Optimal dosing daily dosing makes this an attractive agents. Although linezolid and is important because patients with outpatient option, but serial moni- daptomycin are other potential diabetes may have reduced penetra- toring of creatine phosphokinase treatment options for MRSA, no tion of vancomycin into soft tissue is recommended because of poten- compelling evidence indicates the compared to patients without diabe- tial myopathy.37 In a subset of 103 need to replace vancomycin for the tes.32 Additionally, some strains of S. patients with DFIs, daptomycin had treatment of DFIs. Linezolid and aureus, compared to historic isolates, similar outcomes to either vanco- daptomycin generally should be have shown a decreasing sensitivity mycin or penicillinase-resistant reserved for cases of vancomycin to vancomycin. semisynthetic penicillin (66 and 70%, failure or hypersensitivity. The consensus recommendations respectively).38 The optimal antimicrobial published in 200933 offer guidance Tigecycline is a parenteral broad- treatment of DFIs has yet to be regarding the suggested dosing spectrum glycylcycline antibiotic. determined. Additional prospective, and monitoring for complicated Although active against MRSA, this well-designed trials are needed to MRSA infections. In the setting agent has been found to be inferior clarify which regimen(s) result in the of vancomycin hypersensitivity or to other antimicrobials in the treat- best possible outcomes. clinical failure, alternatives such as ment DFIs.39 daptomycin or linezolid could be Mild DFIs involving MRSA can References considered. be treated with inexpensive oral 1Senneville E, Melliez H, Beltrand E, Legout L, Valette M, Cazaubiel M, Linezolid, an oxazolidinone, has options such as TMP-SMX, minocy- Cordonnier M, Caillaux M, Yazdanpanah been studied in complicated skin cline, or clindamycin. Vancomycin is Y, Mouton Y: Culture of percutaneous bone biopsy specimens for diagnosis of diabetic and skin structure infections includ- still an appropriate choice for MRSA foot osteomyelitis: concordance with ulcer ing DFIs. A pooled review34 of 349 coverage in moderate to severe DFIs. swab cultures. Clin Infect Dis 42:57–62, 2006

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2Bowler PG, Duerden BI, Armstrong β-lactamase-producing bacteria and inten- and susceptibility patterns. Infect Control DG: Wound microbiology and associated sive care unit admission. Emerg Infect Dis Hosp Epidemiol 30:666–671, 2009 approaches to wound management. Clin 13:1144–1149, 2007 25 Microbiol Rev 14:244–269, 2001 Lautenbach E, Synnestvedt M, Weiner 14Al-Hasan MN, Lahr BD, Eckel-Passow MG, Bilker WB, Vo L, Schein J, Kim M: 3Lipsky BA, Berendt AR, Cornia PB, Pile JE, Baddour LM: Imipenem resistance in Pseudomonas aerugi- JC, Peters EJ, Armstrong DG, Deery HG, trends of Escherichia coli bloodstream iso- nosa: emergence, epidemiology, and impact Embil JM, Joseph WS, Karchmer AW, Pinzur lates: a population-based study, 1998–2007. on clinical and economic outcomes. Infect MS, Senneville E: Executive summary: 2012 J Antimicrob Chemother 64:169–174, 2009 Control Hosp Epidemiol 31:47–53, 2010 Infectious Diseases Society of America clini- cal practice guideline for the diagnosis and 15Harkless L, Boghossian J, Pollak R, 26Tenover FC, Tickler IA, Goering RV, treatment of diabetic foot infections. Clin Caputo W, Dana A, Gray S, Wu D: An open- Kreiswirth BN, Mediavilla JR, Persing Infect Dis 54:1679–1684, 2012 label, randomized study comparing efficacy DH; MRSA Consortium: Characterization

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randomized controlled trials. Int J Infect Dis penicillin-resistant pneumococci, and Gregory T. Matsuura, PharmD, 15:e140–e146, 2011 vancomycin-resistant enterococci. Mayo Clin Proc 86:1230–1243, 2011 is a clinical assistant professor of 35Minson Q, Gentry CA: Analysis of linezolid-associated hematologic toxicities 38Lipsky BA, Stoutenburgh U: pharmacotherapy at the Washington in a large veterans affairs medical center. Daptomycin for treating infected diabetic State University College of Pharmacy Pharmacotherapy 30:895–903, 2010 foot ulcers: evidence from a randomized, controlled trial comparing daptomycin with in Spokane and Yakima Valley 36Lawrence KR, Adra M, Gillman PK: vancomycin or semi-synthetic Serotonin toxicity associated with the use for complicated skin and skin-structure Memorial Hospital in Yakima, Wash. of linezolid: a review of postmarketing data. infections. J Antimicrob Chemother Clin Infect Dis 42:1578–1583, 2006 55:240–245, 2005 Neil Barg, MD, is a clinical associate 37Rivera AM, Boucher HW: Current 39Prasad P, Sun J, Danner RL, Natanson professor of medicine at the University concepts in antimicrobial therapy against C: Excess deaths associated with tigecycline of Washington School of Medicine select gram-positive organisms: methi- after approval based on noninferiority trials. cillin-resistant Staphylococcus aureus, Clin Infect Dis 54:1699–1709, 2012 in Seattle.

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