Kosinksi & Lipsky (2010) - Current Medical Management of Diabetic Foot Infections

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People with diabetes are at high risk for develop-ing infections of the foot. It is estimated that inthe USA, 15% of diabetic patients will developa foot ulcer in their lifetime [1] and diabetics

have at least a tenfold greater risk of hospital-ization for foot infections compared with indi-viduals without diabetes [2]. More than 60% ofnon-traumatic lower-limb amputations occur inpeople with diabetes, the majority of which arepreceded by an infected foot wound [3–5]. Thelikelihood of adverse outcomes is even higherin developing countries where access to medicalcare, especially advanced treatment modalities,is often limited. Morbidity and mortality asso-ciated with diabetic foot infections (DFIs) canbe expected to increase in light of the fact that

the number of people with diabetes worldwideis projected to double, reaching approximately366 million by 2030 [6].

Diabetic foot infections result from a complexinterplay among three main complications oflong-term diabetes: immunopathy, neuropathyand arterial disease. In vitro evidence suggeststhat in the diabetic patient neutrophil functionis compromised, with impaired chemotaxis andphagocytosis [7–9]. Diabetic neuropathy leads tofoot deformity, which results in high pressureareas, leading to calluses and eventually breaks in

the protective skin envelope. Sensory neuropathy

leads to a decreased awareness on the part of tpatient of potential risks to the foot, or failuto recognize that a foot wound, especially infected, requires urgent treatment. Peripher

arterial disease jeopardizes the viability of sotissue and bone, and facilitates the spread infection by compromising the penetration leukocytes and antibiotics to the infected site.

Bacteria most commonly gain entry to subcutneous tissues by a disruption of the normal cutanous barrier. This may occur through small fissurbetween the toes, acute traumatic wounds, buror chronic pressure-related ulcers. Infection mremain mild and localized, or spread rapidly alotendon sheaths and fascial planes. An infectiothat begins under a metatarsal head, for examp

may quickly progress to an abscess in the plantspace, which requires urgent surgical interventio

Properly treating DFIs requires knowledin several fields and often special surgical skilThus, a multidisciplinary approach, includinspecialists in infectious diseases, foot surgeo(orthopedic or podiatric), endocrinologistvascular surgeons and wound care expertcan optimize treatment outcomes. Assemblinsuch a team, ensuring that it follows evidencbased guidelines and regularly audits its resuare processes that are likely to provide the be

outcomes for patients with DFI.

Mark A Kosinski†1 andBenjamin A Lipsky2

1Division of Medical Sciences, New

York College of Podiatric Medicine,

53 East 124th Street, New York,

NY 10035, USA2Primary Care Clinic and Antibiotic

Research, VA Puget Sound Health Care

System and University of WashingtonSchool of Medicine, 1660 South

Columbian Way, Seattle,

WA 98108, USA† Author for correspondence:

Tel.: +1 212 410 8178

Fax: +1 212 410 8440

[email protected]

Foot infections are a serious complication of diabetes associated with substantial morbidity anoccasional mortality. Antibiotic therapy for mild infections in patients who have not recentreceived antibiotic therapy can often be directed at just staphylococci and streptococci. Empitherapy for infections that are chronic, moderate or severe, or that occur in patients who hafailed previous antibiotic treatment, should usually be more broad spectrum. Bone infectioalso complicates a substantial percentage of diabetic foot wounds and increases the likelihooof treatment failure, requiring lower extremity amputation. An increasing body of evidensupports the effectiveness of nonsurgical treatment of diabetic foot osteomyelitis in selectepatients, although the optimal choice of agent, route of administration and duration of therahave yet to be defined. This article examines the potential role of standard and newer antibiotithat may be appropriate for treating diabetic foot infections, including ertapenem, vancomycmoxifloxacin, daptomycin, telavancin and tigecycline, as well as several investigational agensuch as dalbavancin, ceftobiprole and nemonoxacin.

KEYWORDS: empiric therapy • foot infections • multidrug-resistant organisms • osteomyelitis

• polymicrobial infections • severity of infection • soft-tissue infections

Current medical management

of diabetic foot infectionsExpert Rev. Anti Infect. Ther. 8(11), 1293–1305 (2010)



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Expert Rev Anti Infect Ther 8(11) (2010)

Microbiology

In the 1980s and early 1990s, some textbook chapters impliedthat nearly all DFIs were polymicrobial [10–12], with Gram-positivecocci accompanied by Gram-negative bacilli, and that even mildinfections often harbored obligately anaerobic pathogens. This

widely held belief has been shown to be largely untrue. While asubstantial minority of infections will have mixed flora, studiesover the past 20 years have shown that many acute infections inpatients who have not recently received antibiotic therapy aremonomicrobial, usually caused by just an aerobic Gram-positivecocci. The most common organisms found in mild DFIs are simi-lar to those found in non-diabetic patients with skin and soft-tissue infections, namely Staphylococcus aureus and streptococcalspecies [13].

When patients present with infections that are chronic, theyhave often already been treated with systemic or topical anti-microbials. It is in these, and in the more severe DFIs, that

the microbiology takes a decidedly polymicrobial turn[14–16]

.S. aureus is still the predominant pathogen, and streptococci arealso common (especially group B, occasionally groups C or G, andless commonly group A ). These organisms have the potential tocause necrotizing infections requiring aggressive surgical debride-ment [17]. Other Gram-positive organisms, including Enterococcus spp., are often cultured in patients who have received antibiotictherapy (especially cephalosporins), as are Gram-negatives, suchas Escherichia coli and species of Klebsiella and Proteus . SomeGram-negatives have been found to confer synergistic virulenceto Bacteroides fragilis in vitro [18,19]. While Gram-negatives areusually part of a mixed infection, it is not clear that antimicro-bial therapy specifically targeted at them is needed in most cases[20]. Pseudomonas aeruginosa , a Gram-negative organism that isresistant to many widely used antibiotics, is a special case [21].This water-borne species is often found in wounds that havebeen soaked or become macerated. Pseudomonas (and a few otherGram-negative bacilli) is also a more common pathogen in hotclimates, perhaps related to increased foot sweating and the daily wearing of the same footwear (e.g., absorbent leather sandals) without socks.

Coagulase-negative staphylococci, while often correctlyregarded as contaminants, especially when isolated from super-ficial swab cultures, can be true pathogens. When isolated fromproperly obtained deep tissue or bone specimens, they should

be regarded as causative organisms and treated accordingly [22].Even relatively avirulent organisms, such as Corynebacterium spp.(diphtheroids), can occasionally cause infection in diabetics whoare immunocompromised, have a foreign body in the wound site,or have received extensive previous antibiotic treatment [23–25].Some species of fungi, such as Candida [22], are also occasionallyfound in cases of DFI. The most common type of fungal infectionin the diabetic foot, however, is certainly tinea pedis.

When anaerobic infection occurs, it is usually in a patient whohas an ischemic limb or a wound with necrotic tissue. Whileusually found in mixed infections, obligate anaerobes are occa-sionally isolated as the sole pathogens [14]. B. fragilis remains one

of the most common and formidable anaerobic pathogens [15]

isolated from moderate-to-severe DFIs. Owing to its resistance tomany commonly used antibiotic agents, B. fragilis is an importantpathogen to identify, if present. Peptococcus and Peptostreptococcus spp., while more commonly seen, are of low virulence and areusually susceptible to commonly used b-lactam antibiotics.

Clinicians should bear in mind that a severely infected, previ-ously treated or neglected diabetic wound can harbor virtuallyany species of bacterium. One question previously asked aboutpolymicrobial infections is whether all of the isolated organisms,especially the Gram-negatives and anaerobes, are pathogenic and worthy of targeted systemic therapy. Although Gram-negativeslike P. aeruginosa are unquestionably important pathogens inrespiratory tract, urinary tract, bone and bloodstream infections,some data suggest that therapy directed against them may notbe necessary to cure a diabetic lower extremity skin and skin-structure infection. In these wounds, P. aeruginosa may representa commensal rather than a truly pathogenic organism. For exam-

ple, in the SIDESTEP DFI study[20]

, clinical response rates forpatients from whom P. aeruginosa was cultured as part of a mixedinfection were similar for ertapenem and piperacillin/tazobactam(83.3 and 70.0%, respectively), despite the fact that ertapenem(unlike piperacillin/tazobactam) has no activity against mostP. aeruginosa spp. Thus, P. aeruginosa may not be as clinicallyimportant a pathogen in DFIs as once believed. When it is associ-ated with using wet dressings or hydrotherapy, discontinuing thistreatment may be all that is necessary [22,26].

In the past decade one of the important changes in the micro-biology of DFIs is the increasing isolation of multidrug-resistantorganisms (MDROs). The most important of these pathogens ismethicillin-resistant S. aureus (MRSA). The increase in preva-

lence of MRSA in DFIs parallels that for other types of skin andsoft-tissue infections, including those originating in the hospitaland community [27]. In a survey of 97 US hospitals conductedbetween 2003 and 2007, the prevalence of MRSA in hospital-ized patients with a DFI almost doubled, from 11.6 to 21.9%[28]. Although isolation of MRSA is not always associated withunderlying risk factors [29], predisposing factors include a long-standing wound, previous hospitalization and chronic kidneydisease [30]. Nasal colonization with MRSA in diabetic patientshas also been found to be a significant risk factor for a foot ulcerinfection with this organism present [31].

Of note is that isolating MRSA from the wound has been

associated with a significantly higher rate of treatment failure inpatients with DFIs. In an analysis of data from published trials ofantibiotic treatment of DFI, Vardakas et al. found that treatmentfailure (defined as persistence of signs and symptoms of infection with or without persistent positive cultures despite antibiot icadministration and proper surgical intervention) was signifi-cantly more common in patients from whom MRSA was isolatedthan in DFIs caused by other bacteria (24 out of 68 [35.3%] vs350 out of 1522 [23%]) [32]. Factors apparently associated with worse outcomes with MRSA infections include their productionof virulence factors such as Panton–Valentine leukocidins andphenol soluble modulins, and their ability to survive after phago-

cytosis by neutrophils [33]. A delay in instituting appropriate

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anti-MRSA therapy may be another reason for the increased rateof treatment failure. Studies by Hartemann-Huertier et al. [34] as well as Richard et al. [35], however, found that the presenceof MDROs, most notably MRSA, had no significant impacton healing time of diabetic foot wounds. The authors attribute

this to early aggressive treatment and prompt intervention withMDRO active antibiotics.

The other MDRO with an increasing incidence isextended-spectrum b-lactamase (ESBL)-producing strains ofEnterobacteriaceae. To date, reports of these isolates in DFIs havecome mostly from warm Southern climates. In a study from Indiaby Varaiya et al., among 134 isolates of E. coli and K. pneumoniae obtained from diabetic foot ulcers, ESBL production was detectedin 31 (23%) isolates [36]. Another study from India found thatthe organisms most frequently isolated from DFIs were Gram-negative aerobes (51%), followed by Gram-positive aerobes (33%)and anaerobes (33%). Of note is that 72% of the isolates were

classified as MDROs, with ESBL production and methicillinresistance noted in 44.7 and 56.0% of bacterial isolates, respec-tively. MDRO-positive status was significantly associated withthe presence of neuropathy, osteomyelitis, ulcer size greater than4 cm2, poor glycemic control and need for surgical treatment, butnot with patient characteristics, ulcer type and duration, or dura-tion of hospital stay [16]. This increase in ESBL-producing strains jeopardizes the usefulness of b-lactam agents for empiric therapy,leading to increases in costs and treatment failures.

Microbiologic sampling is important for helping to direct anti-microbial therapy. Historically, cotton swabs have been the most widely used method for obtaining a sample. [37–39]. However, sev-eral studies have found them to be less reliable than tissue cultures,

obtained by curettage or biopsy [39–41]. A recent review compar-ing superficial swabs and deep tissue cultures of lower extremity wounds found that the sensitivity (49%), specificity (62%), andpositive (1.1) and negative (0.67) likelihood ratios were all ratherlow, suggesting these cultures lack accuracy [42]. Although nota substitute for deep tissue cultures, swabs may be adequate forroutine clinical use.

Soft-tissue infection in diabetics

Using a robust yet simple classification system can assist theclinician in caring for a patient with a DFI in several ways.These include: deciding when to hospitalize a patient, when

to use parenteral (rather than oral) antibiotic agents, when tostart empiric broad spectrum (rather than targeted) antibiotictherapy and when to consider calling a surgeon to evaluate the wound. The Infectious Diseases Society of America (IDSA)Practice Guidelines for the Diagnosis and Treatment of DFIsproposed such a classification for DFIs. This system is very simi-lar to the one proposed by the International Working Group onthe Diabetic Foot [43], and has been validated as a useful toolfor grading foot infections [22]. The system first gives guidanceon determining which foot wounds are clinically infected, thenclassifies DFIs as being mild, moderate or severe. It may be par-ticularly useful for aiding the clinician in selecting appropriate

empirical treatment.

Clinically uninfected wounds

Since cultures of all open wounds will yield organisms, infectioof the wound, that is, the presence of pathogenic microorgaisms in host tissues that are causing damage and eliciting a horesponse is generally defined clinically rather than microbi

logically. Evidence of infection includes the presence of purlent drainage or two or more of the classic signs of inflammtion, which are pain or tenderness, erythema, induration an warmth. Patients with peripheral neuropathy or vasculopathmay not manifest these signs or symptoms. Thus, some suggethat ‘secondary’ or ‘alternate’ signs, such as friable or discoloregranulation tissue, foul odor, delayed healing or undermininmay indicate infection. Still others argue that the best definitioof infection is the presence of more than 105 bacteria per gram tissue on biopsy, a rather impractical technique that is not avaable in most clinical laboratories [44]. While an elevated whiblood cell count, left-shifted leukocyte differential or increase

inflammatory markers (e.g., erythrocyte sedimentation rate C-reactive protein) suggest infection, they are insensitive finings in DFIs. In the absence of a gold standard against which compare these methods, we prefer the classical signs. A commomisconception is that patients with diabetes do not develop typcal cellulitis, that is, infection of the epidermis (and often derm with progressive superficial erythema and induration. Althougthere may be an altered response that dampens some of the symtoms, in most patients, who do not have critical limb ischemcellulitis is a reliable indicator of infection [22].

The key reason to define whether or not infection is present that noninfected wounds almost never require antibiotic therapThus, there is no reason to culture these lesions. Some believe th

treating these wounds with antimicrobials is useful because: oterwise some cases of infection will be missed; treatment may prvent the development of infection; or antimicrobials may reduthe bacterial ‘bioburden’ and enhance wound healing. The uof ‘precautionary’ or prophylactic antibiotic therapy in the hopof preventing infection is not supported by currently availabmedical evidence. Furthermore, this practice is associated withe potential for adverse effects, financial cost and may lead the development of resistant organisms [22].

Mild infection

Mild infections manifest as either limited (<2 cm) cellulitis or

wound with either purulence or at least two of the classic signs symptoms of a host inflammatory response. If there is celluliaround the wound it extends less than 2 cm from the peripheof the ulcer, and there is no penetration deeper than to the sucutaneous tissue (dermis), no lymphangitis or regional lymphdenopathy. Similarly, there are no systemic signs or symptoms infection, and the patient’s white blood cell count and metaboparameters are in or near the usual range.

Mildly infected diabetic wounds can usually be treated on aoutpatient basis with oral antibiotic therapy. Many patients wneed some minor surgical procedure (e.g., debridement, incsion and drainage for a small abscess) or pressure off-loadin

Antibiotic therapy should usually be directed against S. aure

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and Streptococcus spp., with the caveat that there are increasingrates of MRSA in these patients. It is important to ensure thepatient has proper follow-up in a few days to review the results ofculture and sensitivity tests and to ensure there has been a clinicalresponse to treatment [22].

Moderate & severe infections

Moderate infections are defined as those with cellulitis extendingmore than 2 cm or evidence of significant proximal spread, orpenetration of infection into the deeper tissues, such as fascia, ten-don, muscle or bone. Lymphadenopathy or lymphangitis may bepresent. The patient is systemically well and metabolica lly stable,although there may be a mild elevation of the white blood cellcount, and blood glucose levels may be higher than the patient’susual values.

Severe infections are similar to moderate infections, but there isevidence of a septic state. The patient may be febrile, hypotensive,

confused or have significant metabolic imbalance (e.g., azotemiaand acidosis). The presence of severe peripheral arterial insuf-ficiency of the affected leg increases the risk of adverse outcomes with severe infection. While moderate infections may be limb-threatening, severe infections may also be life-threatening. Severeinfections are more often polymicrobial, including S. aureus andstreptococci, as well as Gram-negative and/or obligately anaerobicorganisms [22].

Bone infection of the foot in patients with diabetes

Infection of bone usually occurs by contiguous spread from softtissue. This process usually takes days or weeks, and is uncom-mon in acute infections. In most centers, approximately 20% of

patients who present with a DFI have involvement of the under-lying bone. Some studies have suggested that in selected popula-tions up to two-thirds of patients with a diabetic foot wound haveosteomyelitis. The presence of osteomyelitis increases the likeli-hood of treatment failure and lower extremity amputation. Thus,accurately diagnosing and treating this complication is crucial [45].

Although there have been several recent studies that suggestthat a carefully obtained culture of a sinus tract correlates well with concomitant bone cultures [46–48], bone biopsy with cul-ture or histopathology is still considered the criterion standardfor diagnosing diabetic foot osteomyelitis [49–51]. In addition toconfirming the presence of bone infection, only a bone biopsy can

provide the causative pathogen and its antibiotic susceptibilities.In a retrospective cohort study of 50 consecutive patients withdiabetic foot osteomyelitis treated non-surgically, Senneville et al. found that bone culture-based antibiotic therapy was the onlyvariable significantly associated with remission of infection [52]. Although overall patient management was similar in the differentcenters, rifampin was used more frequently in centers at whicha bone biopsy was available. Future studies will need to define whether and when to obtain a bone specimen in a patient withsuspected diabetic foot osteomyelitis.

The recommended duration of antibiotic therapy for boneinfections has traditionally been 6 weeks. The evidence for select-

ing this duration of treatment, however, is weak, largely resting

on the results of experimental studies of acute staphylococcalosteomyelitis in rabbits [53,54] and observations of the time it takesfor bone healing to occur. The early studies of treating osteo-myelitis largely included children with long bone infection andused parenteral therapy. More recent studies have shown that with

highly bioavailable antibiotics most (and perhaps all) treatmentcan be given orally. The length and type of treatment neededvaries with specific clinical and microbiological issues, that is,the extent of infection, whether or not necrotic and infected bonehas been resected, and the specific organisms isolated. In adults,most cases of osteomyelitis are chronic infections by the time theypresent. The recommended approach has long been to surgicallyresect all necrotic, and at least most infected, bone, but someremissions follow antibiotic therapy alone. Many authorities inthe field still consider 6 weeks of therapy (with at least some, ifnot all of it) parenteral, the standard, but some use either shorteror longer durations depending on the specific situation. Applying

a standardized regimen to every patient may end up overtreatingsome, and undertreating others.The IDSA Clinical Practice Guidelines for the Diagnosis and

Treatment of DFIs (T ABLE 1) are useful for estimating the length oftherapy required based on the extent of resection and viability ofaffected bone [22]. Surgical removal of all infected bone probablygives the best chance for a cure, as leaving infected bone behindincreases the possibility for recurrence. Studies over the pastdecade have shown, however, that patients who are unwilling orunable to undergo surgical debridement can often be successfullytreated with antibiotic therapy alone [55]. Patients who achieve aremission with antibiotics alone must be carefully monitored forat least 1 year as they may develop a recurrence of osteomyelitis

years af ter apparently ‘appropriate’ treatment. Although osteomyelitis has traditionally been considered a sur-

gical disease, several studies have demonstrated the possibilityof antibiotic-only management. Highly bioavailable antibioticsthat are effective in the presence of biofilm [56] and can enter hostcells [57] have changed the way we think about treating chronicosteomyelitis and may make nonsurgical management feasiblein some cases. A recent systematic review found that there iscurrently no evidence that surgical debridement of the infectedbone is routinely necessary nor is there sufficient data to sup-port the superiority of any particular antibiotic agent or routeof delivery [49].

In a retrospective review by Embil et al., remission wasachieved in 80.5% of 93 episodes of diabetic foot osteomy-elitis treated with oral antibiotic agents, among whom 78%had no bone debridement or resection [58]. Of note is thatthe mean duration of oral therapy was rather prolonged – 40 weeks. Ant ibiotic selection was at the individual physic ian’sdiscretion, with the most commonly used agents being met-ronidazole, ciprofloxacin, trimethoprim/sulfamethoxazole,amoxicillin/clavulanate, clindamycin or cephalexin, usually insome combination. Similarly, in a retrospective cohort studyof 50 patients with diabetic forefoot osteomyelitis treated non-surgically, Senneville et al. achieved a remission in 64% of

cases, and with a mean duration of antibiotic therapy of only

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11.5 weeks [52]. The most frequently usedantibiotic combinations in this study werea fluoroquinolone plus either rifampin,pristinamycin, or a third- or fourth-gen-eration cephalosporin. Finally, in a report

on treatment of diabetic foot osteomyeli-tis, Game et al. noted a remission rate of82.3% in patients treated with antibiot-ics but no surgery, compared with 78.6%remission in those treated with antibioticsand only minor amputation [59]. Parenteralantibiotics were required in some patientsto address limb-threatening soft-tissueinfection. Among patients receiving anti-biotics, 82% were treated with oral agents alone, and the meanlength of treatment with oral antibiotics was 60 days. The mostcommonly used antibiotic agents were amoxicillin/clavulanate

or a combination of clindamycin with either ofloxacin or cipro-floxacin. Doxycycline and trimethoprim/sulfamethoxazole wereused for patients infected with MRSA.

Studies such as these have shown that the optimal duration oftherapy, that is, one that will yield the highest remission rate withthe fewest complications and lowest cost, has yet to be defined,and will often be specific to the individual patient. This deci-sion may well need to take into account the infection’s location(forefoot vs rearfoot), the amount of bone involved, the infect-ing organism, the vascularity of the bone and the time elapsedbefore treatment is initiated. Schemes that reliably predicted which patients would be most responsive to nonsurgical treat-ment, and which could receive exclusively oral antibiotic therapy

would be useful.

Anti-infective therapy

Empiric therapy of DFIs should ideally be guided by the severityof the infection and the likely microbiology of the wound. Acute,relatively mild infections in patients who have not recentlyreceived antibiotic therapy can of ten be solely directed at aero-bic Gram-positive cocci. Infections that are chronic, moderateor severe, or that occur in patients who have failed previousantibiotic treatment should usually be more broad spectrum.The need to cover MRSA (or ESBL) isolates depends on thelikelihood of these pathogens in any given patient. Definitive

therapy, to complete the appropriate course, should be basedon both the clinica l response to empiric therapy and the resultsof the culture and sensitivity report. In polymicrobial infec-tions, some organisms may represent contaminants or colonizers,and may therefore not need to be specifically covered by theantibiotic regimen.

The duration of antibiotic therapy for soft-tissue infectionsis governed by the resolution of signs and symptoms of infec-tion. Thus, clinical judgment plays an important role. Generally, when the patient is metabolically stable and the cardinal signsof infection have resolved, systemic antibiotic therapy can bediscontinued [26,38]. Antibiotics are designed to cure infections,

not to heal wounds, which usually takes many weeks. No data

support continuing to treat wounds after evidence of infectioresolves, in an attempt to either hasten healing or to preverecurrent infection.

Traditionally, authorities have advocated for parenteral therapat least initially, for complex musculoskeletal infections includinosteomyelitis. With the advent of more orally bioavailable agenoral therapy (including from the initiation of treatment) hproven to be as effective as parenteral therapy in many situatio[60,61]. The picture that is beginning to emerge is that the role parenteral antibiotics may be primarily to treat acute, severe sotissue infection, which may be life- or limb-threatening. Treatinchronic osteomyelitis is rarely an urgent matter and the resumay be just as good with oral as with parenteral therapy [62,63

Most mild soft-tissue infections can be treated with one several oral antibiotics (T ABLE 2). Dicloxacillin or a first-generaticephalosporin, such as cephalexin, are active against methicilli

sensitive S. aureus and streptococci [22]. Amoxicillin/clavulanacid is also useful for its activity against S. aureus and streptcocci, as well as many aerobic Gram-negative bacilli and obgate anaerobes, but its extended activity is often superfluouClindamycin is an effective agent for Gram-positive infectioand is frequently used for patients with a history of allergy to peicillin. If, however, isolated strains of S. aureus show susceptibilito clindamycin but resistance to erythromycin, the microbiololaboratory should perform a D-test to ensure inducible clindamcin resistance is not present [64]. Levofloxacin, the more actilevo-isomer of ofloxacin, is a widely used fluoroquinolone wimore reliable activity against aerobic Gram-positive cocci tha

ciprofloxacin. Oral treatment options for mild infections wicommunity associated-MRSA include minocycline, doxycyclior trimethoprim/sulfamethoxazole.

Empiric therapy of moderate-to-severe soft-tissue infectiorequire broader spectrum coverage with agents active againS. aureus , streptococci, Gram-negative bacilli and obligate anaeobes (T ABLE 3) . b-lactam/b-lactamase inhibitor compounds, suas ampicillin/sulbactam, ticarcillin/clavulanate and piperacillitazobactam, are useful in this regard. It is important to remembthat ESBL-producing Enterobacteriaceae are being found at aincreasing frequency [36]; because these organisms are not suscetible to these commonly used antibiotics, they require specifica

selected agents, such as a carbapenem.

Table 1. Duration and route of antibiotic therapy for the treatment odiabetic foot osteomyelitis.

Clinical situation Route of therapy Duration of therapy

No residual infected tissue

(e.g., postamputation)

Parenteral or oral 2–5 days

Residual infected soft tissue

(but not bone)

Parenteral or oral 2–4 weeks

Residual infected (but viable)

bone

Initial parenteral, then

consider oral switch

4–6 weeks

No surgery, or residual dead bone

postoperatively

Initial parenteral, then

consider oral switch

>3 months

Adapted from [113].




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Specific antibiotic agents

Ertapenem

Carbapenems are a broad-spectrum class of antibiotics effec-tive for treating moderate-to-severe DFIs. One of the newermembers is ertapenem, a carbapenem with a slightly less broad

spectrum than imipenem or meropenem. Based on large rand-omized controlled trials, ertapenem is approved for the treat-ment of complicated skin and skin-structure infections and ithas received approval by the US FDA specifically for compli-cated DFIs (without osteomyelitis). It has no activity aga instenterococci or MRSA nor against most P. aeruginosa [65,66].Ertapenem’s long half-life allows once daily dosing, makingit particularly attractive for home intravenous therapy. In adouble-blind, multicenter, noninferiority trial enrolling adultpatients with moderate-to-severe DFIs without osteomyelitis,586 adult patients were randomized to receive either ertapenem1 g intravenously once daily or piperacillin/tazobactam 3.375 g

intravenously every 6 h. There were 204 patients randomizedto ertapenem and 202 patients randomized to piperacillin/tazobactam who were clinically evaluable. The clinical suc-cess rates at 10 days post-therapy were 75.0% (153 out of 204)for ertapenem and 70.8% (143 out of 202) for piperacillin/tazobactam. Clinical success (cure or improvement) requiredresolution of all or most (respectively) pretherapy signs andsymptoms of infection (and specifically of fever, lymphangitisand purulent drainage) and no need for additional antibiotictherapy [20].

Although ertapenem can select for P. aeruginosa mutants with cross-resistance to imipenem in vitro, the occurence ofthis event should be minimal under usual clinical conditions.

In a study by Goldstein et al., susceptibility of P. aeruginosa to imipenem actually increased after introducing ertapenemon the formulary as part of a hospital antibiotic stewardshipprogram [66].

Vancomycin

Because MRSA is an increasing problem, vancomycin is currentlyone of the most commonly used agents for treating DFIs. It is per-haps the least expensive parenteral antibiotic (at least by acquisitioncosts) for treating MRSA infections. Furthermore, its lack of activity

against Gram-negative and anaerobic organisms necessitates com-bining it with another agent for patients with mixed infections. Acommon strategy in situations where there is reasonable suspicion ofMRSA infection (e.g., patients with prior hospitalizations, chroniculcerations, previous antibiotic therapy, renal impairment or nasalcolonization with MRSA) [30,31], is to begin empiric therapy by add-ing vancomycin to a b-lactam/b-lactamase inhibitor compound or acarbapenem. Vancomycin can then be discontinued if no strains ofMRSA (or penicillin-resistant enterococci) are isolated on culture.

Vancomycin is known to be associated with a risk of nephro-toxicity, especially when it is combined with other nephrotoxicantibiotics, such as aminoglycosides. In order to keep serum levels

within a therapeutic range and decrease the chance of toxicity,dose adjustments have historically been based on both serum peakand trough levels. More recent evidence supports using just thetrough level to adjust dosing [67–69]. A high vancomycin troughlevel is the variable most associated with the occurrence of nephro-toxicity. Target trough levels of vancomycin have traditionallybeen between 5–10 mg/l. Owing to decreasing sensitivity ofsome strains to vancomycin (‘MIC creep’), the 2009 VancomycinTherapeutic Guideline from the IDSA, the American Society ofHealth-System Pharmacists, and the Society of Infectious DiseasesPharmacists [70] recommends aiming for a trough serum con-centration of 15–20 mg/l. This is intended to provide a target AUC/MIC ratio of at least 400 for S. aureus isolates with a MIC of

up to 1 mg/l. Trough levels below 10 mg/l may promote the emer-gence of resistant strains with vancomycin intermediate S. aureus (VISA)-like characteristics. Although nephrotoxicity is a concern with higher trough concentrations, there are no prospective, ran-

domized controlled trials that definitivelyconfirm this association in patients whodo not have other baseline risk factors [71].For patients with normal renal function,a vancomycin dose of 15–20 mg/kg every8–12 h is recommended when S. aureus MIC is 1 mg/l or less. No evidence cur-rently supports the superior clinical out-

comes with continuous infusion compared with intermittent dosing.

Despite its widespread use, vancomycinis inefficient at penetrating the biofilm thatis so often present in DFIs [72,73]. In fact, astudy by Dunne suggests that vancomycincould potentially enhance biofilm produc-tion by coagulase-negative staphylococci

on implants [74]. Questions have also arisenregarding penetration of vancomycin intosoft tissue in diabetic patients. In a studyby Skhirtladze et al., vancomycin penetra-

tion into target tissues was substantially

Table 2. Suggested oral antibiotic agents for empiric therapy of milddiabetic foot infections.

Drug Dose adjustment neededfor renal impairment?

Class

Dicloxacillin No Penicillin

Amoxicillin/clavulanate† Yes b-lactam/ b-lactamase inhibitor

Cephalexin† Yes Cephalosporin

Cefdinir Yes Cephalosporin

Levofloxacin† Yes Fluoroquinolone

Clindamycin†‡ No Lincosamide

TMP/SMX§ Yes Sulfonamide

Minocycline§ Yes Tetracycline

Doxycycline§ No Tetracycline†Drugs that have been used in published trials of treatment of diabetic foot infections.‡Suspect inducible clindamycin resistance if staphylococcal isolate is susceptible to clindamycin but resistantto erythromycin. Conrm with D-test.§Active against community-associated methicillin-resistant Staphylococcus aureus.TMP/SMX: Trimethoprim/sulfamethoxazole.

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impaired in diabetic compared with non-diabetic patients [75]. After achieving steady state via continuous infusion, vancomy-cin levels were measured in thigh tissue of patients undergoingcardiac surgery. Although mean plasma concentrations were

equivalent, tissue concentrations were lower in diabetic patientscompared with non-diabetics (3.7 vs 11.9 mg/l, respectively).The study involved a small number of patients, but it raises thequestion of whether impaired vancomycin tissue concentrationsmay contribute to treatment failure and consequent developmentof resistance. Vancomycin penetration could be further impairedin a foot when the patient has peripheral arterial disease.

Many add rifampin to vancomycin therapy, in the hope thatthe two drugs are at least additive in effect. The combination intheory offers the advantage of rifampin’s enhanced biofilm pen-etration [76,77] and enhanced intracellular killing in polymorpho-nuclear leukocytes [78]. Clinical trials that support this theoretical

benefit in vitro are, however, lacking [79]. Adding clindamycin tovancomycin therapy offers another interesting possibility. In sub-inhibitory concentrations, clindamycin has been shown to inhibittoxin production by S. aureus and could thus be useful in patients with severe MRSA infections. Stevens et al., however, found thatclindamycin actually produced an antagonistic effect on the anti-staphylococcal activity of vancomycin, as did the combinationof linezolid and vancomycin [80]. Vancomycin combined withlinezolid has been found to be less active against MRSA thaneither agent alone [81]. Linezolid has been found to decrease therate of bacterial killing by 100–1000-fold when combined withvancomycin in vitro [82]. Thus, the available evidence suggests

not combining vancomycin with either clindamycin or linezolid.

Linezolid

Linezolid, a first-in-class oxazolidinone, is active against moknown Gram-positive pathogens, including MRSA and vancomcin-resistant Enterococcus faecalis . It has virtually 100% bioava

ability after oral administration, making it particularly useffor oral step-down therapy, potentially allowing patients to bdischarged from the hospital sooner. Since it has essentially nGram-negative and little anaerobic activity, linezolid must bused in combination with another agent when treating mixeinfections. Although treatment failures and resistant strains S. aureus have been reported [83], linezolid remains a valuabantibiotic for treating skin and soft-tissue infections.

Linezolid has shown good clinical cure rates in treating DFincluding in patients with limb ischemia. A randomized, opelabel, multicenter study of DFIs of all types compared the efficaand safety of parenteral and oral linezolid with parenteral amp

cillin/sulbactam and intravenous or oral amoxicillin/clavulanagiven for 7–28 days [84]. Among 371 patients, clinical cure ratassociated with linezolid and comparators were statistically equivlent overall (81 vs 71%, respectively), but significantly higher flinezolid-treated patients with infected foot ulcers (81 vs 68%and for patients without osteomyelitis (87 vs 72%). Similarly, a randomized, open-label trial involving 1200 adult patients hopitalized with complicated skin and soft-tissue infection suspector proven to be caused by MRSA, Itani et al. compared outcomin patients treated with either linezolid or vancomycin for complicated skin and soft-tissue infections [85]. Linezolid treatme was associated with a significantly shorter length of hospital sta

decreased parenteral antibiotic duration and higher early dischar

Table 3. Suggested agents (parenteral or oral) that may be used for empiric therapy of moderate-to-severe diabetic foot infections†.

Drug Class ActivityagainstMRSA?

Activity againstBacteroidesfragilis?

Dose adjustmentneeded for renalimpairment?

Ampicillin/sulbactam b-lactam/ b-lactamase inhibitor No Yes Yes

Ticarcillin/clavulanate b-lactam/ b-lactamase inhibitor No Yes Yes

Piperacillin/tazobactam b-lactam/ b-lactamase inhibitor No Yes Yes

Imipenem/cilistatin Carbapenem No Yes Yes

Ertapenem‡ Carbapenem No Yes Yes

Moxifloxacin§ Quinolone No Yes No

Clindamycin + ciprofloxacin§ or

levofloxacin

Lincosamide/quinolone Some Yes/no No/yes

Tigecycline¶ Glycylcycline Yes Yes No

Vancomycin¶# Glycopeptide Yes No Yes

Linezolid‡¶# Oxazolidinone Yes No No

Daptomycin¶‡ Cyclic lipopeptide Yes No Yes†All agents have been used in published trials of treatment of diabetic foot infections.‡US FDA indication for complicated diabetic foot infections without osteomyelitis.§For patients with penicillin allergy in whom MRSA is not suspected.¶Healthcare-associated MRSA and community-acquired MRSA activity.#Anaerobic and Gram-negative activity lacking. Use in combination for mixed infections.MRSA: Methicillin-resistant Staphylococcus aureus.




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rates [85]. Although linezolid is considerably more expensive thanolder oral and many parenteral antibiotics, it may be cost saving ifit allows earlier hospital discharge.

One of the major adverse events of linezolid is myelosuppression, which may result in anemia and/or thrombocytopenia [86–88]. In

Phase III comparator-controlled trials the percentage of adultpatients who developed a substantially low platelet count (definedas less than 75% of lower limit of normal and/or baseline) was2.4% [89]. A low baseline platelet count (<200,000/mm3), renaldysfunction (creatinine clearance <30 ml/min) and a daily line-zolid dose of 22 mg/kg or more are risk factors for developingthrombocytopenia while on linezolid [90,91]. The risk of hemato-logic toxicity appears to be dependent on the duration of therapy,generally occurring af ter 2 weeks of treatment [89]. Fortunately,most cases resolve after therapy is discontinued. When treated with linezolid, patients with renal fai lure have been noted todevelop higher rates of anemia, thrombocytopenia, cardiac fail-

ure and mortality compared with those in patients with nor-mal renal function. Tsuji et al. found that platelet count andhemoglobin levels decreased as the AUC of linezolid increasedin patients with renal dysfunction [91].

Other less frequently reported, but potentially irreversible, com-plications of linezolid therapy include peripheral neuropathy andoptic neuropathy. These have usually been noted to occur afterprolonged (e.g., several months) therapy. Also less frequentlyreported is the serotonin syndrome, which may occur after justa few days of therapy, and lactic acidosis, usually occurring afterseveral weeks of linezolid therapy [92,93]. For patients being treated with linezolid for longer than 14 days, weekly monitoring of bloodcounts and clinical symptoms is warranted.

Daptomycin

Daptomycin is a first-in-class cyclic lipopeptide that has bacteri-cidal activity against most Gram-positive pathogens, includingMRSA and vancomycin-resistant strains of S. aureus [94]. It is onlyavailable for parenteral use and is relatively expensive, even whencompared with oral linezolid. In a study comparing its effective-ness to semi-synthetic penicillins or vancomycin in 103 clinicallyevaluable patients with a DFI caused by Gram-positive pathogens,the clinical and microbiological efficacy and safety of daptomycin was not statistically different from comparator antibiotics (66 vs70%, respectively) [95]. Like linezolid and vancomycin, dapto-

mycin lacks both Gram-negative and anaerobic activity; thisnecessitates combination therapy for moderate and severe DFIsin which these organisms are a concern. One theoretically usefulcombination would be daptomycin plus a b-lactam/b-lactamaseinhibitor compound. Interestingly, daptomycin combined withampicillin/sulbactam, ticarcillin/clavulanate or piperacillin/tazo-bactam has shown in vitro synergy against MRSA comparable toor greater than daptomycin with oxacillin or with daptomycinalone. However, no synergy between daptomycin and rifampinagainst MRSA strains has been demonstrated [96]. In a study byTraunmüller et al., daptomycin given at doses of 6 mg/kg oncedaily appeared to be an effective treatment regimen for DFIs

including cases with osteomyelitis [97].

Patients should be monitored for muscle toxicity by solicitingsymptoms of myopathy (muscle pain and weakness) and obtaining weekly serum creatine phosphokinase (CPK) levels. It is recom-mended by the manufacturer that in patients with unexplainedsigns and symptoms of myopathy in conjunction with CPK eleva-

tion above 1000 U/l, or in patients without reported symptoms who have marked elevation in CPK of ten-times or greater theupper limit of normal, daptomycin should be discontinued [98].

Tigecycline

Tigecycline is a first-in-class, parenteral glycylcycline antibiotic with activity aga inst MRSA, vancomycin-resistant E. faecalis ,Gram-negatives and anaerobes. Glycylcyclines are semisyntheticderivatives of tetracycline antibiotics but are resistant to mostmechanisms by which bacteria develop tetracycline resistance[99,100]. The agent received FDA approval in June 2005 for treat-ment of complicated skin and skin-structure infections. It is gen-

erally not active against Proteus , Providencia or P. aeruginosa . Thepharmacokinetic parameters are not significantly affected by renaldisease or hemodialysis [101].

The broad spectrum of activity of tigecycline would seemto make this drug suitable as monotherapy for moderate-to-severe DFIs. Tigecycline was found to be active against83.7% of 315 strains of bacteria recovered from DFIs, includ-ing MRSA strains (96%), Enterobacteriaceae (88.5%) andanaerobes (100%) [102]. However, in an as yet unpublishedstudy evaluating the safety and efficacy against ertapenem inDFIs [201], tigecycline (g iven once daily) treated patients hada non-significantly lower clinical response of cure in both theclinically evaluable and the clinical ly modified intent-to-treat

populations without osteomyelitis (77.5 vs 82.5 and 71.4 vs77.9%, respect ively). Before recommending this agent, furtherstudies are needed to more clearly define the role of tigecyclinein treating DFIs.

Unfortunately, even if tigecycline proves to be more effec-tive in future studies, its potential usefulness may be overshad-owed by its side effects. The most common treatment-emergentadverse events listed in the manufacturers prescribing infor-mation were nausea (29.5%) and vomiting (19.7%) [103]. Mostnausea occurs within 6 h after dosing, with a mean duration of5 h [104]. Since tigecycline is structurally similar to tetracycline-class antibiotics it may have similar adverse effects, including

photosensitivity, increased blood urea nitrogen, azotemia,acidosis and hyperphosphatemia [103].

Moxifloxacin

Moxifloxacin is a broad spectrum, fourth-generation fluoroquino-lone with activity against S. aureus (except for MRSA strains),Gram-negatives and anaerobes. It was FDA-approved for treat-ing complicated skin and skin-structure infections in July 2005.Moxifloxacin does not require dose adjustment for patients withrenal impairment and does not appear to cause altered glucoselevels as often as gatifloxacin. As with other quinolones, moxi-floxacin has high bioavailability after oral administration, and

its long half-life allows once daily dosing.

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In a study by Lipsky et al., adult patients with a moderate-to-severe DFI [105] requiring initial intravenous therapy wererandomized to intravenous therapy with either moxifloxacin(400 mg/day) or piperacillin/tazobactam (3.0/0.375 g every 6 h)for at least 3 days followed by oral therapy with moxifloxacin

(400 mg/day) or amoxicillin/clavulanate (800 mg every 12 h), ifappropriate, for 7–14 days. Among the 78 patients evaluable fortreatment with moxifloxacin or piperacillin–tazobactam/amoxi-cillin–clavulanate, clinical cure rates (68 vs 61%, respectively)and overall pathogen eradication rates in the microbiologicallyvalid population (69 vs 66%, respectively) were similar.

Given its high oral bioavailability, broad spectrum of activityagainst pathogens that cause moderate-to-severe DFI and the con-venience of once daily therapy, this drug may have an important rolein patients who refuse or are otherwise unsuitable for hospitalizationor intravenous therapy, or for oral follow-on therapy.

Telavancin

Telavancin is a lipoglycopeptide antibiotic with activity againstmost Gram-positive organisms, including MRSA. It is availableonly for parenteral use and is dosed once daily. It received approvalby the FDA in 2009 for the treatment of complicated skin andskin-structure infections, but does not have specific FDA approvalfor DFIs. Dosage adjustment is required for a creatinine clearanceof less than 50 ml/min.

In two large, parallel, randomized, double-blind, controlledPhase III studies (ATLAS I and II), telavancin (10 mg/kg oncedaily) was found to be at least as ef fective as vancomycin (500 mgtwice daily) for the treatment of patients with complicated skinand skin-structure infections, including those caused by MRSA[106]. Clinical cure rates in telavancin-treated patients were lowerin patients with baseline creatinine clearance of 50 ml/min or less. While these studies involved patients with the lower extremityas the primary site of infection, there are no published studiesinvolving telavancin specifically for treatment of DFIs. Telavancinhas a black box warning for fetal risk and is a FDA pregnancycategory C drug.

Expert commentary & five-year view

We have made much progress in the past two decades in definingantibiotic regimens for DFIs. There are, however, some importantgaps in our treatment modalities. We hope the next 5 years will

bring new antibiotics with activity against MDROs. Optimally,these drugs will have an extended half-life for more convenientdosing regimens, and some will be oral and topical agents.

One such antibiotic is ceftaroline, a novel extended spectrumdrug that has been classified by some as a fifth generation cephalo-sporin. Ceftaroline was approved in September 2010 by the FDAfor treatment of community-acquired bacterial pneumonia andcomplicated skin and skin-structure infections. Ceftaroline hasactivity against multidrug-resistant S. aureus (including MRSA,VISA, heteroresistant VISA and vancomycin-resistant S. aureus ).It is active against many Gram-negative bacilli but not activeagainst Pseudomonas spp. or extended spectrum b-lactamase pro-

ducers [107]. It is renally excreted and dose adjustment is required

for moderate renal impairment and for patients receiving hemdialysis [108]. Ceftaroline 600 mg intravenously every 12 h hbeen shown to have similar efficacy to vancomycin plus aztrenam for the treatment of complicated skin and skin-structuinfections [109].

Dalbavancin is a parenteral lipoglycopeptide antibiotic wiexcellent activity against Gram-positive organisms, includinMRSA. This agent is unique in having an exceptionally lonhalf-life that allows for once weekly dosing. A randomizedouble-blind comparison found that two doses of dalbavanc(1000 mg given on day 1 followed by 500 mg given on day were as well tolerated and as effective as linezolid given twidaily for 14 days for the treatment of patients with complicatskin and skin-structure infections, including those caused bMRSA [110]. Based on feedback from the FDA, an additionPhase III trial is currently underway so its future is as yuncertain [111].

Nemonoxacin is a new once daily dosed oral nonfluorinatequinolone that is among the first of this antibiotic class to shoactivity against both MRSA and vancomycin-resistant pathogenOpen-label, noncomparative Phase II trials in patients with miDFIs have shown promising results [202], and further trials aplanned. Nemonoxacin has shown better in vitro activity than ciprfloxacin and levofloxacin against various species of staphylococstreptococci and enterococci [112].

Another novel product undergoing trials for treating DFIs iscombination of gentamicin with a collagen sponge. Provisionfindings from a prospective, randomized trial demonstrated ththe gentamicin–collagen sponge resulted in a similar number clinical cures/improvements as oral levofloxacin (750 mg on

daily) for mild infections [203]. This product is also being invetigated as a combined treatment with systemic antibiotics moderate infections; the results are pending.

In 5 years we hope there will be a clearer guidance on whconstitutes the best way to diagnose diabetic foot osteomyelitand what constitutes optimal therapy for this difficult infectioSeveral trials in patients with diabetic foot osteomyelitis that acurrently underway or in grant submission stages are attemptito define: the importance of bone biopsy in treatment outcomthe usual methods clinicians around the world use for diagnosand treatment; the value of antibiotic therapy alone compare with antibiotics plus surgery; and the outcomes with oral ve

sus parenteral antibiotic therapy. We look forward to seeing thresults.

Financial & competing interests disclosure

Mark Kosinski has received speaker fees from Merck. Benjamin Lipsky h

received research funding consultant or speaker fees from Merck, Pfiz

Schering-Plough/Bayer, Cubist, Wyeth, TaiGen and Innocoll. The auth

have no other relevant affiliations or financial involvement with any organ

zation or entity with a financial interest in or financial conflict with t

subject matter or materials discussed in the manuscript apart from tho

disclosed.

No writing assistance was utilized in the production of th

manuscript.




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Key issues

• Diabetic foot infections (DFIs) continue to be the leading proximate cause of non-traumatic lower extremity amputations, and the

incidence of this problem is increasing.

• The increasing incidence of multidrug-resistant organisms, especially methicillin-resistant Staphylococcus aureus and extended-

spectrum b-lactamase-producing strains of Enterobacteriaceae, further complicates the treatment of DFIs.

• Empiric therapy of DFIs should be mainly guided by the clinical severity of the infection, the likely causative organisms and the local

prevalence of antibiotic resistance.

• Most mild soft-tissue infections can be treated with a relatively narrow spectrum oral agent that is active against S. aureus and streptococci.

• Empiric therapy for moderate-to-severe soft-tissue infections require broader spectrum coverage with agents active against S. aureus,streptococci, Gram-negative bacilli and obligate anaerobes.

• Definitive therapy, to complete the appropriate course, should be based on both the clinical response to empiric therapy and the culture

and sensitivity results of a properly obtained wound specimen.

ReferencesPapers of special note have been highlighted as:•• of considerable interest

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managed with oral antibiotics with or

without l imited ofce debridement in

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Websites

201 Study evaluating the safety and efficacy oa once-daily dose of tigecycline vsertapenem in diabetic foot infections withsubstudy in patients with diabetic footinfections complicated by osteomyelitishttp://clinicaltrials.gov/ct2/show/NCT066249?term=tigecycline+ertapenem&ra nk=1(Accessed April 6 2010)

202 TaiGen announces nemonoxacin(TG-873870) once-a-day oral dosing indiabetic foot infection met primaryendpoints promising anti-MRSA activityand excellent pharmacokinetic profile

demonstrated in a Phase II proof ofconcept trial www.taigenbiotech.com/news.html#21(Accessed April 6 2010)

203 Innocoll announces provisional findingsfrom its three Phase 2 clinical trialsinvestigating CollaRx ® gentamycin topic(June 19 2009) www.medicalnewstoday.com/articles/154559.php(Accessed October 11 2010)




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Kosinksi & Lipsky (2010) - Current Medical Management of Diabetic Foot Infections

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