Diagnosing Diabetic Foot Osteomyelitisin PatientsWithout Signs of Soft TissueInfection by Coupling Hybrid 67GaSPECT/CTWith Bedside PercutaneousBone PunctureELISABETH ASLANGUL, MD, PHD

1,2

JOCELYNE M’BEMBA, MD3

NADINE CAILLAT-VIGNERON, MD, PHD4

SOPHIE COIGNARD, MD5

ETIENNE LARGER, MD, PHD1,3

CHRISTIAN BOITARD, MD, PHD1,3

BENJAMIN A. LIPSKY, MD6,7

OBJECTIVEdSuccessful treatment of osteomyelitis is more likely with accurate diagnosis andidentification of the causative pathogens. This typically requires obtaining a specimen of bone,usually by image-guided biopsy. We sought to develop a simpler bedside method for definitivelydiagnosing osteomyelitis.

RESEARCHDESIGNANDMETHODSdOver 2 years, we enrolled consecutive patientspresenting to our diabetic foot clinic with a foot ulcer and clinically suspected osteomyelitis butwithout soft tissue infection. Each underwent hybrid 67Ga single-photon emission computedtomography and X-ray computed tomography (SPECT/CT) imaging; those with a positive scanunderwent bedside percutaneous bone puncture. Patients with a positive bone culture receivedculture-guided antibiotic therapy. Patients with negative 67Ga SPECT/CT imaging or with pos-itive imaging but negative bone culture were not treated with antibiotics. All patients werefollowed up for $1 year.

RESULTSdAmong 55 patients who underwent 67Ga SPECT/CT imaging, 13 had negativeresults and all of their foot ulcers resolved without antibiotic therapy. Among 42 with positiveimaging, 2 were excluded (for recent antibiotic therapy) and 40 had bone punctures (3 punc-tured twice): 19 had negative results, 3 of which were likely false negatives, and 24 had positiveresults (all gram-positive cocci). At follow-up, 3 patients had died, 3 had undergone amputation,and 47 had no evidence of foot infection. The sensitivity and specificity of this combinedmethodwere 88.0 and 93.6%, respectively, and the positive and negative predictive values were 91.7 and90.7%, respectively.

CONCLUSIONSdCoupling of 67Ga SPECT/CT imaging and bedside percutaneous bonepuncture appears to be accurate and safe for diagnosing diabetic foot osteomyelitis in patientswithout signs of soft tissue infection, obviating the need for antibiotic treatment in 55% ofsuspected cases.

Diabetes Care 36:2203–2210, 2013

The worldwide prevalence of diabetesmellitus is expected to exceed 300million people in 2025, and ~25%

will develop a foot ulcer (1). More than

half of these ulcers are clinically infectedat presentation, and among these infec-tions 20–50% involve bone (2,3). Infec-tion of a diabetic foot ulcer, particularly

when accompanied by osteomyelitis,markedly increases the risk of lower-extremity amputation, a highly morbidevent (4,5).

The presentation of foot infection inpersons with diabetes is often atypicalbecause of the frequent presence of pe-ripheral neuropathy or vascular insuffi-ciency (6). Diagnosis of diabetic footosteomyelitis is particularly challenging(7), despite the availability of various clin-ical, serological, and imaging techniques(7–11). Furthermore, cultures of soft tis-sue specimens do not accurately reflectbone pathogens (12). The criterion stan-dard for diagnosing osteomyelitis is stillcontroversial, but the most conservative(albeit not yet validated) definition is cul-ture of a pathogenic organism from a bonespecimen in the presence of characteristichistological changes (13). Bone samplesmay be obtained at the time of surgicaldébridement or percutaneously by biopsyor bone marrow aspiration after punc-ture. A positive culture allows appropriatetailoring of antibiotic treatment, whichmay improve outcomes in diabetic footosteomyelitis (14). Nevertheless, in mostclinical practices osteomyelitis is diag-nosed solely on the basis of clinical andimaging findings (15); bone specimensare infrequently obtained, largely becauseof the perceived complexity of arrangingthe procedure or fear of adverse effects ofbone biopsy. Bone puncture, althoughsimpler than surgical or radiologicallyguided bone biopsy, is rarely undertaken.

Bone imaging, especially by plainradiographs, is usually the first step indiagnosing diabetic foot osteomyelitis(11,16). When this is inadequate, mag-netic resonance imaging (MRI) is consid-ered the best available advanced imagingstudy. MRI sensitivity is 90–100% in os-teomyelitis cases, but its specificity inmost studies is,80% (17). Nuclear med-icine imaging, although highly sensitive,is quite nonspecific (18,19). Conven-tional scintigraphic imaging often cannot

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From the 1Université Paris Descartes, Paris, France; the 2Department of Internal Medicine, AssistancePublique-Hôpitaux de Paris, Hôtel Dieu, Paris, France; the 3Department of Diabetology, AssistancePublique-Hôpitaux de Paris, Hôtel Dieu, Paris, France; the 4Department of Nuclear Medicine, Assis-tance Publique-Hôpitaux de Paris, Hôtel Dieu, Paris, France; the 5Department of Microbiology, As-sistance Publique-Hôpitaux de Paris, Hôtel Dieu, Paris, France; the 6University of Oxford, Oxford, U.K.;and the 7University of Geneva, Geneva, Switzerland.

Corresponding author: Elisabeth Aslangul, elisabeth.aslangul@htd.aphp.fr.Received 16 October 2012 and accepted 25 January 2013.DOI: 10.2337/dc12-2108© 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly

cited, the use is educational and not for profit, and thework is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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C l i n i c a l C a r e / E d u c a t i o n / N u t r i t i o n / P s y c h o s o c i a l R e s e a r c hO R I G I N A L A R T I C L E

identify the precise site of osteomyelitisbecause of low spatial resolution and alack of anatomic specificity. The fusionof scintigraphic and morphologic images,using hybrid single-photon emissioncomputed tomography/computed to-mography (SPECT/CT), is more accuratethan planar scintigraphy alone, correctlydifferentiating foot osteomyelitis and con-tiguous soft tissue infection in 97% of ca-ses compared with 59% for planarscintigraphy (18,20,21). 67Ga, a radioac-tive marker that accumulates in inflam-matory and infected tissues (22),appears to be a good radiotracer to local-ize infection in combination with SPECT/CT (23).

This study investigated the usefulnessin diagnosing diabetic foot osteomyelitisby a sequential procedure that uses theresults of 67Ga SPECT/CT to exclude in-fection when it is negative or to localizesuspected infection when it is positive,followed by a sterile percutaneous bonepuncture to identify the causative patho-gens.

RESEARCH DESIGN ANDMETHODS

Study designWe conducted a single-center prospectivestudy in a university-affiliated hospital(Hôtel Dieu, Paris, France) referral clinicfor diabetic foot conditions. We recruitedconsecutive diabetic inpatients and out-patients with a chronic foot ulcer (presentfor .3 months) in whom osteomyelitiswas suspected on the basis of French con-sensus criteria (24). The study protocolwas approved by the local ethics commit-tee (Comité de Protection des Personnes,Hôtel Dieu, Paris) and classified as a cur-rent care proceeding, because SPECT/CTimaging and bone puncture are currentlyrecommended for diagnosing diabeticfoot osteomyelitis by the French Infec-tious Diseases Society (24).

Study populationWe evaluated all diabetic patients $18years old in whom active osteomyelitiswas clinically suspected on the basis of afoot ulcer with at least one of the follow-ing characteristics: presence for .3months, location over a bony promi-nence, or relapsing infection or slow heal-ing despite adequate arterial flow andappropriate local care for $3 months.There were findings compatible withosteomyelitis on plain radiography in 26of 42 (60%) of the patients who underwent

bone puncture. Thus the enrolled pa-tients were all at high risk for underlyingosteomyelitis. We excluded patients whorequired orthopedic or vascular surgeryor who had received any systemic antibi-otic therapy during the 14 days precedingimaging and bone puncture. We did en-roll patients with a suspicion of osteomy-elitis associated with acute soft tissueinfection; however, imaging and punc-ture were delayed until 14 days after theend of antibiotic therapy because urgenttreatment of soft tissue infection is man-datory.

Detection of bone inflammationAll enrolled patients underwent hybrid67Ga SPECT/CT imaging, which provideshigh-resolution merged 67Ga single-photon emission computed tomographicand computed X-ray transmission tomo-graphic images of the ankles and feet. Weobtained images 48 h after the injection of~150 MBq of [67Ga]gallium citrate andconsidered patients with no increaseduptake on the 67Ga SPECT/CT not tohave osteomyelitis. These patients under-went no further diagnostic studies anddid not receive antibiotic treatment.

Collection of bone marrow samplesIn cases in which imaging revealed a focalaccumulation of radioactivity in boneunderlying the ulcer, we performed abedside percutaneous bone puncturewith a 16 gauge 3 5 cm Mallarmé trocar(Myelo-Gal; Gallini Medical Devices,Mantova, Italy). Punctures were donethrough intact uninfected skin, notthrough the ulcer, after first washing theentire foot twice with foaming povidoneiodine polyvidone solution (Betadinescrub), rinsing it, then disinfecting thepuncture site with Betadine. We insertedthe trocar into the presumed site of boneinfection, selecting a route accordingto the results of three-dimensional67Ga SPECT/CT imaging. We aspiratedbone marrow into a sterile 20-mL syringe;the maximum final volume obtainedranged from 0.5 to 3 mL, depending onthe size of the bone. The gross appearanceof the bone marrow aspirate was likeblood with fatty material.

Microbiological assessmentImmediately after puncture, we inocu-lated the bone marrow sample into ablood culture bottle containing an anaer-obic growth medium (BACTEC Lytic/10Anaerobic/F; Becton Dickinson, Le Pont-de-Claix, France) and another with aerobic

medium (BACTEC Plus aerobi/F). Weprocessed the bottles with the BACTEC9240 system and incubated the bottles foras long as 10 days at 378C. We identifiedany isolates by standard procedures, in-cluding coagulase tests with rabbit plasmaand API 20E strips (bioMérieux, Marcyl’Etoile, France). We identified suscepti-bility to antibiotics by the disk diffusionmethod onMueller-Hinton agar, accordingto the guidelines of the Committee of theFrench Society for Microbiology (http://www.sfm.asso.fr), with disks from Bio-Rad (Marnes-la-Coquette, France). Wealso subcultured any positive blood culturevials on nutrient agar at 378Cand identifiedpathogens as described above.

Patient outcomeOur primary end point for diagnosis ofosteomyelitis was a positive result forboth the 67Ga SPECT/CT and bone cul-ture. We used the 67Ga SPECT/CT imag-ing to determine which patients wouldundergo bone puncture for culture. Ifthe scan showed focal accumulation ofactivity in the bone immediately underly-ing the ulcer, we performed a bone punc-ture; if not, we assumed the patient didnot have osteomyelitis and did not pro-vide antibiotic treatment. Patients whounderwent a bone puncture and had anegative culture also did not receive anti-biotic treatment. In patients who had anegative bone culture but who had poorwound healing and persistent or worsen-ing clinical local symptoms of inflamma-tion suggestive of osteomyelitis, weperformed a second bone puncture. Wetreated all patients with a positive boneculture with 8 weeks of antibiotic therapyselected according to the susceptibilityprofile of the isolates and in line withthe French diabetic foot infection guide-lines (24). We preferred oral antibiotictreatments when possible to avoid theneed for a long hospital stay. We evalu-ated all patients for clinical signs of oste-omyelitis and healing of the ulcer after$12 months of follow-up treatment. Wedid not routinely repeat 67Ga SPECT/CTin patients with a positive bone culture;when performed, however, such imagingwas carried out at $3 months after thestart of antibiotic treatment.

Analysis of the resultsWe assessed end points $1 year after anegative 67Ga SPECT/CT result (for thosewho did not receive antibiotic therapy)or the start of antibiotic treatment (forthose who received it). The primary end

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point was the absence of any clinicalevidence of diabetic foot osteomyelitis.The secondary end point was the clinicalstatus of the ulcer, a surrogate markerfor cure of infection. Ulcer clinical out-come in those treated with antibioticswas categorized as follows: cure if com-pletely healed, failure if the ulcer persistedor displayed progression in its size orappearance that led to surgical treatment,or improvement if the ulcer had de-creased in size by $50% but was notcompletely healed. In those not treatedwith antibiotics, osteomyelitis was pre-sumed to have resolved if there was noclinical evidence of infection after $1year of follow-up.

We considered the patient not tohave had osteomyelitis if the baseline67Ga SPECT/CT result was negative or if67Ga SPECT/CT result was positive butthe bone culture was negative, and if noclinical signs of osteomyelitis were pres-ent after $1 year of follow-up. Patientswere considered to have had osteomy-elitis if 67Ga SPECT/CT and bone cultureresults were both positive at baseline.For patients with a negative initial boneculture who underwent a second bonepuncture at the same location (becauseof a poor clinical response, as explained)that yielded a positive culture, we consid-ered the first culture to have been a falsenegative.

StatisticsWe summarized continuous variableswith descriptive statistics and calculatedthe sensitivity and specificity of our eval-uation procedure (25). We determinedthe comparability of groups for categori-cal variables by the x2 test with a signifi-cance level set at P , 0.05. We used theYouden index (J = sensitivity + specificity2 1) to evaluate the performance of thediagnostic test; it has minimum and max-imum values of 21 and +1, respectively,with a value of +1 representing the opti-mal value for an algorithm.

RESULTSdFrom 1May 2007 to 1 May2009, we enrolled 55 diabetic patientswith suspected foot osteomyelitis in thisstudy (Fig. 1). 67Ga SPECT/CT scans in13 patients were negative, showing no in-creased 67Ga uptake in the bone underly-ing the ulcer. None of these patientsreceived antibiotic therapy, and after $1year of follow-up all their ulcers werehealed without any signs of soft tissueor bone infection. In 42 patients67Ga SPECT/CT showed markedly in-creased bone uptake, consistent with a di-agnosis of osteomyelitis. All the includedpatients with positive imaging were men(93%), with a mean6 SD age of 636 10years and duration of diabetes of 20.3 611.3 years, and most (80%) had type 2 di-abetes (Table 1). All patients had evidence

of peripheral neuropathy (loss of protec-tive sensation) of the feet, 60% had lower-limb arterial insufficiency (ankle brachialpressure index ,0.9), and 42% had al-ready had a distal limb amputation. Dur-ing the year of follow-up, 3 (5.5%) of thepatients died and 3 (all of whom had apositive bone puncture culture) under-went lower-extremity amputation of theaffected limb.

We performed bone puncture on the42 patients with positive 67Ga SPECT/CT imaging; 4 patients underwent bonepuncture twice for a total of 46 bone punc-tures. Only one patient required local an-esthesia for the bone puncture. Weexcluded the results of three bone punc-tures in two different patients from theanalysis because these patients had re-ceived antibiotic therapy in the previous14 days. Among the 40 patients whosebone punctures we included, 19 were cul-ture negative. We deemed three of thesecultures to be false negatives because ineach case a second bone puncture carriedout within a month grew pathogens. Intotal, 24 patients had bone cultures thatwere positive: the isolates were coagulase-negative Staphylococcus species (CoNS) in14, Staphylococcus aureus in 9, and a nu-tritionally deficient Streptococcus in 1.CoNS species were isolated frombone cul-tures after a mean growth period of 1.560.82 days, and 9 of the 14 grew within

Figure 1dFlowchart.

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24 h, as did all the S. aureus isolates. Onlyone culture was polymicrobial, containingtwo methicillin-resistant S. aureus strains.We found antibiotic-resistant strains in 8of the 24 isolates (33%): three methicillin-resistant CoNS species (21% of theCoNS isolates), 1 fluoroquinolone-resistant CoNS species, and 5 methicillin-and fluoroquinolone-resistant S. aureusstrains (44% of the S. aureus isolates).

All the culture-positive patients weretreated with antibiotic therapy that consis-ted of a combination of ofloxacin (200 mgtwice daily) and rifampicin (10mg/kg twicedaily) for fluoroquinolone-sensitive isolatesin 18 patients, linezolid alone (600 mgtwice daily) for the fluoroquinolone-resistant isolates in 6 patients, and amox-icillin (1 g three times a day) plus rifampicin(10mg/kg twice daily) for the 1 patient witha Streptococcus isolate.

Among the patients who had died atfollow-up (two of myocardial infarctionand one of multiple organ failure), onewas from the group with a negative boneculture and two were from the group with

a positive bone culture (one methicillin-resistant S. aureus and one methicillin-sensitive CoNS). At follow-up, none ofthe 13 patients who had negative resultson 67Ga SPECT/CT (who had no antibi-otic treatment) showed clinical evidenceof infection, and all their ulcers had re-solved. Similarly, among the 16 patientswith a true-negative bone culture, 15had no evidence of infection and a re-solved ulcer at follow-up; 1 had died ofa myocardial infarction. In the positivebone culture group, 19 of the 24 patientshad no clinical signs of infection at follow-up (15 ulcers were completely cured and 4had improved), 3 patients had undergoneamputation surgery of an infected meta-tarsal (first, third, and fifth metatarsalhead), and 2 patients had died (Table 2).

We observed no adverse events in anypatient after either 67Ga SPECT/CT imag-ing or bone puncture. All patients withpositive bone cultures completed theirantibiotic treatments; however, 13 hadthe following antibiotic-associated ad-verse effects: gastrointestinal disturbances

in 6 patients receiving the ofloxacin plusrifampicin regimen (resulting in the dis-continuation of rifampicin in 2 cases) andanemia in 7 patients receiving linezolid(which was not severe enough to requiretreatment discontinuation).

CONCLUSIONSdAccurate diagnosisof diabetic foot osteomyelitis and identi-fication of the causative pathogens shouldlead to better outcomes for this highlymorbid infection. Because all currentlyavailable diagnostic tests have some defi-ciencies, newer diagnostic schemes areneeded. The coupling of 67Ga SPECT/CTimaging with subsequent bedside bonepuncture for those with a positive resulthas many potential advantages. This ap-proach uses a highly accurate imaging testto help determine which patients shouldundergo bone sampling and then adds asimple bedside bone puncture that doesnot require concomitant imaging becausethe 67Ga SPECT/CT very precisely marksthe bony part suspected of infection, evenin the forefoot. In this prospective studyof 55 patients with suspected diabetic footosteomyelitis, we found this approach tobe highly effective.

None of the 13 patients with negative67Ga SPECT/CT imaging demonstratedany clinical sign of bone infection after$1 year of follow-up, giving a sensitivityfor this imaging test alone of 100%.Among the 29 patients whom we pre-sumed not to have osteomyelitis (the 13who had negative 67Ga SPECT/CT imag-ing and no osteomyelitis on follow-upand the 16 who had a negative boneculture), 13 had negative imaging, for aspecificity of 45% for imaging alone. Thenegative predictive value for 67Ga SPECT/CT imaging was 100%, similar to that ofMRI (90–100%) (26). Use of 67Ga SPECT/CT made it possible to avoid bone punc-ture in 13 of 55 cases (23.6%). Thus this

Table 2dMicroorganisms isolated on bone puncture and outcome after ‡1 year of follow-up

Location Outcome at 1 year

First metatarsal(N = 11)

Other metatarsal(N = 6)

Digit(N = 3)

Tarse(N = 4)

Cured*(N = 15)

Improved(N = 4)

Failure(N = 3)

Death(N = 2)

S. aureus (n = 9)Methicillin sensitive (n = 5) 2 1 2 2 (40%) 2 1Methicillin resistant (n = 4) 1 1 1 1 2 (50%) 1 1

CoNS (n = 14)Methicillin sensitive (n = 11) 7 1 2 1 8 (73%) 1 1 1Methicillin resistant (n = 3) 1 2 2 (66%) 1

Streptococcus (n = 1) 1 1 (100%)

*% of cured ulcers in S. aureus group vs. CoNS group: P 5 0.38.

Table 1dBaseline demographic and clinical characteristics of patients who underwent bonepuncture for culture by culture results

Characteristic Positive (N = 24) Negative (N = 19) Total (N = 43)

Age (years), mean 6 SD 64 6 9 62 6 12.4 63 6 10Male, n 23 17 40Type 1 diabetes, n (%) 2 (8) 6 (32) 8 (20)Diabetes duration (years), mean 6 SD 20.41 6 12.13 20.63 6 10.27 20.33 6 11.29Serum creatinine (mmol/L), mean 6 SD 86 6 28.2 89.2 6 22.8 88.0 6 5.5Previous infected ulcer (all sites), n 11 9 20Ulcer location, nTarsus, calcaneus 4 2 6Great toeMetatarsal 8 3 11Phalanx 4 3 7

Toes 2–5Metatarsals 6 5 11Phalanges 2–5 2 6 8

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imaging technique appears to be at least asaccurate as other relatively new imagingmethods, such as [18F]fludeoxyglucosepositron emission tomography and99mTc-labeled monoclonal antigranulo-cyte antibody scintigraphy (27). Fur-thermore, the combined imaging andbone puncture technique enabled us toavoid antibiotic therapy in 55% of ourpatients with suspected osteomyelitis(29 of 55).

For diabetic patients with suspectedosteomyelitis, virtually all guidelines rec-ommend plain radiography as the firstline of imaging investigation. Althoughthese tests may be useful in patients athigh risk for bone infection, their overallsensitivity and specificity have been rela-tively low in most studies (28–30). Thusin special subgroups of patients with nor-mal or indeterminate radiographic re-sults, advanced imaging methods maybe needed (24,29,31,32). Among these,MRI has been the preferred technique;however, its specificity is also limited by

other entities that give a similar appear-ance, especially neuro-osteoarthropathy(Charcot foot). Radionuclide bone scanshave good diagnostic sensitivity (gener-ally.90%) (33) but rather poor specific-ity (;40%) related to increased uptakewith any form of inflammation. Leuko-cyte scans are more specific but havepoor resolution and are difficult to per-form (33).

The hybrid imaging SPECT/CT pro-cedure provides the clinician with twotypes of information: functional (scinti-graphic uptake) and anatomic (low-doseX-ray tomographic) definition. When theradiotracer used is specific for activatedmacrophages, as is the case for 67Ga, thismethod can determine the precise loca-tion of inflammation within a bone,even in the forefoot. In a general popula-tion, 67Ga SPECT/CT was found to be asuseful for the diagnosis and localization ofosteomyelitis as the best nuclear test,111In-labeled leukocyte scintigraphy(specificities of 55 and 48% respectively;

P. 0.05) in a series of 12 suspected cases(23). More recently, Heiba et al. (18) dem-onstrated the ability of SPECT/CT imag-ing to discriminate soft tissue from boneinfection specifically in patients with a di-abetic foot infection.Moreover, Gotthardtet al. (34) suggested SPECT/CT as an al-ternative to positron emission tomogra-phy or MRI for diagnosing peripheralosteomyelitis, although no previousstudy has assessed SPECT/CT in the distalforefoot. In our patients, 67Ga SPECT/CTwas sufficiently accurate for precise local-ization of the affected bone part, even inthe proximal phalanx of toes. Thus, 67GaSPECT/CT may be better than MRI formarking the precise site of inflammationin suspected osteomyelitis, helping toplan the bedside bone puncture.

Bone puncture has advantages rela-tive to standard bone biopsy: it is abedside procedure that does not requireconcomitant imaging; it uses a trocarsmaller than the type used for bone bi-opsy; and bone marrow aspiration is

Figure 2dChronic ulcer of the first metatarsal head. A: Photograph. B and C: Plain radiographs. D, F, and H: Three-dimensional X-ray tomo-graphic images. E, G, and I: Corresponding 67Ga SPECT/CT images. The gallium accumulation marks the best puncture place.

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probably less traumatic than bone biopsy.Although bone biopsy is considered to bethe criterion standard for diagnosing os-teomyelitis, it is rarely performed in mostclinical settings. This is probably becauseit generally requires specialized surgicalor radiological facilities, it is seen as time-consuming and expensive, and some fearadverse effects (15). Our experience sug-gests that a bone puncture with bone as-pirationmay be as useful as a bone biopsy,at least for culture although not for histo-pathological studies. It may be especiallyuseful compared with biopsy for smallbones in the forefoot.

A bone aspirate sample can be cul-tured in blood culture bottles. The vol-ume of bone marrow obtained isdependent on the size of the bone sam-pled. We found that negative bone cul-ture results were more frequent forphalanges than for the first metatarsal ortarsal bones (Table 2), but the number ofpatients in our study was small. Studies ofthe microbiological etiology of foot oste-omyelitis in diabetic patients have mostlyrevealed polymicrobial infection, with amean of 1.35–1.54 isolates per samplenoted in recent series (35,36). All butone of our positive cultures yielded a sin-gle gram-positive microorganism, almostall staphylococci. CoNS species are welldocumented as primary pathogens in

diabetic foot osteomyelitis (35,37,38). Indiabetic foot infection, monomicrobialstaphylococcal culture is associatedwith a lower risk of amputation thanother microbial causes (39). In our pa-tients, the amputation rate was low (3 ofthe 24 cases of osteomyelitis), but aboutthree quarters of our patients were outpa-tients and therefore probably had rela-tively less severely infections.

The bone puncture procedure hastwo potential limitations. First, it is es-sentially blind, unlike surgical or radio-logically guided bone biopsy. The highquality of 67Ga SPECT/CT images makesit possible to localize the infection veryprecisely, however, even in the forefoot(Figs. 2 and 3). Furthermore, becausethe bones of the foot are located just un-der the skin, they can be reached percu-taneously without the need for imagingguidance techniques. Second, it usesbroth cultures rather than solid agar;however, recent studies of bone samplesfor hip and knee prosthetic infectionshave shown that the use of blood culturebottles was associated with good specific-ity (40).

The primary end point for our studywas the absence of clinical signs of oste-omyelitis after $1 year of follow-up.Because patients with a negative 67GaSPECT/CT scan did not undergo bone

puncture, we cannot be certain thatthere were no false-negative scans. Thelong-term follow-up of all cases, however,makes this highly unlikely. Because all pa-tients with positive bone cultures receivedantibiotic treatment, it was not possible toexclude false-positive cases in this study. Itis not impossible that some patients haveosteomyelitis that resolves and woundsthat heal without antibiotic therapy, espe-cially in lesser toes. From the frequency ofCoNS as a cause of false-positive bloodcultures during the same period in ourlaboratory (3.3%), we can extrapolate toobtain the rate of false-positive cultures as0.0333 43 positive bone cultures, giving1.4 cases (2 in our count to evaluate spec-ificity). Applying these data, the sensitivityof the procedure should be no worse than88%, its specificity 93.6%, and its positiveand negative predictive values 91.7 and90.7%, respectively. The Youden indexwas 0.82 for the imaging plus puncturecombined vs. 0.45 for 67Ga SPECT/CTalone, supporting the superiority of thecoupled proceedings.

This coupled technique has severalimportant advantages. The SPECT/CTscan allows a substantial minority ofpatients to avoid bone puncture, althoughMRI would probably give similar resultsbecause the two methods have the samesensitivity. 67Ga SPECT/CT has a similar

Figure 3dExample of a large calcaneus ulcer (white arrow) with a marked 67Ga uptake near but not under the ulcer. The precise site of puncturecould not have been determined without 67Ga spotting. A: Three-dimensional X-ray tomographic image. B: Corresponding 67Ga SPECT/CT image.

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cost to MRI and is widely available inFrance, both in public and private hospi-tals. The bone puncture procedure can becarried out at the patient’s bedside, by aclinician, without the need for an ortho-pedic surgeon or radiologist and imagingequipment. It is also less expensive thansurgically or radiologically guided proce-dures. We therefore believe that coupling67Ga SPECT/CT with bedside bone punc-ture is an efficient procedure for the di-agnosis of foot osteomyelitis in diabeticpatients without signs of soft tissue infec-tion. This method is simple, safe, and am-bulatory, and it avoided the unnecessaryuse of antibiotics in more than half of thesuspected osteomyelitis cases in ourstudy.

AcknowledgmentsdNo potential conflicts ofinterest relevant to this article were reported.E.A. and B.A.L. wrote the manuscript. J.M.,

N.C.-V., and S.C. contributed to data collec-tion and analysis. E.L. and C.B. contributed todiscussion and reviewed the manuscript. E.A.is the guarantor of this work and, as such, hadfull access to all the data in the study and takesresponsibility for the integrity of the data andthe accuracy of the data analysis.The authors thank Claire Le Jeunne, Uni-

versité Paris Descartes, Paris, France, for helpduring all stages of the work.

References1. Singh N, Armstrong DG, Lipsky BA. Pre-

venting foot ulcers in patients with di-abetes. JAMA 2005;293:217–228

2. Lavery LA, Peters EJ, Armstrong DG,Wendel CS, Murdoch DP, Lipsky BA. Riskfactors for developing osteomyelitis inpatients with diabetic foot wounds. Di-abetes Res Clin Pract 2009;83:347–352

3. Richard JL, Lavigne JP, Got I, et al. Man-agement of patients hospitalized for di-abetic foot infection: results of the FrenchOPIDIA study. Diabetes Metab 2011;37:208–215

4. Carmona GA, Hoffmeyer P, Herrmann FR,et al. Major lower limb amputations in theelderly observed over ten years: the role ofdiabetes and peripheral arterial disease.Diabetes Metab 2005;31:449–454

5. Lavery LA, Armstrong DG, WunderlichRP, Mohler MJ, Wendel CS, Lipsky BA.Risk factors for foot infections in in-dividuals with diabetes. Diabetes Care2006;29:1288–1293

6. Edmonds M. Double trouble: infectionand ischemia in the diabetic foot. Int J LowExtrem Wounds 2009;8:62–63

7. Berendt AR, Peters EJ, Bakker K, et al.Specific guidelines for treatment of di-abetic foot osteomyelitis. Diabetes MetabRes Rev 2008;24(Suppl. 1):S190–S191

8. Dinh T, Snyder G, Veves A. Currenttechniques to detect foot infection in thediabetic patient. Int J Low ExtremWounds 2010;9:24–30

9. Fleischer AE, Didyk AA, Woods JB, BurnsSE, Wrobel JS, Armstrong DG. Combinedclinical and laboratory testing improvesdiagnostic accuracy for osteomyelitis inthe diabetic foot. J Foot Ankle Surg 2009;48:39–46

10. Lipsky BA. Bone of contention: di-agnosing diabetic foot osteomyelitis. ClinInfect Dis 2008;47:528–530

11. Teh J, Berendt T, Lipsky BA. RationalImaging. Investigating suspected boneinfection in the diabetic foot. BMJ 2009;339:b4690

12. Mutluoglu M, Uzun G, Turhan V,Gorenek L, Ay H, Lipsky BA. How reliableare cultures of specimens from superficialswabs compared with those of deep tissuein patients with diabetic foot ulcers?J Diabetes Complications 2012;26:225–229

13. Berendt AR, Peters EJ, Bakker K, et al.Diabetic foot osteomyelitis: a progressreport on diagnosis and a systematic re-view of treatment. Diabetes Metab Res Rev2008;24(Suppl. 1):S145–S161

14. Senneville E, Lombart A, Beltrand E, et al.Outcome of diabetic foot osteomyelitistreated nonsurgically: a retrospective co-hort study. Diabetes Care 2008;31:637–642

15. Powlson AS, Coll AP. The treatment ofdiabetic foot infections. J AntimicrobChemother 2010;65(Suppl. 3):iii3–iii9

16. Loredo R, Rahal A, Garcia G, Metter D.Imaging of the diabetic foot diagnosticdilemmas. Foot Ankle Spec 2010;3(Spec):249–264

17. Ertugrul MB, Baktiroglu S, Salman S, et al.The diagnosis of osteomyelitis of the footin diabetes: microbiological examinationvs. magnetic resonance imaging and la-belled leucocyte scanning. Diabet Med2006;23:649–653

18. Heiba SI, Kolker D, Mocherla B, et al. Theoptimized evaluation of diabetic foot in-fection by dual isotope SPECT/CT imag-ing protocol. J Foot Ankle Surg 2010;49:529–536

19. Papanas N, Zissimopoulos A, Maltezos E.The role of nuclearmedicine in thediagnosisof common and specific diabetic infections.Hell J Nucl Med 2010;13:150–157

20. Filippi L, Uccioli L, Giurato L, Schillaci O.Diabetic foot infection: usefulness ofSPECT/CT for 99mTc-HMPAO-labeledleukocyte imaging. J Nucl Med 2009;50:1042–1046

21. Horger M, Eschmann SM, Pfannenberg C,et al. The value of SPET/CT in chronicosteomyelitis. Eur J Nucl Med Mol Imag-ing 2003;30:1665–1673

22. AndoA,Nitta K, Ando I, et al.Mechanismofgallium 67 accumulation in inflammatorytissue. Eur J Nucl Med 1990;17:21–27

23. Bar-Shalom R, Yefremov N, Guralnik L,et al. SPECT/CTusing 67Ga and 111In-labeledleukocyte scintigraphy for diagnosis ofinfection. J Nucl Med 2006;47:587–594

24. Société de Pathologie Infectieuse de LangueFrançaise. Management of diabetic foot in-fections. Long text. Société de PathologieInfectieuse de Langue Française. Med MalInfect 2007;37:26–50 [in French]

25. Bland JM, AltmanDG. Regression towardsthe mean. BMJ 1994;308:1499

26. Craig JG, Amin MB, Wu K, et al. Osteo-myelitis of the diabetic foot: MR imaging-pathologic correlation. Radiology 1997;203:849–855

27. Schwegler B, Stumpe KD, Weishaupt D,et al. Unsuspected osteomyelitis is fre-quent in persistent diabetic foot ulcer andbetter diagnosed by MRI than by 18F-FDGPET or 99mTc-MOAB. J Intern Med 2008;263:99–106

28. Lipsky BA, Berendt AR, Cornia PB, et al.;Infectious Diseases Society of America.Executive summary: 2012 InfectiousDiseases Society of America clinical prac-tice guideline for the diagnosis and treat-ment of diabetic foot infections. ClinInfect Dis 2012;54:1679–1684

29. Lipsky BA, Peters EJ, Senneville E, et al.Expert opinion on the management ofinfections in the diabetic foot. DiabetesMetab Res Rev 2012;28(Suppl. 1):163–178

30. Tan T, Shaw EJ, Siddiqui F, Kandaswamy P,Barry PW, Baker M; Guideline Devel-opment Group. Inpatient management ofdiabetic foot problems: summary of NICEguidance. BMJ 2011;342:d1280

31. Apelqvist J, Bakker K, van Houtum WH,Schaper NC; International Working Groupon the Diabetic Foot (IWGDF) EditorialBoard. The development of global consen-sus guidelines on the management of thediabetic foot. DiabetesMetab Res Rev 2008;24(Suppl. 1):S116–S118

32. Apelqvist J, Bakker K, van Houtum WH,Schaper NC; International Working Groupon the Diabetic Foot (IWGDF) EditorialBoard. Practical guidelines on the manage-ment and prevention of the diabetic foot:based upon the International Consensus onthe Diabetic Foot (2007) Prepared by theInternational Working Group on the Di-abetic Foot. Diabetes Metab Res Rev 2008;24(Suppl. 1):S181–S187

33. Palestro CJ, Love C. Nuclear medicine anddiabetic foot infections. Semin Nucl Med2009;39:52–65

34. Gotthardt M, Bleeker-Rovers CP, BoermanOC, OyenWJ. Imaging of inflammation byPET, conventional scintigraphy, and otherimaging techniques. J Nucl Med 2010;51:1937–1949

35. Senneville E, Melliez H, Beltrand E, et al.Culture of percutaneous bone biopsyspecimens for diagnosis of diabetic footosteomyelitis: concordancewith ulcer swabcultures. Clin Infect Dis 2006;42:57–62

care.diabetesjournals.org DIABETES CARE, VOLUME 36, AUGUST 2013 2209

Aslangul and Associates

36. Senneville E, Morant H, Descamps D, et al.Needle puncture and transcutaneous bonebiopsy cultures are inconsistent in patientswith diabetes and suspected osteomyelitis ofthe foot. Clin Infect Dis 2009;48:888–893

37. Armstrong DG, Lanthier J, Lelievre P,EdelsonGW.Methicillin-resistant coagulase-negative staphylococcal osteomyelitis andits relationship to broad-spectrum oral

antibiosis in a predominantly diabeticpopulation. J Foot Ankle Surg 1995;34:563–566

38. Lavery LA, Sariaya M, Ashry H, HarklessLB. Microbiology of osteomyelitis in di-abetic foot infections. J Foot Ankle Surg1995;34:61–64

39. Lipsky BA,Weigelt JA, Sun X, Johannes RS,Derby KG, Tabak YP. Developing and

validating a risk score for lower-extremityamputation in patients hospitalized fora diabetic foot infection. Diabetes Care2011;34:1695–1700

40. Rothman MDA 2011. Presented at the21st European Congress of ClinicalMicrobiology and Infectious Diseases(ECCMID), 7–10 May 2011, Milan,Italy

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