# 18-FDG PET in the Evaluation of Therapeutic Response of Necrotizing Otitis Externa.

Lucie Lécolier, Philippine Toulemonde, Damien Huglo, Clio Baillet, Pauline

Thill, Gauthier Delaby

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Lucie Lécolier, Philippine Toulemonde, Damien Huglo, Clio Baillet, Pauline Thill, et al. 18-FDG PET in the Evaluation of Therapeutic Response of Necrotizing Otitis Externa. Laryngoscope, 2025, Laryngoscope, 10.1002/lary.70102. hal-05303495

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ORIGINAL REPORT

OPEN ACCESS

# 18-FDG PET in the Evaluation of Therapeutic Response of Necrotizing Otitis Externa

Lucie Lécolier<fnref n="1" /> | Philippine Toulemonde² | Damien Huglo<fnref n="1" /> | Clio Baillet<fnref n="1" /> | Pauline Thill<fnref n="1" /> | Gauthier Delaby<fnref n="1" />

**Correspondence:** Gauthier Delaby (gauthier.delaby@chu-lille.fr)

**Received:** 29 April 2025 | **Revised:** 27 July 2025 | **Accepted:** 25 August 2025

**Funding:** The authors received no specific funding for this work.

**Keywords:** antibiotherapy | FDG | necrotizing otitis externa | PET scanner

## ABSTRACT

**Objective:** The duration of antibiotic treatment for necrotizing otitis externa (NEO) and the criteria for discontinuation are currently uncodified. Our study evaluated the performance of [18F]FDG PET to assess the therapeutic response of NEO.

**Methods:** We retrospectively included patients treated for NEO who underwent a PET scan at baseline and 4 to 9 weeks after antibiotic initiation. PET images were analyzed visually and quantitatively (SUVmax, Total Lesion Glycolysis [TLG], and Total Metabolic Volume [TMV]). An intensity-weighted extent score (extent) that we created was also calculated. For each parameter, delta values ("Δ": percentage change from baseline for each parameter) were also calculated.

**Results:** Thirty-nine patients and 40 ears were enrolled. *Pseudomonas aeruginosa* was isolated from 32 (86%) samples. Twenty-nine (72.5%) patients were treated with CEFTAZIDIME and CIPROFLOXACIN for a median of 6.9 weeks. On PET scan re-evaluation, 15 (27.5%) patients were visually in complete response, 17 (42.5%) in partial response, 5 (12.5%) stable, and 3 (7.5%) in progression. The sensitivity and specificity of visual analysis for the diagnosis of recovery were 100% and 43%, respectively. The best performing parameters for predicting recurrence were initial TLG and TMV (sensitivity and specificity of 80% and 100% for respective thresholds of 50.1 g and 8.3 mL). Δextent showed sensitivity and specificity of 80% and 97.1% using a threshold of -4.3%, and ΔTLG showed sensitivity and specificity of 80% and 94.3% using a threshold of -37.4%.

**Conclusion:** PET performed well in assessing the therapeutic response of NEO, with excellent sensitivity but low specificity of visual analysis. A complementary quantitative analysis was useful to distinguish between satisfactory and insufficient partial responses.

**Level of Evidence:** Level 3.

## 1 | Introduction

Necrotizing otitis externa (NOE), also known as malignant otitis externa, is a rare and serious infection that initiates in the external auditory canal (EAC). It then spreads through the fissures of Santorini to the soft tissues and bones, progressing to a skull base osteomyelitis [1-5]. It mainly affects elderly, diabetic, or immunocompromised patients. It is caused in most cases (50% to 90%) by *Pseudomonas aeruginosa*, a saprophytic

and opportunistic gram-negative bacillus, capable of developing multiple antibiotic resistances [1].

The clinical presentation mainly associates severe otalgia, purulent otorrhoea, hypoacusis, and sometimes altered general condition. General infectious signs such as hyperthermia are rare, and a biological inflammatory syndrome is inconsistent [1]. Homolateral cranial nerve deficits are common. The facial nerve is most affected by infiltration of the stylomastoid

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

© 2025 The Author(s). *The Laryngoscope* published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.

<footnote n="1">¹Nuclear Medicine Department, Claude Huriez Hospital, Lille, France | ²Otolaryngology Department, Roger Salengro Hospital, Lille, France</footnote>
foramen, causing peripheral facial paralysis, but other cranial
nerves may be involved. Otoscopy reveals an inflamed duct,
sometimes stenotic, often associated with granulation tissue or
polyps, which is highly specific for NOE [4, 6]. In addition to
the clinical aspect, refractoriness to conventional treatment is
a major argument for questioning the diagnosis of simple otitis
externa. Identification of the causal infectious agent must be a
priority before antibiotic therapy is initiated, as soon as clinical
suspicion arises. Superficial samples of the EAC are obtained
primarily by swabbing an otorrhoea or sampling a polyp/granu-
lation tissue sample and may be supplemented by deep sampling
under general anesthetic.

Imaging also plays an important role in diagnosis [7]. Computed tomography (CT) is the first-line modality, demonstrating the bone lysis characteristic of malignant otitis externa, which occurs after demineralization of 30%-50% of the trabecular bone, approximately 2 weeks after the onset of infection [8]. MRI is complementary and allows a better assessment of the soft tissues and the search for intracranial complications.

Treatment is based on a prolonged bi-antibiotic therapy probabilistically targeting *Pseudomonas aeruginosa* initially (generally an association of a 3rd generation cephalosporin with a quinolone: CEFTAZIDIME and CIPROFLOXACIN), then adjusted according to the antibiogram. The duration of antibiotic therapy is usually at least 6 weeks but is not codified [9, 10]. The assessment of therapeutic response in patients with NOE is a major challenge. The diagnosis of cure is based on a combination of clinical, biological, and imaging evidence. However, there are currently no truly validated criteria to confirm cure. Regression of clinical signs and improvement of otoscopic appearance are the most important criteria (although nerve palsies may not recover). A common limitation of CT and MRI is the prolonged persistence of abnormalities after cure, which limits their use in assessing response to treatment [7, 11, 12].

As early as the 1980s, nuclear medicine studies demonstrated their value in the management of NOE. Technetium-99m-labeled diphosphonate bone scintigraphy and gallium-67 citrate scintigraphy have traditionally been used for early diagnosis of osteitis and therapeutic follow-up [13–18]. However, these modalities have limitations in terms of specificity and spatial resolution and are now being abandoned in favor of higher quality investigations [19, 20].

In a few small retrospective studies, labeled white blood cell scintigraphy has shown good diagnostic sensitivity and potential for assessing therapeutic response [21–25]. In practice, however, it is limited by its modest spatial resolution, time-consuming radiotracer preparation, two-day turnaround time, and limited access to most nuclear medicine centers.

More recently, 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) PET has emerged as a potentially superior technique, offering better spatial resolution, a shorter protocol, and accessibility to the majority of nuclear medicine centers. It quickly demonstrated its interest and high sensitivity for the diagnosis of active infection [26]. A number of studies have demonstrated its satisfactory diagnostic performance for the diagnosis of NOE [8, 20]. In a retrospective study of 77 patients, Kulkarni et al. [27] found

a sensitivity of 97% and a specificity of 93% for the diagnosis of
NEO. The value of PET in assessing response to therapy has also
been demonstrated in a few small studies, with encouraging re-
sults [23, 27, 28]. Kulkarni et al. [27] showed that PET correctly
identified progression or improvement in 100% of 23 patients.
In a retrospective study of 11 patients, Vion et al. [23] found a
sensitivity and specificity of 43% and 100% for the diagnosis of
cure for [18F]FDG PET and 86% and 75% for labeled leukocyte
scintigraphy. More recently, Hurstel et al. [29] found an accu-
racy of 100% of [18F]FDG PET to predict patient recovery using
the SUV-lesion-to-background with a cut-off of 4.1.

The aim of this study was to further evaluate the performance of
[18F]FDG PET compared to clinical practice in the assessment
of therapeutic response to antibiotic therapy in NOE and to iden-
tify interpretation parameters to best guide physician decision
making in antibiotic therapy management.

**2 | Materials and Methods**

## 2.1 | Study Population

This was a single-center retrospective study which included patients with a diagnosis of NOE made between 2016 and 2024, who underwent a [18F]FDG PET scan at initial assessment and then 4 to 9 weeks after the start of antibiotic therapy. This project complies with the reference methodology MR-004 and has been registered to the record of processing activities in accordance with Article 30 of the EU Regulation (2016/679) (reference number DEC24-019). Because this was a retrospective study, the requirement to obtain signed informed consent was waived. Clinical follow-up included a clinical examination close to the re-evaluation PET scan and a follow-up of at least 3 months to ensure the absence of early recurrence. At initial assessment, the following parameters were collected: age at the start of treatment, sex, diabetes, or other immunosuppressive etiology, clinical symptoms (altered general condition, otorrhoea, otalgia, headache, hypoacusis, cranial nerve palsies) and biological parameters (CRP, blood leukocyte levels, β-D-glucans, galactomannans and glycated hemoglobin). The type of microbiological sampling (superficial/deep) and the results of the bacteriological analyses were recorded, together with the duration and the type of antibiotic treatment.

At re-evaluation, clinical symptoms were classified into four
groups: complete response, partial response, stability, and dete-
rioration. Complete clinical response was defined as complete
healing of the EAC on otoscopy and resolution of clinical symp-
toms other than facial paralysis. After this clinical reassess-
ment, the decision to stop, continue, or change antibiotic therapy
was recorded.

## 2.2 | PET Scans

[18F]FDG PET scans were performed on a variety of machines, the majority of which were Biograph mCTs (Siemens Medical Solutions) for 66 scans. Patients fasted for 6 h before intravenous injection of 3-4 MBq/kg of [18F]FDG. Low-dose CT acquisition from the vertex to the mid-thigh was performed 60 min after
tracer administration, without injection of iodine contrast enhancement. PET images were reconstructed using an ordered subsets expectation maximization (OSEM) iterative reconstruction algorithm, with CT images used for attenuation correction.

## 2.3 | PET Image Interpretation

Image processing was performed on a single Siemens Syngo.Via console. A total of 80 PET scans were analyzed, blinded to clinical data and double-read. Images were initially analyzed visually at initial and re-evaluation. NOE were classified as complete response, partial response, stability, and progression on PET according to the visual change in extent and intensity of metabolic uptake. Complete response was defined as an uptake intensity less than or equal to hepatic activity, partial response as an uptake decrease remaining greater than hepatic activity, progression as an increase in extent and/or uptake intensity, and stability as no visual change. Semi-quantitative binding parameters were then measured.

Maximum uptake intensity was measured by standardized uptake value (SUVmax).

Total metabolic volume (TMV) was defined as the sum of the volume of all voxels with intensity above a threshold set at 4.0g/ mL in the region of interest. Total lesion glycolysis (TLG) was calculated by multiplying TMV by the mean SUV in the region of interest. The percentage reduction of each metric in relation to initial PET was calculated (Δ).

An analysis by anatomical region was also performed, with a total of 12 spaces: EAC, middle ear, inner ear, temporomandibular joint, mastoid, petrous apex, carotid space, parapharyngeal space, retropharyngeal space, deep cervical space, clivus, and intracranial space. A region was considered positive if there was any abnormal fixation of any intensity. Hypermetabolism related to residual inflammation from a recent deep biopsy was excluded. NOE were classified as superficial if hypermetabolism was limited to the EAC, middle ear, and/or mastoid, and as deep if hypermetabolism extended to at least one of the other spaces.

A 5-point fixation intensity score was generated for each area:

- 0: no uptake or symmetry with the contralateral region.

- 1: SUVmax less than the vascular SUVmax defined in the descending aorta.

- 2: SUVmax between vascular SUVmax and hepatic SUVmax,

- 3: SUVmax greater than or equal to hepatic SUVmax.

- 4: SUVmax greater than twice the hepatic SUVmax.

A weighted intensity and extent score was generated, named "extent score" calculated as a percentage equal to the sum of the fixation intensity scores for each space divided by 48 (12 spaces; score from 0 to 4). The relative changes of all parameters (SUV, TMV, TLG, extent score) between initial and re-evaluation PET were computed as the decrease in percentage [e.g., $\Delta parameter = (reevaluation - initial)/initial \times 100$].

## 2.4 | Statistical Analysis

Statistical analyses were performed using SPSS software (IBM Corp. 2011, IBM SPSS Statistics for Windows, version 20.0. Armonk, NY: IBM Corp.). Qualitative data were presented as

<table><caption>TABLE 1 | Patient characteristics.</caption><thead><tr><th></th><th></th></tr></thead><tbody><tr><td><strong>Patients</strong></td><td></td></tr><tr><td>Sex (male)</td><td>32 (81.6%)</td></tr><tr><td>Age</td><td>76 ± 9 years (52–91)</td></tr><tr><td>Diabetes</td><td>29 (74.4%)</td></tr><tr><td>Immunosuppression</td><td>5 (12.8%)</td></tr><tr><td><strong>Clinical</strong></td><td></td></tr><tr><td>Otalgia and/or headache</td><td>38 (97.4%)</td></tr><tr><td>Otorrhea</td><td>34 (87.2%)</td></tr><tr><td>Hypoacusis</td><td>26 (66.7%)</td></tr><tr><td>Altered general condition</td><td>11 (28.2%)</td></tr><tr><td>Nerve paralysis</td><td>10 (31.3%)</td></tr><tr><td>Facial nerve paralysis</td><td>9 (23.1%)</td></tr><tr><td>Vagus nerve paralysis</td><td>1 (2.5%)</td></tr><tr><td>Paralysis of oculomotor nerves III, IV and VI</td><td>1 (2.5%)</td></tr><tr><td><strong>Biology</strong></td><td></td></tr><tr><td>CRP increased (&gt; 6 mg/L)</td><td>26 (76.4%)<sup>a</sup></td></tr><tr><td>Hyperleukocytosis (10,000/mm<sup>3</sup>)</td><td>9 (26.5%)<sup>a</sup></td></tr><tr><td>Galactomannans positive (≥ 0.5)</td><td>0 (0%)<sup>a</sup></td></tr><tr><td>β-D-1,3-glucans positive (&gt; 80 pg/mL)</td><td>2 (9.5%)<sup>a</sup></td></tr><tr><td><strong>Areas affected on initial PET scan</strong></td><td></td></tr><tr><td>External auditory canal</td><td>38 (95%)</td></tr><tr><td>Middle ear</td><td>23 (57.5%)</td></tr><tr><td>Mastoid</td><td>17 (42.5%)</td></tr><tr><td>Carotid space</td><td>17 (42.5%)</td></tr><tr><td>Deep cervical space</td><td>17 (42.5%)</td></tr><tr><td>Temporomandibular joint</td><td>10 (25%)</td></tr><tr><td>Petrous apex</td><td>9 (22.5%)</td></tr><tr><td>Retropharyngeal space</td><td>8 (20%)</td></tr><tr><td>Parapharyngeal space</td><td>7 (17.5%)</td></tr><tr><td>Clivus</td><td>5 (12.5%)</td></tr><tr><td>Intracranial</td><td>5 (12.5%)</td></tr><tr><td>Contralateral involvement through crossing of midline</td><td>2 (5%)</td></tr><tr><td>Inner ear</td><td>0 (0%)</td></tr></tbody></table>

Note: Categorical variables are expressed as headcount and proportion. Quantitative variables are expressed as mean, standard deviation and range.

aAs a percentage of available data.
numbers and percentages. Normality of quantitative data was tested using the Shapiro-Wilk test. Quantitative data were expressed as mean and standard deviation in the case of a normal distribution, and as median and range in the case of a non-normal distribution. The distribution of the two groups was compared using Student's t-test for normal distribution and non-parametric Mann-Whitney test for non-normal distribution. Receiver operating characteristic (ROC) curves were analyzed to assess the diagnostic performance of the semi-quantitative parameters. The maximum Youden index was used to select the optimal threshold. A p-value < 0.05 was considered significant.

## 3 | Results

### 3.1 | Population

Thirty-nine patients were included. One patient (2.5%) presented with contralateral recurrence 4years later and was considered as two separate events. Another (2.5%) had bilateral involvement. Forty ears were examined. The baseline clinical and biological characteristics of the patients were summarized

in Table 1. All but one patient had otalgia and/or headache at diagnosis. This patient had limited involvement of the CAE and the deep cervical space. Nine patients (23.1%) had facial nerve paralysis. Eight of them had involvement of the carotid space (4 of them with a mastoid involvement associated) and the ninth had only mastoid involvement. It is to be noted that 14 patients had carotid space and/or mastoid involvement without facial nerve paralysis.

### 3.2 | Microbiology and Antibiotic Therapy

Bacteriological samples were obtained from 37 ears (92.5%). The sample was superficial only in 19 cases (51.4%) and superficial and deep in 18 cases (48.6%). In three patients, no samples were taken. Thirty-two samples (86%) were positive for *Pseudomonas aeruginosa*, isolated in 26 cases (81.3%) and polymicrobial in the others. Of these, 28 (87.5%) were susceptible to CIPROFLOXACIN, CEFTAZIDIME, and CEFEPIME. The median duration of antibiotic treatment was 6.9 weeks [5.4-14.6 weeks]. Twenty-nine patients (72.5%) were treated with CEFTAZIDIME and CIPROFLOXACIN. The fungi found in

<table><caption>TABLE 2 | Microbiology and initial antibiotherapy.</caption><thead><tr><th>Microbiology</th><th></th><th>n (%)</th><th>Initial antibiotherapy</th></tr></thead><tbody><tr><td rowspan="4">Pseudomonas aeruginosa isolate</td><td>Susceptible</td><td>22<br>(59.5%)</td><td><ul><li>19 CEFTAZIDIME and CIPROFLOXACIN</li><li>2 CEFPIME and CIPROFLOXACIN</li><li>1 CEFPIME and DAPTOMYCIN</li></ul></td></tr><tr><td>Resistant to CIPROFLOXACIN</td><td>3<br>(8.1%)</td><td><ul><li>2 CEFTAZIDIME</li><li>1 CEFTAZIDIME and LINEZOLIDE</li></ul></td></tr><tr><td>Resistant to CIPROFLOXACIN and CEFPIME</td><td>1<br>(2.7%)</td><td>CEFTAZIDIME</td></tr><tr><td>Pseudomonas aeruginosa susceptible + MSSM</td><td>3<br>(8.1%)</td><td><ul><li>2 CEFTAZIDIME and CIPROFLOXACIN</li><li>1 CEFPIME and LEVOFLOXACIN 6 weeks then CLINDAMYCINE and LEVOFLOXACIN 6 weeks</li></ul></td></tr><tr><td>Pseudomonas aeruginosa susceptible + Staphylococcus lugdunensis</td><td>1<br>(2.7%)</td><td>CEFPIME, RIFAMPICIN and DOXYCYCLINE</td></tr><tr><td>Pseudomonas aeruginosa susceptible + Candida parapsilosis</td><td>1<br>(2.7%)</td><td>CEFTAZIDIME and CIPROFLOXACIN</td></tr><tr><td>Pseudomonas aeruginosa susceptible + MSSM + Streptococcus pneumoniae</td><td>1<br>(2.7%)</td><td>PIPERACILLIN-TAZOBACTAM, LEVOFLOXACIN and FLUCONAZOLE</td></tr><tr><td>MSSM + Aspergillus fumigatus</td><td>1<br>(2.7%)</td><td>CEFTAZIDIME and CIPROFLOXACIN</td></tr><tr><td>Candida parapsilosis</td><td>1<br>(2.7%)</td><td>CEFTAZIDIME and CIPROFLOXACIN</td></tr><tr><td>Enterococcus faecalis</td><td>1<br>(2.7%)</td><td>AMOXICILLINE and CEFTRIAXONE</td></tr><tr><td>Non-contributory</td><td>2<br>(5.4%)</td><td>CEFTAZIDIME and CIPROFLOXACIN</td></tr></tbody></table>

Abbreviation: MSSM, Methicillin-susceptible *Staphylococcus aureus*.
the samples were not considered pathogenic and were not ini-
tially targeted by antibiotic therapy. The results of microbiolog-
ical sampling and the different therapeutic combinations were
summarized in Table 2.

3.3 | Initial PET Scan

Twenty-five patients (62.5%) had their initial PET scan be-
fore starting antibiotherapy, with a median of 4 [0 to 19] days.
Fifteen patients (37.5%) had their first PET scan after the start
of antibiotic therapy, with a median of 5 [2 to 10] days. Seven
patients had deep sampling prior to the first PET scan, with
a median delay of 7 [2 to 23] days. All PET scans were pos-
itive at initial assessment. The SUVmax was always greater
than liver activity (score ≥ 3) and was greater than twice
liver activity (score = 4) in 30 patients (75%), with a median
SUVmax of 9.4 [3.4 to 21.9] g/mL. The median TLG was 28.3
[0 to 273] g. The median TMV was 4.8 [0 to 45.2] mL. Ten pa-
tients (25%) had superficial involvement and 30 patients (75%)
had deep involvement. Five patients (12.5%) had intracranial
extension. Two patients had contralateral midline crossing.
Hypermetabolic involvement averaged 4 out of 12 regions
±2.5 [1 to 11 regions]. The extent score had a median value of
20.8 [6.3 to 66.7%].

3.4 | PET and Clinical Follow-Up

At re-evaluation after 6 weeks of antibiotic therapy, 34 pa-
tients (85%) had a complete clinical response, 3 (7.5%) had
partial improvement, and 3 (7.5%) had worsening symptoms.
Re-evaluation PET scans were performed a median of 6.1 [4.3
to 8] weeks after the start of antibiotic therapy. When the PET

scans were re-evaluated, 14 patients (35%) had a complete re-
sponse, 18 (45%) had a partial response, 5 (12.5%) had a stable
response, and 3 (7.5%) had a progressive response. The median
SUVmax was 5.6 [2.1 to 14.7] g/mL. The median TLG was 14.7 [0
to 174] g. The median TMV was 1.1 [0 to 28] mL. The distribution
of various PET and clinical responses and patient outcomes is
summarized in Figure 1, and examples of images at initial as-
 sessment and re-assessment are shown in Figure 2.

The 14 patients with a complete response on PET had a com-
plete clinical response, and none of them relapsed. It should
be noted that the two patients with *Candida* treated with
CEFTAZIDIME and CIPROFLOXACIN had a complete re-
sponse on PET, and neither relapsed without antifungal
treatment.

Of the 18 patients with a partial response on PET, 16 had a complete clinical response and only one relapsed. This patient was infected with CIPROFLOXACIN-resistant *Pseudomonas aeruginosa* and treated with CEFTAZIDIME and LINEZOLIDE for 44 days. Two had a partial clinical response (persistent otalgia and inflammatory CAE) and did not relapse.

Of the five patients who were stable on PET, one was clinically
progressive and continued to deteriorate (worsen otorrhea
and altered general condition). He was infected with sensitive
*Pseudomonas aeruginosa* and treated with CEFTAZIDIME and
CIPROFLOXACIN. CEFEPIME and METRONIDAZOLE were
then initiated, with favorable evolution. Four patients had a
complete clinical response and none of them relapsed.

Of the three patients who progressed on PET, two had a
clinical complete response but relapsed early, and one was

<figure><img src="image_3.png" /><figcaption>**FIGURE 1** | Classification of patients included for reassessment according to PET response, clinical response and clinical course. ATB, antibiotherapy.</figcaption></figure>
<figure><img src="image_4.png" /><figcaption>FIGURE 2 | Legend on next page.</figcaption></figure>

clinically progressive and continued to deteriorate (worsen hypoacousis, vestibular disorders, contralateral otitis). One of these patients was infected with CIPROFLOXACIN-resistant *Pseudomonas aeruginosa* treated with CEFTAZIDIME

alone. One other did not have any microbiological sampling and was treated probabilistically with CEFTAZIDIME and CIPROFLOXACIN for 42 days, and then relapsed 1 month later (swab found *Pseudomonas aeruginosa* resistant to
**FIGURE 2** | (a) Example of patient who have achieved a cure. A: initial PET scan; B: re-evaluation PET scan; from left to right, in axial section: CT—PET-CT fusion—PET alone. NOE with susceptible *Pseudomonas aeruginosa* and *MSSM*, treated with CEFTAZIDIME and CIPROFLOXACIN for 7 weeks. A: Intense uptake centered on the right temporomandibular joint, extending to the external auditory canal and middle ear, with erosion of the mandibular condyle and floor of the tympanal bone (SUVmax 21.9). B: Partial regression in intensity and extent of uptake (SUVmax 5.6; ΔTLG: -99%; ΔVMT: -85%; Δextent: -54%). Good clinical evolution thereafter. (b) Example of patient with early progression or recurrence. A: initial PET scan; B: re-evaluation PET scan; from left to right, in axial section: CT—PET-CT fusion—PET alone. NOE with *MSSM* and *Aspergillus fumigatus*, treated with CEFTAZIDIME and CIPROFLOXACINE for 6 weeks. A: Intense uptake of bilateral parapharyngeal, carotid, and retropharyngeal spaces, with extension along the right styloid process, right petrous apex, and right jugular foramen. Erosion of the anterior cortex of the clivus (SUVmax 7.3). B: Progression in extent and stability in intensity of hypermetabolic involvement (SUVmax 7.1; ΔTLG 60%; ΔVMT 29%; Δextent 0%). Clinical worsening thereafter.

CEFTAZIDIME and CIPROFLOXACIN). The last one was in-
fected with *Aspergillus fumigatus* and *SAMS* and was treated
with CEFTAZIDIME and CIPROFLOXACIN.

Of all patients, 15 were still on their initial antibiotic therapy
after reassessment, including 3 who had a complete response
on PET, 11 who had a partial response, and 1 who was stable
on PET.

Table 3 summarizes the microbiology and the antibiotic treat-
ment given to the five patients who relapsed, at initial assess-
ment and at relapse.

In the group of 21 patients, combining patients with a partial
response and patients who were stable on PET and had not re-
lapsed, there was no significant difference in ΔTMV (p = 0.432),
ΔTLG (p = 0.347), ΔSUVmax (p = 0.426), or ΔExtent (p = 0.765)
between patients in whom antibiotic therapy was stopped (n = 9)
or continued (n = 12). Of these patients, 14 had a follow-up PET
scan approximately 3–4 months after the start of antibiotic ther-
apy (median 3.0; 2.5 to 4.7 months) and only five of these were
considered negative.

**3.5** **Quantification at Initial PET Scan**

The median initial TLG, TMV, and extent were significantly
higher in patients who had failed therapy compared to those
who had not relapsed (TLG 64.5 [32.4 to 273.4] g versus 22.8 [0
[0 to 130]g; *p* = 0.003—TMV 13.5 [8.25 to 45.2] mL versus 3.9 [0
to 17.1] mL; *p* = 0.0001—Extent 54.2 [29.2 to 66.7]% versus 18.8
[6.3 to 50.0]%; *p* = 0.001). However, there was no significant
difference in initial SUVmax between patients who relapsed
and those who did not (7.6 [7.3 to 15.9] g/mL versus 9.5 [3.4 to
21.9] g/mL; *p* = 0.968). All patients who relapsed had initial deep
involvement, compared with 71.4% of patients who were cured
(25/35 cured patients).

**3.6 | Diagnostic Performance of Follow-Up**
**PET Scans**

Visual analysis alone, considering complete response as maxi-
mal intensity less than liver activity, predicted cure with 100%
sensitivity, 42.9% specificity, and 50.0% accuracy. The SUVmax,
TLG, TMV, Extent, ΔSUVmax, ΔTLG, ΔTMV, and ΔExtent
were all significantly lower in patients who did not relapse than
in those who did. The summary of quantitative data at baseline

and at recurrence are shown in Table 4. The diagnostic perfor-
mance values of the different quantitative data are summarized
in Table 5. The best performing parameters for predicting re-
currence were TLG and TMV with sensitivity and specificity of
80% and 100% using respective thresholds of 50.1 g and 8.3 mL.
ΔExtent showed a sensitivity and specificity of 80% and 97.1%
using a threshold of -4.3% (i.e., a decrease of approximately two
points on the sum of intensity scores). ΔTLG and ΔSUVmax
showed a sensitivity and specificity of 80% and 94.3% using
thresholds of -37.4% and -4.4%, respectively, then ΔTMV with
a sensitivity and specificity of 80% and 82.9% using a threshold
of -45.5%.

4 | Discussion

The duration of antibiotic treatment for necrotising otitis ex-
terna is not yet codified and the decision to stop or continue
antibiotic therapy is a complex one based on several clinical,
biological, and imaging factors. At present, there is no standard-
ized criterion to determine cure with certainty. [18F]FDG-PET
is used in routine practice in many centers, but the literature
evaluating its performance in assessing therapeutic response is
poor and limited to a few retrospective studies with small num-
bers [23, 27, 28]. Our aim was to evaluate its performance in a
larger population and to identify interpretation criteria to facili-
tate clinical decision making.

The patients in our study presented the typical ONE profile, in
line with the literature and in particular the systematic review
by Takata et al. [10], i.e., predominantly male (82% vs. 68%), di-
betic (74.4% vs. 84%), and elderly (76 ± 9 vs. 69.2 years). The clin-
ical presentation was also typical, with the main symptom being
otalgia (and/or headache), which was almost constant (97.4%),
followed by otorrhoea (87.2%), hypoacusis (66.7%), altered gen-
eral condition (28.2%) and peripheral facial paralysis (23.1%). As
widely reported, *Pseudomonas aeruginosa* was the most isolated
germ (86% vs. 62% in the review by Takata et al.) with ciproflox-
acin resistance in 10.8% (vs. 8%) of samples.

Firstly, our results highlight that the treatments offered for NOE
are now effective, with only 5 out of 40 patients failing treat-
ment (12.5%). All patients had a positive PET scan at baseline,
which is consistent with studies by Vion et al. [23] and Kulkarni
et al. [27]

One of the most important results of our study was that the 15
patients (100%) with a complete visual response on PET showed
<table><caption>TABLE 3 | Microbiology and treatment of patients not cured.</caption><thead><tr><th rowspan="2">Patient no.</th><th colspan="3">Initial</th><th colspan="4">Relapse</th></tr><tr><th>Type of sampling</th><th>Microbiology</th><th>Treatment</th><th>Type of sampling</th><th>Microbiology</th><th>Treatment</th><th>Evolution</th></tr></thead><tbody><tr><td>24</td><td>Superficial</td><td><i>Pseudomonas aeruginosa</i> resistant to Ciprofloxacin</td><td>Ceftazidime 5.6 weeks</td><td>Superficial and deep</td><td>Non contributive</td><td>Meropenem</td><td>Pancytopenia and progression</td></tr><tr><td>11</td><td>None</td><td>None</td><td>Ceftazidime and Ciprofloxacin 6 weeks</td><td>Deep</td><td><i>Pseudomonas aeruginosa</i> resistant to Ceftazidime and Ciprofloxacin</td><td>Colimycin and Meropenem</td><td>Favorable</td></tr><tr><td>14</td><td>Superficial</td><td><i>Aspergillus fumigatus</i> and SAMS</td><td>Ceftazidime and Ciprofloxacin 6.4 weeks</td><td>Superficial and deep</td><td><i>Aspergillus fumigatus</i></td><td>Meropenem Zyvoxid and Voriconazole</td><td>Favorable</td></tr><tr><td>18</td><td>Superficial and deep</td><td><i>Pseudomonas aeruginosa</i> susceptible</td><td>Ceftazidime and Ciprofloxacin 6.7 weeks</td><td>Superficial</td><td>Non contributive</td><td>Cefepime and Metronidazole</td><td>Favorable</td></tr><tr><td>21</td><td>Superficial</td><td><i>Pseudomonas aeruginosa</i> resistant to Ciprofloxacin</td><td>Ceftazidime and Linezolid 6.3 weeks</td><td>None</td><td>None</td><td>Ceftazidime</td><td>Favorable</td></tr></tbody></table>

Abbreviation: MSSM, Methicillin-susceptible *Staphylococcus aureus*.

a favorable progression, reflecting a specificity of 100% for the diagnosis of cure. Conversely, visual progression on PET was systematically associated with treatment failure (three patients), even in the presence of a good clinical response. This suggests that PET was reliable for identifying cured patients in whom antibiotic therapy can be safely discontinued, and patients with treatment failure in whom a change in antibiotic therapy or new bacteriological samples should be considered. On the other hand, the sensitivity of PET complete visual response for identifying a cure was only 43%. Indeed, more than half of the cured patients had an incomplete (partial or stable) PET response, but only one in 17 partial responses relapsed, suggesting that these are also predominantly associated with a favorable outcome.

These results were in agreement with the retrospective study of 11 patients by Vion et al. [23]. [18F]FDG-PET/CT was truly positive in 4/4 uncured patients (i.e., sensitivity 100%) and truly negative in 3/7 cured patients (i.e., specificity 43%). Though, lack of complete response was defined in this study as “focal increase of radiotracer compared to the contralateral side,” sometimes with low fixations still considered positive at re-evaluation (four patients with a SUVmax of less than three considered positive). In our study, a complete response was defined as a residual fixation lower than the hepatic uptake. This hepatic threshold has been widely accepted in the literature as a good physiological reference, particularly in the context of haemopathies (lymphoma) [30] and inflammatory diseases (vasculitis) [31]. It seems to be an easy parameter to use, which allows to avoid an over-positivisation of low residual hypermetabolisms, which are likely to be of inflammatory origin. It is important to reiterate that this visual analysis remains subjective (particularly the classification of patients as stable, partial response or progression) was not based on strict quantification criteria and remained at the discretion of the observer.

Though PET is not often used in patient follow-up after antibiotherapy discontinuation, observation of the few surveillance PET scans of our cured patients showed that PET scans regularly remained weakly positive for several months. This residual uptake may be related to a significant inflammatory component in the metabolism of NEO and to scarring phenomena that may be active for a prolonged period. This suggests that the persistence of moderate uptake should not systematically justify prolongation of antibiotic treatment. Reasonably, there seemed to be no justification for PET monitoring until complete negativity, as long as the clinical course was favorable.

In situations where patients are metabolically stable or in partial response, quantification may be of interest to compensate for the lack of sensitivity of visual PET analysis. Indeed, all parameters were significantly higher in patients who had failed therapy than in those with favorable outcomes. Sensitivity was 80% for all parameters. This equivalent sensitivity is explained by the fact that one patient had a significant response for all parameters, improved clinically at reassessment, and yet relapsed early (one false negative out of five patients who relapsed). TLG and TMV had the best specificity of 100%, with respective thresholds of 50.1 g and 8.3 mL. ΔTLG and ΔTMV are also effective and appear to be reliable in doubtful
<table><caption>**TABLE 4** | Quantification on initial and re-evaluation PET scans.</caption><thead><tr><th rowspan="2"></th><th colspan="5">Re-evaluation PET scan</th></tr><tr><th>Initial PET scan</th><th>Complete response</th><th>Partial response</th><th>Stability</th><th>Progression</th></tr></thead><tbody><tr><td>n (%)</td><td>40 (100%)</td><td>14 (35%)</td><td>18 (45%)</td><td>5 (12.5%)</td><td>3 (7.5%)</td></tr><tr><td>SUVmax</td><td>9.4 [3.4 to 21.9] g/mL</td><td>3.1 [2.1 to 4.6] g/mL</td><td>6.1 [3.3 to 8.3] g/mL</td><td>9.5 [6.7 to 13.3] g/mL</td><td>11 [7.1 to 14.7] g/mL</td></tr><tr><td>TLG</td><td>28.3 [0 to 273] g</td><td>0 [0 to 0.9] g</td><td>0 [0 to 14.6] g</td><td>15.2 [13.4 to 173.8] g</td><td>53.4 [51.7 to 129] g</td></tr><tr><td>TMV</td><td>4.8 [0 to 45.2] mL</td><td>0 [0 to 0.04] mL</td><td>0 [0 to 4.4] mL</td><td>3.2 [2.6 to 28.2] mL</td><td>10.6 [8.7 to 22.8] mL</td></tr><tr><td>Extent</td><td>20.8 [6.3 to 66.7]%</td><td>4.2 [0 to 6.3]%</td><td>14.6 [0 to 41.7]%</td><td>22.9 [10.4 to 64.6]%</td><td>41.7 [35.4 to 79]%</td></tr><tr><td>SUVmax</td><td></td><td>-56.8 [-78 to -31.9]%</td><td>-33.4 [-74.6 to -6.4]%</td><td>-0.3 [-31.4 to 1.5]%</td><td>47.5 [-2 to 92]%</td></tr><tr><td>TLG</td><td></td><td>-100 [-100 to 0]%</td><td>-84.7 [-100 to -3.8]%</td><td>-39.4 [-53.8 to 67.8]%</td><td>59.7 [21 to 100]%</td></tr><tr><td>TMV</td><td></td><td>-100 [-100 to 0]%</td><td>-81.2 [-100 to -3.1]%</td><td>-35.1 [-54.1 to 69.1]%</td><td>28.7 [0.5 to 68.5]%</td></tr><tr><td>Extent</td><td></td><td>-70.8 [-100 to -33.3]%</td><td>-48.5 [-100 to -15.4]%</td><td>-0.55% [-11.1 to 0]%</td><td>21.4 [0 to 46]%</td></tr></tbody></table>

Note: Quantitative variables are expressed as median and range. Qualitative variables are expressed as headcount and percentage of the population. Abbreviations: SUV, standardized uptake value; TLG, total lesion glycolysis; TMV, total metabolic volume.

<table><caption>**TABLE 5** | Quantitative parameters on PET according to clinical course.</caption><thead><tr><th></th><th>Recovery</th><th>Relapse</th><th>p</th><th>Threshold</th><th>AUC</th><th>Se</th><th>Sp</th></tr></thead><tbody><tr><td colspan="8">Initial parameters</td></tr><tr><td>SUVmax</td><td>9.5 [3.4 to 21.9] g/mL</td><td>7.6 [7.3 to 15.9] g/mL</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>TLG</td><td>22.8 [0 to 130] g</td><td>64.5 [32.4 to 273.4] g</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>TMV</td><td>3.9 [0 to 17.1] mL</td><td>13.5 [8.3 to 45.2] mL</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Extent</td><td>18.8 [6.3 to 50.0]%</td><td>54.2 [29.2 to 66.7]%</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="8">Parameters at re-evaluation</td></tr><tr><td>SUVmax</td><td>5.4 [2.1 to 13.3] g/mL</td><td>11.0 [5.5 to 14.7] g/mL</td><td>0.008</td><td>7.0</td><td>0.857</td><td>80%</td><td>82.9%</td></tr><tr><td>TLG</td><td>1.7 [0 to 48.5] g</td><td>53.4 [6.8 to 173.8] g</td><td>&gt; 0.001</td><td>50.1</td><td>0.937</td><td>80%</td><td>100%</td></tr><tr><td>TMV</td><td>0.5 [0 to 8.0] mL</td><td>10.6 [1.6 to 28.2] mL</td><td>&gt; 0.001</td><td>8.3</td><td>0.943</td><td>80%</td><td>100%</td></tr><tr><td>ΔSUVmax</td><td>-40.8 [-78.0 to 0.4]%</td><td>-1.5 [-65.7 to 92.4]%</td><td>0.021</td><td>-4.4%</td><td>0.817</td><td>80%</td><td>94.3%</td></tr><tr><td>ΔTLG</td><td>-90.8 [-100 to -67.8]%</td><td>-21.1 [-94.6 to 100]%</td><td>0.014</td><td>-37.4%</td><td>0.869</td><td>80%</td><td>94.3%</td></tr><tr><td>ΔTMV</td><td>-85.2 [-100 to -69.1]%</td><td>-0.5 [-92.7 to 68.5]%</td><td>0.006</td><td>-45.5%</td><td>0.834</td><td>80%</td><td>82.9%</td></tr><tr><td>ΔExtent</td><td>-54.5 [-100 to 0]%</td><td>0 [-57.7 to 46.2]%</td><td>0.003</td><td>-4.3%</td><td>0.889</td><td>80%</td><td>97.1%</td></tr></tbody></table>

Note: p significant if less than 0.05.

Abbreviations: Se, sensitivity; Sp, specificity; SUV, standardized uptake value; TLG, total lesion glycolysis; TMV, total metabolic volume.

situations, with respective specificity of 94.3% (threshold of -37.4%) and 82.9% (threshold of -45.5%). ΔExtent also showed an excellent specificity of 97.1% for a threshold of -4%, corresponding to a 2-point decrease in the sum of intensity score with the extent score we defined. The global performance of our quantitative parameters matches those of Hurstel et al. using a different method; their study found an accuracy of 100% based on a SUVmax-lesion-to-background-threshold of

4.1 on re-evaluation PET for predicting recovery from NOE. It is to be noted that our extent score is new, homemade, unvalidated, and deserves to be studied in a larger cohort. It was inspired by the Summed Stress Score (SSS) used in cardiology for myocardial scintigraphy, and we felt that the analogy was relevant in terms of weighting different anatomical spaces according to their intensity. We are aware of certain biases in the design of this score. Firstly, the anatomical regions were all
given the same weight despite being very different in size (e.g., middle ear versus mastoid). Very high intensities retained an identical score on re-evaluation if the intensity decreased but remained greater than twice the hepatic metabolism. Inter-observer reproducibility was uncertain, and obtaining this score was often time-consuming and difficult to implement in everyday practice.

In current practice, it may be useful to speak of a “satisfactory” response when these quantitative parameters are below their optimal thresholds and of an inadequate response above these thresholds.

These results pave the way for optimizing treatment, in particular by reducing the duration of antibiotics when PET shows a complete or satisfactory response based on quantitative indices, if clinical evolution is favorable. Limiting the prolongation of antibiotic therapy in these patients would limit the emergence of bacterial resistance, reduce the incidence of antibiotic-related side effects (such as encephalopathy from overdosage) and reduce the costs associated with prolonged treatment. Another promising aspect of our study was that initial disease extension, as measured by TLG, TMV, and our extent score, was significantly greater in patients who subsequently relapsed, whereas this was not the case for initial uptake intensity. One of the particularities in the one partial response patient who relapsed was the extent of his initial involvement (TLG 126.4 g, TMV 21.1 mL, extent 54.2%). It would be interesting to evaluate the prognostic character of these indices.

Our study had several limitations, the first being its retrospective nature. The population and methodology were representative of current practice and literature, with various bacteriology and antibiotic regimens reflecting the diversity of therapeutic approaches observed in practice. The overall sample size was relatively small, with only a small number of treatment failures; the overall performance of our quantification indices should therefore be treated with caution, especially sensitivity. However, the number of patients was satisfactory given the rarity of the disease and compared to previous studies [23, 27, 28]. The choice of our gold standard could also be discussed given the lack of a validated imaging gold standard for therapeutic response in NOE; we chose to use clinical improvement and sustained remission after antibiotic withdrawal as our reference. This pragmatic approach, commonly used in infectious disease studies, reflects real-world therapeutic success and remained for us the most robust endpoint available.

Another major limitation of our study was that more than half of the patients with an incomplete PET response continued antibiotic therapy at re-evaluation (11 of 16 patients with a partial response), making it impossible to assess retrospectively whether this continuation was essential for cure. PET may have played a role in this decision, but it was difficult to assess a posteriori the reasons for continuing or stopping antibiotic therapy. What's more, we found no significant difference between the quantitative PET parameters of patients with a partial or stable response who continued or stopped antibiotic therapy that might have motivated this decision. This highlights the uncertainty and heterogeneity of current practice regarding the optimal management of antibiotic therapy

at re-evaluation in the absence of clear decision-making criteria. The high proportion of patients with prolonged antibiotic therapy after PET re-evaluation, a fortiori in patients with partial response, made it impossible to assess retrospectively whether this continuation of antibiotic therapy was essential for cure.

Second, as with all PET studies of metabolic volume, the choice of segmentation threshold was controversial. There was no specific recommendation for this choice in the area of infections. We chose a fixed threshold of 4.0 g/mL SUV rather than, for example, one based on SUVmax (which is widely used in onco-hematology) because it was easier to evaluate a large volume when the damage was extensive, of complex shape, or close to cerebral metabolism. In addition, as fixation intensities were often moderate (median SUVmax 9.4 [3.4 to 21.9] g/mL), using a relative threshold based on SUVmax risked over-inclusion of weak, non-pathological fixations (such as residual inflammation). Finally, our study included different PET devices and therefore different reconstructions of the images, which could introduce a bias in the quantification. However, this bias appeared to be minimal given the fact that most of the examinations were performed on Biograph mCT devices (82.5%).

## 5 | Conclusion

This study confirms the value of using [18F]FDG PET to assess therapeutic response in necrotising otitis externa. A combination of visual and quantitative analysis appeared to be effective in identifying patients who could be confidently considered cured. PET was reliable in cases of complete response or visual progression. Quantitative indices were used to refine decision making in patients with incomplete response, with thresholds appearing to be effective in stratifying them into satisfactory or unsatisfactory responses. A prospective study would be interesting to validate the promising results of these quantitative indices.

## Conflicts of Interest

The authors declare no conflicts of interest.

## Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author.

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