Auris Nasus Larynx 41 (2014) 380–383

Intra-arterial administration of antibiotics for refractory skull baseosteomyelitis

Hiroshi Yamazaki a,b,c,*, Masahiro Kikuchi a,b, Shogo Shinohara a,b, Yasushi Naito a,c,Keizo Fujiwara a, Yuji Kanazawa a,b, Risa Tona c

a Department of Otolaryngology, Kobe City Medical Center General Hospital, Kobe City, Japanb Department of Head and Neck Surgery, Kobe City Medical Center General Hospital, Kobe City, Japanc Institute of Biomedical Research and Innovation, Kobe City, Japan

A R T I C L E I N F O

Article history:

Received 7 July 2013

Accepted 9 December 2013

Available online 30 December 2013

Keywords:

Skull base osteomyelitis

Malignant external otitis

Intra-arterial administration of antibiotics

A B S T R A C T

We report two cases of elderly diabetic men with skull base osteomyelitis (SBO) originating from

malignant external otitis (MEO). In both, a devastating infection and neural paralysis deteriorated after

conventional therapy, including long-term intravenous administration of culture-directed antibiotics

with strict control of blood sugar levels and surgical debridement of infectious granulation tissue. Since

poor perfusion of antibiotics in the lesion may be associated with serious nature of MEO/SBO, we

administered antibiotics intra-arterially via a retrograde catheter with the tip set at the proximal point of

the external carotid artery to increase the tissue drug concentration in the maxillary artery (MA) and

ascending pharyngeal artery (APA) supply areas, in which intense inflammation was observed. This

intra-arterial administration of antibiotics (IA therapy) followed by long-term intravenous and oral

antibiotic treatments eliminated their infection and no recurrence was observed in 2 years follow-up

period. Interestingly, CT images of angiography via the catheter demonstrated stronger enhancement in

the MA supply area compared to the APA supply area and IA therapy was more effective in the former.

These results suggest that IA therapy, which might achieve high antibiotic concentration at the site of

infection, is effective in patients with MEO/SBO refractory to conventional treatments.

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Auris Nasus Larynx

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1. Introduction

Malignant external otitis (MEO) is a devastating infectiousdisease and usually originates from the external ear canal inelderly patients with diabetes [1,2]. Pseudomonas aeruginosa isoften the primary causative organism of MEO. The disease canprogress to skull base osteomyelitis (SBO) and may cause fatalcomplications such as multiple cranial nerve paralysis, meningitis,and sepsis [1–3]. The serious nature of infection in MEO isattributable to the immunosuppressed state of hosts caused by ageand diabetes, and poor perfusion of antimicrobial agents into theinfected area due to diabetic microangiopathy and necrotizingvasculitis induced by P. aeruginosa infection [1–5].

The principal therapy for MEO/SBO is long-term intravenousand oral administration of antibiotics. Development of antibioticsagainst P. aeruginosa including oral quinolones with broadspectrum activity and high permeability in peripheral tissue have

* Corresponding author. Tel.: +81 78 302 4321;

fax: +81 78 302 2487.

E-mail address: h_yamazaki@ent.kuhp.kyoto-u.ac.jp (H. Yamazaki).

0385-8146/$ – see front matter � 2014 Elsevier Ireland Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.anl.2013.12.003

markedly improved the outcome of MEO/SBO [6], but mortalityremains high in patients meeting all major clinical and radio-graphic criteria for MEO [7]. Surgical debridement of necrotictissue and drainage of abscesses is thought to be important formanagement of MEO/SBO [2,8], but the efficacy of surgicalintervention is controversial [3]. Here, we describe successfultreatment of MEO/SBO using intra-arterial administration ofantibiotics (IA therapy) in two cases that were refractory toconventional therapy.

2. Cases

The patients were both males with diabetes who had noprevious ear disease including chronic otitis media and chronicexternal otitis, and were aged 73 year-old (Case 1) and 59 year-old(Case 2), respectively. Both were diagnosed as MEO on the left sidebased on otorrhea, otalgia, hearing loss, and detection of P.

aeruginosa in otorrhea as well as exudate, edema, and granulationin the external auditory canal, all of which deteriorated afterseveral weeks of treatment with topical and oral administration ofculture-directed antibiotics [8,9]. Then, 3 months of intravenousadministration of culture-directed antibiotics (IV therapy) with

Fig. 1. Temporal bone CT images of Case 1 after the conventional therapies. Axial (A)

and coronal (B) images. Bony erosion is observed at the skull base (arrows)

including clivus, apex of the temporal bone, and carotid canal (*).

H. Yamazaki et al. / Auris Nasus Larynx 41 (2014) 380–383 381

strict control of blood sugar levels as well as a mastoidectomy forsurgical debridement of infectious and inflammatory granulationtissue was performed as the conventional therapies for MEO. In theIV therapy, we used meropenem (2 g/day, 1-h infusion of 0.5 gevery 6 h) in Case 1 and imipenem/cilastatin (1 g/day, 1-h infusionof 0.5 g every 12 h) and piperacillin (4 g/day, 1-h infusion of 1 gevery 6 h) in Case 2 on the basis of the patient’s renal function. InCase 1, vancomycin (0.75–1 g/day with 1- to 2-h infusion) was alsoadministrated in the first two weeks because methicillin-resistant

Staphylococcus aureus was also detected in the otorrhea duringthis period.

Despite these conventional treatments, both showed aggrava-tion of hearing loss, otalgia and otorrhea. Ninth and 10th cranialnerve paralysis and Horner’s symptom newly developed in Case 1and facial palsy also developed in Case 2. At that time, CT revealedbony erosion at the clivus and carotid canal in addition to softtissue density in the external auditory canal and middle ear,suggesting that the severe inflammation in the external auditorycanal had extended to the skull base (Fig. 1A and B). Decrease ofsignal intensity on T1-weighted MRI and clear gadolinium-enhancement was observed at the affected side of the clivus,indicating osteomyelitis (Fig. 2A and B and Supplemental Fig. 1Aand B). These data demonstrated that MEO had developed to SBO inboth [3]. MRI also showed enhancement of the middle fossa duracovering the affected temporal bone, which strongly suggestedimpending development of meningitis (Supplemental Fig. 1C).Therefore, we adopted more intense antibiotic therapy using intra-arterial administration of antibiotics.

In this study, we used fluorine 18 fluorodeoxyglucose-positronemission tomography/computed tomography (FDG-PET/CT) underthe strict control of blood sugar levels to evaluate the area of MEO/SBO because FDG-PET is exquisitely sensitive and offers high-resolution images in evaluation for inflammation [10]. AbnormalFDG uptake was observed in the maxillary artery (MA) feeding areaincluding the mastoid, tympanic cavity, and external auditorycanal as well as the ascending pharyngeal artery (APA) feeding areaincluding the clivus (Fig. 3A and Supplemental Fig. 2A). A catheterwas, therefore, inserted from the superficial temporal artery withthe tip set at the proximal point of the external carotid artery (ECA)by interventional radiology. Digital subtraction angiography usingthis catheter permitted visualization of all branches of the ECA,including the MA and APA. We also evaluated peripheral perfusionby CT images of angiography with injection of contrast mediumfrom the catheter. Enhancement was observed in both the MA andAPA supply areas, but relatively faint in the APA supply area(Fig. 3B). Using this retrograde catheter, 3 g of piperacillin, a time-dependent bactericidal agent, was administered continuously and0.3 g of ciprofloxacin, a concentration-dependent bactericidal

Fig. 2. MRI of Case 1. At the left side of the clivus, the intensity of signal on T1-weighted

indicates osteomyelitis at this area.

agent, was injected twice a day with 2-h infusion. We alsocontinuously administrated an anticoagulant agent, heparin(5000 units/day), via the catheter to prevent catheter blockage.However, the catheter of Case 1 was clogged 2 weeks later and,therefore, this catheter was removed and another catheter was re-inserted from the occipital artery with the tip of the catheter set atthe same position to continue IA therapy. During IA therapy, bothpatients were kept hospitalized and their blood sugar levels werestrictly controlled.

Immediately after the start of IA therapy, their otalgia, otorrhea,and headache started to improve and after 8 weeks of IA therapyonly mild headache and slight neural paralysis remained. FDG-PET/CT imaging showed that inflammation had disappeared in theMA supply area, but high FDG uptake persisted in the APA feedingarea around the clivus and carotid arteries in both (Fig. 3C andSupplemental Fig. 2B). Infectious pseudoaneurysm of the internal

MRI is decreased (A, arrow), but strong enhancement is observed (B, arrow), which

Fig. 4. CT angiography. The pseudoaneurysm (white arrow) develops at the distal

part of the internal carotid artery. At the bifurcation, the stenosis of the internal

carotid artery is observed (black arrow). The retrograde catheter is inserted from

the occipital artery (arrowheads) and the tip of the catheter locates at the proximal

point of the ECA (*).

Fig. 3. Evaluation of the effect of IA therapy in Case 1. (A) FDG-PET/CT image before IA therapy. Strong FDG uptake is observed in the mastoid (white arrow) and skull base

(black arrows). (B) CT images of angiography using the retrograde ECA catheter. Strong enhancement is observed mainly in MA feeding area, including the external auditory

canal, mastoid, tympanic cavity, temporomandibular joint, infratemporal fossa, and masticator space (blue dotted line). APA feeding area shows only faint enhancement (red

dotted line). (C) FDG-PET/CT image after IA therapy. FDG uptake disappears in the mastoid and around the temporomandibular joint (white arrows), while strong FDG uptake

remains around the left side of the clivus (black arrow). The arrowhead indicates the site of the infectious pseudoaneurysm. (D) FDG-PET/CT image after IA therapy and

adjuvant intravenous and oral administration of antibiotics. The remaining FDG uptake is considerably reduced (arrowhead).

H. Yamazaki et al. / Auris Nasus Larynx 41 (2014) 380–383382

carotid artery (ICA) had newly developed in Case 1, suggestingremaining intense inflammation in this area (Figs. 2C and 4). SinceCase 1 originally had an ICA stenosis at the same side of thepseudoaneurysm (Fig. 4), endovascular treatment was notindicated.

IA therapy was followed by additional IV therapy for 3 monthsand oral intake of quinolones for a year. FDG-PET/CT imagingconfirmed that these adjuvant therapies almost diminished theabnormal FDG uptake in the APA supply area (Fig. 3D andSupplemental Fig. 2C). The pseudoaneurysm in Case 1 was alsoreduced in size and spontaneously occluded as infection aroundthe carotid canal decreased. No recurrence was observed in 2 yearsfollow-up period after the treatments.

3. Discussion

Our two cases with MEO/SBO fulfilled all major signs for MEO,which suggests a high mortality rate [8]. The symptoms clearlyaggravated despite conventional treatment for MEO/SBO, includ-ing long-term IV therapy and surgical debridement, and MRIshowed that inflammation had extended to the middle fossa dura.These results led to the choice of more intense antibiotic therapy toprevent potentially fatal complications such as meningitis andintracranial abscess.

As described above, poor perfusion of antimicrobial agents intothe affected lesion is thought to be associated with serious natureof infection of MEO [1–5]. IV therapy using a higher dose canelevate the tissue concentration of antibiotics in a lesion with poorperfusion, but a very high dose may induce undesirable systemic

H. Yamazaki et al. / Auris Nasus Larynx 41 (2014) 380–383 383

side effects, such as renal or hepatic failure. In contrast, intra-arterial drug administration, which is sometimes used in selectivecancer chemotherapy, can achieve a several-fold higher drugconcentration only in the targeted lesion, without adverse effectson other systemic organs [11]. Therefore, we administeredantibiotics intra-arterially from an ECA catheter at the similartotal dose as that in IV therapy, with the aim of increasing thetissue drug concentration in the MA and APA supply areas, inwhich intense inflammation was observed.

CT images of angiography via the ECA catheter showed strongerenhancement in the feeding area for the MA compared to that forthe APA, and IA therapy using the same catheter decreasedinfection more effectively in the MA supply area. These resultssuggest that establishment of a higher tissue antibiotic concentra-tion gave better therapeutic results. The APA is a long vessel with asmall diameter [12], and thus diabetes-induced arteriosclerosisand intense inflammation may easily damage blood flow in theAPA, which might result in a low tissue drug level and refractoryinfection in this area. Interestingly, IV therapy and oral intake ofantibiotics were not effective at the start, but considerably reducedthe residual infection in the APA supply area after IA therapy, eventhough similar antibiotics were used. This might be because the IAtherapy reduced infection and improved tissue perfusion, whichthen allowed a sufficient antibiotic concentration in the APA areato be reached using normal methods.

Hyperbaric oxygenation with conventional antibiotic therapyhas been reported to be effective for refractory MEO/SBO [4]. Thisapproach is relatively safe, but we were unable to use hyperbaricoxygen therapy because a chamber is not available at our hospital.

In both cases reported here, there were no obvious complica-tions in IA therapy. A pseudoaneurysm developed in Case 1, butwas not induced by IA therapy because the ECA catheter does notaffect the distal portion of the ICA, in which the pseudoaneurysmwas observed. However, the safety of IA therapy has not beenestablished, especially with regard to its latent side effects. Forexample, long-term catheterization in the ECA may inducethrombotic embolization and intra-arterial injection of someantibiotics, such as benzathine penicillin G, can produce arterialvasospasm, which results in tissue ischemia distal to the injectionsite [13]. Therefore, the indication for IA therapy should berestricted to cases with refractory MEO/SBO in which symptomscontinue to deteriorate after standard long-term IV therapy.

In conclusion, IA therapy for two cases with refractoryMEO/SBO improved infection in the area in which antibioticswere directly infused via the retrograde catheter, and had a weakereffect in the APA supply area compared to the MA supply area. Eventhough intravenous and oral administration of antibiotics showed

no effect before IA therapy, adjuvant intravenous and oralantibiotics were useful for reducing residual infection afterIA therapy. These results suggest that IA therapy is effective forMEO/SBO refractory to conventional treatment.

Acknowledgment

This study was supported by a Grant-in-Aid for ScientificResearch (C): 22591894 and a Grant-in-Aid for Young Scientists(B): 22791642 from the Japanese Ministry of Education, Culture,Sports, Science and Technology. Funding was from internal sourcesonly.

Appendix A. Supplementary data

Supplementary material related to this article can be found, in the

online version, at http://dx.doi.org/10.1016/j.anl.2013.12.003.

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