Auris Nasus Larynx 41 (2014) 380–383
Contents lists available at ScienceDirect
Auris Nasus Larynx journal homepage: www.elsevier.com/locate/anl
Intra-arterial administration of antibiotics for refractory skull base osteomyelitis 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 b c
Department of Otolaryngology, Kobe City Medical Center General Hospital, Kobe City, Japan Department of Head and Neck Surgery, Kobe City Medical Center General Hospital, Kobe City, Japan Institute of Biomedical Research and Innovation, Kobe City, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 7 July 2013 Accepted 9 December 2013 Available online 30 December 2013
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. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Skull base osteomyelitis Malignant external otitis Intra-arterial administration of antibiotics
1. Introduction Malignant external otitis (MEO) is a devastating infectious disease and usually originates from the external ear canal in elderly patients with diabetes [1,2]. Pseudomonas aeruginosa is often the primary causative organism of MEO. The disease can progress to skull base osteomyelitis (SBO) and may cause fatal complications such as multiple cranial nerve paralysis, meningitis, and sepsis [1–3]. The serious nature of infection in MEO is attributable to the immunosuppressed state of hosts caused by age and diabetes, and poor perfusion of antimicrobial agents into the infected area due to diabetic microangiopathy and necrotizing vasculitis induced by P. aeruginosa infection [1–5]. The principal therapy for MEO/SBO is long-term intravenous and oral administration of antibiotics. Development of antibiotics against P. aeruginosa including oral quinolones with broad spectrum activity and high permeability in peripheral tissue have
* Corresponding author. Tel.: +81 78 302 4321; fax: +81 78 302 2487. E-mail address: [email protected] (H. Yamazaki). 0385-8146/$ – see front matter ß 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 mortality remains high in patients meeting all major clinical and radiographic criteria for MEO [7]. Surgical debridement of necrotic tissue and drainage of abscesses is thought to be important for management of MEO/SBO [2,8], but the efficacy of surgical intervention is controversial [3]. Here, we describe successful treatment of MEO/SBO using intra-arterial administration of antibiotics (IA therapy) in two cases that were refractory to conventional therapy. 2. Cases The patients were both males with diabetes who had no previous ear disease including chronic otitis media and chronic external otitis, and were aged 73 year-old (Case 1) and 59 year-old (Case 2), respectively. Both were diagnosed as MEO on the left side based on otorrhea, otalgia, hearing loss, and detection of P. aeruginosa in otorrhea as well as exudate, edema, and granulation in the external auditory canal, all of which deteriorated after several weeks of treatment with topical and oral administration of culture-directed antibiotics [8,9]. Then, 3 months of intravenous administration of culture-directed antibiotics (IV therapy) with
H. Yamazaki et al. / Auris Nasus Larynx 41 (2014) 380–383
strict control of blood sugar levels as well as a mastoidectomy for surgical debridement of infectious and inflammatory granulation tissue was performed as the conventional therapies for MEO. In the IV therapy, we used meropenem (2 g/day, 1-h infusion of 0.5 g every 6 h) in Case 1 and imipenem/cilastatin (1 g/day, 1-h infusion of 0.5 g every 12 h) and piperacillin (4 g/day, 1-h infusion of 1 g every 6 h) in Case 2 on the basis of the patient’s renal function. In Case 1, vancomycin (0.75–1 g/day with 1- to 2-h infusion) was also administrated in the first two weeks because methicillin-resistant Staphylococcus aureus was also detected in the otorrhea during this period. Despite these conventional treatments, both showed aggravation of hearing loss, otalgia and otorrhea. Ninth and 10th cranial nerve paralysis and Horner’s symptom newly developed in Case 1 and facial palsy also developed in Case 2. At that time, CT revealed bony erosion at the clivus and carotid canal in addition to soft tissue density in the external auditory canal and middle ear, suggesting that the severe inflammation in the external auditory canal had extended to the skull base (Fig. 1A and B). Decrease of signal intensity on T1-weighted MRI and clear gadoliniumenhancement was observed at the affected side of the clivus, indicating osteomyelitis (Fig. 2A and B and Supplemental Fig. 1A and B). These data demonstrated that MEO had developed to SBO in both [3]. MRI also showed enhancement of the middle fossa dura covering the affected temporal bone, which strongly suggested impending development of meningitis (Supplemental Fig. 1C). Therefore, we adopted more intense antibiotic therapy using intraarterial administration of antibiotics. In this study, we used fluorine 18 fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) under the strict control of blood sugar levels to evaluate the area of MEO/ SBO because FDG-PET is exquisitely sensitive and offers highresolution images in evaluation for inflammation [10]. Abnormal FDG uptake was observed in the maxillary artery (MA) feeding area including the mastoid, tympanic cavity, and external auditory canal as well as the ascending pharyngeal artery (APA) feeding area including the clivus (Fig. 3A and Supplemental Fig. 2A). A catheter was, therefore, inserted from the superficial temporal artery with the tip set at the proximal point of the external carotid artery (ECA) by interventional radiology. Digital subtraction angiography using this catheter permitted visualization of all branches of the ECA, including the MA and APA. We also evaluated peripheral perfusion by CT images of angiography with injection of contrast medium from the catheter. Enhancement was observed in both the MA and APA supply areas, but relatively faint in the APA supply area (Fig. 3B). Using this retrograde catheter, 3 g of piperacillin, a timedependent bactericidal agent, was administered continuously and 0.3 g of ciprofloxacin, a concentration-dependent bactericidal
381
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 (*).
agent, was injected twice a day with 2-h infusion. We also continuously 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 reinserted from the occipital artery with the tip of the catheter set at the same position to continue IA therapy. During IA therapy, both patients were kept hospitalized and their blood sugar levels were strictly controlled. Immediately after the start of IA therapy, their otalgia, otorrhea, and headache started to improve and after 8 weeks of IA therapy only mild headache and slight neural paralysis remained. FDGPET/CT imaging showed that inflammation had disappeared in the MA supply area, but high FDG uptake persisted in the APA feeding area around the clivus and carotid arteries in both (Fig. 3C and Supplemental Fig. 2B). Infectious pseudoaneurysm of the internal
Fig. 2. MRI of Case 1. At the left side of the clivus, the intensity of signal on T1-weighted MRI is decreased (A, arrow), but strong enhancement is observed (B, arrow), which indicates osteomyelitis at this area.
382
H. Yamazaki et al. / Auris Nasus Larynx 41 (2014) 380–383
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).
carotid artery (ICA) had newly developed in Case 1, suggesting remaining intense inflammation in this area (Figs. 2C and 4). Since Case 1 originally had an ICA stenosis at the same side of the pseudoaneurysm (Fig. 4), endovascular treatment was not indicated. IA therapy was followed by additional IV therapy for 3 months and oral intake of quinolones for a year. FDG-PET/CT imaging confirmed that these adjuvant therapies almost diminished the abnormal FDG uptake in the APA supply area (Fig. 3D and Supplemental Fig. 2C). The pseudoaneurysm in Case 1 was also reduced in size and spontaneously occluded as infection around the carotid canal decreased. No recurrence was observed in 2 years follow-up period after the treatments. 3. Discussion
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 (*).
Our two cases with MEO/SBO fulfilled all major signs for MEO, which suggests a high mortality rate [8]. The symptoms clearly aggravated despite conventional treatment for MEO/SBO, including long-term IV therapy and surgical debridement, and MRI showed that inflammation had extended to the middle fossa dura. These results led to the choice of more intense antibiotic therapy to prevent potentially fatal complications such as meningitis and intracranial abscess. As described above, poor perfusion of antimicrobial agents into the affected lesion is thought to be associated with serious nature of infection of MEO [1–5]. IV therapy using a higher dose can elevate the tissue concentration of antibiotics in a lesion with poor perfusion, but a very high dose may induce undesirable systemic
H. Yamazaki et al. / Auris Nasus Larynx 41 (2014) 380–383
side effects, such as renal or hepatic failure. In contrast, intraarterial drug administration, which is sometimes used in selective cancer chemotherapy, can achieve a several-fold higher drug concentration only in the targeted lesion, without adverse effects on other systemic organs [11]. Therefore, we administered antibiotics intra-arterially from an ECA catheter at the similar total dose as that in IV therapy, with the aim of increasing the tissue drug concentration in the MA and APA supply areas, in which intense inflammation was observed. CT images of angiography via the ECA catheter showed stronger enhancement in the feeding area for the MA compared to that for the APA, and IA therapy using the same catheter decreased infection more effectively in the MA supply area. These results suggest that establishment of a higher tissue antibiotic concentration gave better therapeutic results. The APA is a long vessel with a small diameter [12], and thus diabetes-induced arteriosclerosis and intense inflammation may easily damage blood flow in the APA, which might result in a low tissue drug level and refractory infection in this area. Interestingly, IV therapy and oral intake of antibiotics were not effective at the start, but considerably reduced the residual infection in the APA supply area after IA therapy, even though similar antibiotics were used. This might be because the IA therapy reduced infection and improved tissue perfusion, which then allowed a sufficient antibiotic concentration in the APA area to be reached using normal methods. Hyperbaric oxygenation with conventional antibiotic therapy has been reported to be effective for refractory MEO/SBO [4]. This approach is relatively safe, but we were unable to use hyperbaric oxygen therapy because a chamber is not available at our hospital. In both cases reported here, there were no obvious complications in IA therapy. A pseudoaneurysm developed in Case 1, but was not induced by IA therapy because the ECA catheter does not affect the distal portion of the ICA, in which the pseudoaneurysm was observed. However, the safety of IA therapy has not been established, especially with regard to its latent side effects. For example, long-term catheterization in the ECA may induce thrombotic embolization and intra-arterial injection of some antibiotics, such as benzathine penicillin G, can produce arterial vasospasm, which results in tissue ischemia distal to the injection site [13]. Therefore, the indication for IA therapy should be restricted to cases with refractory MEO/SBO in which symptoms continue to deteriorate after standard long-term IV therapy. In conclusion, IA therapy for two cases with refractory MEO/SBO improved infection in the area in which antibiotics were directly infused via the retrograde catheter, and had a weaker effect in the APA supply area compared to the MA supply area. Even though intravenous and oral administration of antibiotics showed
383
no effect before IA therapy, adjuvant intravenous and oral antibiotics were useful for reducing residual infection after IA therapy. These results suggest that IA therapy is effective for MEO/SBO refractory to conventional treatment. Acknowledgment This study was supported by a Grant-in-Aid for Scientific Research (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 sources only. 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. References [1] Chandler JR. Malignant external otitis. The Laryngoscope 1968;78:1257–94. [2] Chandler JR, Grobman L, Quencer R, Serafini A. Osteomyelitis of the base of the skull. The Laryngoscope 1986;96:245–51. [3] Jackler RK, Brackmann DE. Neurotology. second ed. Philadelphia, PA: Mosby; 2005. [4] Davis JC, Gates GA, Lerner C, Davis Jr MG, Mader JT, Dinesman A. Adjuvant hyperbaric oxygen in malignant external otitis. Archives of Otolaryngology Head & Neck Surgery 1992;118:89–93. [5] Ziegler EJ, Douglas H. Pseudomonas aeruginosa vasculitis and bacteremia following conjunctivitis: a simple model of fatal pseudomonas infection in neutropenia. Journal of Infectious Diseases Letters 1979;139:288–96. [6] Levenson MJ, Parisier SC, Dolitsky J, Bindra G. Ciprofloxacin: drug of choice in the treatment of malignant external otitis (MEO). The Laryngoscope 1991;101: 821–4. [7] Soudry E, Joshua BZ, Sulkes J, Nageris BI. Characteristics and prognosis of malignant external otitis with facial paralysis. Archives of Otolaryngology Head & Neck Surgery 2007;133:1002–4. [8] Joshua BZ, Sulkes J, Raveh E, Bishara J, Nageris BI. Predicting outcome of malignant external otitis. Otology & Neurotology 2008;29:339–43. Official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. [9] Cohen D, Friedman P. The diagnostic criteria of malignant external otitis. Journal of Laryngology and Otology 1987;101:216–21. [10] Love C, Tomas MB, Tronco GG, Palestro CJ. FDG PET of infection and inflammation. Radiographics 2005;25:68. A review publication of the Radiological Society of North America, Inc.. [11] Munck JN, Riggi M, Rougier P, Chabot GG, Ramirez LH, Zhao Z, et al. Pharmacokinetic and pharmacodynamic advantages of pirarubicin over adriamycin after intraarterial hepatic administration in the rabbit VX2 tumor model. Cancer Research 1993;53:1550–4. [12] Hacein-Bey L, Daniels DL, Ulmer JL, Mark LP, Smith MM, Strottmann JM, et al. The ascending pharyngeal artery: branches, anastomoses, and clinical significance. AJNR—American Journal of Neuroradiology 2002;23:1246–56. [13] Schanzer H, Jacobson 2nd JH. Tissue damage caused by the intramuscular injection of long-acting penicillin. Pediatrics 1985;75:741–4.
Contents lists available at ScienceDirect
Auris Nasus Larynx journal homepage: www.elsevier.com/locate/anl
Intra-arterial administration of antibiotics for refractory skull base osteomyelitis 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 b c
Department of Otolaryngology, Kobe City Medical Center General Hospital, Kobe City, Japan Department of Head and Neck Surgery, Kobe City Medical Center General Hospital, Kobe City, Japan Institute of Biomedical Research and Innovation, Kobe City, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 7 July 2013 Accepted 9 December 2013 Available online 30 December 2013
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. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Skull base osteomyelitis Malignant external otitis Intra-arterial administration of antibiotics
1. Introduction Malignant external otitis (MEO) is a devastating infectious disease and usually originates from the external ear canal in elderly patients with diabetes [1,2]. Pseudomonas aeruginosa is often the primary causative organism of MEO. The disease can progress to skull base osteomyelitis (SBO) and may cause fatal complications such as multiple cranial nerve paralysis, meningitis, and sepsis [1–3]. The serious nature of infection in MEO is attributable to the immunosuppressed state of hosts caused by age and diabetes, and poor perfusion of antimicrobial agents into the infected area due to diabetic microangiopathy and necrotizing vasculitis induced by P. aeruginosa infection [1–5]. The principal therapy for MEO/SBO is long-term intravenous and oral administration of antibiotics. Development of antibiotics against P. aeruginosa including oral quinolones with broad spectrum activity and high permeability in peripheral tissue have
* Corresponding author. Tel.: +81 78 302 4321; fax: +81 78 302 2487. E-mail address: [email protected] (H. Yamazaki). 0385-8146/$ – see front matter ß 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 mortality remains high in patients meeting all major clinical and radiographic criteria for MEO [7]. Surgical debridement of necrotic tissue and drainage of abscesses is thought to be important for management of MEO/SBO [2,8], but the efficacy of surgical intervention is controversial [3]. Here, we describe successful treatment of MEO/SBO using intra-arterial administration of antibiotics (IA therapy) in two cases that were refractory to conventional therapy. 2. Cases The patients were both males with diabetes who had no previous ear disease including chronic otitis media and chronic external otitis, and were aged 73 year-old (Case 1) and 59 year-old (Case 2), respectively. Both were diagnosed as MEO on the left side based on otorrhea, otalgia, hearing loss, and detection of P. aeruginosa in otorrhea as well as exudate, edema, and granulation in the external auditory canal, all of which deteriorated after several weeks of treatment with topical and oral administration of culture-directed antibiotics [8,9]. Then, 3 months of intravenous administration of culture-directed antibiotics (IV therapy) with
H. Yamazaki et al. / Auris Nasus Larynx 41 (2014) 380–383
strict control of blood sugar levels as well as a mastoidectomy for surgical debridement of infectious and inflammatory granulation tissue was performed as the conventional therapies for MEO. In the IV therapy, we used meropenem (2 g/day, 1-h infusion of 0.5 g every 6 h) in Case 1 and imipenem/cilastatin (1 g/day, 1-h infusion of 0.5 g every 12 h) and piperacillin (4 g/day, 1-h infusion of 1 g every 6 h) in Case 2 on the basis of the patient’s renal function. In Case 1, vancomycin (0.75–1 g/day with 1- to 2-h infusion) was also administrated in the first two weeks because methicillin-resistant Staphylococcus aureus was also detected in the otorrhea during this period. Despite these conventional treatments, both showed aggravation of hearing loss, otalgia and otorrhea. Ninth and 10th cranial nerve paralysis and Horner’s symptom newly developed in Case 1 and facial palsy also developed in Case 2. At that time, CT revealed bony erosion at the clivus and carotid canal in addition to soft tissue density in the external auditory canal and middle ear, suggesting that the severe inflammation in the external auditory canal had extended to the skull base (Fig. 1A and B). Decrease of signal intensity on T1-weighted MRI and clear gadoliniumenhancement was observed at the affected side of the clivus, indicating osteomyelitis (Fig. 2A and B and Supplemental Fig. 1A and B). These data demonstrated that MEO had developed to SBO in both [3]. MRI also showed enhancement of the middle fossa dura covering the affected temporal bone, which strongly suggested impending development of meningitis (Supplemental Fig. 1C). Therefore, we adopted more intense antibiotic therapy using intraarterial administration of antibiotics. In this study, we used fluorine 18 fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) under the strict control of blood sugar levels to evaluate the area of MEO/ SBO because FDG-PET is exquisitely sensitive and offers highresolution images in evaluation for inflammation [10]. Abnormal FDG uptake was observed in the maxillary artery (MA) feeding area including the mastoid, tympanic cavity, and external auditory canal as well as the ascending pharyngeal artery (APA) feeding area including the clivus (Fig. 3A and Supplemental Fig. 2A). A catheter was, therefore, inserted from the superficial temporal artery with the tip set at the proximal point of the external carotid artery (ECA) by interventional radiology. Digital subtraction angiography using this catheter permitted visualization of all branches of the ECA, including the MA and APA. We also evaluated peripheral perfusion by CT images of angiography with injection of contrast medium from the catheter. Enhancement was observed in both the MA and APA supply areas, but relatively faint in the APA supply area (Fig. 3B). Using this retrograde catheter, 3 g of piperacillin, a timedependent bactericidal agent, was administered continuously and 0.3 g of ciprofloxacin, a concentration-dependent bactericidal
381
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 (*).
agent, was injected twice a day with 2-h infusion. We also continuously 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 reinserted from the occipital artery with the tip of the catheter set at the same position to continue IA therapy. During IA therapy, both patients were kept hospitalized and their blood sugar levels were strictly controlled. Immediately after the start of IA therapy, their otalgia, otorrhea, and headache started to improve and after 8 weeks of IA therapy only mild headache and slight neural paralysis remained. FDGPET/CT imaging showed that inflammation had disappeared in the MA supply area, but high FDG uptake persisted in the APA feeding area around the clivus and carotid arteries in both (Fig. 3C and Supplemental Fig. 2B). Infectious pseudoaneurysm of the internal
Fig. 2. MRI of Case 1. At the left side of the clivus, the intensity of signal on T1-weighted MRI is decreased (A, arrow), but strong enhancement is observed (B, arrow), which indicates osteomyelitis at this area.
382
H. Yamazaki et al. / Auris Nasus Larynx 41 (2014) 380–383
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).
carotid artery (ICA) had newly developed in Case 1, suggesting remaining intense inflammation in this area (Figs. 2C and 4). Since Case 1 originally had an ICA stenosis at the same side of the pseudoaneurysm (Fig. 4), endovascular treatment was not indicated. IA therapy was followed by additional IV therapy for 3 months and oral intake of quinolones for a year. FDG-PET/CT imaging confirmed that these adjuvant therapies almost diminished the abnormal FDG uptake in the APA supply area (Fig. 3D and Supplemental Fig. 2C). The pseudoaneurysm in Case 1 was also reduced in size and spontaneously occluded as infection around the carotid canal decreased. No recurrence was observed in 2 years follow-up period after the treatments. 3. Discussion
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 (*).
Our two cases with MEO/SBO fulfilled all major signs for MEO, which suggests a high mortality rate [8]. The symptoms clearly aggravated despite conventional treatment for MEO/SBO, including long-term IV therapy and surgical debridement, and MRI showed that inflammation had extended to the middle fossa dura. These results led to the choice of more intense antibiotic therapy to prevent potentially fatal complications such as meningitis and intracranial abscess. As described above, poor perfusion of antimicrobial agents into the affected lesion is thought to be associated with serious nature of infection of MEO [1–5]. IV therapy using a higher dose can elevate the tissue concentration of antibiotics in a lesion with poor perfusion, but a very high dose may induce undesirable systemic
H. Yamazaki et al. / Auris Nasus Larynx 41 (2014) 380–383
side effects, such as renal or hepatic failure. In contrast, intraarterial drug administration, which is sometimes used in selective cancer chemotherapy, can achieve a several-fold higher drug concentration only in the targeted lesion, without adverse effects on other systemic organs [11]. Therefore, we administered antibiotics intra-arterially from an ECA catheter at the similar total dose as that in IV therapy, with the aim of increasing the tissue drug concentration in the MA and APA supply areas, in which intense inflammation was observed. CT images of angiography via the ECA catheter showed stronger enhancement in the feeding area for the MA compared to that for the APA, and IA therapy using the same catheter decreased infection more effectively in the MA supply area. These results suggest that establishment of a higher tissue antibiotic concentration gave better therapeutic results. The APA is a long vessel with a small diameter [12], and thus diabetes-induced arteriosclerosis and intense inflammation may easily damage blood flow in the APA, which might result in a low tissue drug level and refractory infection in this area. Interestingly, IV therapy and oral intake of antibiotics were not effective at the start, but considerably reduced the residual infection in the APA supply area after IA therapy, even though similar antibiotics were used. This might be because the IA therapy reduced infection and improved tissue perfusion, which then allowed a sufficient antibiotic concentration in the APA area to be reached using normal methods. Hyperbaric oxygenation with conventional antibiotic therapy has been reported to be effective for refractory MEO/SBO [4]. This approach is relatively safe, but we were unable to use hyperbaric oxygen therapy because a chamber is not available at our hospital. In both cases reported here, there were no obvious complications in IA therapy. A pseudoaneurysm developed in Case 1, but was not induced by IA therapy because the ECA catheter does not affect the distal portion of the ICA, in which the pseudoaneurysm was observed. However, the safety of IA therapy has not been established, especially with regard to its latent side effects. For example, long-term catheterization in the ECA may induce thrombotic embolization and intra-arterial injection of some antibiotics, such as benzathine penicillin G, can produce arterial vasospasm, which results in tissue ischemia distal to the injection site [13]. Therefore, the indication for IA therapy should be restricted to cases with refractory MEO/SBO in which symptoms continue to deteriorate after standard long-term IV therapy. In conclusion, IA therapy for two cases with refractory MEO/SBO improved infection in the area in which antibiotics were directly infused via the retrograde catheter, and had a weaker effect in the APA supply area compared to the MA supply area. Even though intravenous and oral administration of antibiotics showed
383
no effect before IA therapy, adjuvant intravenous and oral antibiotics were useful for reducing residual infection after IA therapy. These results suggest that IA therapy is effective for MEO/SBO refractory to conventional treatment. Acknowledgment This study was supported by a Grant-in-Aid for Scientific Research (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 sources only. 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. References [1] Chandler JR. Malignant external otitis. The Laryngoscope 1968;78:1257–94. [2] Chandler JR, Grobman L, Quencer R, Serafini A. Osteomyelitis of the base of the skull. The Laryngoscope 1986;96:245–51. [3] Jackler RK, Brackmann DE. Neurotology. second ed. Philadelphia, PA: Mosby; 2005. [4] Davis JC, Gates GA, Lerner C, Davis Jr MG, Mader JT, Dinesman A. Adjuvant hyperbaric oxygen in malignant external otitis. Archives of Otolaryngology Head & Neck Surgery 1992;118:89–93. [5] Ziegler EJ, Douglas H. Pseudomonas aeruginosa vasculitis and bacteremia following conjunctivitis: a simple model of fatal pseudomonas infection in neutropenia. Journal of Infectious Diseases Letters 1979;139:288–96. [6] Levenson MJ, Parisier SC, Dolitsky J, Bindra G. Ciprofloxacin: drug of choice in the treatment of malignant external otitis (MEO). The Laryngoscope 1991;101: 821–4. [7] Soudry E, Joshua BZ, Sulkes J, Nageris BI. Characteristics and prognosis of malignant external otitis with facial paralysis. Archives of Otolaryngology Head & Neck Surgery 2007;133:1002–4. [8] Joshua BZ, Sulkes J, Raveh E, Bishara J, Nageris BI. Predicting outcome of malignant external otitis. Otology & Neurotology 2008;29:339–43. Official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. [9] Cohen D, Friedman P. The diagnostic criteria of malignant external otitis. Journal of Laryngology and Otology 1987;101:216–21. [10] Love C, Tomas MB, Tronco GG, Palestro CJ. FDG PET of infection and inflammation. Radiographics 2005;25:68. A review publication of the Radiological Society of North America, Inc.. [11] Munck JN, Riggi M, Rougier P, Chabot GG, Ramirez LH, Zhao Z, et al. Pharmacokinetic and pharmacodynamic advantages of pirarubicin over adriamycin after intraarterial hepatic administration in the rabbit VX2 tumor model. Cancer Research 1993;53:1550–4. [12] Hacein-Bey L, Daniels DL, Ulmer JL, Mark LP, Smith MM, Strottmann JM, et al. The ascending pharyngeal artery: branches, anastomoses, and clinical significance. AJNR—American Journal of Neuroradiology 2002;23:1246–56. [13] Schanzer H, Jacobson 2nd JH. Tissue damage caused by the intramuscular injection of long-acting penicillin. Pediatrics 1985;75:741–4.
