This article has Open Peer Review reports available.
Prolonged and high dosage of tigecycline – successful treatment of spondylodiscitis caused by multidrug-resistant Acinetobacter baumannii: a case report
© The Author(s). 2017
Received: 6 February 2017
Accepted: 18 June 2017
Published: 8 July 2017
The incidence of infectious spondylodiscitis has been increasing over the last few years. This reflects the expanding elderly and immunocompromised populations and the rising implementation of invasive spinal procedures. Infection may be inoculated into the disc space directly during invasive spinal procedures. Osteomyelitis caused by Acinetobacter species is rare and mainly caused by multidrug-resistant strains.
We present the case of a 72-year-old Greek woman with postoperative spondylodiscitis caused by a multidrug-resistant Acinetobacter baumannii strain that was successfully treated, after she declined surgical treatment, with prolonged and high dosage of tigecycline. She received intravenously administered tigecycline 200 mg per day for 60 days and then 100 mg per day for a total of 102 days and was infection-free.
We reviewed the literature on the role of Acinetobacter baumannii as a cause of osteomyelitis, emphasizing the difficulty of treatment and the potential role of tigecycline in conservative treatment of the infection. We believe that 102 days in total is the longest time that any patient has received tigecycline in the literature, thus our patient is a unique case of successful treatment of spondylodiscitis.
In recent years, the incidence of infectious spondylodiscitis has risen due to improvements in health care and prolonged life expectancy. This infection is associated with older age, immunocompromised status, and presence of comorbidities. Infection may be inoculated into the disc space directly during invasive spinal procedures, of which 0.1 to 4.0% are complicated by septic discitis. This accounts for 20 to 30% of all cases of spondylodiscitis . Staphylococcus aureus is the most commonly isolated pathogen in discitis complicating invasive spinal procedures (17 to 33%), followed by coagulase-negative staphylococci (13 to 29%), Gram-negative bacilli including Pseudomonas aeruginosa and Stenotrophomonas maltophilia (9 to 27%), streptococci (2 to 6%), and anaerobes, such as Propionibacterium acnes and Peptostreptococcus . Osteomyelitis caused by Acinetobacter species is rare. A large number of cases have been reported in soldiers from Iraq. In most cases in the literature, infections were caused by multidrug-resistant (MDR) strains .
In the present report, a woman with postoperative spondylodiscitis caused by MDR Acinetobacter baumannii was treated successfully with prolonged and high dosage of tigecycline. She received tigecycline 200 mg per day for 60 days and then 100 mg per day for a total of 102 days.
Tigecycline (MIC 0.75) susceptibility was performed by Etest (AB Biodisk; Solna, Sweden); breakpoints were inferred from the available literature for Enterobacteriaceae (<2.0 is susceptible) as no current Clinical and Laboratory Standards Institute breakpoints are established. Despite our patient’s allergy history, she was originally administered imipenem intravenously, but she developed high fever, rash, and respiratory discomfort which were treated as an allergic reaction with H-1 histamine blockers and corticosteroids. Subsequently, tigecycline (50 mg twice a day, after loading dose of 100 mg) replaced imipenem and gentamicin (1 mg/kg administered intravenously three times a day) was added. Five days later, she developed severe vertigo and we decided to withdraw gentamicin.
She could not walk or do any other physical activity due to severe pain, but she refused any kind of surgical intervention that was suggested to her. Because of the lack of available data on the role of tigecycline in the treatment of osteomyelitis, especially for an infection caused by A. baumannii, we decided to double the dose of tigecycline (100 mg twice daily) after notifying our patient of the potential risks of higher doses of tigecycline (increased probability of developing tigecycline’s side effects such as nausea, vomiting, diarrhea, abdominal pain, pruritus, rash, headache, hepatotoxicity). She consented prior to starting enhanced dosage of tigecycline.
She had no adverse reactions and tolerated the regimen well, apart from slight nausea the first 2 days, which was managed with metoclopramide 10 mg administered intravenously. She was afebrile after 15 days and 30 days later she requested less opiate analgesics. Her CRP and erythrocyte sedimentation rate (ESR) were still elevated: CRP 5.7 mg/dL and ESR at 70 mm/hour. A new MRI, 30 days post the initiation of treatment with tigecycline revealed partial improvement in the soft tissue. She still refused any surgical intervention. She continued conservative therapy with high dosage for another 30 days, but then she developed severe hypoalbuminemia (serum albumin measuring at 1.9 g/dL while baseline serum albumin was 3.8 g/dL) and peripheral edema that resolved after reducing the dose to 50 mg twice daily. After completing 75 days of therapy, she could walk again and was free of analgesics, although her CRP and ESR were not yet normal. She was discharged from our hospital and continued tigecycline administered intravenously at home for a total 102 days. She had no infection relapse (clinical or radiographic signs) 18 months after the end of therapy and her CRP and ESR levels were finally normalized. Her remaining laboratory values were as follows: Hb 12.1 g/dL, WBC 5.4 cells/μL, platelets 283,000/mm3, blood glucose 88 mg/dL, serum Na 145 mEq/L, serum K 4.1 mEq/L, serum creatinine 0.8 mg/dL, total bilirubin 0.7 mg/dL, SGOT 35 U/L, and SGPT 29 U/L.
A. baumannii is a rare cause of osteomyelitis and especially of spondylodiscitis. Clinical management of A. baumannii bone infections in humans has not been well established, especially for MDR isolates. Only one case series study, by Davis et al., has been published regarding MDR Acinetobacter extremity infections in soldiers from Iraq . All 18 patients with osteomyelitis underwent multiple surgical debridements of necrotic bone. Ten of the patients with osteomyelitis were treated with dual antimicrobial agents, seven with monotherapy, and one with surgical debridement alone. The primary combination of antimicrobial agents was imipenem (500 mg every 6 hours) in combination with high-dose amikacin (15 to 20 mg/kg daily). In a few instances, when imipenem was not active against the isolated organism, ampicillin/sulbactam or ceftazidime was used. They reported successful therapy in all cases with no relapses . Schafer and Mangino published a case report of probable osteomyelitis caused by MDR A. baumannii treated successfully with tigecycline for 43 days. Again this patient underwent surgical debridement . Sipahi et al. reported a case of postoperative spondylodiscitis due to MDR A. baumannii . This patient received intravenously administered tigecycline for a total of 45 days, and was discharged with orally administered doxycycline, netilmicin, and sulbactam.
Besides the lack of clinical data, we had to address the refusal of our patient to undergo surgical debridement and the fact that tigecycline was the only therapeutic option due to allergic and adverse reactions to other antibiotic options. Furthermore, data regarding the bone concentrations of tigecycline are conflicting. Tigecycline concentration in bone has been evaluated in an experimental rat model and a single-dose human study . The rat model showed an area under the curve (AUC) in bone ≈ 250× higher than plasma. The investigation in humans showed an AUC 0 to 24 ratio (site:serum) of 0.41/0.28 and the discrepancy was attributed to either tight binding of tigecycline to bone or poor extraction methods . Bhattacharya et al. evaluated tigecycline bone concentrations in patients undergoing elective orthopedic surgery, using multiple doses . The bone to serum ratio calculated using the AUCt values was 4.77, confirming tigecycline penetration into bone. The mean of all the bone concentrations reported in this study (range, 259 to 2262 ng/g) was 898 ng/g. The bone AUCt value was 11,465 ng h/g .
In addition, pharmacodynamic data suggest that an AUC/MIC >6.96 is more likely to lead to successful clinical and microbiological outcomes in patients with complicated intra-abdominal infections . Koomanachai et al. in a pharmacodynamic evaluation of tigecycline against A. baumannii in a murine pneumonia model suggested that tigecycline doses of up to 200 mg/day may be required to provide adequate exposure for A. baumannii . Based on these data we decided to administer high doses of tigecycline (100 mg twice a day) for 60 days. After 60 days of therapy, we were forced to reduce the dose due to severe hypoalbuminemia and peripheral edema. The symptoms resolved with reduction of dose to normal and our patient could continue the regimen for another 42 days. In a study by Griffin et al. the use of tigecycline was evaluated in 13 patients with osteomyelitis but none with Acinetobacter species. Eleven patients (85%) achieved clinical success. The median length of treatment was 6 weeks. Of the patients, 47% experienced some adverse event with the most prevalent being gastrointestinal in nature and five patients required discontinuation of treatment . In another study by De Pascale et al., a high dose of tigecycline was evaluated in critically ill patients with severe infections due to MDR bacteria . A high dose of tigecycline was given to 33 patients, 15 of them due to extensively drug-resistant (XDR) A. baumannii. There was no statistical difference for adverse events between standard and high dose of tigecycline. The clinical cure rate and microbiological eradication percentage were higher when tigecycline was used at higher doses (57.5 versus 33.3, P = 0.05; and 57.1% versus 30.4%, P = 0.07, respectively) .
To the best of our knowledge, 102 days in total is the longest time that any patient has received tigecycline in the literature for any reason. Our patient is free of disease 18 months after the end of treatment despite multiple complications during her medical management. Further clinical and pharmacokinetic studies are required to assess and define the role of tigecycline in the treatment of osteomyelitis.
There are no sources of funding to be declared.
Availability of data and materials
The authors can confirm that all relevant data are included in the article.
OT participated in the writing of the article. AG, SN, TC, GL, PM, and PZ edited the text. SM participated in the writing and editing of the article. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Ethics approval and consent to participate
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Cottle L, Riordan T. Infectious spondylodiscitis. J Infect. 2008;56:401–12.View ArticlePubMedGoogle Scholar
- Silber JS, Anderson DG, Vaccaro AR, Anderson PA, McCormick P. Management of postprocedural discitis. Spine J. 2002;2:279–87.View ArticlePubMedGoogle Scholar
- Davis KA, Moran KA, McAllister CK, Gray PJ. Multidrug-Resistant Acinetobacter Extremity Infections in Soldiers. Emerg Infect Dis. 2005;11(8):1218–24.View ArticlePubMedPubMed CentralGoogle Scholar
- Schafer JJ, Mangino JE. Multidrug-Resistant Acinetobacter baumannii Osteomyelitis from Iraq. Emerg Infect Dis. 2008;14(3):512–4.View ArticlePubMedPubMed CentralGoogle Scholar
- Sipahi OR, Kahraman H, Mermer S, Pullukcu H, Tasbakan M, Arda B, Yamazhan T, Yurtseven T, Aydemir S, Ulusoy S. Tigecycline in the management of post-neurosurgical spondylodiscitis: a review of eight cases. Int J Infect Dis. 2014;23:16–9. doi:10.1016/j.ijid.2014.01.027. Epub 2014 Mar 18.View ArticlePubMedGoogle Scholar
- Tombs NL. Tissue distribution of GAR- 936, a broad spectrum antibiotic in male rats. In: Program and abstracts of the Thirty-ninth Interscience Conference on Antimicrobial Agents and Chemotherapy. Sep 26–29 (San Francisco). Washington: American Society for Microbiology; 1999. p. 413.Google Scholar
- Rodvold KA, Gotfried MH, Cwik M, Korth-Bradley JM, Dukart G, Ellis- Grosse EJ. Serum, tissue and body fluid concentrations of tigecycline after a single 100 mg dose. J Antimicrob Chemother. 2006;58:1221–9.View ArticlePubMedGoogle Scholar
- Bhattacharya I, Gotfried MH, Ji AJ, Saunders JP, Gourley I, Diehl A, Korth-Bradley JM. Reassessment of tigecycline bone concentrations in volunteers undergoing elective orthopedic procedures. J Clin Pharmacol. 2014;54(1):70–4. doi:10.1002/jcph.201. Epub 2013 Oct 24.View ArticlePubMedGoogle Scholar
- MacGowan AP. Tigecycline pharmacokinetic/pharmacodynamics update. J Antimicrob Chemother. 2008;62(Supplement 1):i11–6.View ArticlePubMedGoogle Scholar
- Koomanachai P, Kim A, Nicolau DP. Pharmacodynamic evaluation of tigecycline against Acinetobacter baumannii in a murine pneumonia model. J Antimicrob Chemother. 2009;63(5):982–7.View ArticlePubMedGoogle Scholar
- Griffin AT, Harting JA, Christensen DM. Tigecycline in the management of osteomyelitis: a case series from the bone and joint infection (BAJIO) database. Diagn Microbiol Infect Dis. 2013;77(3):273–7. doi:10.1016/j.diagmicrobio.2013.07.014. Epub 2013 Sep 9.View ArticlePubMedGoogle Scholar
- De Pascale G, Montini L, Pennisi MA, Bernini V, Maviglia R, Bello G, Spanu T, Tumbarello M, Antonelli M. High dose tigecycline in critically ill patients with severe infections due to multidrug-resistant bacteria. Crit Care. 2014;18:R90.View ArticlePubMedPubMed CentralGoogle Scholar