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Tigecycline

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Tigecycline
Clinical data
Pronunciation/ˌtɡəˈskln/
Trade namesTygacil
AHFS/Drugs.comMonograph
MedlinePlusa614002
License data
Pregnancy
category
Routes of
administration
Intravenous (IV)
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding71–89%
MetabolismNot metabolized
Elimination half-life42.4 hours
Excretion59% Bile duct, 33% kidney
Identifiers
  • N-[(5aR,6aS,7S,9Z,10aS)-9-(amino-hydroxy-methylidene)-4,7-bis(dimethylamino)-1,10a,12-trihydroxy-8,10,11-trioxo-5a,6,6a,7-tetrahydro-5H-tetracen-2-yl]-2-(tert-butylamino) acetamide[5]
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.211.439 Edit this at Wikidata
Chemical and physical data
FormulaC29H39N5O8
Molar mass585.658 g·mol−1
3D model (JSmol)
  • CC(C)(C)NCC(=O)Nc1cc(c2C[C@H]3C[C@H]4[C@H](N(C)C)C(\O)=C(\C(N)=O)C(=O)[C@@]4(O)C(/O)=C3/C(=O)c2c1O)N(C)C
  • InChI=1S/C29H39N5O8/c1-28(2,3)31-11-17(35)32-15-10-16(33(4)5)13-8-12-9-14-21(34(6)7)24(38)20(27(30)41)26(40)29(14,42)25(39)18(12)23(37)19(13)22(15)36/h10,12,14,21,31,36,38-39,42H,8-9,11H2,1-7H3,(H2,30,41)(H,32,35)/t12-,14-,21-,29-/m0/s1 checkY
  • Key:FPZLLRFZJZRHSY-HJYUBDRYSA-N checkY
  (verify)

Tigecycline, sold under the brand name Tygacil, is a tetracycline antibiotic medication for a number of bacterial infections.[3][6][7] It is a glycylcycline class drug that is administered intravenously. It was developed in response to the growing rate of antibiotic resistant bacteria such as Staphylococcus aureus, Acinetobacter baumannii, and E. coli.[6] As a tetracycline derivative antibiotic, its structural modifications has expanded its therapeutic activity to include Gram-positive and Gram-negative organisms, including those of multi-drug resistance.

It was given a U.S. Food and Drug Administration (FDA) fast-track approval and was approved on 17 June 2005.[6][7] It was approved for medical use in the European Union in April 2006.[4]

It was removed from the World Health Organization's List of Essential Medicines in 2019.[8][9] The World Health Organization classifies tigecycline as critically important for human medicine.[10]

Medical uses

[edit]

Antibacterial use

[edit]

Tigecycline is used to treat different kinds of bacterial infections, including complicated skin and structure infections, complicated intra-abdominal infections and community-acquired bacterial pneumonia.[citation needed] Tigecycline is a glycylcycline antibiotic that covers MRSA and Gram-negative organisms:

Tigecycline is given intravenously and has activity against a variety of Gram-positive and Gram-negative bacterial pathogens, many of which are resistant to existing antibiotics. Tigecycline successfully completed phase III trials in which it was at least equal to intravenous vancomycin and aztreonam to treat complicated skin and skin structure infections, and to intravenous imipenem and cilastatian to treat complicated intra-abdominal infections.[12] Tigecycline is active against many Gram-positive bacteria, Gram-negative bacteria and anaerobes – including activity against methicillin-resistant Staphylococcus aureus (MRSA), Stenotrophomonas maltophilia, Haemophilus influenzae, and Neisseria gonorrhoeae (with MIC values reported at 2 μg/mL) and multi-drug resistant strains of Acinetobacter baumannii. It has no activity against Pseudomonas spp. or Proteus spp. The drug is licensed for the treatment of skin and soft tissue infections as well as intra-abdominal infections.[citation needed]

"Tigecycline is also active against Clostridioides difficile strains. Most C. difficile isolates have MICs <0.25 for tigecycline[13] The European Society of Clinical Microbiology and Infection recommends tigecycline as a potential salvage therapy for severe and/or complicated or refractory Clostridium difficile infection.[14]

Tigecycline can also be used in vulnerable populations such as immunocompromised patients or patients with cancer.[14]

Non-Antibacterial use

[edit]

It is well established that tigecycline works as an effective antibiotic, however it may have other properties that are not yet fully understood.[15] Minocycline has been shown to have anti-inflammatory and anti-apoptotic activities, inhibition of proteolysis and suppression of angiogenesis and tumor metastasis.[15] This is a feature not unique to minocycline, with many tetracyclines exhibiting non-antibiotic clinical benefits.[16][17] Tigecycline has shown in vitro and in vivo activity against acute myeloid leukemia. The antileukemic activity of tigecycline can be attributed to the inhibition of mitochondrial protein translation in eukaryotic cells. Leukemic cells have an increased dependence on mitochondrial function, causing a heightened sensitivity to tigecycline.[18] Tigecycline has also shown anti-cancer properties against several other kinds of tumors, including non-small cell lung cancer, gastric cancer, hepatocellular carcinoma, and glioblastoma.[19] It also shows good activity against the causative agent of pythiosis.[20]

Susceptibility data

[edit]

Tigecycline targets both Gram-positive and Gram-negative bacteria including a few key multi-drug resistant pathogens. The following represents MIC susceptibility data for a few medically significant bacterial pathogens.

  • Escherichia coli: 0.015 μg/mL — 4 μg/mL[citation needed]
  • Klebsiella pneumoniae: 0.06 μg/mL — 16 μg/mL[citation needed]
  • Staphylococcus aureus (methicillin-resistant): 0.03 μg/mL — 2 μg/mL[21]

Tigecycline generally has poor activity against most strains of Pseudomonas.[22]

Liver or kidney problems

[edit]

Tigecycline does not require dose adjustment for people with mild to moderate liver problems. However, in people with severe liver problems dosing should be decreased and closely monitored.[11]

Tigecycline does not require dose changes in people with poor kidney function or having hemodialysis.[11]

Resistance mechanisms

[edit]

Bacterial resistance towards tigecycline in Enterobacteriaceae (such as E. coli) is often caused by genetic mutations leading to an up-regulation of bacterial efflux pumps, such as the RND type efflux pump AcrAB. Some bacterial species such as Pseudomonas spp. can be naturally resistant to tigecycline through the constant over-expression of such efflux pumps. In some Enterobacteriaceae species, mutations in ribosomal genes such as rpsJ have been found to cause resistance to tigecycline.[23]

Side effects

[edit]

As a tetracycline derivative, tigecycline exhibits similar side effects to the class of antibiotics. Gastrointestinal (GI) symptoms are the most common reported side effect.[14]

Common side effects of tigecycline include nausea and vomiting.[24] Nausea (26%) and vomiting (18%) tend to be mild or moderate and usually occur during the first two days of therapy.[3]

Rare adverse effects (<2%) include: swelling, pain, and irritation at injection site, anorexia, jaundice, hepatic dysfunction, pruritus, acute pancreatitis, and increased prothrombin time.[3]

Precautions

[edit]

Precaution is needed when taken in individuals with tetracycline hypersensitivity, pregnant women, and children. It has been found to cause fetal harm when administered during pregnancy and therefore is classified as pregnancy category D.[11] In rats or rabbits, tigecycline crossed the placenta and was found in the fetal tissues, and is associated with slightly lower birth weights as well as slower bone ossification. Even though it was not considered teratogenic, tigecycline should be avoided unless benefits outweigh the risks.[3] In addition, its use during childhood can cause yellow-grey-brown discoloration of the teeth and should not be used unless necessary.[citation needed]

More so, there are clinical reports of tigecycline-induced acute pancreatitis, with particular relevance to patients also diagnosed with cystic fibrosis.[25]

Tigecycline showed an increased mortality in patients treated for hospital-acquired pneumonia, especially ventilator-associated pneumonia (a non-approved use), but also in patients with complicated skin and skin structure infections, complicated intra-abdominal infections and diabetic foot infection.[3] Increased mortality was in comparison to other treatment of the same types of infections. The difference was not statistically significant for any type, but mortality was numerically greater for every infection type with Tigecycline treatment, and thus prompted a black box warning by the FDA.[26][27]

Black box warning

[edit]

The FDA issued a black box warning in September 2010, for tigecycline regarding an increased risk of death compared to other appropriate treatment.[26][3][28] As a result of increase in total death rate (cause is unknown) in individuals taking this drug, tigecycline is reserved for situations in which alternative treatment is not suitable.[11][28] The FDA updated the black box warning in 2013.[27]

Drug interactions

[edit]

Tigecycline has been found to interact with medications, such as:

  • Warfarin: Since both tigecycline and warfarin bind to serum or plasma proteins, there is potential for protein-binding interactions, such that one drug will have more effect than the other. Although dose adjustment is not necessary, INR and prothrombin time should be monitored if given concurrently.[29]
  • Oral contraceptives: Effectiveness of oral contraceptives are decreased with concurrent use due to reduction in the concentration levels of oral contraceptives. [citation needed]

However, the mechanism behind these drug interactions have not been fully analyzed.[3]

History

[edit]

Minocycline was a commonly used tetracycline synthesized in Lederle Laboratories in 1970, but antibiotic resistance to the drug began growing in prevalence throughout the 70's and 80's.[30][31] While the problem of antibiotic resistance was known to scientists during the 1980s, apathy led to little federal attention given to the emerging crisis. However, by the late 1980s the worldwide threat began to be treated more seriously, which led to the renewed funding of antibiotic research.[32]

In 1993, researchers in the same laboratories that first synthesized minocycline created a new generation of tetracycline antibacterial agents, known as the glycylcyclines. These antibiotics were the first new drugs of the tetracycline class to be reported since the discovery of minocycline in 1970.[33] The glycylcyclines were found to be active against a broad spectrum of tetracycline susceptible and resistant Gram (-) and Gram (+) aerobic and anaerobic bacteria. This initial research resulted in numerous studies being done on the antibacterial activity of various glycylcyclines, with extra focus being put on N,N-dimethylglycyl-amino derivatives, due to their reported potency.[34][35] The aforementioned research culminated in a 1999 paper describing the discovery of a compound known as GAR-936, which would later be known as Tigecycline.[36]

Mechanism of action

[edit]

Tigecycline is a broad-spectrum antibiotic that acts as a protein synthesis inhibitor. It exhibits bacteriostatic activity by binding to the 30S ribosomal subunit of bacteria and thereby blocking the interaction of aminoacyl-tRNA with the A site of the ribosome.[37] In addition, tigecycline has demonstrated bactericidal activity against isolates of S. pneumoniae and L. pneumophila.[3]

Studies have shown that tigecycline binds to the 70S ribosome with 5 fold and >100 fold greater affinity than minocycline and tetracycline, respectively .[38] As previously mentioned, tigecycline still binds to the A site of the 30S ribosomal subunit, however the binding of the novel antibiotic involves substantial interactions with residues of helix H34 of that same subunit. These interactions are not observed in the binding of tetracycline.[39] The findings indicate that tigecycline likely has a unique mechanism of action that prevents inhibition from ribosomal protection.[38]

It is a third-generation tetracycline derivative within a class called glycylcyclines which carry a N,N-dimethyglycylamido (DMG) moiety attached to the 9-position of tetracycline ring D.[40] With structural modifications as a 9-DMG derivative of minocycline, tigecycline has been found to improve minimal inhibitory concentrations against Gram-negative and Gram-positive organisms, when compared to tetracyclines.[40]

Pharmacokinetics

[edit]

Tigecycline is metabolized through glucuronidation into glucuronide conjugates and a N-acetyl-9-aminominocycline metabolite.[41] Therefore, dose adjustments are needed for patients with severe hepatic impairment.[3] More so, it is primarily eliminated unchanged in the feces and secondarily eliminated by the kidneys.[41] No renal adjustments are necessary.

Society and culture

[edit]

Approval

[edit]

It is approved to treat complicated skin and soft tissue infections (cSSTI), complicated intra-abdominal infections (cIAI), and community-acquired bacterial pneumonia (CAP) in individuals 18 years and older.[6][7][41][3] In the United Kingdom it is approved in adults and in children from the age of eight years for the treatment of complicated skin and soft tissue infections (excluding diabetic foot infections) and complicated intra-abdominal infections in situations where other alternative antibiotics are not suitable.[42]

Other names

[edit]
  • GAR-936[43]
  • Tygacil
  • Tigeplug (marketed by Biocon, India)
  • Tigilyn (Marketed by Real Value therapy pharmaceuticals company in Myanmar, Manufactured by Lyka)
  • TIGILITE (marketed in INDIA, Scutonix Lifesciences, Bombay)

References

[edit]
  1. ^ "Tigecycline (Tygacil) Use During Pregnancy". Drugs.com. 6 July 2020. Retrieved 26 September 2020.
  2. ^ "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 30 March 2024.
  3. ^ a b c d e f g h i j k "Tygacil- tigecycline injection, powder, lyophilized, for solution". DailyMed. 20 July 2020. Retrieved 26 September 2020.
  4. ^ a b "Tygacil EPAR". European Medicines Agency (EMA) (in Aragonese). 17 September 2018. Retrieved 26 September 2020.
  5. ^ "EP2181330". European Patent Office. Retrieved 29 September 2017.
  6. ^ a b c d Rose WE, Rybak MJ (August 2006). "Tigecycline: first of a new class of antimicrobial agents". Pharmacotherapy. 26 (8): 1099–1110. doi:10.1592/phco.26.8.1099. PMID 16863487. S2CID 29714610.
  7. ^ a b c Kasbekar N (July 2006). "Tigecycline: a new glycylcycline antimicrobial agent". American Journal of Health-System Pharmacy. 63 (13): 1235–1243. doi:10.2146/ajhp050487. PMID 16790575.
  8. ^ World Health Organization (2019). Executive summary: the selection and use of essential medicines 2019: report of the 22nd WHO Expert Committee on the selection and use of essential medicines. Geneva: World Health Organization. hdl:10665/325773. WHO/MVP/EMP/IAU/2019.05. License: CC BY-NC-SA 3.0 IGO.
  9. ^ World Health Organization (2019). The selection and use of essential medicines: report of the WHO Expert Committee on Selection and Use of Essential Medicines, 2019 (including the 21st WHO Model List of Essential Medicines and the 7th WHO Model List of Essential Medicines for Children). Geneva: World Health Organization. hdl:10665/330668. ISBN 9789241210300. ISSN 0512-3054. WHO technical report series;1021.
  10. ^ World Health Organization (2019). Critically important antimicrobials for human medicine (6th revision ed.). Geneva: World Health Organization. hdl:10665/312266. ISBN 9789241515528.
  11. ^ a b c d e f g "TYGACIL U.S. Physician Prescribing Information". Pfizer. Retrieved 31 October 2015.
  12. ^ Scheinfeld N (2005). "Tigecycline: a review of a new glycylcycline antibiotic". The Journal of Dermatological Treatment. 16 (4): 207–212. doi:10.1080/09546630510011810. PMID 16249141. S2CID 28869637.
  13. ^ Di Bella S, Nisii C, Petrosillo N (July 2015). "Is tigecycline a suitable option for Clostridium difficile infection? Evidence from the literature". International Journal of Antimicrobial Agents. 46 (1): 8–12. doi:10.1016/j.ijantimicag.2015.03.012. PMID 25982915.
  14. ^ a b c Kaewpoowat Q, Ostrosky-Zeichner L (February 2015). "Tigecycline : a critical safety review". Expert Opinion on Drug Safety. 14 (2): 335–342. doi:10.1517/14740338.2015.997206. PMID 25539800. S2CID 43407481.
  15. ^ a b Garrido-Mesa N, Zarzuelo A, Gálvez J (January 2013). "What is behind the non-antibiotic properties of minocycline?". Pharmacological Research. 67 (1): 18–30. doi:10.1016/j.phrs.2012.10.006. PMID 23085382.
  16. ^ Amin AR, Attur MG, Thakker GD, Patel PD, Vyas PR, Patel RN, et al. (November 1996). "A novel mechanism of action of tetracyclines: effects on nitric oxide synthases". Proceedings of the National Academy of Sciences of the United States of America. 93 (24): 14014–14019. Bibcode:1996PNAS...9314014A. doi:10.1073/pnas.93.24.14014. PMC 19486. PMID 8943052.
  17. ^ Whiteman M, Halliwell B (January 1997). "Prevention of peroxynitrite-dependent tyrosine nitration and inactivation of alpha1-antiproteinase by antibiotics". Free Radical Research. 26 (1): 49–56. doi:10.3109/10715769709097783. PMID 9018471.
  18. ^ Skrtić M, Sriskanthadevan S, Jhas B, Gebbia M, Wang X, Wang Z, et al. (November 2011). "Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia". Cancer Cell. 20 (5): 674–688. doi:10.1016/j.ccr.2011.10.015. PMC 3221282. PMID 22094260.
  19. ^ Arora R, Jain S, Rahimi H (1 April 2018). "Evaluating the efficacy of Tigecycline to target multiple cancer-types: A Review". STEM Fellowship Journal. 4 (1): 5–11. doi:10.17975/sfj-2018-002. ISSN 2369-0399.
  20. ^ Worasilchai N, Chindamporn A, Plongla R, Torvorapanit P, Manothummetha K, Chuleerarux N, et al. (March 2020). "In Vitro Susceptibility of Thai Pythium insidiosum Isolates to Antibacterial Agents". Antimicrobial Agents and Chemotherapy. 64 (4). doi:10.1128/AAC.02099-19. PMC 7179303. PMID 32015039.
  21. ^ "Tigecycline : Susceptibility and Minimum Inhibitory Concentration (MIC) Data" (PDF). Toku-e.com. Retrieved 13 March 2017.
  22. ^ Tygacil [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals; 2005. Updated July 2010.
  23. ^ Pournaras S, Koumaki V, Spanakis N, Gennimata V, Tsakris A (July 2016). "Current perspectives on tigecycline resistance in Enterobacteriaceae: susceptibility testing issues and mechanisms of resistance". International Journal of Antimicrobial Agents. 48 (1): 11–18. doi:10.1016/j.ijantimicag.2016.04.017. PMID 27256586.
  24. ^ Muralidharan G, Micalizzi M, Speth J, Raible D, Troy S (January 2005). "Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects". Antimicrobial Agents and Chemotherapy. 49 (1): 220–229. doi:10.1128/aac.49.1.220-229.2005. PMC 538906. PMID 15616299.
  25. ^ Hemphill MT, Jones KR (January 2016). "Tigecycline-induced acute pancreatitis in a cystic fibrosis patient: A case report and literature review". Journal of Cystic Fibrosis. 15 (1): e9-11. doi:10.1016/j.jcf.2015.07.008. PMID 26282838.
  26. ^ a b "FDA Drug Safety Communication: Increased risk of death with Tygacil (tigecycline) compared to other antibiotics used to treat similar infections". U.S. Food and Drug Administration (FDA). 1 September 2010. Retrieved 13 March 2017.
  27. ^ a b "FDA Drug Safety Communication: FDA warns of increased risk of death with IV antibacterial Tygacil (tigecycline) and approves new Boxed Warning". U.S. Food and Drug Administration (FDA). 27 September 2013. Retrieved 26 September 2020.
  28. ^ a b Dixit D, Madduri RP, Sharma R (April 2014). "The role of tigecycline in the treatment of infections in light of the new black box warning". Expert Review of Anti-Infective Therapy. 12 (4): 397–400. doi:10.1586/14787210.2014.894882. PMID 24597542. S2CID 36614422.
  29. ^ Zimmerman JJ, Raible DG, Harper DM, Matschke K, Speth JL (July 2008). "Evaluation of a potential tigecycline-warfarin drug interaction". Pharmacotherapy. 28 (7): 895–905. doi:10.1592/phco.28.7.895. PMID 18576904. S2CID 3474652.
  30. ^ Church RF, Schaub RE, Weiss MJ (March 1971). "Synthesis of 7-dimethylamino-6-demethyl-6-deoxytetracycline (minocycline) via 9-nitro-6-demethyl-6-deoxytetracycline". The Journal of Organic Chemistry. 36 (5): 723–725. doi:10.1021/jo00804a025. PMID 5545572.
  31. ^ Macdonald H, Kelly RG, Allen ES, Noble JF, Kanegis LA (September 1973). "Pharmacokinetic studies on minocycline in man". Clinical Pharmacology and Therapeutics. 14 (5): 852–861. doi:10.1002/cpt1973145852. PMID 4199710. S2CID 30279473.
  32. ^ Podolsky SH (December 2018). "The evolving response to antibiotic resistance (1945–2018)". Palgrave Communications. 4 (1): 124. doi:10.1057/s41599-018-0181-x. ISSN 2055-1045. S2CID 53086078.
  33. ^ Sum PE, Lee VJ, Testa RT, Hlavka JJ, Ellestad GA, Bloom JD, et al. (January 1994). "Glycylcyclines. 1. A new generation of potent antibacterial agents through modification of 9-aminotetracyclines". Journal of Medicinal Chemistry. 37 (1): 184–188. doi:10.1021/jm00027a023. PMID 8289194.
  34. ^ Goldstein FW, Kitzis MD, Acar JF (September 1994). "N,N-dimethylglycyl-amido derivative of minocycline and 6-demethyl-6-desoxytetracycline, two new glycylcyclines highly effective against tetracycline-resistant gram-positive cocci". Antimicrobial Agents and Chemotherapy. 38 (9): 2218–2220. doi:10.1128/AAC.38.9.2218. PMC 284718. PMID 7811053.
  35. ^ Petersen PJ, Jacobus NV, Weiss WJ, Sum PE, Testa RT (April 1999). "In vitro and in vivo antibacterial activities of a novel glycylcycline, the 9-t-butylglycylamido derivative of minocycline (GAR-936)". Antimicrobial Agents and Chemotherapy. 43 (4): 738–744. doi:10.1128/AAC.43.4.738. PMC 89200. PMID 10103174.
  36. ^ Sum PE, Petersen P (May 1999). "Synthesis and structure-activity relationship of novel glycylcycline derivatives leading to the discovery of GAR-936". Bioorganic & Medicinal Chemistry Letters. 9 (10): 1459–1462. doi:10.1016/S0960-894X(99)00216-4. PMID 10360756.
  37. ^ Slover CM, Rodvold KA, Danziger LH (June 2007). "Tigecycline: A Novel Broad-Spectrum Antimicrobial". The Annals of Pharmacotherapy. 41 (6): 965–72. doi:10.1345/aph.1H543. PMID 17519296. S2CID 5686856.
  38. ^ a b Hawkey P, Finch R (April 2007). "Tigecycline: in-vitro performance as a predictor of clinical efficacy". Clinical Microbiology and Infection. 13 (4): 354–362. doi:10.1111/j.1469-0691.2006.01621.x. PMID 17359318.
  39. ^ Olson MW, Ruzin A, Feyfant E, Rush TS, O'Connell J, Bradford PA (June 2006). "Functional, biophysical, and structural bases for antibacterial activity of tigecycline". Antimicrobial Agents and Chemotherapy. 50 (6): 2156–2166. doi:10.1128/AAC.01499-05. PMC 1479133. PMID 16723578.
  40. ^ a b Nguyen F, Starosta AL, Arenz S, Sohmen D, Dönhöfer A, Wilson DN (May 2014). "Tetracycline antibiotics and resistance mechanisms". Biological Chemistry. 395 (5): 559–575. doi:10.1515/hsz-2013-0292. PMID 24497223. S2CID 12668198.
  41. ^ a b c Hoffmann M, DeMaio W, Jordan RA, Talaat R, Harper D, Speth J, et al. (September 2007). "Metabolism, excretion, and pharmacokinetics of [14C]tigecycline, a first-in-class glycylcycline antibiotic, after intravenous infusion to healthy male subjects". Drug Metabolism and Disposition. 35 (9): 1543–1553. doi:10.1124/dmd.107.015735. PMID 17537869. S2CID 5070076.
  42. ^ "Tygacil 50mg powder for solution for infusion - Summary of Product Characteristics (SPC) - (eMC)". Medicines.org.uk. Retrieved 13 March 2017.
  43. ^ Betriu C, Rodríguez-Avial I, Sánchez BA, Gómez M, Picazo JJ (November 2002). "Comparative in vitro activities of tigecycline (GAR-936) and other antimicrobial agents against Stenotrophomonas maltophilia". The Journal of Antimicrobial Chemotherapy. 50 (5): 758–759. doi:10.1093/jac/dkf196. PMID 12407139.