Pyrazinamide

Last updated

Pyrazinamide
Pyrazinamide.svg
Pyrazinamide ball-and-stick.png
Clinical data
Trade names Rifater, Tebrazid, others [1]
AHFS/Drugs.com Monograph
MedlinePlus a682402
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability >90%
Metabolism liver
Elimination half-life 9 to 10 hours
Excretion kidney
Identifiers
  • pyrazine-2-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard 100.002.470 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C5H5N3O
Molar mass 123.115 g·mol−1
3D model (JSmol)
  • O=C(N)c1nccnc1
  • InChI=1S/C5H5N3O/c6-5(9)4-3-7-1-2-8-4/h1-3H,(H2,6,9) Yes check.svgY
  • Key:IPEHBUMCGVEMRF-UHFFFAOYSA-N Yes check.svgY
   (verify)

Pyrazinamide is a medication used to treat tuberculosis. [2] For active tuberculosis, it is often used with rifampicin, isoniazid, and either streptomycin or ethambutol. [3] It is not generally recommended for the treatment of latent tuberculosis. [2] It is taken by mouth. [1]

Contents

Common side effects include nausea, loss of appetite, muscle and joint pains, and rash. [2] [4] More serious side effects include gout, liver toxicity, and sensitivity to sunlight. [2] It is not recommended in those with significant liver disease or porphyria. [3] It is unclear if use during pregnancy is safe but it is likely okay during breastfeeding. [3] Pyrazinamide is in the antimycobacterial class of medications. [2] How it works is not entirely clear. [2]

Pyrazinamide was first made in 1936, but did not come into wide use until 1972. [5] It is on the World Health Organization's List of Essential Medicines. [6] Pyrazinamide is available as a generic medication. [2]

Medical uses

Pyrazinamide is only used in combination with other drugs such as isoniazid and rifampicin in the treatment of Mycobacterium tuberculosis and as directly observed therapy (DOT). [4] It is never used on its own. It has no other indicated medical uses. In particular, it is not used to treat other mycobacteria; Mycobacterium bovis and Mycobacterium leprae are innately resistant to pyrazinamide.

Pyrazinamide is used in the first 2 months of treatment to reduce the duration of treatment required. [7] Regimens not containing pyrazinamide must be taken for 9 months or more.

Pyrazinamide is a potent antiuricosuric drug [8] and consequently has an off-label use in the diagnosis of causes of hypouricemia and hyperuricosuria. [9] It acts on URAT1. [9]

Adverse effects

The most common (roughly 1%) side effect of pyrazinamide is joint pains (arthralgia), but this is not usually so severe that patients need to stop taking it. [10] [11] Pyrazinamide can precipitate gout flares by decreasing renal excretion of uric acid. [12]

The most dangerous side effect of pyrazinamide is hepatotoxicity, which is dose-related. The old dose for pyrazinamide was 40–70 mg/kg daily and the incidence of drug-induced hepatitis has fallen significantly since the recommended dose has been reduced to 12–30 mg/kg daily. In the standard four-drug regimen (isoniazid, rifampicin, pyrazinamide, ethambutol), pyrazinamide is the most common cause of drug-induced hepatitis. [13] It is not possible to clinically distinguish pyrazinamide-induced hepatitis from hepatitis caused by isoniazid or rifampicin; test dosing is required (this is discussed in detail in tuberculosis treatment)[ citation needed ]

Other side effects include nausea and vomiting, anorexia, sideroblastic anemia, skin rash, urticaria, pruritus, dysuria, interstitial nephritis, malaise, rarely porphyria, and fever.[ citation needed ]

Pharmacokinetics

Pyrazinamide is well absorbed orally. It crosses inflamed meninges and is an essential part of the treatment of tuberculous meningitis. It is metabolised by the liver and the metabolic products are excreted by the kidneys.[ citation needed ]

Pyrazinamide is routinely used in pregnancy in the UK and the rest of the world; the World Health Organization (WHO) recommends its use in pregnancy; and extensive clinical experience shows that it is safe. In the US, pyrazinamide is not used in pregnancy, citing insufficient evidence of safety. [14] Pyrazinamide is removed by haemodialysis, so doses should always be given at the end of a dialysis session.[ medical citation needed ]

Mechanism of action

Pyrazinamide is a prodrug that stops the growth of M. tuberculosis.[ citation needed ]

Pyrazinamide diffuses into the granuloma of M. tuberculosis, where the tuberculosis enzyme pyrazinamidase converts pyrazinamide to the active form pyrazinoic acid. [15] Under acidic conditions of pH 5 to 6, the pyrazinoic acid that slowly leaks out converts to the protonated conjugate acid, which is thought to diffuse easily back into the bacilli and accumulate. The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH. [15] [16]

Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase (FAS) I, which is required by the bacterium to synthesize fatty acids [17] although this has been discounted. [18] [19] The accumulation of pyrazinoic acid was also suggested to disrupt membrane potential and interfere with energy production, necessary for survival of M. tuberculosis at an acidic site of infection. However, since an acidic environment is not essential for pyrazinamide susceptibility and pyrazinamide treatment does not lead to intrabacterial acidification nor rapid disruption of membrane potential, this model has also been discounted. [20] Pyrazinoic acid was proposed to bind to the ribosomal protein S1 (RpsA) and inhibit trans-translation, [21] but more detailed experiments have shown that it does not have this activity. [22]

The current hypothesis is that pyrazinoic acid blocks synthesis of coenzyme A. Pyrazinoic acid binds weakly to aspartate decarboxylase ( PanD ), triggering its degradation. [23] This is an unusual mechanism of action in that pyrazinamide does not directly block the action of its target, but indirectly triggers its destruction.[ citation needed ]

Resistance

Mutations in the pncA gene of M. tuberculosis, which encodes a pyrazinamidase and converts pyrazinamide to its active form pyrazinoic acid, are responsible for the majority of pyrazinamide resistance in M. tuberculosis strains. [24] A few pyrazinamide-resistant strains with mutations in the rpsA gene have also been identified. [21] However, a direct association between these rpsA mutations and pyrazinamide resistance has not been established. The pyrazinamide-resistant M. tuberculosis strain DHMH444, which harbors a mutation in the carboxy terminal coding region of rpsA, is fully susceptible to pyrazinoic acid and pyrazinamide resistance of this strain was previously associated with decreased pyrazinamidase activity. [25] Further, this strain was found to be susceptible to pyrazinamide in a mouse model of tuberculosis. [26] Thus, current data indicate that rpsA mutations are not likely to be associated with pyrazinamide resistance. Currently, three main methods of testing are used for pyrazinamide resistance: 1) phenotypic tests where a tuberculosis strain is grown in the presence of increasing concentrations of pyrazinamide, 2) measuring levels of pyrazinamidase enzyme produced by the tuberculosis strain, or 3) looking for mutations in the pncA gene of tuberculosis. [15] Concerns exist that the most widely used method for phenotypic resistance testing may overestimate the number of resistant strains. [27] [28]

Global resistance of tuberculosis to pyrazinamide has been estimated to be in 16% of all cases,[ when? ] and 60% of people with multidrug-resistant tuberculosis. [15]

Abbreviations

The abbreviations PZA and Z are standard, and used commonly in the medical literature, although best practice discourages the abbreviating of drug names to prevent mistakes.[ medical citation needed ]

Presentation

Pyrazinamide is a generic drug, and is available in a wide variety of presentations. Pyrazinamide tablets form the bulkiest part of the standard tuberculosis treatment regimen. Pyrazinamide tablets are so large, some people find them impossible to swallow: pyrazinamide syrup is an option.[ citation needed ]

Pyrazinamide is also available as part of fixed-dose combinations with other TB drugs such as isoniazid and rifampicin ( Rifater is an example).[ citation needed ]

History

Pyrazinamide was first discovered and patented in 1936, but not used against tuberculosis until 1952. [19] Its discovery as an antitubercular agent was remarkable since it has no activity against tuberculosis in vitro , due to not being active at a neutral pH, so would ordinarily not be expected to work in vivo . [29] However, nicotinamide was known to have activity against tuberculosis and pyrazinamide was thought to have a similar effect. Experiments in mice at Lederle and Merck confirmed its ability to kill tuberculosis and it was rapidly used in humans. [29]

Related Research Articles

<i>Mycobacterium tuberculosis</i> Species of pathogenic bacteria that causes tuberculosis

Mycobacterium tuberculosis, also known as Koch's bacillus, is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, M. tuberculosis has an unusual, waxy coating on its cell surface primarily due to the presence of mycolic acid. This coating makes the cells impervious to Gram staining, and as a result, M. tuberculosis can appear weakly Gram-positive. Acid-fast stains such as Ziehl–Neelsen, or fluorescent stains such as auramine are used instead to identify M. tuberculosis with a microscope. The physiology of M. tuberculosis is highly aerobic and requires high levels of oxygen. Primarily a pathogen of the mammalian respiratory system, it infects the lungs. The most frequently used diagnostic methods for tuberculosis are the tuberculin skin test, acid-fast stain, culture, and polymerase chain reaction.

<span class="mw-page-title-main">Isoniazid</span> Antibiotic for treatment of tuberculosis

Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic used for the treatment of tuberculosis. For active tuberculosis, it is often used together with rifampicin, pyrazinamide, and either streptomycin or ethambutol. For latent tuberculosis, it is often used alone. It may also be used for atypical types of mycobacteria, such as M. avium, M. kansasii, and M. xenopi. It is usually taken by mouth, but may be used by injection into muscle.

<span class="mw-page-title-main">Rifamycin</span> Group of antibiotics

The rifamycins are a group of antibiotics that are synthesized either naturally by the bacterium Amycolatopsis rifamycinica or artificially. They are a subclass of the larger family of ansamycins. Rifamycins are particularly effective against mycobacteria, and are therefore used to treat tuberculosis, leprosy, and mycobacterium avium complex (MAC) infections.

<span class="mw-page-title-main">Rifampicin</span> Antibiotic medication

Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), Mycobacterium avium complex, leprosy, and Legionnaires’ disease. It is almost always used together with other antibiotics with two notable exceptions: when given as a "preferred treatment that is strongly recommended" for latent TB infection; and when used as post-exposure prophylaxis to prevent Haemophilus influenzae type b and meningococcal disease in people who have been exposed to those bacteria. Before treating a person for a long period of time, measurements of liver enzymes and blood counts are recommended. Rifampicin may be given either by mouth or intravenously.

<span class="mw-page-title-main">Fusidic acid</span> Antibiotic

Fusidic acid, sold under the brand names Fucidin among others, is an antibiotic that is often used topically in creams or ointments and eyedrops but may also be given systemically as tablets or injections.
As of October 2008, the global problem of advancing antimicrobial resistance has led to a renewed interest in its use.

<span class="mw-page-title-main">Tuberculosis management</span>

Tuberculosis management describes the techniques and procedures utilized for treating tuberculosis (TB).

Denis Anthony Mitchison was a British bacteriologist.

<span class="mw-page-title-main">4-Aminosalicylic acid</span> Anti-tuberculosis and anti-inflammatory drug

4-Aminosalicylic acid, also known as para-aminosalicylic acid (PAS) and sold under the brand name Paser among others, is an antibiotic primarily used to treat tuberculosis. Specifically it is used to treat active drug resistant tuberculosis together with other antituberculosis medications. It has also been used as a second line agent to sulfasalazine in people with inflammatory bowel disease such as ulcerative colitis and Crohn's disease. It is typically taken by mouth.

The rpoB gene encodes the β subunit of bacterial RNA polymerase and the homologous plastid-encoded RNA polymerase (PEP). It codes for 1342 amino acids in E. coli, making it the second-largest polypeptide in the bacterial cell. It is targeted by the rifamycin family of antibacterials, such as rifampin. Mutations in rpoB that confer resistance to rifamycins do so by altering the protein's drug-binding residues, thereby reducing affinity for these antibiotics.

<span class="mw-page-title-main">Ethionamide</span> Chemical compound

Ethionamide is an antibiotic used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, to treat active multidrug-resistant tuberculosis. It is no longer recommended for leprosy. It is taken by mouth.

<span class="mw-page-title-main">Extensively drug-resistant tuberculosis</span> Tuberculosis that is resistant to the most effective drugs

Extensively drug-resistant tuberculosis (XDR-TB) is a form of tuberculosis caused by bacteria that are resistant to some of the most effective anti-TB drugs. XDR-TB strains have arisen after the mismanagement of individuals with multidrug-resistant TB (MDR-TB).

<span class="mw-page-title-main">Multidrug-resistant tuberculosis</span> Medical condition

Multidrug-resistant tuberculosis (MDR-TB) is a form of tuberculosis (TB) infection caused by bacteria that are resistant to treatment with at least two of the most powerful first-line anti-TB medications (drugs): isoniazid and rifampin. Some forms of TB are also resistant to second-line medications, and are called extensively drug-resistant TB (XDR-TB).

β-Lactamase inhibitor Family of enzymes

Beta-lactamases are a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. In bacterial resistance to beta-lactam antibiotics, the bacteria have beta-lactamase which degrade the beta-lactam rings, rendering the antibiotic ineffective. However, with beta-lactamase inhibitors, these enzymes on the bacteria are inhibited, thus allowing the antibiotic to take effect. Strategies for combating this form of resistance have included the development of new beta-lactam antibiotics that are more resistant to cleavage and the development of the class of enzyme inhibitors called beta-lactamase inhibitors. Although β-lactamase inhibitors have little antibiotic activity of their own, they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against.

<span class="mw-page-title-main">Thiocarlide</span> Chemical compound

Thiocarlide is a thiourea drug used in the treatment of tuberculosis, inhibiting synthesis of oleic acid and tuberculostearic acid.

<span class="mw-page-title-main">Beta-ketoacyl-ACP synthase III</span> Enzyme

In enzymology, a β-ketoacyl-[acyl-carrier-protein] synthase III (EC 2.3.1.180) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Pyrazinoic acid</span> Chemical compound

Pyrazinoic acid is a pyrazinamide metabolite.

PncA is a gene encoding pyrazinamidase in Mycobacterium species. Pyrazinamidase converts the drug pyrazinamide to the active form pyrazinoic acid. There is a strong correlation between mutations in pncA and resistance of M. tuberculosis to pyrazinamide.

Totally drug-resistant tuberculosis (TDR-TB) is a generic term for tuberculosis strains that are resistant to a wider range of drugs than strains classified as extensively drug-resistant tuberculosis. Extensively drug resistant tuberculosis is tuberculosis that is resistant to isoniazid and rifampicin, any fluoroquinolone, and any of the three second line injectable TB drugs. TDR-TB has been identified in three countries; India, Iran, and Italy. The term was first presented in 2006, in which it showed that TB was resistant to many second line drugs and possibly all the medicines used to treat the disease. Lack of testing made it unclear which drugs the TDR-TB were resistant to.

KatG is an enzyme that functions as both catalase and peroxidase. Its mutation is the cause for Mycobacterium resistance with the drug isoniazid, which targets the mycolic acids within the tuberculosis bacteria. Due to both its catalase and peroxidase activity, this enzyme protects M. Tuberculosis against reactive oxygen species. M. tuberculosis' survival within macrophages depends on the KatG enzyme.

References

  1. 1 2 Hamilton R (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 415. ISBN   9781284057560.
  2. 1 2 3 4 5 6 7 "Pyrazinamide". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
  3. 1 2 3 World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary. World Health Organization. pp. 136, 140, 594, 608. hdl: 10665/44053 . ISBN   978-9241547659.
  4. 1 2 Lewis SM, Dirksen SR, Heitkemper MM, Bucher L, Harding M (5 December 2013). Medical-surgical nursing : assessment and management of clinical problems (9th ed.). St. Louis, MO: Mosby. ISBN   978-0-323-10089-2. OCLC   228373703.
  5. ↑ Donald PR, van Helden PD (2011). Antituberculosis Chemotherapy. Karger Medical and Scientific Publishers. p. 8. ISBN   978-3805596282. Archived from the original on 10 September 2017.
  6. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  7. ↑ "Controlled trial of four thrice-weekly regimens and a daily regimen all given for 6 months for pulmonary tuberculosis". Lancet. 1 (8213): 171–174. January 1981. doi:10.1016/S0140-6736(02)95623-0. PMID   6109855.
  8. ↑ Spaia S, Magoula I, Tsapas G, Vayonas G (2000). "Effect of pyrazinamide and probenecid on peritoneal urate transport kinetics during continuous ambulatory peritoneal dialysis". Peritoneal Dialysis International. 20 (1): 47–52. doi: 10.1177/089686080002000109 . PMID   10716583. S2CID   19352495. Archived from the original on 9 December 2019. Retrieved 29 December 2008.
  9. 1 2 Ichida K, Hosoyamada M, Hisatome I, Enomoto A, Hikita M, Endou H, Hosoya T (January 2004). "Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion". Journal of the American Society of Nephrology. 15 (1): 164–173. doi: 10.1097/01.ASN.0000105320.04395.D0 . PMID   14694169.
  10. ↑ "Controlled clinical trial of 4 short-couse regimens of chemotherapy (three 6-month and one 8-month) for pulmonary tuberculosis". Tubercle. 64 (3): 153–166. September 1983. doi:10.1016/0041-3879(83)90011-9. PMID   6356538.
  11. ↑ British Thoracic Society (October 1984). "A controlled trial of 6 months' chemotherapy in pulmonary tuberculosis. Final report: results during the 36 months after the end of chemotherapy and beyond. British Thoracic Society". British Journal of Diseases of the Chest. 78 (4): 330–336. doi:10.1016/0007-0971(84)90165-7. PMID   6386028.
  12. ↑ "Treatment of tuberculosis" (PDF). MMWR. Recommendations and Reports. 52 (RR-11): 1–77. June 2003. PMID   12836625.
  13. ↑ Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D (June 2003). "Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis". American Journal of Respiratory and Critical Care Medicine. 167 (11): 1472–1477. doi:10.1164/rccm.200206-626OC. PMID   12569078.
  14. ↑ Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, et al. (February 2003). "American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis". American Journal of Respiratory and Critical Care Medicine. 167 (4): 603–662. doi:10.1164/rccm.167.4.603. PMID   12588714.
  15. 1 2 3 4 Whitfield MG, Soeters HM, Warren RM, York T, Sampson SL, Streicher EM, et al. (28 July 2015). "A Global Perspective on Pyrazinamide Resistance: Systematic Review and Meta-Analysis". PloS One. 10 (7): e0133869. Bibcode:2015PLoSO..1033869W. doi: 10.1371/journal.pone.0133869 . PMC   4517823 . PMID   26218737.
  16. ↑ Zhang Y, Mitchison D (January 2003). "The curious characteristics of pyrazinamide: a review". The International Journal of Tuberculosis and Lung Disease. 7 (1): 6–21. PMID   12701830.
  17. ↑ Zimhony O, Cox JS, Welch JT, Vilchèze C, Jacobs WR (September 2000). "Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis". Nature Medicine. 6 (9): 1043–1047. doi:10.1038/79558. PMID   10973326. S2CID   7409751.
  18. ↑ Boshoff HI, Mizrahi V, Barry CE (April 2002). "Effects of pyrazinamide on fatty acid synthesis by whole mycobacterial cells and purified fatty acid synthase I". Journal of Bacteriology. 184 (8): 2167–2172. doi:10.1128/JB.184.8.2167-2172.2002. PMC   134955 . PMID   11914348.
  19. 1 2 Zhang Y, Shi W, Zhang W, Mitchison D (2014). "Mechanisms of Pyrazinamide Action and Resistance". Microbiology Spectrum. 2 (4): 1–12. doi:10.1128/microbiolspec.mgm2-0023-2013. PMC   4268777 . PMID   25530919.
  20. ↑ Peterson ND, Rosen BC, Dillon NA, Baughn AD (December 2015). "Uncoupling Environmental pH and Intrabacterial Acidification from Pyrazinamide Susceptibility in Mycobacterium tuberculosis". Antimicrobial Agents and Chemotherapy. 59 (12): 7320–7326. doi:10.1128/aac.00967-15. PMC   4649215 . PMID   26369957.
  21. 1 2 Shi W, Zhang X, Jiang X, Yuan H, Lee JS, Barry CE, et al. (September 2011). "Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis". Science. 333 (6049): 1630–1632. Bibcode:2011Sci...333.1630S. doi:10.1126/science.1208813. PMC   3502614 . PMID   21835980.
  22. ↑ Dillon NA, Peterson ND, Feaga HA, Keiler KC, Baughn AD (July 2017). "Anti-tubercular Activity of Pyrazinamide is Independent of trans-Translation and RpsA". Scientific Reports. 7 (1): 6135. Bibcode:2017NatSR...7.6135D. doi:10.1038/s41598-017-06415-5. PMC   5522395 . PMID   28733601.
  23. ↑ Gopal P, Sarathy JP, Yee M, Ragunathan P, Shin J, Bhushan S, et al. (April 2020). "Pyrazinamide triggers degradation of its target aspartate decarboxylase". Nature Communications. 11 (1): 1661. Bibcode:2020NatCo..11.1661G. doi:10.1038/s41467-020-15516-1. PMC   7125159 . PMID   32245967.
  24. ↑ Scorpio A, Zhang Y (June 1996). "Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus". Nature Medicine. 2 (6): 662–667. doi:10.1038/nm0696-662. PMID   8640557. S2CID   8579133.
  25. ↑ Speirs RJ, Welch JT, Cynamon MH (June 1995). "Activity of n-propyl pyrazinoate against pyrazinamide-resistant Mycobacterium tuberculosis: investigations into mechanism of action of and mechanism of resistance to pyrazinamide". Antimicrobial Agents and Chemotherapy. 39 (6): 1269–1271. doi:10.1128/aac.39.6.1269. PMC   162725 . PMID   7574514.
  26. ↑ Klemens SP, Sharpe CA, Cynamon MH (January 1996). "Activity of pyrazinamide in a murine model against Mycobacterium tuberculosis isolates with various levels of in vitro susceptibility". Antimicrobial Agents and Chemotherapy. 40 (1): 14–16. doi:10.1128/AAC.40.1.14. PMC   163048 . PMID   8787871.
  27. ↑ Chedore P, Bertucci L, Wolfe J, Sharma M, Jamieson F (January 2010). "Potential for erroneous results indicating resistance when using the Bactec MGIT 960 system for testing susceptibility of Mycobacterium tuberculosis to pyrazinamide". Journal of Clinical Microbiology. 48 (1): 300–301. doi:10.1128/JCM.01775-09. PMC   2812260 . PMID   19923479.
  28. ↑ Piersimoni C, Mustazzolu A, Iacobino A, Giannoni F, Santoro G, Gherardi G, et al. (December 2016). "Pyrazinamide susceptibility testing: proposed new standard with the BACTECTM MGITTM 960 system". The International Journal of Tuberculosis and Lung Disease. 20 (12): 1677–1680. doi:10.5588/ijtld.16.0360. PMID   27931346.
  29. 1 2 Zhang Y, Mitchison D (January 2003). "The curious characteristics of pyrazinamide: a review". The International Journal of Tuberculosis and Lung Disease. 7 (1): 6–21. PMID   12701830.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.