Multi-drug
resistant TB-Focus on Linezolid
Background
Multi-drug resistant TB (MDRTB) is now seen in 2.2 per
cent of all new cases and up to 18 per cent of relapse cases in Nepal and 80 XDR-TB cases in Nepal each year. One in four patients with MDRTB dies and many more go
undetected.
Every year there are an estimated 45,000 new TB cases, of
which 35,000 are administered DOTS treatment. Up to 5 per cent of them will not
be cured and will have to come back for a second treatment, which takes up to
20 months to complete, has severe side effects, and cost much more to treat.
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Where does linezolid fit into DR-TB
treatment?
Linezolid is
a good treatment option which could be used effectively within a multi-drug
regimen for DR-TB patients in whom standard second-line TB treatment is
unlikely to provide an adequate chance of a cure. While not originally
developed to treat TB, a number of clinical studies have found the antibiotic
to be effective against DR-TB (see here and here). In its 2011 guidelines, the
World Health Organisation (WHO) recommends linezolid as a Group 5 drug for
selected DR-TB cases, meaning the drug is of unproven efficacy. The drug is
also recognised in the South African National Department of Health’s policy
guidelines for the “Management of DR-TB,” which says that linezolid should be
considered as a third-line drug in the treatment of DR-TB if cost permits. In
Khayelitsha, Doctors Without Borders (MSF) has found linezolid-containing
regimens to be effective in treating DR-TB in both HIV-positive and
HIV-negative individuals. Seven patients have completed the two-year treatment
on a linezolid-containing regimen, and been pronounced cured, with 25 others
still on treatment.
LINEZOLID
(LINEZ)
Linezolid was the
first oxazolidinoneantibacterial agent discovered. It is used for the treatment
of serious infections caused by Gram-positive
bacteria that
are resistant to several
other antibioticsLinezolid is recommended by the WHO to treat drug resistant
tuberculosis as a medicine with “unclear efficacy”. Linezolid was discovered in
the 1990s and first approved in 2000..Linezolid is marketed by Pfizer under the
trade names Zyvox (in the United States, United Kingdom,
Australia, and several other countries), Zyvoxid (in Europe), andZyvoxam (in Canada and Mexico). Generics are
also available, such as Linospan (in
India, by Cipla) and Linzolid (in Bangladesh, by Incepta)
and Linez(in Nepal,by Alive).
Classification : Antibiotic,
Oxazolidinone
Pharmacology:
Linezolid is a
synthetic antibacterial agent. It
inhibits bacterial protein synthesis
by binding to
bacterial 23S ribosomal RNA of the 50S subunit.
This prevents the formation of a functional 70S initiation complex that
is essential for the bacterial translation process. Linezolid is bacteriostatic against
enterococci and staphylococci and bactericidal against most strains of
streptococci.
Pharmacokinetics:
Absorption: Rapidly and extensively absorbed after oral
dosing.
Maximum plasma
concentrations are reached approximately 1 to 2 hours after dosing, and the absolute
bioavailability is approximately 100%.
Therefore, linezolid may be given orally or intravenously without dose
adjustment.
Distribution: Linezolid readily distributes to
well-perfused tissues. The
plasma
protein binding of linezolid is approximately 31% and is
concentration-independent. The volume of
distribution of linezolid at steady-state averaged 40 to 50 liters in healthy
adult volunteers.
Metabolism: Hepatic via oxidation of the morpholine ring,
resulting in
two inactive
metabolites (aminoethoxyacetic acid, hydroxyethyl glycine);
does not involve CYP.
Bioavailability:
100%
Elimination: Half-life elimination in adults 4-5 hours.
Time to peak in adults,
oral is 1-2 hours.
Indications:
Vancomycin-Resistant
Enterococcus faecium infections,
including cases with concurrent bacteremia. Nosocomial pneumonia, complicated
skin and skin structure infections, community acquired pneumonia including
concurrent bacteremia.
Non-FDA approved
indication: Treatment of mycobacterial
infections. Linezolid
has been used as
a third-line regimen for the treatment of multidrug-resistant tuberculosis
(MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB).
Dosage and Administration:
Dosage Guidelines for Linezolid
|
Infection
|
Dosage and Route of Administration
Adults and Adolescents
(12 Years and Older)
|
Recommended Duration of
Treatment (consecutive days)
|
|
Complicated skin and skin
structure infections
|
600 mg IV or oral q 12h
|
10 to 14
|
|
Community-acquired pneumonia,
including concurrent bacteremia
|
|
|
|
Nosocomial pneumonia
|
|
|
|
Vancomycin-resistant
Enterococcus faecium infections, including concurrent bacteremia
|
600 mg IV or oral q 12h
|
14 to 28
|
|
Uncomplicated skin and skin structure
infections
|
Adults: 400mg oral q12h
Adolescents: 600mg oral q12h
|
10 to 14
|
|
|
|
|
|
Tuberculosis (MDR-TB or XDR-TB)
|
600 mg IV or oral daily
|
Up to 2 yrs until sputum
culture conversion if tolerated
|
Take with or
without food. Avoid tyramine-containing
foods/beverages.
The
optimal dosage for linezolid remains unclear. It is generally prescribed at 600
mg daily or twice daily. A number of studies have looked at whether this can be
replaced by 300 mg daily to reduce side effects. Further research to establish
dosage is recommended.
Contraindications:
Linezolid
formulations are contraindicated for use in patients who have known
hypersensitivity
to linezolid or any of the other product components.
Warnings/Precautions:
Myelosuppression
has been reported and may be dependent on duration of therapy (generally >2
weeks of treatment); use with caution in patients with pre-existing
myelosuppression, in patients receiving other drugs which may cause bone marrow
suppression, or in chronic infection (previous or concurrent antibiotic
therapy). Weekly CBC monitoring is
recommended. Discontinue linezolid in
patients developing myelosuppression (or in whom myelosuppression worsens during
treatment).
Lactic acidosis
had been reported with use. Linezolid
exhibits mild MAO inhibitor properties and has the potential to have the same
interactions as other MAO inhibitors; use with caution in uncontrolled
hypertension, pheochromocytoma, carcinoid syndrome, or untreated
hyperthyroidism; avoid use with
serotonergic agents such as TCAs, venlafaxine, trazodone, sibutrimine,
meperidine, destromethorphan, and SSRIs; concomitant use has been associated
with the development of serotonin syndrome.
Unnecessary use may lead to the development of resistance to linezolid;
consider alternatives before initiating outpatient treatment.
Peripheral and
optic neuropathy has been reported in patients treated with linezolid,
primarily those patients treated for longer than the maximum recommended
duration of 28 days. Visual function should be monitored in all patients taking
linezolid for extended periods (=> 3 months) and in all patients reporting
new visual symptoms regardless of length of therapy with linezolid.
Seizures have
been reported; use with caution in patients with a history of seizures. Prolonged use may result in fungal or
bacterial superinfection, including C.
difficile associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has
been observed >2 months after antibiotic treatment.
Interactions:
Linezolid is a
reversible, nonselective inhibitor of MAO.
Serotenergic agents (e.g., TCA’s, venlafaxine, trazodone, sibutramine,
meperidine, dextromethorphan, and SSRIs) may cause a serotonin syndrome (eg,
agitation, confusion, hallucinations, hyper-reflexia, myoclonus, shivering,
tachycardia, hyperpyrexia, cognitive dysfunction) when used concomitantly. Adrenergic agents (eg, phenylpropanolamine,
pseudoephedrine, sympathomimetic agents, vasopressor or dopaminergic agents)
may cause hypertension. Tramadol may
increase the risk of seizures when used concurrently with linezolid. Myelosuppressive medications may increase
risk of myelosuppression when used concurrently with linezolid.
Adverse Reactions:
The most
common adverse events in patients
treated with linezolid were diarrhea (incidence across studies: 2.8% to 11.0%),
headache (incidence across studies: 0.5% to 11.3%), and nausea (incidence
across studies: 3.4% to 9.6%).
Other adverse
events reported in Phase 2 and Phase 3 studies included oral moniliasis,
vaginal moniliasis, hypertension, dyspepsia, localized abdominal pain,
pruritis, and tongue discoloration.
Other side effects include anaemia,
peripheral neuropathy, bone marrow suppression and lactic acidosis. Vitamin B6
at 50 mg daily may prevent/ reverse anaemia.
Cost:
|
Generic Name
|
Brand Name
|
Strength
|
Cost
(per tablet)
|
|
Linezolid
|
Linez
|
600 mg
|
Rupes 60
|
Monitoring:
Weekly CBC and
platelet counts, particularly in patients at increased risk of bleeding, with
pre-existing myelosuppression, on concomitant
medications that cause bone marrow suppression, in those that require
>2 weeks of therapy, or in those with chronic infection who have received
previous or concomitant antibiotic therapy; visual function with extended
therapy (=>3 months) or in patients with new onset visual symptoms,
regardless of therapy length.
Efficacy:
Linezolid
formulations are indicated in the treatment of the following infections caused
by susceptible strains of the designated microorganisms: Vancomycin-resistant Enterococcus faecium (VRE) infections, including cases with
concurrent bacteremia; nosocomial pneumonia causes by Staphylococcus aureus (methicillin-susceptible and –resistant
strains) or Streptococcus pneumoniae
(including multi-drug resistant strains, which refer to isolates resistant to 2
or more of the following antibiotics: penicillin, second-generation
cephalosporins, macrolides, tetracycline, and trimethoprim/sulfamethoxazole);
community-acquired pneumonia caused by S.
pneumoniae (including multi-drug resistant strains), including cases with
concurrent bacteremia, or S. aureus
(methicillin-susceptible strains only); complicated skin and skin structure
infections, including diabetic foot infections, without concomitatnt
osteomyelitis, caused by S. Aureus (methicillin-susceptible and-resistant
strains), Streptococcus pyogenes, or Streptococcus agalactiae; and
uncomplicated skin and skin structure infections caused by S. Aureus (methicillin-susceptible strains only) or S. pyogenes.
Linezolid has
significant in vitro acitivity against M.
tuberculosis, and has occasionally been used to treat TB. There have been a few anecdotal reports of
linezolid for the treatment of MDR-TB and XDR-TB.
Conclusion:
Linezolid
it the first oral antibiotic to be approved from the oxazolidinone class with
demonstrated in vitro activity
against both drug-susceptible and drug-resistant isolates of Mycobacterium tuberculosis without
cross-resistance with the standard antituberculous agents.
Recommendation:
Add to formulary
reserve class drug for Texas Center for Infectious Disease for MDR-TB and
XDR-TB. Linezolid is a third-line
regimen for the treatment of XDR-TB according to drug sensitivities where no
acceptable alternative exists among the available drugs.Add to formulary
reserve class for FDA indications when prescribed by Infectious Disease
Specialist.
Clinical evidence and approval:
Linezolid
was first approved for use in 2000, although its use in the treatment of drug
resistant TB has not been approved by any stringent regulatory authorities and
it is therefore used “off-label” in this function.
In a
review of thirty patients given linezolid as part of their treatment for MDR
TB, it was concluded that linezolid was well tolerated, had low rates of
discontinuation, and may have efficacy in the treatment of MDR TB.
Another
retrospective assessment of 85 patients treated with linezolid reported high
rates of adverse events. 35 patients (41.2%) experienced major side effects,
requiring discontinuation in 27 (77%) cases. The study reported that adverse
events were lower for patients prescribed 600 mg daily than patients given 1200
mg daily. The study also found that linezolid is potentially important for
patients with XDR TB.
The
study concluded that “the data suggest that linezolid may be useful in
improving the chances of smear and culture conversion and may provide a better
chance at treatment success in only the most complicated cases of MDR/XDR-TB
when other treatment alternatives are not available, but that its safety
profile does not warrant its use in cases for which other, safer second-line or
third-line drugs are available.”
While
there is little evidence on paediatric safety and efficacy of linezolid, an
infant in Italy was successfully treated for TB with no adverse reactions. A review
of 4 patients, ages 4 to 17, concluded “[linezolid] is an option to consider in
the treatment of refractory MDR- and XDR-TB, although the optimal dose, timing
of introduction and associations are yet to be established, especially in
younger patients.”
References:
1.
Zyvox® (linezolid) [package insert]. New York, NY:
Pfizer Inc., America; July 2006.
2.
Lacy C, Armstrong L, Goldman M, Lance L, Linezolid,
Drug Information Handbook Lexi-Comp Inc., 17th Edition, 2008-2009,
927-929.
3.
Brown-Elliott
et al.,Abstr. Annu. Meet.Infect. 2002
4.
Alla A, [Letter], Pfizer U.S. Medical Information,
March 2009.
5.
Condos R, Hadgiangelis N, Leibert E, Jacquette G,
Harkin T, Rom W. Case Series Report of a Linezolid-Containing Regimen for
Extensively Drug-Resistant Tuberculosis. Chest 2008;134;187-192.
6.
Alcala, L,
Ruiz-Serrano, MJ, Perez-Fernandez Turegano, C, et al. In vitro
acitivities of linezolid against clinical isolates of Mycobacterium
tuberculosis that are susceptible or resistant to first-line antituberculosis
drugs. Antimicrob Agents Chemother 2003; 47:416
7.
Ntziora,F, Falagas,ME. Linezolid for the treatment of
patients with [corrected]
Mycobacterial
infections[corrected] a systematic review. Int J Tuberc Lung Dis 2007; 11:606
Prepared by:
PME Santosh Adhikari
Alive Pharmaceutical (P) Ltd,Nepal
santosh.adhikari@alivenepal.com
