Update on antibiotic linezolid Dr surendra patel Intensivist and anaesthetist Mishika super speciality hospital Presentation 14/05/2023 Linezolid is a synthetic oxazolidinone with bacteriostatic activity against gram-positive organisms. Tedizolid is a newer drug in the same class with comparable spectrum of activity

1. Update on antibiotic
linezolid
Dr surendra patel
Intensivist and anaesthetist
Mishika super speciality hospital
Presentation 14/05/2023

2. • Linezolid is a synthetic oxazolidinone with bacteriostatic activity
against gram-positive organisms.
• Tedizolid is a newer drug in the same class with comparable spectrum
of activity

3. SPECTRUM AND INDICATIONS
• Linezolid demonstrate activity in vitro
against a variety of gram-positive
bacteria including
• Streptococci,
• Enterococci (Including Vancomycin-
resistant Enterococci [VRE]),
• Coagulase-negative Staphylococci,
• Methicillin-sensitive Staphylococcus
Aureus,
• Methicillin-resistant S. Aureus (MRSA),
• Bacillus Species,
• Corynebacterium Species,
• Listeria Monocytogenes.
• Linezolid demonstrate activity in vitro
against several
• Mycobacterium spp,
including Mycobacterium tuberculosis and
nontuberculous mycobacterium.
• Active in vitro against
numerous Nocardia spp.
• Linezolid abolishes toxin production and
reduces sporulation in Bacillus anthracis in
vitro; therefore, it is a treatment option for
select infections due to anthrax .

4. • Linezolid is approved for adults and children with
• Pneumonia (Nosocomial And Community Acquired)
• Skin And Skin structure infections (complicated and uncomplicated), including those
due to MRSA and VRE related bacteremia and osteomyelitis.

5. MECHANISM OF ACTION
• Linezolid and tedizolid are that inhibit initiation of bacterial
protein synthesis at the 50S ribosome. The 50S subunit contains
5S rRNA, 23S rRNA, and 34 proteins. These agents also suppress
production of bacterial toxins such as
• Panton-valentine Leukocidin,
• Alpha-hemolysin, And
• Toxic Shock Syndrome Toxin.

6. RESISTANCE
• Among staphylococci, linezolid resistance appears to occur most frequently among coagulase-negative staphylococci isolates,
mainly Staphylococcus epidermidis.
• However, S. aureus linezolid resistance, while infrequent, has also been described.
• Vancomycin-resistant enterococci with linezolid resistance has also been described. Resistance in enterococci is also
infrequent, occurring in <1 percent of isolates in large surveillance studies.
• Resistance to linezolid typically occurs through multiple mutations of the 23S rRNA genes.
• Resistance also can emerge from mutations or by acquisition from other organisms.
• A mobile gene, cfr, encoding a methyltransferase that modifies 23S rRNA (causing failure of linezolid binding to its bacterial
target site, conferring resistance) has been identified in staphylococci and in enterococci.
• In vitro data demonstrating retained tedizolid activity against cfr isolates suggest this may be an effective alternative agent
against some linezolid-resistant pathogens, most notably S. aureus. Such isolates, although susceptible, may also demonstrate
increases in tedizolid minimum inhibitory concentration (MIC).
• Other plasmid-borne resistant determinants, optrA and poxtA, encode ribosomal protection factors leading to increased MICs
for linezolid and tedizolid.
• In one study including 154 linezolid-resistant Enterococcus isolates (Enterococcus faecium and Enterococcus faecalis), 26.3
percent of isolates carrying the poxtA-encoding plasmid also harbored the vanA gene.

7. PHARMACOKINETICS AND
PHARMACODYNAMICS
• General principles —
• The systemic absorption of linezolid approaches 100 percent following oral
administration.
• Linezolid binds poorly to serum proteins (31 percent). Therefore, it penetrates well
into most body compartments (including bone, alveoli, and the cerebrospinal
fluid).
• As a result, linezolid has a volume of distribution that is similar to total body
water (30 to 50 L). The overall tissue distribution of linezolid is stable and is not
adversely affected by sepsis or peripheral vascular disease or obesity.
• The drug undergoes hepatic oxidative metabolism into two inactive metabolites
eliminated predominantly in the urine.
• Linezolid has an elimination half-life of four hours.

8. • Other populations —
• Significant variability in linezolid trough concentrations have
been reported in hospitalized patients. Patients >80 years of age
age and those with renal dysfunction have demonstrated
elevated trough concentrations.
• In contrast, critical care patients and those with cystic fibrosis or
major burns may be at increased risk of subtherapeutic
exposure with standard dosing. Pharmacokinetic studies also
indicate altered pharmacokinetics of linezolid in patients with
obesity and hepatic dysfunction.

9. • Children — In general, the clearance of linezolid in children is
influenced by age, weight, and renal function.
• In studies of linezolid in children with critical illness, drug
clearance correlated directly with body weight and inversely
with aspartate aminotransferase. While clearance in newborns is
comparable with clearance in adults, children <12 years of age
exhibit more rapid clearance than adults.
• Published data for tedizolid pharmacokinetics in pediatric
patients are limited to adolescents and were generally
comparable with parameters seen in adult patients [69].

10. • Based largely on in vitro modeling, the antimicrobial
effectiveness of both linezolid and tedizolid is best predicted by
the ratio of the 24-hour area under the time-concentration
curve to minimum inhibitory concentration (MIC). Based on
these targets, simulations examining target attainment suggest
that isolates with an MIC ≥2 mcg/mL may not respond to
standard dosing.
• Linezolid displays moderate postantibiotic effects against S.
aureus.

11. DOSING AND ADMINISTRATION
• General principles — Linezolid may be given orally or parenterally. The
adult dose is 600 mg intravenously or orally twice daily.
• The pediatric dose is 10 mg/kg intravenously or orally either every 8 hours
(≤12 years of age) or every 12 hours (>12 years of age).
• Renal insufficiency — No dose adjustments are recommended for patients
with renal insufficiency. However, renal impairment leads to accumulation
of linezolid and its metabolites, and observational data has demonstrated
increased risk of thrombocytopenia in patients with renal insufficiency. Use
of serum drug concentration monitoring with dose adjustment may be
useful in patients with renal insufficiency.
• Hepatic insufficiency — Despite reductions in linezolid clearance in
patients with cirrhosis, dose adjustments for linezolid and tedizolid are not
recommended for patients with hepatic insufficiency.

12. • Use of ECMO — Reduced serum concentrations of linezolid have been observed
in patients undergoing extracorporeal membrane oxygenation (ECMO) while
receiving standard dosing. Use of serum drug concentration monitoring with dose
adjustment may be useful in such cases.
• Obesity — Standard linezolid dosing may be inadequate for patients who are
overweight and patients with obesity. In such cases, some favor that linezolid
dose adjustments be based on creatinine clearance (estimated utilizing the
Chronic Kidney Diseases Epidemiology formula [CrCLCKD-EPI]), rather than based
on weight (using body mass index or total body weight).. For patients ≥140 kg
with invasive infection due to pathogen with minimum inhibitory concentration
≥2 mcg/mL in the setting of weight ≥140 kg and CrCLCKD-EPI ≥60 mL/min/1.73
m2, dose escalation (up to 450 mg every 8 hours) may be appropriate.
• Duration of treatment — Linezolid and tedizolid are a maximum treatment
duration of 28 days and 6 days, respectively.
• Coadministration with other agents — Ideally, patients on serotonergic agent(s)
who require linezolid or tedizolid should discontinue the serotonergic agent at
least two weeks prior to beginning oxazolidinone therapy

13. • Patients on linezolid or tedizolid should avoid tyramine-containing foods
• PREGNANCY AND BREASTFEEDING
• Data on use of linezolid and tedizolid in pregnancy and breastfeeding are
limited.
• However, there are no controlled studies in pregnant women.
• Linezolid and tedizolid should be given to pregnant women only if the
potential benefits justify the potential risk to the fetus.
• Linezolid concentrations in breast milk are similar to maternal serum
concentrations. If linezolid is required by the mother, it is not a reason to
discontinue breastfeeding. However, because there is no published
experience with linezolid during breastfeeding, an alternate drug may be
preferred, especially while nursing a newborn or preterm infant
• It is unknown whether tedizolid is excreted in human breast milk.

14. ADVERSE EFFECTS
• General principles —
• In general, safety concerns limit widespread and extended use
of linezolid.
• The most significant adverse effects include gastrointestinal
symptoms, myelosuppression, neuropathy (peripheral and optic), and
lactic acidosis.
• Less frequently observed adverse effects include hepatotoxicity,
hypoglycemia, and SIADH-syndrome of inappropriate antidiuretic
hormone secretion.

15. • Myelosuppression —
• suppression of all blood cell lineages
• the incidence is less than 1 percent
• generally dependent on dose and duration of treatment.
• Thrombocytopenia (<100,000 platelets/mcL) is the most common
presentation of linezolid-induced myelosuppression.
• Risk factors for linezolid-induced myelosuppression include
• low baseline blood cell counts,
• renal impairment, and
• duration of linezolid therapy ≥14 days.
• Count recovery typically occurs within one to three weeks after
discontinuation of linezolid.
• There are no known effective measures for prevention of linezolid-
induced myelosuppression. Use of pre-emptive pyridoxine was not
associated with prevention of myelosuppression in one study
including 24 patients treated with a prolonged course of linezolid.
The time to recovery varies with the cell line and degree of
suppression.

16. • Neuropathy — associated with peripheral neuropathy and optic neuropathy
• These Effects Are Time And Dose Dependent
• Their Incidence Is Unknown.
• The Reported Duration Of Use Prior To Development Of Neuropathy Is 5 To 11
Months.
• The Mechanism Of Neural Toxicity Is Uncertain.
• Possibilities Include Impairment Of Mitochondrial Protein Synthesis Or Direct Toxic
Effects.
• Peripheral neuropathy typically presents as a "glove and stocking" sensory
impairment. Nerve conduction studies demonstrate a sensory-motor axonal
pattern.
• Optic neuropathy presents with diminished visual acuity, development of
scotomas, and diminished color perception.
• Linezolid should be discontinued in patients with peripheral or optic neuropathy.
There is no specific treatment for linezolid-induced neuropathy.
• Optic neuropathy may be reversible.
• In one report including two patients with linezolid-induced optic neuropathy,
visual function gradually recovered three to four months after drug
discontinuation. Peripheral neuropathy may be irreversible in some cases.

17. Linezolid-induced Lactic acidosis — LILA
• occur more frequently with prolonged administration (40 to 50 days).
• The mechanism may be attributable to mitochondrial toxicity
• Onset may be 1 to 16 weeks after drug initiation.
• Clinical manifestations may be nonspecific and include abdominal pain,
nausea, vomiting, and generalized weakness, in the setting of low serum
bicarbonate concentration. –measure ABG
• Such manifestations should prompt measurement of serum lactate
concentration.
• Linezolid should be discontinued in patients with lactic acidosis.
• lactic acidosis has a mortality rate of 25 percent.
• In recovery, lactate levels generally normalize in 2 to 14 days.

18. DRUG INTERACTIONS
• Administration of linezolid with concomitant serotonergic agents (notably
selective serotonin-reuptake inhibitors [SSRIs] and serotonin
norepinephrine reuptake inhibitors [SNRIs]) has been associated with
serotonin syndrome.
• Linezolid does not interact with the cytochrome P450 oxidative system.
Inducers of CYP3A may increase the clearance of linezolid. Concomitant
administration of agents that either induce (eg, rifampin, levothyroxine) or
inhibit (eg, clarithromycin, select proton pump inhibitors) p-glycoprotein
may decrease or increase linezolid concentrations, respectively.
• Coadministration of linezolid with warfarin may be associated with
increased prothrombin time; the mechanism is not known.

19. Serotonin syndrome
• — Linezolid can reversibly inhibit monoamine oxidase (MAO).
• Coadministration of linezolid with nonselective MAO inhibitors, SSRIs, SNRIs, or bupropion can precipitate serotonin
toxicity.
• Similarly, ingestion of tyramine-containing foods can cause hypertensive crisis or serotonin syndrome.
• The incidence of serotonin syndrome is less than 5 percent in most reports..
• Clinical manifestations of serotonin syndrome include a broad range of symptoms, from mild tremor to life-threatening
hyperthermia and shock.
• Onset of symptoms may be hours to days following coadministration of linezolid with serotonergic agents and
• may include tachycardia, hypertension, hyperthermia, agitation, tremor, myoclonus, hyperreflexia, muscle rigidity, dilated
pupils, dry mucus membranes, increased bowel sounds, flushed skin, and diaphoresis.
• The approach to management depends on the severity of illness.
• In patients with severe serotonergic syndrome, all serotonergic agents should be discontinued. "Serotonin syndrome
(serotonin toxicity)".)
• Symptoms usually resolve within 24 hours of drug discontinuation and initiating care, but drugs with long durations of
action or active metabolites may cause prolonged symptoms.

20. • The linezolid should be used in patients taking SSRIs or SNRIs only
when absolutely needed. If use of linezolid is required, the
serotonergic medication should be stopped at least two weeks in
advance of linezolid treatment, if feasible. However, abrupt
withdrawal of SSRIs or SNRIs can be problematic due to the concern
for withdrawal. In such situations, dose reduction may be an
acceptable alternative. While concomitant use of linezolid with an
SSRI or SNRI is not absolutely contraindicated, patients should be
instructed regarding the signs and symptoms of serotonin syndrome.

21. MONITORING
• Clinical monitoring —
• For patients receiving linezolid longer than 28 days, routine ophthalmologic and
neurologic assessment should be performed .
• Patients on serotonergic agents who are receiving linezolid or tedizolid should be
monitored for signs and symptoms of serotonin syndrome.
• Laboratory monitoring — For patients receiving linezolid or tedizolid for longer than
seven days, routine laboratory monitoring includes weekly complete blood count, basic
metabolic panel, and liver function panel.
• In addition, twice-weekly blood count monitoring is warranted for patients with
underlying myelosuppression or receiving other potentially myelosuppressive
medications.

22. Serum concentration monitoring
• Serum concentration monitoring done to reduce toxicity.
• Such monitoring may be useful in patient groups demonstrating high interpatient
variability in serum concentrations; these include
• patients on renal replacement therapy,
• patients receiving high doses and/or prolonged therapy,
• older adult patients,
• patients with severe hepatic insufficiency, and
• patients with extremes of body weight.
• However, the role of routine serum concentration monitoring of linezolid is hampered by
lack of established peak and trough targets and absence of a readily available assay.
• Thus far, clinical trial data for tedizolid have not established a relationship between
exposure and clinical response

23. Diet during therapeutic use of
monoamine oxidase inhibitors
• DIET THAT Not allowed
• Tap (draft) beer, Korean beer, vermouth
• Sourdough bread; crackers and breads that contain aged cheese
• All aged cheeses are absolutely not allowed
• All aged, smoked, pickled, or cured meats/fish/poultry are absolutely not allowed
• Soy products (eg, tofu, tempeh) Fava or broad beans (Italian green beans) and their
pods, Kim chee (Kimchi), sauerkraut, snow peas, soy beans, bean pastes, edamame
beans
• Avocado (over-ripened), banana (over-ripened), banana peel, dried fruit, any kind of
fruit that is over-ripened
• Soups, gravies, casseroles, pizzas that contain aged cheese; soups or casseroles with
flavoring meat extracts (eg, flavor cubes, bouillon), miso, broad or fava beans and
their pods, tofu, tempeh, soy products (eg, soy sauce, teriyaki sauce) or yeast extracts
• Snack foods containing aged cheeses
• All aged or fermented soy and yeast products (eg, soy sauce, teriyaki sauce, soy paste,
Thai or Vietnamese fish sauce, marmite/vegemite and other concentrated yeast
extracts), sauerkraut

24. Treatment indication
• Methicillin-resistant Staphylococcus aureus (MRSA) in adults:
Treatment of bacteremia
• Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations
• Methicillin-resistant Staphylococcus aureus (MRSA) in adults:
Treatment of skin and soft tissue infections
• Treatment of enterococcal infections
• Antituberculous drugs: An overview
• Acute cellulitis and erysipelas in adults
• Treatment of hospital-acquired and ventilator-associated pneumonia
in adults

25. New drug
•TEDIZOLID

26. • Plasma concentrations of oral Breast Cancer Resistance Protein
(BCRP) substrates may be increased by coadministration with
oral tedizolid due to its inhibition of BCRP in the intestine.
Coadministration of tedizolid with BCRP substrates with a narrow
therapeutic index (such as methotrexate or topotecan) should be
avoided if possible.
• Tedizolid exhibits weak and reversible MAO inhibition; thus far,
tedizolid has not been associated with serotonin syndrome. There are
no formal restrictions regarding coadministration of tedizolid with
serotonin syndrome agents or tyramine-containing foods; however,
thus far, such patients have not been included in phase 2 and 3 trials.

27. summary
• Linezolid is a synthetic oxazolidinone with bacteriostatic activity
• Tedizolid is a newer drug in the same class with comparable spectrum of activity. Use of these drugs
has been limited by cost and concern for adverse effects.
• In general, they are reserved for patients who do not respond to or cannot tolerate other agents.
• These drugs also suppress production of bacterial toxins.
• Linezolid failure and resistance have been described.
• ●Linezolid and tedizolid may be administered orally or intravenously.
• Both drugs exhibit high oral bioavailability and do not require dosing adjustment in patients with
hepatic or renal dysfunction.
• Ideally, patients on serotonergic agent(s) who require linezolid or tedizolid should discontinue the
serotonergic agent at least two weeks prior to beginning oxazolidinone therapy and avoid tyramine-
containing foods.
• Safety concerns limit use of linezolid, particularly for extended durations.

28. • The neuropathic effects are time and dose dependent.
• The likelihood of linezolid-associated lactic acidosis increases with the duration of
administration.
• Concomitant administration of linezolid with serotonergic agents has been associated
with serotonin syndrome.
• ●Tedizolid has been associated with myelosuppression and neuropathy; thus far, it has not
been associated with lactic acidosis or serotonin syndrome.
• ●For patients receiving linezolid or tedizolid for longer than seven days, routine
laboratory monitoring includes weekly complete blood count, basic metabolic panel, and
liver function panel. For patients with underlying myelosuppression or receiving other
potentially myelosuppressive medications, twice-weekly blood count monitoring is
warranted.
• For patients receiving linezolid longer than 28 days, routine ophthalmologic and
neurologic assessment should be performed.

29. • Thank you for patience's listening