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Tobramycin (Systemic)

Pronunciation

Pronunciation

(toe bra MYE sin)

Index Terms

  • Tobramycin Sulfate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection:

Generic: 10 mg/mL (2 mL); 80 mg/2 mL (2 mL); 1.2 g/30 mL (30 mL); 2 g/50 mL (50 mL)

Solution, Intravenous:

Generic: 80 mg (100 mL)

Solution Reconstituted, Injection:

Generic: 1.2 g (1 ea)

Solution Reconstituted, Injection [preservative free]:

Generic: 1.2 g (1 ea)

Pharmacologic Category

  • Antibiotic, Aminoglycoside

Pharmacology

Interferes with bacterial protein synthesis by binding to 30S and 50S ribosomal subunits, resulting in a defective bacterial cell membrane

Absorption

Oral: Poorly absorbed

IM: Rapid and complete

Distribution

Distributes to extracellular fluid, including serum, abscesses, ascitic, pericardial, pleural, synovial, lymphatic, and peritoneal fluids; poor penetration into CSF, eye, bone, prostate; Vd: Higher in neonates than older pediatric and adult patients; also increased in patients with edema, ascites, fluid overload; decreased in patients with dehydration; Systemic:

Neonates: 0.45 ± 0.1 L/kg

Infants: 0.4 ± 0.1 L/kg

Children: 0.35 ± 0.15 L/kg

Adolescents: 0.3 ± 0.1 L/kg

Adults: 0.2 to 0.3 L/kg

Excretion

Normal renal function: Urine (~90% to 95%) within 24 hours

Time to Peak

Serum: IM: 30 to 60 minutes; IV: ~30 minutes; Note: Distribution may be prolonged after larger doses. One study reported a 1.7-hour distribution period after a 60-minute, high-dose aminoglycoside infusion (Demczar 1997).

Half-Life Elimination

Neonates: ≤1,200 g: 11 hours; >1,200 g: 2 to 9 hours

Infants: 4 ± 1 hour

Children: 2 ± 1 hour

Adolescents: 1.5 ± 1 hour

Adults: IV: 2 to 3 hours; directly dependent upon glomerular filtration rate

Adults with impaired renal function: 5 to 70 hours

Protein Binding

<30%

Special Populations: Renal Function Impairment

Clearance is decreased in renal impairment.

Use: Labeled Indications

Treatment of documented or suspected infections caused by susceptible gram-negative bacilli, including Pseudomonas aeruginosa.

Contraindications

Hypersensitivity to tobramycin, other aminoglycosides, or any component of the formulation

Dosing: Adult

Note: Individualization is critical because of the low therapeutic index.

In underweight and nonobese patients, use of total body weight (TBW) instead of ideal body weight for determining the initial mg/kg/dose is widely accepted (Nicolau 1995). Ideal body weight (IBW) also may be used to determine doses for patients who are neither underweight nor obese (Gilbert 2009).

Initial and periodic plasma drug levels (eg, peak and trough with conventional dosing, post dose level at a prespecified time with extended-interval dosing) should be determined, particularly in critically-ill patients with serious infections or in disease states known to significantly alter aminoglycoside pharmacokinetics (eg, cystic fibrosis, burns, or major surgery).

Severe life-threatening infections: IM, IV:

Conventional: 1 to 2.5 mg/kg/dose every 8 to 12 hours; to ensure adequate peak concentrations early in therapy, higher initial dosage may be considered in selected patients when extracellular water is increased (edema, septic shock, postsurgical, and/or trauma)

Once-daily: 4 to 7 mg/kg/dose once daily; some clinicians recommend this approach for all patients with normal renal function; this dose is at least as efficacious with similar, if not less, toxicity than conventional dosing.

Brucellosis: IM, IV: 240 mg (IM) daily or 5 mg/kg (IV) daily for 7 days; either regimen recommended in combination with doxycycline

Cholangitis: IM, IV: 4 to 6 mg/kg once daily with ampicillin

CNS shunt infection: Intrathecal (off-label route): 5 to 20 mg/day (Tunkel, 2004)

Diverticulitis, complicated: IM, IV: 1.5 to 2 mg/kg every 8 hours (with ampicillin and metronidazole)

Meningitis (Enterococcus or Pseudomonas aeruginosa): IV: 5 mg/kg/day in divided doses every 8 hours (administered with another bacteriocidal drug)

Pelvic inflammatory disease: IM, IV: Loading dose: 2 mg/kg, then 1.5 mg/kg every 8 hours or 4.5 mg/kg once daily

Plague (Yersinia pestis): IM, IV: Treatment: 5 mg/kg/day, followed by postexposure prophylaxis with doxycycline

Pneumonia, hospital- or ventilator-associated: IM, IV: 7 mg/kg/day (with antipseudomonal beta-lactam or carbapenem)

Prophylaxis against endocarditis (dental, oral, upper respiratory procedures, GI/GU procedures): IM, IV: 1.5 mg/kg with ampicillin (50 mg/kg) 30 minutes prior to procedure. Note: AHA guidelines now recommend prophylaxis only in patients undergoing invasive procedures and in whom underlying cardiac conditions may predispose to a higher risk of adverse outcomes should infection occur. As of April 2007, routine prophylaxis no longer recommended by the AHA.

Tularemia: IM, IV: 5 mg/kg/day divided every 8 hours for 1 to 2 weeks

Urinary tract infection: IM, IV: 1.5 mg/kg/dose every 8 hours

Dosing: Geriatric

Dosage should be based on an estimate of ideal body weight.

IM, IV: 1.5 to 5 mg/kg/day in 1 to 2 divided doses

IV: Once daily or extended interval: 5 to 7 mg/kg/dose given every 24, 36, or 48 hours based on creatinine clearance

Dosing: Pediatric

Individualization is critical because of the low therapeutic index

Use of ideal body weight (IBW) for determining the mg/kg/dose appears to be more accurate than dosing on the basis of total body weight (TBW).

Usual dosage range: IM, IV:

Infants and Children <5 years: 2.5 mg/kg/dose every 8 hours

Children >5 years: 2 to 2.5 mg/kg/dose every 8 hours

CNS shunt infection: Intrathecal (off-label route): Refer to adult dosing.

Cystic fibrosis: IM, IV: 2.5 to 3.3 mg/kg every 6 to 8 hours. Note: Some patients may require larger or more frequent doses if serum levels document the need (eg, cystic fibrosis or febrile granulocytopenic patients).

Dosing: Renal Impairment

IM, IV:

Conventional dosing:

CrCl >60 mL/minute: Administer every 8 hours.

CrCl 40 to 60 mL/minute: Administer every 12 hours.

CrCl 20 to 39 mL/minute: Administer every 24 hours.

CrCl <20 mL/minute: Loading dose, then monitor levels.

High-dose therapy: Interval may be extended (eg, every 48 hours) in patients with moderate renal impairment (CrCl 30 to 59 mL/minute) and/or adjusted based on serum level determinations.

Intermittent hemodialysis (IHD) (administer after hemodialysis on dialysis days) (Heintz 2009): Dialyzable (25% to 70%; variable; dependent on filter, duration, and type of HD): IV:

Loading dose of 2 to 3 mg/kg, followed by:

Mild UTI or synergy: 1 mg/kg/dose every 48 to 72 hours; consider redosing for pre-HD or post-HD serum concentrations <1 mg/L

Moderate to severe UTI: 1 to 1.5 mg/kg/dose every 48 to 72 hours; consider redosing for pre-HD serum concentrations <1.5 to 2 mg/L or post-HD concentrations <1 mg/L

Systemic gram-negative infection: 1.5 to 2 mg/kg/dose every 48 to 72 hours; consider redosing for pre-HD serum concentrations <3 to 5 mg/L or post-HD serum concentrations <2 mg/L

Note: Dosing dependent on the assumption of 3 times/week, complete IHD sessions.

Peritoneal dialysis (PD):

Administration via peritoneal dialysis (PD) fluid:

Gram-negative infection: 4 to 8 mg/L (4 to 8 mcg/mL) of PD fluid

Gram-positive infection (ie, synergy): 3 to 4 mg/L (3 to 4 mcg/mL) of PD fluid

Administration IVPB/IM: Dose as for CrCl <10 mL/minute and follow levels

Continuous renal replacement therapy (CRRT) (Heintz 2009; Trotman 2005): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as target drug concentrations (if appropriate). Note: The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 to 2 L/hour and minimal residual renal function) and should not supersede clinical judgment:

CVVH/CVVHD/CVVHDF: IV:

Mild UTI or synergy: Loading dose of 2 to 3 mg/kg, followed by 1 mg/kg/dose every 24 to 36 hours (redose when serum concentration <1 mg/L [Heintz 2009])

Moderate-severe UTI: Loading dose of 2 to 3 mg/kg, followed by 1 to 1.5 mg/kg/dose every 24 to 36 hours (redose when serum concentration <1.5 to 2 mg/L [Heintz 2009])

Systemic gram-negative infection: Loading dose of 2 to 3 mg/kg, followed by 1.5 to 2.5 mg/kg/dose every 24 to 48 hours (generally accepted to redose when serum concentration <2 mg/L; one reference suggests redosing when <3 mg/L [Heintz 2009])

Dosing: Hepatic Impairment

No dosage adjustment necessary; does not undergo hepatic metabolism.

Dosing: Obesity

In moderate obesity (TBW/IBW ≥1.25) or greater, (eg, morbid obesity [TBW/IBW >2]), initial dosage requirement may be estimated using a dosing weight of IBW + 0.4 (TBW - IBW) (Traynor 1995).

Reconstitution

Solution for injection: Dilute in 50-100 mL NS or D5W for IV infusion.

Administration

IV: Administer by intermittent infusion over 20 to 60 minutes; higher doses are generally administered over 60 minutes (Aminimanizani 2002; Demsczar 1997). Flush line with saline before and after administration.

Dietary Considerations

May require supplementation of calcium, magnesium, potassium.

Compatibility

Stable in dextran 40 10% in dextrose, D5NS, D5W, D10W, mannitol 20%, LR, NS.

Y-site administration: Incompatible with allopurinol, amphotericin B cholesteryl sulfate complex, azithromycin, hetastarch NS, indomethacin, pantoprazole, pemetrexed, piperacillin, piperacillin/tazobactam, propofol, sargramostim.

Storage

Stable at room temperature both as the clear, colorless solution and as the dry powder. Reconstituted solutions remain stable for 24 hours at room temperature and 96 hours when refrigerated.

Drug Interactions

AbobotulinumtoxinA: Aminoglycosides may enhance the neuromuscular-blocking effect of AbobotulinumtoxinA. Monitor therapy

Amphotericin B: May enhance the nephrotoxic effect of Aminoglycosides. Monitor therapy

Arbekacin: May enhance the nephrotoxic effect of Aminoglycosides. Arbekacin may enhance the ototoxic effect of Aminoglycosides. Monitor therapy

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Bisphosphonate Derivatives: Aminoglycosides may enhance the hypocalcemic effect of Bisphosphonate Derivatives. Monitor therapy

Capreomycin: May enhance the neuromuscular-blocking effect of Aminoglycosides. Monitor therapy

CARBOplatin: Aminoglycosides may enhance the ototoxic effect of CARBOplatin. Especially with higher doses of carboplatin. Monitor therapy

Cefazedone: May enhance the nephrotoxic effect of Aminoglycosides. Monitor therapy

Cephalosporins (2nd Generation): May enhance the nephrotoxic effect of Aminoglycosides. Monitor therapy

Cephalosporins (3rd Generation): May enhance the nephrotoxic effect of Aminoglycosides. Monitor therapy

Cephalosporins (4th Generation): May enhance the nephrotoxic effect of Aminoglycosides. Monitor therapy

Cephalothin: May enhance the nephrotoxic effect of Aminoglycosides. Monitor therapy

Cephradine: May enhance the nephrotoxic effect of Aminoglycosides. Monitor therapy

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Avoid combination

CISplatin: May enhance the nephrotoxic effect of Aminoglycosides. Monitor therapy

Colistimethate: Aminoglycosides may enhance the nephrotoxic effect of Colistimethate. Aminoglycosides may enhance the neuromuscular-blocking effect of Colistimethate. Consider therapy modification

CycloSPORINE (Systemic): Aminoglycosides may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Monitor therapy

Distigmine: Aminoglycosides may diminish the therapeutic effect of Distigmine. Monitor therapy

Foscarnet: May enhance the nephrotoxic effect of Aminoglycosides. Avoid combination

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

Loop Diuretics: May enhance the adverse/toxic effect of Aminoglycosides. Specifically, nephrotoxicity and ototoxicity. Monitor therapy

Mannitol (Systemic): May enhance the nephrotoxic effect of Aminoglycosides. Avoid combination

Mecamylamine: Aminoglycosides may enhance the neuromuscular-blocking effect of Mecamylamine. Avoid combination

Neuromuscular-Blocking Agents: Aminoglycosides may enhance the respiratory depressant effect of Neuromuscular-Blocking Agents. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May decrease the excretion of Aminoglycosides. Data only in premature infants. Monitor therapy

OnabotulinumtoxinA: Aminoglycosides may enhance the neuromuscular-blocking effect of OnabotulinumtoxinA. Monitor therapy

Oxatomide: May enhance the ototoxic effect of Aminoglycosides. Monitor therapy

Penicillins: May decrease the serum concentration of Aminoglycosides. Primarily associated with extended spectrum penicillins, and patients with renal dysfunction. Exceptions: Amoxicillin; Ampicillin; Cloxacillin; Dicloxacillin; Nafcillin; Oxacillin; Penicillin G (Parenteral/Aqueous); Penicillin G Benzathine; Penicillin G Procaine; Penicillin V Potassium. Consider therapy modification

RimabotulinumtoxinB: Aminoglycosides may enhance the neuromuscular-blocking effect of RimabotulinumtoxinB. Monitor therapy

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification

Tenofovir Products: Aminoglycosides may increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Aminoglycosides. Monitor therapy

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Vancomycin: May enhance the nephrotoxic effect of Aminoglycosides. Monitor therapy

Test Interactions

Some penicillin derivatives may accelerate the degradation of aminoglycosides in vitro, leading to a potential underestimation of aminoglycoside serum concentration.

Adverse Reactions

Frequency not defined.

Central nervous system: Confusion, disorientation, dizziness, headache, lethargy, vertigo

Dermatologic: Exfoliative dermatitis, pruritus, skin rash, urticaria

Endocrine & metabolic: Decreased serum calcium, decreased serum magnesium, decreased serum potassium, decreased serum sodium, increased lactate dehydrogenase, increased nonprotein nitrogen

Gastrointestinal: Diarrhea, nausea, vomiting

Genitourinary: Casts in urine, oliguria, proteinuria

Hematologic & oncologic: Anemia, eosinophilia, granulocytopenia, leukocytosis, leukopenia, thrombocytopenia

Hepatic: Increased serum ALT, increased serum AST, increased serum bilirubin

Local: Pain at injection site

Otic: Auditory ototoxicity, hearing loss, tinnitus, vestibular ototoxicity

Renal: Increased blood urea nitrogen, increased serum creatinine

Miscellaneous: Fever

<1% (Limited to important or life-threatening): Anaphylaxis, clostridium difficile associated diarrhea, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis

ALERT: U.S. Boxed Warning

Ototoxicity:

Neurotoxicity, manifested as both auditory and vestibular ototoxicity, can occur. The auditory changes are irreversible, are usually bilateral, and may be partial or total. Eighth nerve impairment and nephrotoxicity may develop, primarily in patients having preexisting renal damage and in those with healthy renal function to whom aminoglycosides are administered for longer periods or in higher doses than those recommended. Other manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching, and convulsions. The risk of aminoglycoside-induced hearing loss increases with the degree of exposure to either high peak or high trough serum concentrations. Patients who develop cochlear damage may not have symptoms during therapy to warn them of eighth-nerve toxicity, and partial or total irreversible bilateral deafness may continue to develop after the drug has been discontinued. Keep patients treated with tobramycin injection and other aminoglycosides under close clinical observation because these drugs have an inherent potential for causing ototoxicity.

Nephrotoxicity:

Rarely, nephrotoxicity may not become apparent until the first few days after cessation of therapy. Aminoglycoside-induced nephrotoxicity usually is reversible. Keep patients treated with tobramycin injection and other aminoglycosides under close clinical observation because these drugs have an inherent potential for causing nephrotoxicity.

Monitoring:

Closely monitor renal and eighth nerve function in patients with known or suspected renal impairment and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy. Periodically monitor peak and trough serum concentrations of aminoglycosides during therapy to assure adequate levels and to avoid potentially toxic levels. Prolonged serum concentrations above 12 mcg/mL should be avoided. Rising trough levels (above 2 mcg/mL) may indicate tissue accumulation. Such accumulation, excessive peak concentrations, advanced age, and cumulative dose may contribute to ototoxicity and nephrotoxicity. Examine urine for decreased specific gravity and increased excretion of protein, cells, and casts. Periodically measure serum urea nitrogen (BUN), serum creatinine, and creatinine clearance. When feasible, it is recommended that serial audiograms be obtained in patients old enough to be tested, particularly high-risk patients. Evidence of impairment of renal, vestibular, or auditory function requires discontinuation of the drug or dosage adjustment.

Use tobramycin injection with caution in premature and neonatal infants because of their renal immaturity and the resulting prolongation of serum half-life of the drug.

Concurrent therapy:

Avoid concurrent and sequential use of other neurotoxic or nephrotoxic antibiotics, particularly other aminoglycosides (eg, amikacin, streptomycin, neomycin, kanamycin, gentamicin, paromomycin), cephaloridine, viomycin, polymyxin B, colistin, cisplatin, and vancomycin. Other factors that may increase patient risk are advanced age and dehydration.

Do not give aminoglycosides concurrently with potent diuretics, such as ethacrynic acid and furosemide. Some diuretics themselves cause ototoxicity, and intravenously (IV) administered diuretics enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue.

Pregnancy:

Aminoglycosides can cause fetal harm when administered to a pregnant woman.

Warnings/Precautions

Concerns related to adverse effects:

• Nephrotoxicity: [US Boxed Warning]: May cause nephrotoxicity; usual risk factors include pre-existing renal impairment, concomitant nephrotoxic medications, advanced age, and dehydration. Discontinue treatment if signs of nephrotoxicity occur; renal damage is usually reversible.

• Neuromuscular blockade and respiratory paralysis: May cause neuromuscular blockade, respiratory failure, and prolonged respiratory paralysis, especially when given soon after anesthesia or muscle relaxants.

• Neurotoxicity: [US Boxed Warning]: May cause neurotoxicity; usual risk factors include pre-existing renal impairment, concomitant neuro-/nephrotoxic medications, advanced age, and dehydration. Ototoxicity is proportional to the amount of drug given and the duration of treatment. Tinnitus or vertigo may be indications of vestibular injury and impending bilateral irreversible damage. Tinnitus and/or hearing loss have also been reported. Discontinue treatment if signs of ototoxicity occur.

• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Hearing impairment: Use with caution in patients with pre-existing vertigo, tinnitus, or hearing loss.

• Hypocalcemia: Use with caution in patients with hypocalcemia.

• Neuromuscular disorders: Use with caution in patients with neuromuscular disorders, including myasthenia gravis and Parkinson disease.

• Renal impairment: Use with caution in patients with pre-existing renal insufficiency; dosage modification required during systemic therapy.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pregnancy: [US Boxed Warnings]: Aminoglycosides may cause fetal harm if administered to a pregnant woman.

Dosage form specific issues:

• Sulfite: Solution for injection may contain sodium metabisulfate; use caution in patients with sulfite allergy.

Other warnings/precautions:

• Long-term use: Systemic therapy is not intended for long-term therapy due to toxic hazards associated with extended administration.

Monitoring Parameters

Urinalysis, urine output, BUN, serum creatinine, peak and trough plasma tobramycin levels. Levels are typically obtained after the third dose in conventional dosing. Be alert to ototoxicity; hearing should be tested before and during treatment

Some penicillin derivatives may accelerate the degradation of aminoglycosides in vitro. This may be clinically-significant for certain penicillin (ticarcillin, piperacillin, carbenicillin) and aminoglycoside (gentamicin, tobramycin) combination therapy in patients with significant renal impairment. Close monitoring of aminoglycoside levels is warranted.

Pregnancy Risk Factor

D

Pregnancy Considerations

[US Boxed Warning]: Aminoglycosides may cause fetal harm if administered to a pregnant woman. Tobramycin crosses the placenta. There are several reports of total irreversible bilateral congenital deafness in children whose mothers received another aminoglycoside (streptomycin) during pregnancy. Although serious side effects to the fetus/infant have not been reported following maternal use of all aminoglycosides, a potential for harm exists.

Due to pregnancy-induced physiologic changes, some pharmacokinetic parameters of tobramycin may be altered (Bourget 1991). Tobramycin injection may be used for the management of cystic fibrosis in pregnant patients with Pseudomonas aeruginosa (inhalation is preferred unless risk of infection is great) (Edenborough 2008).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, diarrhea, nausea, vomiting, or injection site pain. Have patient report immediately to prescriber signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), change in balance, dizziness, passing out, chills, pharyngitis, muscle weakness, burning or numbness feeling, twitching, tinnitus, hearing impairment, hearing loss, seizures, bruising, bleeding, severe loss of strength and energy, confusion, signs of Clostridium difficile (C. diff)-associated diarrhea (abdominal pain or cramps, severe diarrhea or watery stools, or bloody stools), or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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