Aminoglycoside Antibiotics

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Chapter: Essential pharmacology : Aminoglycoside Antibiotics

These are a group of natural and semisynthetic antibiotics having polybasic amino groups linked glycosidically to two or more aminosugar (streptidine, 2deoxy streptamine, garosamine) residues.


AMINOGLYCOSIDE ANTIBIOTICS

 

These are a group of natural and semisynthetic antibiotics having polybasic amino groups linked glycosidically to two or more aminosugar (streptidine, 2deoxy streptamine, garosamine) residues.

 

Unlike penicillin, which was a chance discovery, aminoglycosides are products of deliberate search for drugs effective against gram-negative bacteria. Streptomycin was the first member discovered in 1944 by Waksman and his colleagues. It assumed great importance because it was active against tubercle bacilli. Others have been produced later; now aminoglycosides are a sizable family. All aminoglycosides are produced by soil actinomycetes and have many common properties.

 

Systemic Aminoglycosides

 

Streptomycin       

Amikacin

Gentamicin          

Sisomicin

Kanamycin          

Netilmicin

Tobramycin

 

Topical Aminoglycosides

 

Neomycin            

Framycetin

 

Common Properties Of Aminoglycoside Antibiotics

 

·     All are used as sulfate salts, which are highly water soluble; solutions are stable for months.

 

·     They ionize in solution; are not absorbed orally; distribute only extracellularly; do not penetrate brain or CSF.

 

·     All are excreted unchanged in urine by glomerular filtration.

 

·     All are bactericidal and more active at alkaline pH.

 

·     They act by interferring with bacterial protein synthesis.

 

·  All are active primarily against aerobic gram-negative bacilli and do not inhibit anaerobes.

 

·     There is only partial cross resistance among them.

 

·     They have relatively narrow margin of safety.

 

·     All exhibit ototoxicity and nephrotoxicity.

 

Mechanism Of Action

 

The aminoglycosides are bactericidal antibiotics, all having the same general pattern of action which may be described in two main steps:

 

a) Transport of the aminoglycoside through the bacterial cell wall and cytoplasmic membrane.

b)   Binding to ribosomes resulting in inhibition of protein synthesis.

 

Transport of aminoglycoside into bacteria is a multistep process. They diffuse across the outer coat of gram-negative bacteria through porin channels. Entry from the periplasmic space across the cytoplasmic membrane is carrier mediated which is linked to the electron transport chain. Thus, penetration is dependent upon maintenance of a polarized membrane and on oxygen dependent active processes. These processes are inactivated under anaerobic conditions; anaerobes are not sensitive and facultative anaerobes are more resistant when O2 supply is deficient, e.g. inside big abscesses. Penetration is also favoured by high pH; aminoglycosides are ~20 times more active in alkaline than in acidic medium. Inhibitors of bacterial cell wall (βlactams, vancomycin) enhance entry of aminoglycosides and exhibit synergism.

 

Once inside the bacterial cell, streptomycin binds to 30S ribosomes, but other aminoglycosides bind to additional sites on 50S subunit, as well as to 30S50S interface. They freeze initiation of protein synthesis, prevent polysome formation and promote their disaggregation to monosomes so that only one ribosome is attached to each strand of mRNA. Binding of aminoglycoside to 30S50S juncture causes distortion of mRNA codon recognition resulting in misreading of the code: one or more wrong amino acids are entered in the peptide chain and/ or peptides of abnormal lengths are produced. Different aminoglycosides cause misreading at different levels depending upon their selective affinity for specific ribosomal proteins.

 

The cidal action of these drugs appears to be based on secondary changes in the integrity of bacterial cell membrane, because other antibiotics which inhibit protein synthesis (tetracyclines, chloramphenicol, erythromycin) are only static. After exposure to aminoglycosides, sensitive bacteria become more permeable; ions, amino acids and even proteins leak out followed by cell death. This probably results from incorporation of the defective proteins into the cell membrane. One of the consequences of aminoglycoside induced alteration of cell membrane is augmentation of the carrier-mediated entry of the antibiotic. This reinforces the lethal action.

 

The cidal action of aminoglycosides is concentration dependent, i.e. rate of bacterial cell killing is directly related to the ratio of the peak antibiotic concentration to the MIC value. They also exert a long and concentration dependent ‘post-antibiotic effect’. It has, therefore, been argued that despite their short t½ (2–4 hr), single injection of the total daily dose of aminoglycoside may be more effective and possibly less toxic than its conventional division into 2–3 doses.

 

 

Mechanism Of Resistance

 

Resistance to aminoglycosides is acquired by one of the following mechanisms:

 

a)    Acquisition of cell membrane bound inactivating enzymes which phosphorylate/ adenylate or acetylate the antibiotic. The conjugated aminoglycosides do not bind to the target ribosomes and are incapable of enhancing active transport like the unaltered drug. These enzymes are acquired mainly by conjugation and transfer of plasmids. Nosocomial microbes have become rich in such plasmids, some of which encode for multidrug resistance. This is the most important mechanism of development of resistance to aminoglycosides. Susceptibility of different aminoglycosides to these enzymes differs. Thus, cross resistance among different members is partial or absent.

 

b)   Mutation decreasing the affinity of ribosomal proteins that normally bind the aminoglycoside: this mechanism can confer high degree resistance, but operates to a limited extent, e.g. E. coli that develop streptomycin resistance by single step mutation do not bind the antibiotic on the polyribosome. Only a few other instances are known. This type of resistance is specific for a particular aminoglycoside.

 

c)      Decreased efficiency of the aminoglycoside transporting mechanism: either the pores in the outer coat become less permeable or the active transport is interfered. This again is not frequently encountered in the clinical setting. In some Pseudomonas which develop resistance, the antibiotic induced 2nd phase active transport has been found to be deficient.

 

Shared Toxicities

 

The aminoglycosides produce toxic effects which are common to all members, but the relative propensity differs (see Table 53.1).

 


 

1. Ototoxicity

 

This is the most important dose and duration of treatment related adverse effect. The vestibular or the cochlear part may be primarily affected by a particular aminoglycoside. These drugs are concentrated in the labyrinthine fluid and are slowly removed from it when the plasma concentration falls. Ototoxicity is greater when plasma concentration of the drug is persistently high and above a threshold value. The vestibular/ cochlear sensory cells and hairs undergo concentration dependent destructive changes. Aminoglycoside ear drops can cause ototoxicity when instilled in patients with perforated eardrum; contraindicated in them.

 

Cochlear Damage It starts from the base and spreads to the apex; hearing loss affects the high frequency sound first, then progressively encompasses the lower frequencies. No regeneration of the sensory cells occurs; auditory nerve fibres degenerate in a retrograde manner—deafness is permanent. Older patients and those with preexisting hearing defect are more susceptible. Initially, the cochlear toxicity is asymptomatic; can be detected only by audiometry. Tinnitus then appears, followed by progressive hearing loss. On stopping the drug, tinnitus disappears in 4–10 days, but frequency loss persists.

 

Vestibular Damage Headache is usually first to appear, followed by nausea, vomiting, dizziness, nystagmus, vertigo and ataxia. When the drug is stopped at this stage, it passes into a chronic phase lasting 6 to 10 weeks in which the patient is asymptomatic while in bed and has difficulty only during walking. Compensation by visual and proprioceptive positioning and recovery (often partial) occurs over 1–2 years. Permanency of changes depends on the extent of initial damage and the age of the patient (elderly have poor recovery).

 

2. Nephrotoxicity

 

It manifests as tubular damage resulting in loss of urinary concentrating power, low g.f.r., nitrogen retention, albuminuria and casts. Aminoglycosides attain high concentration in the renal cortex and toxicity is related to the total amount of the drug received by the patient. It is more in the elderly and in those with preexisting kidney disease. Essentially, renal damage caused by aminoglycosides is totally reversible, provided the drug is promptly discontinued. It has been suggested that aminoglycosides interfere with the production of PGs in the kidney and that this is causally related to the reduced g.f.r. An important implication of aminoglycoside-induced nephrotoxicity is reduced clearance of the antibiotic higher blood levels enhanced ototoxicity.

 

3. Neuromuscular Blockade

 

All aminoglycosides reduce ACh release from the motor nerve endings: interfere with mobilization of centrally located synaptic vesicles to fuse with the terminal membrane (probably by antagonizing Ca2+) as well as decrease the sensitivity of the muscle endplates to Ach. The effect of this action is not manifested ordinarily in the clinical use of these drugs. However, apnoea and fatalities have occurred when these antibiotics were put into peritoneal or pleural cavity after an operation, especially if a curare-like muscle relaxant was administered during surgery. Rapid absorption form the peritoneum/pleura produces high blood levels and adds to the residual action of the neuromuscular blocker.

 

Neomycin and streptomycin have higher propensity than kanamycin, gentamicin or amikacin; tobramycin is least likely to produce this effect. The neuromuscular block can be partially antagonized by i.v. injection of a calcium salt. Neostigmine has inconsistent reversing action.

 

Myasthenic weakness is accentuated by these drugs. Neuromuscular blockers should be used cautiously in patients receiving aminoglycosides.

 

Precautions And Interactions

 

1.   Avoid aminoglycosides during pregnancy: risk of foetal ototoxicity.

2.   Avoid concurrent use of other ototoxic drugs, e.g. high ceiling diuretics, minocycline.

3.  Avoid concurrent use of other nephrotoxic drugs, e.g. amphotericin B, vancomycin, cyclosporine and cisplatin.

4.   Cautious use in patients past middle age and in those with kidney damage.

5.   Cautious use of muscle relaxants in patients receiving an aminoglycoside.

6.   Do not mix aminoglycoside with any drug in the same syringe/infusion bottle.

 

 

STREPTOMYCIN

 

It is the oldest aminoglycoside antibiotic obtained from Streptomyces griseus; used extensively in the past, but now practically restricted to treatment of tuberculosis. It is less potent (MICs are higher) than other aminoglycosides. The antimicrobial spectrum of streptomycin is relatively narrow: active primarily against aerobic gram-negative bacilli, but potency is low. Sensitive organisms are—H. ducreyi, Brucella, Yersinia pestis, Francisella tularensis, Nocardia, Calym. granulomatis, M. tuberculosis. Only few strains of E. coli, H. influenzae, V. cholerae, Shigella, Klebsiella, enterococci and some gram-positive cocci are now inhibited, that too at higher concentrations. All other organisms including Pseudomonas are unaffected.

 

Resistance

 

Many organisms develop rapid resistance to streptomycin, either by onestep mutation or by acquisition of plasmid which codes for inactivating enzymes. In the intestinal and urinary tracts, resistant organisms may emerge within 2 days of therapy. E. coli., H. influenzae, Str. pneumoniae, Str. pyogenes, Staph. aureus have become largely resistant. If it is used alone, M. tuberculosis also become resistant.

 

Streptomycin Dependence

 

Certain mutants grown in the presence of streptomycin become dependent on it. Their growth is promoted rather than inhibited by the antibiotic. This occurs when the antibiotic induced misreading of the genetic code becomes a normal feature for the organism. This phenomenon is probably significant only for use of streptomycin in tuberculosis.

 

Cross Resistance

 

Only partial and often unidirectional cross resistance occurs between streptomycin and other aminoglycosides.

 

Pharmacokinetics

 

Streptomycin is highly ionized. It is neither absorbed nor destroyed in the g.i.t. However, absorption from injection site in muscles is rapid. It is distributed only extracellularly: volume of distribution (0.3 L/kg) is nearly equal to the extracellular fluid volume. Low concentrations are attained in serous fluids like synovial, pleural, peritoneal. Concentrations in CSF and aqueous humour are often nontherapeutic, even in the presence of inflammation. Plasma protein binding is clinically insignificant.

 

Streptomycin is not metabolized—excreted unchanged in urine. Glomerular filtration is the main channel: tubular secretion and reabsorption are negligible. The plasma t½ is 2–4 hours, but the drug persists longer in tissues. Renal clearance of streptomycin parallels creatinine clearance and is approximately 2/3 of it. Halflife is prolonged and accumulation occurs in patients with renal insufficiency, in the elderly and neonates who have low g.f.r. Reduction in dose or increase in dose-interval is essential in these situations.

 

These pharmacokinetic features apply to all systemically administered aminoglycosides.

 

Adverse Effects

 

About 1/5 patients given streptomycin 1 g BD i.m. experience vestibular disturbances. Auditory disturbances are less common.

 

Streptomycin has the lowest nephrotoxicity among aminoglycosides; probably because it is not concentrated in the renal cortex. Hypersensitivity reactions are rare; rashes, eosinophilia, fever and exfoliative dermatitis have been noted. Anaphylaxis is very rare. Topical use is contraindicated for fear of contact sensitization.

 

Superinfections are not significant. Pain at injection site is common. Paraesthesias and scotoma are occasional.

 

AMBISTRYNS 0.75, 1 g dry powder per vial for inj.

 

Acute infections: 1 g (0.75 g in those above 50 yr age) i.m. BD for 7–10 days.

 

Tuberculosis: 1 g or 0.75 g i.m. OD or twice weekly for 30–60 days.

 

Uses

 

1.  Tuberculosis: see Ch. No. 55.

 

2. Subacute bacterial endocarditis (SABE): Streptomycin (now mostly gentamicin) is given in conjunction with penicillin. A 4–6 weeks treatment is needed.

 

3. Plague: It effects rapid cure (in 7–12 days), may be employed in confirmed cases, but tetracyclines have been more commonly used for mass treatment of suspected cases during an epidemic.

 

4. Tularemia: Streptomycin is the drug of choice for this rare disease: effects cure in 7–10 days. Tetracyclines are the alternative drugs, especially in milder cases.

 

In most other situations, e.g. urinary tract infection, peritonitis, septicaemias, etc. where streptomycin was used earlier, gentamicin or one of the newer aminoglycosides is now preferred due to low potency and widespread resistance to streptomycin.

 

Oral use of streptomycin for diarrhoea is banned in India.

 

GENTAMICIN

 

It was obtained from Micromonospora purpurea in 1964; has become the most commonly used aminoglycoside for acute infections. The properties of gentamicin including plasma t½ of 2–4 hours after i.m. injection are the same as described above for streptomycin, but there are following differences:

 

a)    It is more potent (MIC for most organisms is 4–8 times lower.)

 

b)    It has a broader spectrum of action: effective against Ps. aeruginosa and most strains of Proteus, E. coli, Klebsiella, Enterobacter, Serratia.

 

c)   It is ineffective against M. tuberculosis, Strep. pyogenes and Strep. pneumoniae, but inhibits many Strep. faecalis and some Staph. aureus.


d)     It is relatively more nephrotoxic.

 

Dose: The dose of gentamicin must be precisely calculated according to body weight and level of renal function. For an average adult with normal renal function (creatinine clearance > 100 ml/ min) 3–5 mg/kg/day i.m. either as single dose or divided in three 8 hourly doses is recommended.

 

Because of concentration dependent bactericidal and post-antibiotic effect of aminoglycosides, it was theorised that high plasma concentration attained after the single daily dose will be more effective. It is also likely to be less ototoxic because plasma concentrations will remain subthreshold for ototoxicity for a longer period each day allowing washout of the drug from the endolymph. The efficacy and safety of many aminoglycosides by the conventional (thrice daily) and once daily regimens has been compared in several studies. The data indicate similar efficacy and a trend towards less toxicity. As such, many hospitals now practice once daily dosing of aminoglycosides. It is more convenient as well.

 

The daily dose of gentamicin (and other aminoglycosides) should be reduced in patients with impaired renal function according to measured creatinine clearance. A general guideline is:

 


 

GARAMYCIN, GENTASPORIN, GENTICYN 20, 60, 80, 240 mg per vial inj; also 0.3% eye/ear drops, 0.1% skin cream.

 

Uses

 

Gentamicin is the cheapest (other than streptomycin) and the first line aminoglycoside antibiotic. However, because of low therapeutic index, its use should be restricted to serious gram-negative bacillary infections.

 

1. Gentamicin is very valuable for preventing and treating respiratory infections in critically ill patients; in those with impaired host defence (receiving anticancer drugs or highdose corticosteroids; AIDS; neutropenic), patients in resuscitation wards, with tracheostomy or on respirators; postoperative pneumonias; patients with implants and in intensive care units. It is often combined with a penicillin/cephalosporin or another antibiotic in these situations. However, resistant strains have emerged in many hospitals and nosocomial infections are less amenable to gentamicin now. Another aminoglycoside (tobramycin, amikacin, sisomicin, netilmicin) is then selected on the basis of the local sensitivity pattern. Aminoglycosides should not be used to treat community acquired pneumonias caused by gram-positive cocci and anaerobes.

 

Gentamicin is often added to the peritoneal dialysate to prevent or treat peritonitis.

 

2. Pseudomonas, Proteus or Klebsiella infections: burns, urinary tract infection, pneumonia, lung abscesses, osteomyelitis, middle ear infection, septicaemia, etc. are an important area of use of gentamicin. It may be combined with piperacillin or a third generation cephalosporin for serious infections. Topical use on infected burns and in conjunctivitis is permissible.

 

3. Meningitis caused by gram-negative bacilli: in addition to the usual i.m. dose, 4 mg intrathecal injection may be given daily, but benefits are uncertain. Because this is a serious condition, drug combinations including an aminoglycoside are often used. The third generation cephalosporins alone or with an aminoglycoside are favoured for this purpose.

 

4. SABE: gentamicin is more commonly used in place of streptomycin to accompany penicillin.

 

Gentamicin-PMMA (polymethyl methacrylate) chains (SEPTOPAL) is a special drug delivery system for use in osteomyelitis. It consists of small acrylic beads each impregnated with 7.5 mg gentamicin sulph. and threaded over surgical grade wire. Implanted in the bone cavity after thorough removal of sequestra and left in place for 10 days, it has improved cure rates.

 

KANAMYCIN

 

Obtained from S. kanamyceticus (in 1957), it was the second systemically used aminoglycoside to be developed after streptomycin. It is similar to streptomycin in all respects including efficacy against M. tuberculosis and lack of activity on Pseudomonas. However, it is more toxic, both to the cochlea and to kidney. Hearing loss is more common than vestibular disturbance.

 

Because of toxicity and narrow spectrum of activity, it has been largely replaced by other aminoglycosides for treatment of gram-negative bacillary infections. It is occasionally used as a second line drug in resistant tuberculosis.

 

Dose: 0.5 g i.m. BD–TDS: KANAMYCIN, KANCIN, KANAMAC 0.5, 1 g inj.

 

 

TOBRAMYCIN

 

It was obtained from S. tenebrarius in the 1970s. The antibacterial and pharmacokinetic properties, as well as dosage are almost identical to gentamicin, but it is 2–4 times more active against Pseudomonas and Proteus, including those resistant to gentamicin. However, it is not useful for combining with penicillin in the treatment of enterococcal endocarditis. It should be used only as a reserve alternative to gentamicin. Serious infections caused by Pseudomonas and Proteus are its major indications. Ototoxicity and nephrotoxicity is probably lower than gentamicin.

 

Dose: 3–5 mg/kg day in 1–3 doses.

 

TOBACIN 20, 60, 80 mg in 2 ml inj. 0.3% eye drops. TOBRANEG 20, 40, 80 mg per 2 ml inj, TOBRABACT 0.3% eye drops.

 

AMIKACIN

 

It is a semisynthetic derivative of kanamycin to which it resembles in pharmacokinetics, dose and toxicity. The outstanding feature of amikacin is its resistance to bacterial aminoglycoside inactivating enzymes. Thus, it has the widest spectrum of activity, including many organisms resistant to other aminoglycosides. However, relatively higher doses are needed for Pseudomonas, Proteus and Staph. infections.

 

The range of conditions in which amikacin can be used is the same as for gentamicin. It is recommended as a reserve drug for hospital acquired gram-negative bacillary infections where gentamicin/tobramycin resistance is high. It is effective in tuberculosis, but rarely used for this purpose. More hearing loss than vestibular disturbance occurs in toxicity.

Dose: 15 mg/kg/day in 1–3 doses; urinary tract infection 7.5 mg/kg/day.

 

AMICIN, MIKACIN, MIKAJECT 100 mg, 250 mg, 500 mg in 2 ml inj.

 

SISOMICIN

 

Introduced in 1980s, it is a natural aminoglycoside from Micromonospora inyoensis that is chemically and pharmacokinetically similar to gentamicin, but somewhat more potent on Pseudomonas, a few other gram-negative bacilli and β haemolytic Streptococci. It is moderately active on faecal Streptococci—can be combined with penicillin for SABE. However, it is susceptible to aminoglycoside inactivating enzymes and offers no advantage in terms of ototoxicity and nephrotoxicity. It can be used interchangeably with gentamicin for the same purposes in the same doses.

 

ENSAMYCIN, SISOPTIN 50 mg, 10 mg (pediatric) per ml in 1 ml amps, 0.3% eyedrops, 0.1% cream.

 

NETILMICIN

 

This semisynthetic derivative of sisomicin has a broader spectrum of activity than gentamicin. It is relatively resistant to aminoglycoside inactivating enzymes and thus effective against many gentamicin-resistant strains. It is more active against Klebsiella, Enterobacter and Staphylococci, but less active against Ps. aeruginosa.

 

Pharmacokinetic characteristics and dosage of netilmicin are similar to gentamicin. Experimental studies have shown it to be less ototoxic than gentamicin and tobramycin, but clinical evidence is inconclusive: hearing loss occurs, though fewer cases of vestibular damage have been reported.

 

A marginal improvement in antibacterial spectrum, clinical efficacy and possibly reduced toxicity indicates that netilmicin could be preferable in critically ill and neutropenic patients, and retain activity in hospitals where gentamicin resistance has spread.

 

Dose: 4–6 mg/kg/day in 1–3 doses; NETROMYCIN 10, 25, 50 mg in 1 ml, 200 mg in 2 ml and 300 mg in 3 ml inj., NETICIN 200 mg (2 ml), 300 mg (3 ml) inj.

 

NEOMYCIN

 

Obtained from S. fradiae , it is a widespectrum aminoglycoside, active against most gram-negative bacilli and some gram-positive cocci.

However, Pseudomonas and Strep. pyogenes are not sensitive. Neomycin is highly toxic to the internal ear (mainly auditory) and to kidney. It is, therefore, not used systemically. Absorption from the g.i.t. is minimal. Oral and topical administration does not ordinarily cause systemic toxicity.

 

Dose: 0.25–1 g QID oral, 0.3–0.5% topical.

 

NEOMYCIN SULPHATE 350, 500 mg tab, 0.3% skin oint, 0.5% skin cream, eye oint.

 

NEBASULF: Neomycin sulph. 5 mg, bacitracin 250 U, sulfacetamide 60 mg/g oint. and powder for surface application.

 

POLYBIOTIC CREAM: Neomycin sulph. 5 mg, polymyxin 5,000 IU, gramicidin 0.25 mg/g cream.

 

NEOSPORIN: Neomycin 3400 iu, polymyxin B 5000 iu, bacitracin 400 iu/g oint and powder for surface application. NEOSPORINH: Neomycin 3400 iu, polymyxin B 5000 iu, hydrocortisone 10 mg per g oint and per ml ear drops.

 

Uses

 

1. Topically (often in combination with polymyxin, bacitracin, etc.) for infected wound, ulcers, burn, external ear infections, conjunctivitis, but like other topical antiinfective preparations, benefits are limited.

 

2. Orally for:

 

a) Preparation of bowel before surgery: (3 doses of 1.0 g along with metronidazole 0.5 g on day before surgery) may reduce postoperative infections.

b) Hepatic coma: Normally NH3 is produced by colonic bacteria. This is absorbed and converted to urea by liver. In severe hepatic failure, detoxication of NH3 does not occur, blood NH3 levels rise and produce encephalopathy. Neomycin, by suppressing intestinal flora, diminishes NH3 production and lowers its blood level; clinical improvement is seen within 2–3 days. However, because of toxic potential it is infrequently used for this purpose; lactulose is preferred.

 

Adverse Effects

 

Applied topically neomycin has low sensitizing potential. However, rashes do occur.

 

Oral neomycin has a damaging effect on intestinal villi—prolonged treatment can induce malabsorption syndrome with diarrhoea and steatorrhoea. It can decrease the absorption of digoxin and many other drugs, as well as bile acids.

 

Due to marked suppression of gut flora, superinfection by Candida can occur.

 

Small amounts that are absorbed from the gut or topical sites are excreted unchanged by kidney. This may accumulate in patients with renal insufficiency—cause further kidney damage and ototoxicity. Neomycin is contraindicated if renal function is impaired.

 

Applied to serous cavities (peritoneum), it can cause apnoea due to muscle paralysing action. Neomycin containing anti-diarrhoeal formulations are banned in India.

 

FRAMYCETIN

 

Obtained from S. lavendulae, it is very similar to neomycin. It is too toxic for systemic administration and is used topically on skin, eye, ear in the same manner as neomycin.

 

SOFRAMYCIN, FRAMYGEN 1% skin cream, 0.5% eye drops or oint.


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