Gentamicin Sulfate

Name: Gentamicin Sulfate

Introduction

Antibacterial; aminoglycoside antibiotic obtained from cultures of Micromonospora purpurea.a b c h

Gentamicin Sulfate Dosage and Administration

Administration

Administer by IV infusion or IM injection.a b c Also has been administered without preservatives intrathecally or intraventricularly to supplement IM or IV administration in the treatment of CNS infections.h

IV Infusion

For solution and drug compatibility information, see Compatibility under Stability.

Reconstitution and Dilution

For adults, prepare IV infusions by diluting the calculated dose of gentamicin with 50–200 mL of 0.9% sodium chloride or 5% dextrose injection.h

ADD-Vantage vials should be diluted according to the manufacturer’s directions prior to IV infusion.h

Rate of Administration

IV infusions are given over 30 minutes to 2 hours.h

IM Injection

For IM injection, the appropriate dose should be withdrawn from multiple-dose vials.h

Solutions prepared from or commercially available in pharmacy bulk packages, those available in ADD-Vantage vials, or the commercially available injections in 0.9% sodium chloride should not be used for IM administration of the drug.h

Dosage

Available as gentamicin sulfate; dosage is expressed in terms of gentamicin.a b c

Dosage is identical for either IV or IM administration.a b c

Dosage should be based on patient’s pretreatment body weight.a b c

Many clinicians recommend that dosage be determined using appropriate pharmacokinetic methods for calculating dosage requirements and patient-specific pharmacokinetic parameters (e.g., elimination rate constant, volume of distribution) derived from serum concentration-time data; in determining dosage, the susceptibility of the causative organism, the severity of infection, and the patient’s immune and clinical status also must be considered.214 215 216 217 218 242 243 244 245 246 247 248 249

Peak and trough serum gentamicin concentrations should be determined periodically and dosage adjusted to maintain desired serum concentrations whenever possible, especially in patients with life-threatening infections, suspected toxicity or nonresponse to treatment, decreased or varying renal function, and/or when increased aminoglycoside clearance (e.g., patients with cystic fibrosis, burns) or prolonged therapy is likely.235 236 237 238 239 240 241 242 250

In general, desirable peak serum concentrations of gentamicin are 4–12 mcg/mL and trough concentrations of the drug should not exceed 1–2 mcg/mL.h Some evidence suggests that an increased risk of toxicity may be associated with prolonged peak serum gentamicin concentrations >10–12 mcg/mL and/or trough concentrations >2 mcg/mL.h

Once-daily administration† of aminoglycosides is at least as effective as, and may be less toxic than, conventional dosage regimens employing multiple daily doses.218 219 220 221 222 223 224 225 226 227 228 229 230 231 251 252 253 254

Pediatric Patients

General Dosage for Neonates IV or IM

Manufacturer recommends 2.5 mg/kg every 12 hours in premature or full-term neonates ≤1 week of age and 2.5 mg/kg every 8 hours for older neonates.a b c

Neonates <1 week of age: AAP recommends 2.5 mg/kg every 18–24 hours for those weighing <1.2 kg and 2.5 mg/kg every 12 hours for those weighing ≥1.2 kg.f

Neonates 1–4 weeks of age: AAP recommends 2.5 mg/kg every 18–24 hours for those weighing <1.2 kg, 2.5 mg/kg every 8 or 12 hours for those weighing 1.2–2 kg, and 2.5 mg/kg every 8 hours for those weighing >2 kg.f

General Dosage for Infants and Children IV or IM

Older infants and children: manufacturer recommends 2.5 mg/kg every 8 hours for older neonates.a b c

Children ≥1 month of age: AAP recommends 3–7.5 mg/kg given in 3 divided doses for treatment of severe infections.f Inappropriate for mild to moderate infections according to AAP.f

Endocarditis† Treatment of Staphylococcal Endocarditis† IV or IM

3 mg/kg daily in 3 divided doses; dosage adjusted to achieve peak serum gentamicin concentrations approximately 3 mcg/mL and trough concentrations <1 mcg/mL.k

Used in conjunction with nafcillin, oxacillin, cefazolin, or vancomycin; gentamicin used only during the first 3–5 days for native valve infections or during the first 2 weeks for prosthetic valve infections.k

Treatment of Endocarditis Caused by Viridans Streptococci or S. bovis† IV or IM

3 mg/kg daily in 3 divided doses; dosage adjusted to achieve peak serum gentamicin concentrations approximately 3 mcg/mL and trough concentrations <1 mcg/mL.k

Used in conjunction with penicillin G or ceftriaxone; usual duration is 2 weeks for penicillin-susceptible strains (MIC ≤0.1 mcg/mL), 2 weeks for relatively resistant strains (MIC >0.1–0.5 mcg/mL), or 4–6 weeks for strains with high level penicillin resistance (MIC >0.5 mcg/mL).k If used with vancomycin in patients unable to receive a β-lactam, a 6-week regimen is recommended.k

Treatment of Enterococcal Endocarditis† IV or IM

3 mg/kg daily in 3 divided doses; dosage adjusted to achieve peak serum gentamicin concentrations approximately 3 mcg/mL and trough concentrations <1 mcg/mL.k

Used in conjunction with penicillin G or ceftriaxone; usual duration is 2 weeks for penicillin-susceptible strains (MIC ≤0.1 mcg/mL), 2 weeks for relatively resistant strains (MIC >0.1–0.5 mcg/mL), or 4–6 weeks for strains with high level penicillin resistance (MIC >0.5 mcg/mL).k If used with vancomycin in patients unable to receive a β-lactam, a 6-week regimen is recommended.k

Prevention of Endocarditis in Patients Undergoing Certain Genitourinary or GI (except Esophageal) Procedures† IV or IM

For high-risk patients: 1.5 mg/kg (up to 120 mg) given within 30 minutes prior to the procedure; used in conjunction with recommended regimens of ampicillin or vancomycin.255

Plague† Treatment of Plague† IV or IM

Premature neonates and neonates ≤1 week of age: 2.5 mg/kg twice daily.256

Infants and older children: 2.5 mg/kg 3 times daily.256

Usual duration is 10 days;256 some experts recommend 10–14 days.258

Tularemia† Treatment of Tularemia† IV or IM

2.5 mg/kg 3 times daily for 10 days.257

Adults

General Adult Dosage Treatment of Serious Infections IV or IM

3 mg/kg daily given in 3 equally divided doses every 8 hours.a b c

Treatment of Life-threatening Infections IV or IM

≤5 mg/kg daily given in 3 or 4 equally divided doses.a b c Dosage should be reduced to 3 mg/kg daily when clinically indicated.a b c

Endocarditis† Treatment of Staphylococcal Endocarditis† IV or IM

1 mg/kg every 8 hours.l Used in conjunction with nafcillin, oxacillin, cefazolin, or vancomycin; gentamicin used only during the first 3–5 days of therapy for native valve infections or during the first 2 weeks for prosthetic valve infections.l

Treatment of Endocarditis Caused by Viridans Streptococci or S. bovis† IV or IM

1 mg/kg every 8 hours.l Used in conjunction with penicillin G, ceftriaxone, or vancomycin; gentamicin used only during the first 2 weeks of therapy.l

Treatment of Enterococcal Endocarditis† IV or IM

1 mg/kg every 8 hours.l Used in conjunction with penicillin G, ampicillin, or vancomycin; usual duration is 4–6 weeks.l

Treatment of Endocarditis Caused by HACEK group† IV

1 mg/kg every 8 hours.l Used in conjunction with ampicillin; usual duration is 4 weeks.l (HACEK: H. parainfluenzae, H. aphrophilus, A. actinomycetemcomitans, C. hominis, E. corrodens, K. kingae)

Prevention of Endocarditis in Patients Undergoing Certain Genitourinary or GI (except Esophageal) Procedures† IV or IM

For high-risk patients: 1.5 mg/kg (up to 120 mg) given within 30 minutes prior to the procedure; used in conjunction with recommended regimens of ampicillin or vancomycin.255

Gynecologic Infections† Pelvic Inflammatory Disease† (PID) IV or IM

Initially, 2 mg/kg followed by 1.5 mg/kg every 8 hours;201 212 used in conjunction with IV clindamycin (900 mg every 8 hours).201 212 After clinical improvement occurs, discontinue IV clindamycin and gentamicin and switch to oral clindamycin (450 mg 4 times daily) or oral doxycycline (100 mg twice daily) to complete 14 days of therapy.201

Granuloma Inguinale (Donovanosis)† IV

1 mg/kg every 8 hours; added as an adjunct to the recommended or alternative drugs (doxycycline, co-trimoxazole, ciprofloxacin, erythromycin, azithromycin) if improvement is not evident within the first few days of therapy or in pregnant or HIV-infected patients.201

Plague† Treatment of Plague† IV or IM

5 mg/kg once daily or, alternatively, a 2-mg/kg loading dose following by 1.7 mg/kg 3 times daily.256 258 Usual duration is 10 days;256 some experts recommend 10–14 days.258

Tularemia† Treatment of Tularemia† IV or IM

5 mg/kg once daily for 10 days;257 some experts recommend 3–5 mg/kg daily for 10–14 days.258

Special Populations

Renal Impairment

Dosage adjustments necessary in patients with renal impairment.a b c Whenever possible monitor serum gentamicin concentrations, especially in patients with changing renal function.a b c

Various methods have been used to determine aminoglycoside dosage for patients with renal impairment and there is wide variation in dosage recommendations for these patients.h The manufacturers recommend an initial dose of 1–1.7 mg/kg, followed by 1-mg/kg doses given at intervals (in hours) calculated by multiplying the patient’s steady-state serum creatinine (in mg/dL) by 8.h The dosing method of Sarubbi and Hull, which is based on corrected Clcr also has been recommended.h Specialized references should be consulted for specific information on dosage for patients with renal impairment.

Dosage calculation methods should not be used in patients undergoing hemodialysis or peritoneal dialysis.h In patients with renal failure undergoing hemodialysis, the manufacturers recommend supplemental doses of 1–1.7 mg/kg at the end of each dialysis period in adults and supplemental doses of 2–2.5 mg/kg at the end of each dialysis period in children.h

Geriatric Patients

Select dosage with caution and closely monitor renal function because of age-related decreases in renal function.a b c

No dosage adjustments except those related to renal impairment.a b c (See Renal Impairment under Dosage and Administration.)

Cautions for Gentamicin Sulfate

Contraindications

  • History of hypersensitivity or serious toxic reactions to gentamicin or other aminoglycosides.a b c

Warnings/Precautions

Warnings

Ototoxicity

Patients receiving aminoglycosides should be under close clinical observation because of possible ototoxicity.a b c

Vestibular and permanent bilateral auditory ototoxicity occurs most frequently in those with past or present history of renal impairment, those receiving other ototoxic drugs, and those who receive high dosage or prolonged treatment.a b c

Serial audiograms should be obtained, if feasible, in patients old enough to be tested, particularly in high-risk patients.a b c

Discontinue gentamicin or adjust dosage if there is evidence of ototoxicity (dizziness, vertigo, tinnitus, roaring in the ears, hearing loss).a b c

Some aminoglycosides have caused fetal ototoxicity when administered to pregnant women.a b c (See Pregnancy under Cautions.)

Nephrotoxicity

Patients receiving aminoglycosides should be under close clinical observation because of possible nephrotoxicity.a b c Renal function should be assessed prior to and periodically during therapy.a b c

Nephrotoxicity occurs most frequently in those with past or present history of renal impairment, those receiving other nephrotoxic drugs, and those who receive high dosage or prolonged treatment.a b c

Dosage reduction may be desirable if other evidence of renal dysfunction occurs (e.g., decreased Clcr, decreased urine specific gravity, increased BUN or Scr, oliguria).a b c

If azotemia increases or if a progressive decrease in urinary output occurs, discontinue gentamicin.a b c

Neuromuscular Blockade

Neuromuscular blockade and respiratory paralysis reported with high gentamicin dosage (40 mg/kg) in animal studies.a b c

Possibility of neuromuscular blockade should be considered, especially in patients receiving anesthetics or neuromuscular blocking agents (e.g., tubocurarine, succinylcholine, decamethonium) or in those receiving massive transfusions of citrate-anticoagulated blood.a b c

Calcium salts may reverse neuromuscular blockade.a b c

Sensitivity Reactions

Cross-Hypersensitivity

Cross-allergenicity occurs among the aminoglycosides.a b c

Sulfite Sensitivity

Gentamicin injection contains sodium metabisulfite, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.a b c

General Precautions

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of gentamicin and other antibacterials, use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.c

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.c In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.c

Usually used in conjunction with other anti-infectives (e.g., penicillins, cephalosporins) for empiric treatment of serious infections pending results of in vitro susceptibility tests.a b c If anaerobic bacteria are suspected, concomitant use of an anti-infective active against anaerobes is necessary.a b c

Superinfection

Possible emergence and overgrowth of nonsusceptible bacteria or fungi.a b c Discontinue drug and institute appropriate therapy if superinfection occurs.a b c

Interactions

Because of possible additive toxicity, avoid concurrent and/or sequential use of other neurotoxic or nephrotoxic drugs (systemic, oral, or topical), particularly bacitracin, cisplatin, amphotericin B, cephaloridine (no longer available in US), paromomycin, viomycin, polymyxin B, colistin, vancomycin, or other aminoglycosides.a b c Do not administer concurrently with potent diuretics.b c (See Specific Drugs under Interactions.)

Consider possibility of neuromuscular blockade and respiratory paralysis in patients receiving anesthetics or neuromuscular blocking agents (e.g., tubocurarine, succinylcholine, decamethonium).a b c (See Specific Drugs under Interactions.)

Use with caution in patients with muscular disorders such as myasthenia gravis or parkinsonism since drugs used in these patients may aggravate muscle weakness because of their potential curare-like effect on the neuromuscular junction.a b c

Topical Instillation

Aminoglycoside may be absorbed in significant quantities from body surfaces after topical instillation† and may cause neurotoxicity and nephrotoxicity.a b c

Specific Populations

Pregnancy

Category D.a c

Possibility of fetal harm if administered to a pregnant woman.a b c Complete, irreversible, bilateral congenital deafness reported when another aminoglycoside (i.e., streptomycin) was used during pregnancy.a b c

If used during pregnancy or if patient becomes pregnant while receiving gentamicin, the patient should be apprised of the potential hazard to the fetus.a b c

Lactation

Low concentrations of aminoglycosides may be distributed into milk.i Use with caution.i

Pediatric Use

Use with caution in neonates and premature infants because renal immaturity in these patients may result in prolonged serum half-life.i

Geriatric Use

Select dosage with caution and closely monitor renal function because of age-related decreases in renal function.a b c d

Monitoring renal function during aminoglycoside therapy is particularly important in geriatric patients.a b c d Clcr may be more useful than determining BUN or Scr.a b c d

Renal Impairment

Risk of neurotoxicity (manifested as vestibular and permanent bilateral auditory ototoxicity) is greater in patients with renal damage than in other patients.a b c

Renal function should be assessed prior to and during therapy.a b c

Eighth-cranial nerve function should be monitored closely, especially in patients who have known or suspected renal impairment at the start of treatment and also in those whose renal function is initially normal but who develop signs of renal dysfunction during treatment.a b c

Common Adverse Effects

Ototoxicity or nephrotoxicity.a b c i

Gentamicin Sulfate Pharmacokinetics

Absorption

Bioavailability

Not absorbed orally; must be given parenterally.d i

Rapidly absorbed following IM injection; peak plasma concentrations attained within 30–90 minutes.a b c i

Distribution

Extent

Distributed into bone, heart, gallbladder, lung tissue, bile, sputum, bronchial secretions, and interstitial, pleural, and synovial fluids.a b c d h

Only low concentrations distributed into CSF following IM or IV administration.i

Crosses the placenta.d Aminoglycosides may be distributed into milk in low concentrations.i

Plasma Protein Binding

Only minimally bound to plasma proteins.a b c

Elimination

Metabolism

Not metabolized.i

Elimination Route

50–93% of a single IM dose excreted unchanged by glomerular filtration within 24 hours.h

May be removed by hemodialysisa b c i or peritoneal dialysis.i

Half-life

2–3 hours in adults with normal renal function.h

3–3.5 hours in infants 1 week to 6 months of age and 5.5 hours in full-term infants and large premature infants <1 week of age.h In small premature infants, plasma half-life is approximately 5 hours in those weighing >2 kg, 8 hours in those weighing 1.5–2 kg, and 11.5 hours in those weighing <1.5 kg.h

Special Populations

Half-life is 24–60 hours in adults with severe renal impairment.h

Stability

Storage

Parenteral

Injection for IV Infusion or IM Injection

15–30°C.a c

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible

Amino acids 4.25%, dextrose 25%

Dextrose 5 or 10% in water

Mannitol 20%

Ringer’s injection

Ringer's injection, lactated

Sodium chloride 0.9%

Incompatible

Fat emulsion 10%, intravenous

Drug Compatibility Admixture CompatibilityHID

Compatible

Atracurium besylate

Aztreonam

Bleomycin sulfate

Cefoxitin sodium

Ciprofloxacin

Clindamycin phosphate

Fluconazole

Linezolid

Meropenem

Metronidazole

Midazolam HCl

Penicillin G sodium

Ranitidine HCl

Verapamil HCl

Incompatible

Amphotericin B

Ampicillin sodium

Cefazolin sodium with clindamycin phosphate

Cefepime HCl

Ceftazidime

Heparin sodium

Nafcillin sodium

Variable

Cefotaxime sodium

Ceftriaxone sodium

Cefuroxime sodium

Cytarabine

Dopamine HCl

Furosemide

Y-site CompatibilityHID

Compatible

Alprostadil

Amifostine

Amiodarone HCl

Anidulafungin

Atracurium besylate

Aztreonam

Bivalirudin

Caspofungin acetate

Cefepime HCI

Ceftaroline fosamil

Ceftazidime

Ciprofloxacin

Cisatracurium besylate

Clarithromycin

Cyclophosphamide

Cytarabine

Daptomycin

Dexmedetomidine HCl

Diltiazem HCl

Docetaxel

Doxapram HCl

Doxorubicin HCl liposome injection

Enalaprilat

Esmolol HCl

Etoposide phosphate

Famotidine

Fenoldopam mesylate

Fluconazole

Fludarabine phosphate

Foscarnet sodium

Gemcitabine HCl

Granisetron HCl

Hetastarch in lactated electrolyte injection (Hextend)

Hydromorphone HCl

Hydroxyethyl starch 130/0.4 in sodium chloride 0.9%

Labetalol HCl

Levofloxacin

Linezolid

Lorazepam

Magnesium sulfate

Melphalan HCl

Meperidine HCl

Meropenem

Midazolam HCl

Milrinone lactate

Morphine sulfate

Multivitamins

Nicardipine HCl

Ondansetron HCl

Paclitaxel

Palonosetron HCl

Pancuronium bromide

Potassium chloride

Remifentanil HCl

Sargramostim

Tacrolimus

Telavancin HCl

Teniposide

Theophylline

Thiotepa

Tigecycline

Vasopressin

Vecuronium bromide

Vinorelbine tartrate

Zidovudine

Incompatible

Allopurinol sodium

Amphotericin B cholesteryl sulfate complex

Azithromycin

Furosemide

Heparin sodium

Hetastarch in sodium chloride 0.9%

Indomethacin sodium trihydrate

Iodipamide meglumine

Pemetrexed disodium

Propofol

Warfarin sodium

Variable

Acyclovir sodium

Filgrastim

Clinical Pharmacology

After intramuscular administration of Gentamicin Sulfate, peak serum concentrations usually occur between 30 to 60 minutes and serum levels are measurable for 6 to 8 hours. When gentamicin is administered by intravenous infusion over a two-hour period, the serum concentrations are similar to those obtained by intramuscular administration.

In patients with normal renal function, peak serum concentrations of gentamicin (mcg/mL) are usually up to four times the single intramuscular dose (mg/kg); for example, a 1 mg/kg injection in adults may be expected to result in a peak serum concentration up to 4 mcg/mL; a 1.5 mg/kg dose may produce levels up to 6 mcg/mL. While some variation is to be expected due to a number of variables such as age, body temperature, surface area and physiologic differences, the individual patient given the same dose tends to have similar levels in repeated determinations. Gentamicin administered at 1 mg/kg every eight hours for the usual 7- to 10-day treatment period to patients with normal renal function does not accumulate in the serum.

Gentamicin, like all aminoglycosides, may accumulate in the serum and tissues of patients treated with higher doses and for prolonged periods, particularly in the presence of impaired renal function. In adult patients, treatment with gentamicin dosages of 4 mg/kg/day or higher for seven to ten days may result in a slight, progressive rise in both peak and trough concentrations. In patients with impaired renal function, gentamicin is cleared from the body more slowly than in patients with normal renal function. The more severe the impairment, the slower the clearance.

Dosage must be adjusted.

Since gentamicin is distributed in extracellular fluid, peak serum concentrations may be lower than usual in adult patients who have a large volume of this fluid. Serum concentrations of gentamicin in febrile patients may be lower than those in afebrile patients given the same dose. When body temperature returns to normal, serum concentrations of the drug may rise. Febrile and anemic states may be associated with a shorter than usual serum half-life. (Dosage adjustment is usually not necessary.) In severely burned patients, the half-life may be significantly decreased and resulting serum concentrations may be lower than anticipated from the mg/kg dose.

Protein binding studies have indicated that the degree of gentamicin binding is low, depending upon the methods used for testing, this may be between 0 and 30%.

After initial administration to patients with normal renal function, generally 70% or more of the gentamicin dose is recoverable in the urine in 24 hours; concentrations in urine above 100 mcg/mL may be achieved. Little, if any metabolic transformation occurs; the drug is excreted principally by glomerular filtration. After several days of treatment, the amount of gentamicin excreted in the urine approaches the daily dose administered. As with other aminoglycosides, a small amount of the gentamicin dose may be retained in the tissues, especially in the kidneys. Minute quantities of aminoglycosides have been detected in the urine weeks after drug administration was discontinued. Renal clearance of gentamicin is similar to that of endogenous creatinine.

In patients with marked impairment of renal function, there is a decrease in the concentration of aminoglycosides in urine and in their penetration into defective renal parenchyma. This decreased drug excretion, together with the potential nephrotoxicity of aminoglycosides, should be considered when treating such patients who have urinary tract infections.

Probenecid does not affect renal tubular transport of gentamicin.

The endogenous creatinine clearance rate and the serum creatinine level have a high correlation with the half-life of gentamicin in serum. Results of these tests may serve as guides for adjusting dosage in patients with renal impairment (see DOSAGE AND ADMINISTRATION).

Following parenteral administration, gentamicin can be detected in serum, lymph, tissues, sputum, and in pleural, synovial, and peritoneal fluids. Concentrations in renal cortex sometimes may be eight times higher than the usual serum levels. Concentrations in bile, in general, have been low and have suggested minimal biliary excretion. Gentamicin crosses the peritoneal as well as the placental membranes. Since aminoglycosides diffuse poorly into the subarachnoid space after parenteral administration, concentrations of gentamicin in cerebrospinal fluid are often low and dependent upon dose, rate of penetration and degree of meningeal inflammation. There is minimal penetration of gentamicin into ocular tissues following intramuscular or intravenous administration.

Microbiology
Mechanism of Action

Gentamicin, an aminoglycoside, binds to the prokaryotic ribosome, inhibiting protein synthesis in susceptible bacteria. It is bactericidal in vitro against Gram-positive and Gram-negative bacteria.

Mechanism of Resistance

Bacterial resistance to gentamicin is generally developed slowly. Bacteria resistant to one aminoglycoside may be resistant to one or more other aminoglycosides. The following bacteria are usually resistant to the aminoglycosides, including gentamicin: most streptococcal species (including Streptococcus pneumoniae and the Group D streptococci), most enterococcal species (including Enterococcus faecalis, E. faecium, and E. durans), and anaerobic organisms, such as Bacteroides species and Clostridium species.

Aminoglycosides are known to be not effective against Salmonella and Shigella species in patients. Therefore, in vitro susceptibility test results should not be reported.

Interactions with Other Antimicrobials

In vitro studies show that an aminoglycoside combined with an antibiotic that interferes with cell wall synthesis may act synergistically against some enterococcal strains. The combination of gentamicin and penicillin G has a synergistic bactericidal effect against strains of Enterococcus faecalis, E. faecium and E. durans. An enhanced killing effect against many of these strains has also been shown in vitro with combinations of gentamicin and ampicillin, carbenicillin, nafcillin or oxacillin.

The combined effect of gentamicin and carbenicillin is synergistic for many strains of Pseudomonas aeruginosa. In vitro synergism against other Gram-negative organisms has been shown with combinations of gentamicin and cephalosporins.

Gentamicin may be active against clinical isolates of bacteria resistant to other aminoglycosides.

Antibacterial Activity

Gentamicin has been shown to be active against most of the following bacteria, both in vitro and in clinical infections [see INDICATIONS AND USAGE].

Gram-Positive Bacteria

Staphylococcus species

Gram-Negative Bacteria

Citrobacter species
Enterobacter species
Escherichia coli
Klebsiella species
Proteus species
Serratia species
Pseudomonas aeruginosa

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility tests for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antimicrobial drug for treatment.

Dilution technique

Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method.1, 3 Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of gentamicin powder. The MIC values should be interpreted according to the criteria provided in TABLE 1.

Diffusion technique

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method. The standardized procedure requires the use of standardized inoculum concentrations and paper disks impregnated with 10 mcg of gentamicin.2, 3 The disk diffusion values should be interpreted according to the criteria provided in TABLE 1.

A report of Susceptible (S) indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration usually achievable at the infection site necessary to inhibit growth of the pathogen. A report of Intermediate (I) indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of the drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1, 2, 3 Standard gentamicin powder should provide the following range of MIC values provided in TABLE 2. For the diffusion technique using the 10-mcg gentamicin disk the criteria provided in TABLE 2 should be achieved.

Precautions

Neurotoxic and nephrotoxic antibiotics may be almost completely absorbed from body surfaces (except the urinary bladder) after local irrigation and after topical application during surgical procedures. The potential toxic effects of antibiotics administered in this fashion (neuromuscular blockade, respiratory paralysis, oto- and nephrotoxicity) should be considered (see WARNINGS box). Increased nephrotoxicity has been reported following concomitant administration of aminoglycoside antibiotics and cephalosporins. Neuromuscular blockade and respiratory paralysis have been reported in the cat receiving high doses (40 mg/kg) of gentamicin. The possibility of these phenomena occurring in man should be considered if aminoglycosides are administered by any route to patients receiving anesthetics, or to patients receiving neuromuscular blocking agents, such as succinylcholine, tubocurarine, or decamethonium, or in patients receiving massive transfusions of citrate anticoagulated blood. If neuromuscular blockade occurs, calcium salts may reverse it. Aminoglycosides should be used with caution in patients with neuromuscular disorders, such as myasthenia gravis or parkinsonism, since these drugs may aggravate muscle weakness because of their potential curare-like effects on the neuromuscular junction. During or following gentamicin therapy, paresthesias, tetany, positive Chvostek and Trousseau signs and mental confusion have been described in patients with hypomagnesemia, hypocalcemia and hypokalemia. When this has occurred in infants, tetany and muscle weakness has been described. Both adults and infants required appropriate corrective electrolyte therapy. Elderly patients may have reduced renal function which may not be evident in the results of routine screening tests, such as BUN or serum creatinine. A creatinine clearance determination may be more useful. Monitoring of renal function during treatment with gentamicin, as with other aminoglycosides, is particularly important in such patients. A Fanconi-like syndrome, with aminoaciduria and metabolic acidosis has been reported in some adults and infants being given gentamicin injections. Cross-allergenicity among aminoglycosides has been demonstrated. Patients should be well hydrated during treatment. Although the in vitro mixing of gentamicin and carbenicillin results in a rapid and significant inactivation of gentamicin, this interaction has not been demonstrated in patients with normal renal function who received both drugs by different routes of administration. A reduction in gentamicin serum half-life has been reported in patients with severe renal impairment receiving carbenicillin concomitantly with gentamicin. Treatment with gentamicin may result in overgrowth of nonsusceptible organisms. If this occurs, appropriate therapy is indicated. See WARNINGS box regarding concurrent use of potent diuretics and regarding concurrent and/or sequential use of other neurotoxic and/or nephrotoxic antibiotics and for other essential information. Do not administer unless solution is clear and package undamaged.

Pregnancy Category D.
(See WARNINGS section.)

General
Prescribing gentamicin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Information for Patients
Patients should be counseled that antibacterial drugs including gentamicin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When gentamicin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by gentamicin or other antibacterial drugs in the future.

References

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Tenth Edition. CLSI document M07-A10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition. CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fifth Informational Supplement. CLSI document M100-S25. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

Revised: 10/2015

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