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Aminoglycosides: Amikacin, Gentamicin, Kanamycin, or Tobramycin

Amikacin Sulfate, Gentamicin Sulfate, Kanamycin Sulfate, Neomycin Sulfate, Paromomycin Sulfate, Streptomycin Sulfate, Tobramycin Sulfate

Aminoglycosides are antibiotics that generally are active against many aerobic gram-negative bacteria and some aerobic gram-positive bacteria and principally are used for serious infections.

Tobramycin

Uses

Parenteral

Amikacin, gentamicin, kanamycin, or tobramycin is used IM or IV in the short-term treatment of serious infections such as septicemia (including neonatal sepsis), bone and joint infections, skin and soft tissue infections (including those resulting from burns), respiratory tract infections, and postoperative and intra-abdominal infections (including peritonitis) caused by susceptible strains of gram-negative bacteria.

Paromomycin Sulfate

The drugs also are effective in serious, complicated, recurrent urinary tract infections caused by susceptible gram-negative bacteria; however, they are not indicated for the initial treatment of uncomplicated urinary tract infections unless the causative organisms are resistant to other less toxic anti-infectives. Amikacin, gentamicin, kanamycin, or tobramycin also may be used IM or IV in the treatment of serious infections caused by susceptible gram-positive bacteria, but only when other less toxic anti-infectives are ineffective or contraindicated.

Although the manufacturers state that amikacin, gentamicin, or tobramycin is effective in CNS infections (including meningitis) caused by susceptible organisms, CSF concentrations of the drugs following IM or IV administration are unpredictable and generally low. Gentamicin (without preservatives) has been used intrathecally or intraventricularly to supplement IM or IV administration of the drug in the treatment of CNS infections (including meningitis and ventriculitis) caused by susceptible Pseudomonas; however, an injectable preparation of gentamicin without preservatives currently is not commercially available in the US. Amikacin, kanamycin, and tobramycin have been administered intrathecally or intraventricularly to supplement IM or IV administration of the drugs in the treatment of meningitis caused by susceptible organisms. Streptomycin, kanamycin, or amikacin is used parenterally in conjunction with other antituberculosis agents in the treatment of clinical tuberculosis and other mycobacterial diseases; however, the manufacturers state that kanamycin is not indicated for long-term therapy (e.g., tuberculosis). For further information on general principles in the treatment of tuberculosis and other mycobacterial diseases, see the Antituberculosis Agents General Statement 8:16.04.

Streptomycin is used IM in the treatment of plague, glanders, granuloma inguinale, and chancroid; streptomycin or gentamicin also is used IM for the treatment of brucellosis, and gentamicin has been used as an alternative to streptomycin for tularemia and plague. Although streptomycin has also been used IM in the treatment of bacteremias, endocarditis, meningitis, respiratory tract infections, and urinary tract infections caused by susceptible organisms, the drug should be used in these infections only when other parenteral aminoglycosides or other appropriate anti-infectives are ineffective or contraindicated.

Because of reported in vitro synergism, many clinicians recommend concomitant use of an extended-spectrum penicillin with antipseudomonal activity (e.g., carbenicillin, mezlocillin, piperacillin, piperacillin and tazobactam, ticarcillin, ticarcillin and clavulanate) and an aminoglycoside (e.g., amikacin, gentamicin, tobramycin) in the treatment of serious Pseudomonas infections, especially in immunosuppressed patients. However, in vitro inactivation of aminoglycosides by β-lactam antibiotics indicates that the drugs should be administered separately and in vitro mixing of the drugs should be avoided. Aminoglycosides (amikacin, gentamicin, tobramycin) are used in conjunction with a b-lactam antibiotic (e.g., ceftazidime, ceftriaxone), a carbapenem (e.g., imipenem or meropenem), an extended-spectrum penicillin (e.g., azlocillin [no longer commercially available in the US], mezlocillin, piperacillin, ticarcillin), or a fixed combination of an extended-spectrum penicillin and a b-lactamase inhibitor (e.g., piperacillin sodium and tazobactam sodium or ticarcillin disodium and clavulanate potassium) for empiric anti-infective therapy of presumed bacterial infections in febrile neutropenic patients.

Most strains of enterococci are resistant to aminoglycosides alone, and penicillin therapy alone is usually inadequate in infections caused by these organisms; however, because antibacterial activity may be additive or synergistic, gentamicin or streptomycin used concomitantly with penicillin G or ampicillin is often effective in the treatment of enterococcal endocarditis. Some clinicians currently recommend use of gentamicin, since strains of enterococci resistant to streptomycin which do not demonstrate a synergistic effect in vitro with penicillins have been reported with increasing frequency; however, the clinical importance of in vitro enterococcal resistance to streptomycin in the treatment of endocarditis has not been conclusively determined to date, and treatment failures have been reported when gentamicin was used in conjunction with IV penicillin G potassium or sodium for the treatment of enterococcal endocarditis.

Enterococci (e.g.,E. faecalis [formerly Streptococcus faecalis]) are generally resistant to netilmicin (no longer commercially available in the US) alone but have been susceptible to synergistic combinations of the drug and a penicillin (e.g., penicillin G); synergistic combinations of netilmicin and a penicillin have been active against some strains of enterococci that are resistant to combinations of streptomycin and a penicillin. Although the efficacy of concomitant therapy as compared to penicillin therapy has not been definitely established, gentamicin or streptomycin is also used concomitantly with penicillin G or ampicillin in the treatment of streptococcal (viridans group) endocarditis. The American Academy of Pediatrics (AAP) states that in invasive enterococcal infections, including endocarditis and meningitis, ampicillin and vancomycin combined with an aminoglycoside (usually gentamicin) should be administered until in vitro susceptibility is known and appropriate combination therapy can be selected. In the treatment of mixed aerobic-anaerobic bacterial infections, clindamycin has been used in conjunction with an IM or IV aminoglycoside.

The US Centers for Disease Control and Prevention (CDC) and many clinicians suggest a regimen of IM or IV gentamicin in combination with IV clindamycin as one possible parenteral regimen for the treatment of acute pelvic inflammatory disease (PID) in hospitalized adult and adolescent patients. Gentamicin is used in conjunction with parenteral ampicillin (or in conjunction with parenteral vancomycin in penicillin-allergic patients) for prophylaxis of bacterial (e.g., enterococcal) endocarditis in adults and children at high risk undergoing certain genitourinary or nonesophageal GI tract procedures likely to cause transient bacteremia. (See Prophylaxis of Bacterial Endocarditis under Uses: Prophylaxis, in the Aminopenicillins General Statement 8:12..08) When selecting anti-infectives for prophylaxis of recurrent rheumatic fever or prophylaxis of bacterial endocarditis, the current recommendations published by the AHA should be consulted.

Gentamicin encapsulated in liposomes (TLC G-65, available from the Liposome Company) currently is being investigated for the treatment of disseminated Mycobacterium avium complex infections, including those in patients with acquired immunodeficiency syndrome (AIDS); this preparation is designated an orphan drug by the FDA for the treatment of this condition. Prior to and during parenteral aminoglycoside therapy, the causative organism should be cultured and in vitro susceptibility tests conducted. In patients in whom serious gram-negative bacterial infections are suspected, aminoglycoside therapy may be started pending results of susceptibility tests.

In certain serious infections when the causative organism is unknown, concomitant therapy with a penicillin or a cephalosporin may be indicated pending results of susceptibility tests because of the possibility of infections due to aminoglycoside-resistant gram-positive organisms.In general, the choice of a specific parenteral aminoglycoside should be based on the usual spectrum and pattern of aminoglycoside resistance in the hospital or community until results of in vitro tests are available. If the causative organism is found to be resistant to the aminoglycoside selected, another aminoglycoside or other anti-infective to which the organism is susceptible should be substituted. Generally, given a susceptible organism, amikacin, gentamicin, kanamycin, and tobramycin appear to be equally effective when administered in appropriate dosages. Amikacin may be effective in infections caused by gentamicin-, kanamycin-, and/or tobramycin-resistant organisms, especially P. rettgeri, P. stuartii, S. marcescens, K. pneumoniae, and Ps. aeruginosa. However, there are also strains of bacteria resistant to amikacin that may be susceptible to gentamicin and/or tobramycin. Oral Kanamycin, neomycin, or paromomycin has been used orally to inhibit ammonia-forming bacteria in the GI tract as an adjunct to protein restriction and supportive therapy in patients with hepatic encephalopathy. The subsequent decrease in blood ammonia may result in neurologic improvement.

Kanamycin or neomycin is used orally for preoperative intestinal antisepsis as an adjunct to mechanical cleansing of the large intestines. The drugs primarily reduce intestinal aerobes, and some clinicians recommend concomitant administration of erythromycin base or tetracycline to suppress the growth of anaerobic bacteria. For perioperative prophylaxis in patients undergoing colorectal surgery, many clinicians recommend a regimen of oral neomycin and oral erythromycin; a regimen of IV cefotetan or IV cefoxitin; or a regimen of IV cefazolin and IV metronidazole. It has been suggested that the oral regimen may be as effective as the parenteral regimens in patients undergoing elective colorectal surgery.

Many clinicians use both the oral and a parenteral regimen in patients undergoing colorectal surgery; however, it is unclear whether this combined regimen is more effective than use of either an oral or parenteral regimen alone. Neomycin is used orally as an adjunct to fluid and electrolyte replacement in the treatment of severe diarrhea caused by susceptible strains of enteropathogenic E. coli. Some strains of enteropathogenic E. coli are resistant to neomycin; therefore, prior to initiation of neomycin therapy appropriate specimens should be collected for culture and susceptibility tests.

Although the role of anti-infectives in patients with hemorrhagic colitis caused by enterohemorrhagic E. coli is unclear, the AAP suggests that a 5-day oral regimen of a nonabsorbable aminoglycoside (neomycin or gentamicin) can be used in infants with mild diarrhea related to enteropathogenic E. coli. However, resistance may develop and these oral aminoglycosides should not be used in infants with inflammatory or bloody diarrhea because of potential toxicity if the drug is absorbed. Oral neomycin has no effect on organisms that have entered the circulation or tissues.

Oral paromomycin also is used in the treatment of intestinal amebiasis and is used for the treatment of various other parasitic infections (e.g., cryptosporidiosis, Dientamoeba fragilis infections, giardiasis). Oral neomycin has been used with some success in the treatment of hypercholesterolemia. The therapeutic value of the drug in hypercholesterolemia may be due in part to a reduction in GI absorption of lipids.

Oral Inhalation

Aminoglycosides have been administered by oral inhalation for the management of bronchopulmonary Ps. aeruginosa infections in cystic fibrosis patients. Tobramycin is commercially available as a preservative-free solution specifically formulated for oral inhalation via a nebulizer. Gentamicin and tobramycin also have been administered by oral inhalation as aerosols prepared extemporaneously from parenteral preparations of the drugs. Orally inhaled aminoglycosides generally are used for long-term suppressive therapy for prophylaxis of exacerbations of bronchopulmonary Ps. aeruginosa infections in cystic fibrosis patients, and are not routinely recommended for the treatment of acute exacerbations of these infections.

When used for suppressive therapy in controlled clinical studies in cystic fibrosis patients with Ps. aeruginosa, an intermittent 28-day regimen of the commercially available tobramycin solution for oral inhalation given in conjunction with standard therapy for cystic fibrosis has resulted in improved pulmonary function, decreased density of Ps. aeruginosa in expectorated sputum (during the weeks that the patient was receiving the drug), and reduced need for hospitalization and parenteral therapy with antipseudomonal anti-infectives. For topical uses of gentamicin, neomycin, and tobramycin, see 52:04.04 and 84:04.04.

Dosage and Administration

Administration

Aminoglycosides, in appropriate dosage forms, are usually administered by IM injection, IV infusion, or orally. Some clinicians recommend IV infusion of amikacin, gentamicin, kanamycin, tobramycin, or streptomycin (see Dosage and Administration: Administration, in Streptomycin 8:12.02) in patients with life-threatening infections, shock, severe hypotension, severe burns, or reduced muscle mass.

Tobramycin solution for oral inhalation is administered via a nebulizer; tobramycin and gentamicin also have been administered by oral inhalation as aerosols prepared extemporaneously from parenteral preparations of the drugs. Gentamicin (without preservatives) has been administered intrathecally or intraventricularly; however, an injectable preparation of gentamicin without preservatives currently is not commercially available in the US. Amikacin, kanamycin, and tobramycin have also been administered intrathecally or intraventricularly.

Most clinicians prefer intraventricular administration of aminoglycosides to intrathecal administration of the drugs, especially in cases of ventriculitis, to ensure adequate drug concentrations throughout the CSF. If other drugs are administered concomitantly with an aminoglycoside, the drugs should be administered separately. Parenteral aminoglycoside solutions should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Dosage

IM or IV dosage should be based on an estimate of ideal body weight. Because of the potential toxicity of aminoglycosides, fixed-dosage recommendations that are not based on body weight are not advised. The duration of aminoglycoside therapy depends on the type of infection. Parenteral aminoglycoside therapy usually is continued for 7-10 days. Uncomplicated infections caused by susceptible organisms generally respond to usual dosages in 24-48 hours. If definitive clinical response has not occurred within 3-5 days, the susceptibility of the causative organism should be reevaluated.

Failure of the infection to respond to the aminoglycoside administered may be due to inadequate serum concentrations of the drug, resistance of the organism, or the presence of septic foci which require surgical drainage. Safety of aminoglycoside therapy for longer than 14 days has not been established. Once-Daily Dosing Current evidence suggests that once-daily (single-daily) dosing of aminoglycosides is at least as effective as, and may be less toxic than, conventional dosage regimens employing multiple daily doses of the drugs. Use of once-daily dosing regimens can provide rapidly effective serum aminoglycoside concentrations and may reduce time and expense associated with aminoglycoside monitoring and therapy (e.g., decreased number of IV infusions and associated administration costs). However, most studies of once-daily aminoglycoside dosing generally have consisted of administration of the total daily dosage as a single daily dose without dosage optimization according to individualized pharmacokinetic parameters or microbiologic endpoints (e.g., peak plasma concentration/MIC ratio), and other methodologic problems (e.g., small sample size, failure to isolate/identify a pathogen, use of concomitant anti-infective therapy) limit definitive conclusions about efficacy.

Results of several analyses of pooled data from randomized, controlled studies in adults found that once-daily administration of aminoglycosides was associated with similar or greater efficacy (e.g., bacteriologic and/or clinical cure), less nephrotoxicity, and no greater risk of ototoxicity compared with administration of multiple daily doses of these drugs. However, various definitions of nephrotoxicity were used in these studies, and only a few studies in which once-daily dosing regimens were used have included infants or children, pregnant women, or patients with renal dysfunction, neutropenia, or life-threatening infections (e.g., endocarditis, bacteremia). Additional well-controlled studies in these and other appropriate patient groups, including comparisons with individualized pharmacokinetic dosing regimens (e.g., high-dose, extended-interval regimens), are needed to fully define the optimal use of once-daily aminoglycoside dosing regimens. Current pharmacodynamic data suggest that the use of larger, less frequent doses of aminoglycosides may enhance the antimicrobial efficacy of these drugs. Unlike some other antibiotics (e.g., b-lactams), aminoglycosides have concentration-dependent bactericidal effects against many pathogens; higher serum concentrations are associated with increased bactericidal effects.

The drugs also exhibit a prolonged, concentration-dependent postantibiotic effect (PAE) against a variety of gram-negative and gram-positive pathogens. In addition, less frequent (e.g., once-daily) dosing may minimize or prevent the occurrence of aminoglycoside-induced adaptive resistance (i.e., reversible refractoriness to the antimicrobial effects of subsequent aminoglycoside doses because of decreased uptake of the drug following the initial dose) and selection of aminoglycoside-resistant subpopulations in gram-negative bacteria by allowing a recovery period during the dosing interval in which serum aminoglycoside concentrations are negligible. Aminoglycoside-related toxicity appears to be reduced, or at least not increased, with once-daily dosing regimens because infrequent administration of large doses results in less drug accumulation in tissue than does multiple daily dosing or continuous IV infusion.

Once-daily dosing of aminoglycosides may minimize the risk of nephrotoxicity because renal cortical uptake for most aminoglycosides appears to be saturable, reaching a plateau despite increasing serum concentrations.

Although results have not been entirely consistent, evidence in animals indicates that administration of larger, less frequent doses of aminoglycosides results in lower renal cortical aminoglycoside concentrations than those found with multiple daily dosing or continuous IV infusion, while the efficacy of these dosing regimens has been reported to be similar. Limited data in humans also suggest that the renal cortical concentrations and nephrotoxicity of aminoglycosides may be reduced with once-daily dosing while efficacy comparable to that observed with multiple daily dosing is maintained. In a study in patients undergoing nephrectomy who received identical single doses of gentamicin or netilmicin (no longer commercially available in the US) given by IV infusion over 30 minutes or 24 hours, aminoglycoside concentrations in renal cortical tissue were 30 or 50% higher with 24-hour infusion of netilmicin or gentamicin, respectively.

In addition, nephrotoxicity (defined as an increase in serum creatinine concentration of approximately 0.5 mg/dL) was observed less frequently in patients with serious infections who received gentamicin as a single daily dose than in those who received the same daily dose in 3 divided doses.

Although less is known about the relationship between ototoxicity and aminoglycoside dosing regimen or maintenance of aminoglycoside serum concentrations above or below a certain level, available data suggest that once-daily dosing of aminoglycosides at least does not appear to result in increased ototoxicity compared with multiple daily dosing.

Some clinicians have suggested that use of once-daily dosing of aminoglycosides may not be advisable in patients with serious infections and impaired host defenses (e.g., Pseudomonas aeruginosa infections in patients with neutropenia) and/or clinical conditions associated with rapid clearance or unpredictable pharmacokinetics of aminoglycosides (e.g., extensive burns, cystic fibrosis, massive ascites) since these regimens could allow prolonged intervals of undetectable aminoglycoside concentrations that could outlast the PAE. Aminoglycosides usually are administered as adjunctive therapy with other anti-infective agents (e.g., b-lactam antibiotics) in patients with serious gram-negative infections to provide synergistic antimicrobial effects, and limited data from studies employing such combined therapy in neutropenic patients suggest no substantial detrimental effects on clinical outcomes.

Some clinicians, however, suggest that multiple-daily dosing of aminoglycosides is preferred in patients with endocarditis caused by gram-positive organisms (e.g., enterococci) who require concomitant synergistic antimicrobial therapy. Once-daily dosing regimens may also be inappropriate in some patients with renal dysfunction in whom aminoglycoside half-life is prolonged since such patients would be unlikely to have an aminoglycoside-free period with dosing every 24 hours; more prolonged dosing intervals or reduced dosage of the aminoglycoside should be used in such patients. The optimum dosage for once-daily dosing of aminoglycosides has not been established. Dosages used in studies of once-daily aminoglycoside dosing generally have ranged from approximately 4-6. mg/kg for gentamicin or tobramycin and from approximately 15-20 mg/kg for amikacin. In most studies, the dosage used for the once-daily dose was simply the total daily dose that was given in 2 or more divided doses in the conventional regimen, although higher doses (e.g., 10-15 mg/kg of tobramycin) also have been used.

Concomitant therapy with other anti-infective agents (e.g., b-lactam antibiotics) was administered in most studies of once-daily aminoglycoside therapy confounding accurate determination of the efficacy of the aminoglycoside alone as once-daily therapy. Therefore, some clinicians have suggested that it is possible that aminoglycoside doses lower than those used as monotherapy may be effective in once-daily combination regimens. Laboratory Monitoring of Therapy For gentamicin and tobramycin, a commonly defined therapeutic range of serum concentrations is represented by peak serum aminoglycoside concentrations of approximately 4-12 mcg/mL and trough concentrations of less than 2 mcg/mL; peak and trough serum concentrations of 15-40 and less than 5-10 mcg/mL, respectively, have been suggested for amikacin and kanamycin.

The ratio of the peak serum aminoglycoside concentration to the MIC of the pathogen also has been evaluated as an indicator of aminoglycoside bactericidal efficacy by which to adjust aminoglycoside dosage and serum concentrations. Limited data in patients receiving multiple daily doses of aminoglycosides have suggested an association between clinical response and a peak (i.e., one-hour postinfusion) serum concentration/MIC ratio up to 12. When MIC data are unavailable for patients receiving once-daily aminoglycoside dosing regimens, some clinicians have used a high target peak serum concentration (e.g., 20 mcg/mL for gentamicin or tobramycin) to ensure optimal peak/MIC ratios.However, a causal relationship between maintenance of certain peak or trough serum concentrations or other pharmacodynamic endpoints and clinical response or toxicity has not been established to date for aminoglycoside dosing regimens.

Currently recommended therapeutic ranges for aminoglycosides generally are based on data in patients receiving aminoglycosides in multiple daily doses and often were derived by retrospective evaluation of data on efficacy and toxicity. In addition, definitions of nephrotoxicity and ototoxicity have varied among clinical studies, and toxicity often was attributed to aminoglycoside therapy without considering the potential contributory effects of concomitant anti-infective therapy. Nevertheless, pending the availability of more definitive methods for ensuring efficacy and minimizing toxicity of aminoglycoside therapy, most clinicians recommend monitoring of aminoglycoside serum concentrations and/or peak serum concentration/MIC ratio, particularly 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. Blood specimens for peak serum aminoglycoside drug concentrations should be obtained approximately 1 hour following IM administration.

When an IV infusion is used, the timing for collection of blood specimens depends on the rate of the infusion. Most clinicians recommend that blood specimens for peak drug concentrations be obtained 30 minutes after completion of a 30-minute infusion or at the completion of a 1-hour infusion. Blood specimens for trough drug concentrations should be obtained immediately prior to the next IM or IV dose.

Dosage in Renal Impairment

In patients with impaired renal function, doses and/or frequency of administration of aminoglycosides must be modified in response to serum concentrations of the drugs and the degree of renal impairment. When serum aminoglycoside concentrations are not available, there are various formulae, tables, nomograms, and computer-assisted programs based on serum creatinine or creatinine clearance to aid in dosage adjustment. T he method of Sarubbi and Hull, which is based on corrected creatinine clearance, has been recommended for determination of amikacin, gentamicin, kanamycin, and tobramycin dosage in patients with renal impairment.However, even when one of these methods is used, peak and trough serum aminoglycoside concentrations should be monitored, especially in patients with changing renal function. These dosage calculation methods should not be used in patients undergoing hemodialysis or peritoneal dialysis; supplemental doses of aminoglycosides may be required after dialysis.

Aminoglycoside Dosing for Adults with Renal Impairment

(Do not use in hemodialysis or peritoneal dialysis patients or in children.) Select Loading Dose in mg/kg (based on estimated ideal body weight) to provide peak serum concentrations in range listed below for desired aminoglycoside.

AMINOGLYCOSIDE USUAL LOADING DOSES EXPECTED PEAK SERUM CONCENTRATIONS

Tobramycin 1 to 2 mg/kg 4 to 10 mcg/mL Gentamicin Amikacin 5.0 to 7.5 mg/kg 15 to 30 mcg/mL Kanamycin Select Maintenance Dose (as percentage of chosen loading dose) to continue peak serum concentrations indicated above according to desired dosing interval and the patient’s corrected (for a 70-kg ideal body weight) creatinine clearance [C(c)cr]. C(c)cr half-life ** 8 hrs 12 hrs 24 hrs (mL/min) (hrs) 90 3.1 84% — — 80 3.4 80 91% — 70 3.9 76 88 — 60 4.5 71 84 — 50 5.3 65 79 — 40 6.5 57 72 92% 30 8.4 48 63 86 25 9.9 43 57 81 20 11. 37 50 75 17 13. 33 46 70 15 15. 31 42 67 12 17. 27 37 61 10 **# 20. 24 34 56 7 25. 19 28 47 5 31. 16 23 41 2 46. 11 16 30 0 69. 8 11 21 ** ** Alternatively, one-half of the chosen loading dose may be given at an interval approximately equal to the estimated half-life. # Dosing for patients with C(c)cr = 10 mL/min should be assisted by measured serum concentrations.

Tobramycin

Modified from Sarubbi FA Jr, Hull JH. Amikacin serum concentrations:prediction of levels and dosage guidelines. Ann Intern Med. 1978; 89:612-8. Alternatively, many clinicians recommend that dosage of these aminoglycosides 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, presence of a postantibiotic effect (PAE), severity of infection, and the patient’s immune and clinical status also must be considered.

Cautions

Ototoxicity and nephrotoxicity are the most serious adverse effects of aminoglycoside therapy and are most likely to occur in geriatric or dehydrated patients, patients with renal impairment, or patients who are receiving one of the drugs in high doses or for long periods, or who are also receiving or have received other ototoxic and/or nephrotoxic drugs.

Otic Effects

Eighth cranial nerve damage may be manifested by vestibular symptoms such as dizziness, nystagmus, vertigo, and ataxia, and/or by auditory symptoms such as tinnitus, roaring in the ears, and varying degrees of hearing impairment. Loss of high-frequency perception, detectable only by audiometric testing, usually occurs before clinical hearing loss. Loss of hearing may be permanent if damage is extensive. Rarely, progressive eighth cranial nerve damage, with total or partial irreversible bilateral deafness, may occur after aminoglycoside therapy has been discontinued. Although the distinctions are not absolute and either or both forms of ototoxicity may occur with any of the aminoglycosides, vestibular symptoms are more frequently associated with streptomycin, gentamicin, or tobramycin and auditory symptoms are more frequently associated with amikacin, kanamycin, neomycin, or paromomycin.

Renal and Electrolyte Effects

Aminoglycoside-induced nephrotoxicity may be evidenced by tubular necrosis; increases in BUN, nonprotein nitrogen (NPN), and serum creatinine concentration; decreases in urine specific gravity and creatinine clearance; proteinuria; or cells or casts in the urine. Most patients with aminoglycoside nephrotoxicity develop nonoliguric azotemia; oliguria occurs rarely. A Fanconi-like syndrome (proximal renal tubular dysfunction) characterized by aminoaciduria and metabolic acidosis also has occurred in patients receiving aminoglycosides (e.g., gentamicin). Rarely, renal electrolyte wasting manifested as hypocalcemia, hypomagnesemia, and hypokalemia that may be associated with paresthesia, tetany, confusion, and positive Chvostek and Trousseau signs has been reported with aminoglycosides. When this electrolyte wasting occurs in infants, tetany and muscle weakness appear to be the predominant manifestations. If such renal and electrolyte abnormalities develop in patients receiving aminoglycosides, appropriate therapy to correct any electrolyte imbalance(s) associated with the syndrome should be instituted. Aminoglycoside-induced renal toxicity is usually reversible following discontinuance of the drug; however, death due to uremia has occurred rarely. At usual dosages, streptomycin appears to be less nephrotoxic than the other aminoglycosides. The relative nephrotoxicities of the other aminoglycosides in humans have not been definitely established; however, tobramycin appears to be less nephrotoxic than gentamicin, and amikacin and gentamicin appear to be approximately equal in nephrotoxic potential.

Nervous System Effects

Aminoglycosides produce varying degrees of neuromuscular blockade; neomycin probably is the most potent neuromuscular blocking agent of the currently available aminoglycosides. Although the blockade induced by an aminoglycoside is generally dose related and self-limiting, it may rarely result in respiratory paralysis. Neuromuscular effects are most likely to occur when an aminoglycoside is applied to serosal surfaces (as in intrapleural injection or peritoneal instillation) or is administered to patients with neuromuscular disease (e.g., myasthenia gravis) or hypocalcemia or to patients who are receiving general anesthetics, neuromuscular blocking agents, or massive transfusions of citrated blood. Drug-induced neuromuscular blockade is not easily reversed and its reversibility seems dependent on the severity of the blockade; calcium salts have been used successfully in some cases, but mechanically assisted respiration may be necessary. T he efficacy of neostigmine in reversing aminoglycoside-induced neuromuscular blockade is highly variable. Peripheral neuropathy or encephalopathy, including numbness, skin tingling, muscle twitching, seizures, and a myasthenia gravis-like syndrome, has been reported during aminoglycoside (e.g., gentamicin) therapy. Other neurotoxic effects including headache, tremor, lethargy, paresthesia, peripheral neuritis, arachnoiditis, encephalopathy, and acute organic brain syndrome have occurred rarely with aminoglycoside therapy. CNS depression characterized by stupor and flaccidity, and in some cases, coma and respiratory depression, has been reported in infants receiving high dosages of streptomycin. Optic neuritis with blurred vision, visual disturbances, scotomas, and enlargement of the blind spot have also been reported with aminoglycoside therapy. Intrathecal administration of the drugs has caused nerve root pain, burning at the injection site, paraplegia, radiculitis, transverse myelitis, and arachnoiditis. Changes in renal and eighth cranial nerve function, leg cramps, rash, fever, seizures, and an increase in CSF protein have been reported in patients receiving intrathecal gentamicin in conjunction with IM or IV administration of the drug.

Sensitivity Reactions

Occasionally, hypersensitivity reactions including rash, urticaria, stomatitis, pruritus, generalized burning, fever, and eosinophilia have occurred in patients receiving an aminoglycoside. The manufacturers caution that contact with streptomycin injections during handling or preparation may cause sensitization to the drug. Transient agranulocytosis, anaphylaxis, and serious dermatologic reactions including exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, and Stevens-Johnson syndrome, have been reported rarely; fatalities also have occurred rarely. Cross-allergenicity among the aminoglycosides has been demonstrated. If an allergic reaction occurs in patients receiving an aminoglycoside, the drug should be discontinued and appropriate therapy instituted.

Other Adverse Effects

Other less frequently reported adverse effects of aminoglycosides include nausea and vomiting, anemia, leukopenia, granulocytopenia, thrombocytopenia, tachycardia, arthralgia, transient hepatomegaly, splenomegaly, hepatic necrosis, myocarditis, hypotension, increases or decreases in reticulocyte count, and transient increases in serum AST (SGOT), ALT (SGPT), LDH, alkaline phosphatase, and bilirubin concentrations. Anorexia, weight loss, mental depression, increased salivation, hypertension, alopecia, purpura, pseudotumor cerebri, pulmonary fibrosis, and laryngeal edema have also been reported rarely with gentamicin. Local irritation, pain, sterile abscess, subcutaneous atrophy, fat necrosis, and thrombophlebitis have occurred with IM or IV administration of aminoglycosides. The most frequent adverse reactions of orally administered aminoglycosides are nausea, vomiting, and diarrhea. Malabsorption of lipids, protein, sodium, calcium, various sugars, iron, cyanocobalamin, and certain drugs (see Drug Interactions: Neomycin); increased fecal excretion of bile acids, potassium, and calcium; and decreased serum concentrations of cholesterol, carotene, and vitamin K have been reported rarely. A sprue-like syndrome with steatorrhea, malabsorption, and electrolyte imbalances has occurred following oral administration of kanamycin or neomycin. The effects of malabsorption are not usually clinically important in patients who receive short courses of oral neomycin or kanamycin but may be pronounced in patients who receive the drugs for prolonged periods. Rarely, enterocolitis has been reported following prolonged oral aminoglycoside therapy. Although relatively small amounts of kanamycin or neomycin are usually absorbed following oral administration, the drugs may accumulate in patients with renal impairment and produce systemic toxicity. Ototoxicity and nephrotoxicity have occurred following prolonged high dosage oral neomycin therapy. An anamnestic photosensitivity (photo recall)-like dermatitis, characterized by a pruritic, erythematous, maculopapular eruption distributed in the area of a recent sunburn on the upper abdomen and chest, has been reported in at least one patient receiving concomitant IV therapy with cefazolin and gentamicin sulfate. Whether this phenomenon was caused by one or both drugs has not been determined; however, the reaction resolved within 48 hours following discontinuance of both drugs.

Precautions and Contraindications

Some commercially available formulations of aminoglycosides contain sulfites, which may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals. Patients with preexisting tinnitus, vertigo, subclinical high-frequency hearing loss, or renal impairment and patients who are receiving high dosages and/or prolonged therapy with aminoglycosides or who have received prior ototoxic drugs are especially susceptible to ototoxicity and should be carefully observed for signs of eighth cranial nerve damage during aminoglycoside therapy. The risk of toxicity appears to be low in well-hydrated patients with normal renal function if usual dosage is not exceeded. Neurotoxic and nephrotoxic antibiotics such as aminoglycosides may be absorbed in substantial amounts from body surfaces after local irrigation or application, and the potential toxic effects associated with such administration should be considered. (See Pharmacokinetics: Absorption.) Patients receiving an aminoglycoside (by any route of administration) should be under close medical supervision. Renal function should be assessed prior to initiation of aminoglycoside therapy and should be monitored at regular intervals during therapy. Eighth cranial nerve function should be monitored in geriatric patients; patients with prior auditory, vestibular, or renal impairment; and patients receiving prolonged aminoglycoside therapy. Since geriatric patients may have reduced renal function which is not evident from BUN or serum creatinine concentrations, creatinine clearance may be a more useful indicator of renal function in these patients. The difference between therapeutic and toxic serum concentrations of the aminoglycosides may be narrow. Although a causal relationship has not been established, ototoxicity and nephrotoxicity may be related to high peak serum aminoglycoside concentrations and/or high trough drug concentrations between doses. Therefore, whenever possible, and especially in patients with renal impairment, peak and trough serum concentrations of aminoglycosides should be determined periodically and dosage adjusted to maintain desired serum concentration.Prolonged peak serum concentrations of amikacin or kanamycin above 30-35 mcg/mL, gentamicin or tobramycin above 10-12 mcg/mL, streptomycin above 40 mcg/mL, or neomycin above 5-10 mcg/mL may be associated with an increased risk of toxicity. If signs of renal irritation (cells, casts, or protein in the urine) occur during aminoglycoside therapy, hydration of the patient should be increased as indicated and a decrease in dosage may be required. If evidence of ototoxicity (e.g., dizziness, vertigo, tinnitus, roaring in the ears, hearing loss) or nephrotoxicity (e.g., decreased creatinine clearance or urine specific gravity, increased BUN and/or serum creatinine concentrations, oliguria) develops during aminoglycoside therapy, the drug should be discontinued or dosage should be reduced. Aminoglycoside therapy should be discontinued if urinary output decreases progressively or azotemia increases. In the event of overdosage or toxic reactions, hemodialysis or peritoneal dialysis may aid in removal of the drug. Exchange transfusions may also be considered in neonates. Aminoglycosides should be used with caution in patients with neuromuscular disorders such as myasthenia gravis or parkinsonian syndrome, since the drugs may aggravate muscle weakness as a result of their potential to produce neuromuscular blockade. If signs of respiratory paralysis occur during aminoglycoside therapy, respiration should be assisted and the drug discontinued. The manufacturers state that individuals who handle or prepare streptomycin injections should use care to avoid contact and resultant sensitization to the drug. The use of aminoglycosides by any route may result in the overgrowth of nonsusceptible organisms including fungi. If superinfection occurs, appropriate therapy should be instituted. A specific aminoglycoside preparation is contraindicated in patients with a history of hypersensitivity to that preparation or any ingredient in the formulation. Because there is evidence of cross-sensitivity among aminoglycosides, a history of toxic or hypersensitivity reaction to one aminoglycoside preparation may contraindicate the use of any other aminoglycoside. Oral administration of kanamycin or neomycin is contraindicated in patients with intestinal obstruction.

Pediatric Precautions

Aminoglycosides should be used with caution and in reduced dosage in premature and full-term neonates because of the renal immaturity of these patients and resulting prolongation of serum half-life of the drugs.

Pregnancy and Lactation

Aminoglycosides can cause fetal harm when administered to pregnant women, but potential benefits from use of the drugs may be acceptable in certain conditions despite possible risks to the fetus. Aminoglycosides have been shown to cross the placenta and there have been several reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Although serious adverse effects have not been reported in fetuses or neonates whose mothers received other aminoglycosides during pregnancy, the potential for fetal toxicity exists with these antibiotics. Aminoglycosides should be used during pregnancy only in life-threatening situations or severe infections for which safer drugs cannot be used or are ineffective. When an aminoglycoside is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus. Small amounts of aminoglycosides are distributed into milk. Because of the potential for serious adverse reactions to an aminoglycoside in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Neurotoxic, Ototoxic, or Nephrotoxic Drugs

Since neurotoxic, ototoxic, or nephrotoxic effects may be additive, concurrent and/or sequential use of an aminoglycoside and other drugs (administered systemically, orally, or topically) with similar toxic potentials (e.g., other aminoglycosides, acyclovir, amphotericin B, bacitracin, capreomycin, cephalosporins, colistin, cisplatin, methoxyflurane, polymyxin B, vancomycin) should be avoided, if possible. In addition, because of the possibility of an increased risk of ototoxicity due to additive effects or altered serum and tissue concentrations of the antibiotics, aminoglycosides should not be given concurrently with ethacrynic acid, furosemide, urea, or mannitol. The possibility that dimenhydrinate and other antiemetics may mask symptoms of vestibular ototoxicity should be kept in mind.

General Anesthetics and Neuromuscular Blocking Agents

Concurrent use of an aminoglycoside with general anesthetics or neuromuscular blocking agents (e.g., succinylcholine, tubocurarine) may potentiate neuromuscular blockade and cause respiratory paralysis. Aminoglycosides should be used with caution in patients receiving such agents, and patients should be observed for signs of respiratory depression.

Neomycin

Oral neomycin may potentiate the effects of oral anticoagulants, possibly by interfering with GI absorption or synthesis of vitamin K. Prothrombin times should be monitored in patients receiving concomitant oral aminoglycoside and oral anticoagulant therapy, and dosage of the anticoagulant should be adjusted as required. Although the clinical importance is unclear, oral neomycin has been reported to decrease GI absorption of digoxin and methotrexate. However, administration of oral neomycin to digitalized patients apparently does not affect the terminal plasma half-life of digoxin. Some clinicians recommend that serum digoxin concentrations be monitored when oral neomycin therapy is initiated or discontinued in patients stabilized on digoxin. Oral neomycin is also reported to decrease the rate but not the extent of absorption of spironolactone.

Anti-infective Agents

In vitro studies indicate that the antibacterial activity of aminoglycosides and b-lactam antibiotics or vancomycin may be additive or synergistic against some organisms including enterococci and Ps. aeruginosa. In vitro studies indicate that aminoglycosides and extended-spectrum penicillins also exert a synergistic bactericidal effect against some Enterobacteriaceae. The synergistic effect of aminoglycosides and these anti-infectives is usually used to therapeutic advantage, especially in the treatment of infections caused by enterococci or Ps. aeruginosa. Although the exact mechanism of this synergistic effect has not been determined, it appears that by inhibiting bacterial cell-wall synthesis the penicillin allows more effective ingress of the aminoglycoside to the ribosomal binding site. Synergism between aminoglycosides and extended-spectrum penicillins is generally unpredictable and antagonism has been reported rarely in vitro when these penicillins were used in conjunction with amikacin, gentamicin, or tobramycin. Therefore, some clinicians suggest that when concomitant therapy is indicated it may be advisable to use appropriate in vitro studies to demonstrate synergism against the isolated organism. Concomitant administration of an extended-spectrum penicillin and an aminoglycoside has resulted in decreased serum aminoglycoside concentrations and elimination t1/2, especially in patients with renal impairment. Therefore, serum aminoglycoside concentrations should be monitored in patients receiving concomitant therapy, especially when very high doses of an extended-spectrum penicillin are used or when the patient has impaired renal function. Penicillins can also inactivate aminoglycosides in vitro and the presence of penicillins in serum samples to be assayed for aminoglycoside concentrations may result in falsely decreased aminoglycoside concentrations. Amikacin appears to be the least susceptible and tobramycin the most susceptible to inactivation by b-lactam antibiotics, and most studies indicate that carbenicillin inactivates aminoglycosides at a faster rate than do other currently available extended-spectrum penicillins. To ensure accurate serum aminoglycoside assays in patients receiving concomitant therapy, penicillinase should be added to blood collection tubes whenever samples cannot be assayed immediately for aminoglycoside concentrations. Chloramphenicol, clindamycin, and tetracycline have been reported to antagonize the bactericidal activity of aminoglycosides in vitro, and some clinicians recommend that these drugs not be used concomitantly. However, in vivo antagonism has not been demonstrated, and aminoglycosides have been administered successfully in conjunction with chloramphenicol or clindamycin with no apparent decrease in activity. The antibacterial activity of imipenem and aminoglycosides is additive or synergistic in vitro against some gram-positive bacteria including Enterococcus faecalis (formerly Streptococcus faecalis), Staphylococcus aureus, and Listeria monocytogenes. Depending on the method used to determine in vitro synergism, the combination of imipenem and an aminoglycoside is synergistic against 35-98% of E. faecalis tested.

Nonsteroidal Anti-inflammatory Agents

Indomethacin has been reported to increase trough and peak serum aminoglycoside (e.g., amikacin, gentamicin) concentrations in premature neonates who were receiving the drugs concomitantly. Increases in serum aminoglycoside concentrations appeared to be related to indomethacin-induced decreases in urine output. It also has been postulated that inhibitors of prostaglandin synthesis (e.g., aspirin) may increase nephrotoxicity of aminoglycosides. Serum aminoglycoside concentrations and renal function should be closely monitored and aminoglycoside dosage adjusted accordingly when aminoglycosides are used concomitantly with indomethacin in premature neonates.

Laboratory Test Interferences

Tests for Urinary Glucose

Streptomycin reportedly causes false-positive results in urine glucose determinations using cupric sulfate solution. Mechanism of Action Aminoglycosides are usually bactericidal in action. Although the exact mechanism of action has not been fully elucidated, the drugs appear to inhibit protein synthesis in susceptible bacteria by irreversibly binding to 30S ribosomal subunits. Spectrum In general, aminoglycosides are active against many aerobic gram-negative bacteria and some aerobic gram-positive bacteria. However, there are differences in spectra of activity of the individual drugs. Aminoglycosides are inactive against fungi, viruses, and most anaerobic bacteria.

Susceptibility Testing

In vitro, susceptible organisms are generally inhibited by gentamicin or tobramycin concentrations of 1-8 mcg/mL; amikacin, kanamycin, neomycin, or paromomycin concentrations of 1-12. mcg/mL; or streptomycin concentrations of 1-16 mcg/mL. However, different species and different strains of the same species may exhibit wide variations in susceptibility to a specific aminoglycoside in vitro. In addition, in vitro susceptibility does not always correlate with in vivo activity.

Gram-negative Aerobic Bacteria

Aminoglycosides are generally active against Acinetobacter, Citrobacter, Enterobacter, Escherichia coli, Klebsiella, indole-positive and indole-negative Proteus, Providencia, Pseudomonas, Salmonella, Serratia, and Shigella. A large percentage of these organisms are susceptible to amikacin, gentamicin, and tobramycin; resistance is more common with kanamycin, and a large percentage of these organisms are resistant to streptomycin, neomycin, and paromomycin. Amikacin, gentamicin, and tobramycin are active against most strains of Ps. aeruginosa; however, these organisms are generally resistant to kanamycin, neomycin, paromomycin, and streptomycin. Amikacin is active against some strains of bacteria, especially Proteus, Pseudomonas, and Serratia, which are not susceptible to the other aminoglycosides. However, there are also strains of bacteria resistant to amikacin which may be susceptible to gentamicin and/or tobramycin. Streptomycin and gentamicin are active against Brucella and Yersinia pestis; streptomycin also is active against Calymmatobacterium granulomatis, Francisella tularensis, Haemophilus influenzae, H. ducreyi, and Pasteurella multocida.

Gram-positive Bacteria

Aminoglycosides are active against most strains of Staphylococcus aureus and S. epidermidis. The drugs are only minimally active against streptococci; most strains of enterococci are resistant to the aminoglycosides. Streptomycin is active against Nocardia, Enterococcus faecalis (formerly Streptococcus faecalis), and Erysipelothrix.

Mycobacteria

Streptomycin is active in vitro and in vivo against Mycobacterium tuberculosis, M. bovis, M. marinum, and some strains of M. kansasii, M. intracellulare, and M. avium; streptomycin is also active against M. leprae in experimental leprosy in mice. In vitro, other aminoglycosides have some activity against M. tuberculosis and M. fortuitum. Kanamycin is also active in vitro against some strains of M. kansasii, M. marinum, and M. intracellulare.

Parasites

Paromomycin is active against protozoa, especially Entamoeba histolytica, and has some anthelmintic activity against Taenia saginata, Hymenolepis nana, Diphyllobothrium latum, and Taenia solium. Limited in vitro studies indicate that neomycin and paromomycin have some activity against Acanthamoeba, and that neomycin concentrations of 12. mcg/mL or paromomycin concentrations of 5 mcg/mL may be amebistatic against these organisms. Resistance Natural and acquired resistance to one or more of the aminoglycosides has been reported in both gram-negative and gram-positive bacteria. Resistance to a specific aminoglycoside may be due to decreased permeability of the bacterial cell wall, alterations in the ribosomal binding site, or the presence of a plasmid-mediated resistance factor which is acquired by conjugation. Plasmid-mediated resistance enables the resistant bacteria to enzymatically modify the drug by acetylation, phosphorylation, or adenylylation and can be transferred between organisms of the same or different species. Resistance to other aminoglycosides and several other anti-infectives (e.g., chloramphenicol, sulfonamides, tetracycline) may be transferred on the same plasmid. Amikacin is not a suitable substrate for most of the common aminoglycoside-modifying enzymes. There is partial cross-resistance among the aminoglycosides; cross-resistance occurs frequently between kanamycin, neomycin, and paromomycin. There is no evidence of cross-resistance between kanamycin and streptomycin in mycobacteria; however, partial cross-resistance has been demonstrated between kanamycin and capreomycin in M. tuberculosis. Resistant strains of initially susceptible M. tuberculosis develop rapidly if streptomycin or kanamycin is used alone in the treatment of clinical tuberculosis. When one of these drugs is combined with other antituberculosis agents in the treatment of the disease, emergence of resistant strains may be delayed or prevented.

Pharmacokinetics

Absorption

Aminoglycosides are poorly absorbed from the GI tract. The drugs are well absorbed following parenteral administration; however, there may be considerable interpatient variation in plasma concentrations achieved with a specific IM dose because of differences in rates of absorption from IM injection sites. Following IM administration in adults with normal renal function, peak plasma concentrations of the drugs are usually attained within 0.5-2 hours and measurable concentrations may persist 8-12 hours. Aminoglycosides are rapidly and almost completely absorbed following topical administration (except to the urinary bladder) during surgical procedures (e.g., from the peritoneum). Serious adverse systemic effects, including irreversible deafness, renal failure, and death resulting from neuromuscular blockade, have been reported following irrigation of small and large surgical sites with an aminoglycoside preparation. Aminoglycosides are also rapidly absorbed from the bronchial tree, wounds, or denuded skin after local instillation, or when used to irrigate joints; use of large doses at these sites may also result in substantial plasma concentrations of the drugs.

Distribution

Following absorption, aminoglycosides are widely distributed into body fluids including ascitic, pericardial, peritoneal, pleural, synovial, and abscess fluids. Aminoglycosides are distributed primarily in the extracellular fluid volume. At a concentration of 15 mcg/mL, approximately 35% of streptomycin is bound to plasma proteins; other aminoglycosides are only minimally protein bound. Aminoglycosides diffuse poorly into the CSF following IM or IV administration; even in patients with inflamed meninges, aminoglycoside concentrations in CSF are unpredictable and generally low (0-50% of concurrent serum concentrations). Following intralumbar administration, there may be limited upward diffusion of the drugs, presumably because of the direction of the CSF flow. Intraventricular administration usually produces high drug concentrations throughout the CNS. The drugs do not readily penetrate ocular tissue. Streptomycin does not penetrate thick-walled abscesses, but does penetrate tuberculosis cavities and caseous tissues. A small portion of each aminoglycoside dose accumulates in body tissues and is tightly bound intracellularly. Most body compartments and tissues including the inner ear and kidneys become progressively saturated with an aminoglycoside over the course of therapy, and the drug is slowly released from these areas. It has been postulated that this accumulation may account for the ototoxicity and nephrotoxicity associated with aminoglycosides. The individual aminoglycosides differ in their affinity for renal tissue; streptomycin has less affinity for renal tissue than the other aminoglycosides. In general, aminoglycosides readily cross the placenta, and fetal serum concentrations of the drugs are reported to be 16-50% of maternal serum concentrations. Small amounts of the drugs are also distributed into bile, saliva, sweat, tears, sputum, and milk.

Elimination

The plasma elimination half-lives (t1/2s) of aminoglycosides are usually 2-4 hours in adults with normal renal function. Plasma concentrations are higher and plasma elimination t1/2s are more prolonged in patients with impaired renal function. Plasma concentrations and plasma elimination t1/2s of the drugs are not usually affected by hepatic impairment; however, the plasma elimination t1/2 of streptomycin has been reported to be more prolonged in patients with both renal and hepatic impairment than in patients with renal impairment alone. In infants, aminoglycoside plasma elimination t1/2s are inversely proportional to birthweight and gestational age and probably reflect renal maturity. Studies using gentamicin indicate that febrile patients may have slightly lower plasma concentrations of the drug than afebrile patients given the same dose; however, the clinical importance of this effect is unclear. Plasma concentrations of gentamicin (and presumably other aminoglycosides) may also be lower and the plasma elimination t1/2 prolonged in patients with marked edema or pathologic fluid collections because of altered distribution of the drug. Aminoglycosides are not metabolized and are excreted unchanged in the urine primarily by glomerular filtration. In patients with normal renal function, 40-97% of a single IM or IV dose of an aminoglycoside is excreted in the urine within 24 hours. Because a small portion of each aminoglycoside dose accumulates in body tissues, complete recovery of a single dose in urine requires approximately 10-20 days in patients with normal renal function. Terminal elimination t1/2s of greater than 100 hours have been reported for amikacin, gentamicin, and tobramycin in adults with normal renal function following repeated IM or IV administration of the drugs. Following oral administration, unabsorbed kanamycin or neomycin is excreted unchanged in the feces. Aminoglycosides are readily removed by hemodialysis and to a lesser extent by peritoneal dialysis; the amount of drug removed depends on several factors (e.g., type of coil used, flow-rate).

Chemistry and Stability

Chemistry

Aminoglycosides are antibiotics and semisynthetic antibiotic derivatives obtained from cultures of Streptomyces or Micromonospora. The drugs contain 1 or 2 amino sugars glycosidically linked to an aminocyclitol nucleus and are more accurately termed aminoglycosidic aminocyclitols. Streptidine is the aminocyclitol nucleus of streptomycin, and 2-deoxystreptamine is the aminocyclitol nucleus of amikacin, gentamicin, kanamycin, neomycin, netilmicin (no longer commercially available in the US), paromomycin, and tobramycin. streptidine 2-deoxystreptamine Amikacin, gentamicin, kanamycin, streptomycin, and tobramycin are commercially available for parenteral administration as sulfate salts; kanamycin, neomycin, and paromomycin are commercially available for oral administration as sulfate salts; and tobramycin is commercially available as the base for oral inhalation via nebulization. Aminoglycosides are highly polar molecules and are relatively lipid insoluble.

Stability

In general, aminoglycosides are stable at pH 2-11 and are most active at alkaline pH. The 2-deoxystreptamine derivatives are heat stable; however, streptomycin deteriorates if heated and should not be autoclaved. Aqueous solutions of the aminoglycosides may be discolored by light and are subject to darkening by air oxidation; discoloration does not appear to affect potency. Aminoglycosides are potentially physically and/or chemically incompatible with many drugs including b-lactam antibiotics (e.g., penicillins, cephalosporins), but the compatibility depends on the specific drug and several other factors (e.g., concentration of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific compatibility information. For specific dosages and additional information on chemistry and stability, pharmacokinetics, and uses of the aminoglycosides, see the individual monographs in 8:12.02 and Paromomycin 8:04.

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