VA Class:AM300

AHFS Class:

• Aminoglycosides 8:12.02

Associated Monographs

• Amikacin Sulfate

• Gentamicin 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.

Parenteral

Amikacin, gentamicin, or tobramycin is used IM or IV in the short-term treatment of serious infections, including bone and joint infections, intra-abdominal infections (including peritonitis), respiratory tract infections, septicemia, or skin and soft tissue infections (including those resulting from burns), caused by susceptible gram-negative bacteria.1,2,3,4,5,6,7,13,15,19,20,21,329,418,419,420 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.1,2,3,4,5,6,7,13,15,19,20,21

Although IM streptomycin also has been used in the treatment of urinary tract infections, respiratory tract infections, and bacteremia caused by susceptible gram-negative bacteria12 and IM or IV kanamycin has been used for the short-term treatment of serious infections caused by susceptible gram-negative bacteria,8 these drugs are not considered drugs of choice for these infections and should be used only when in vitro susceptibility has been demonstrated and other parenteral aminoglycosides or other appropriate anti-infectives are ineffective or contraindicated.12,18 When a parenteral aminoglycoside is indicated in the treatment of serious infections caused by Enterobacteriaceae or Pseudomonas , amikacin, gentamicin, or tobramycin usually is preferred.18,22

Because of reported in vitro synergism (see Drug Interactions: Anti-infective Agents), aminoglycosides (amikacin, gentamicin, tobramycin) are used concomitantly with an extended-spectrum penicillin with antipseudomonal activity (e.g., carbenicillin, piperacillin and tazobactam, ticarcillin and clavulanate) 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. (See β-Lactams under Drug Interactions: Anti-infective Agents.)

In the treatment of mixed aerobic-anaerobic bacterial infections, an IM or IV aminoglycoside is used in conjunction with another appropriate anti-infective (e.g., clindamycin, metronidazole, piperacillin and tazobactam, ampicillin and sulbactam).205,216,401,434 (See Other Anti-infectives under Drug Interactions: Anti-infective Agents.) The US Centers for Disease Control and Prevention (CDC) and many clinicians suggest a regimen of IM or IV gentamicin and IV clindamycin as one of several possible parenteral regimens for the treatment of acute pelvic inflammatory disease (PID).205,216,401 (See Uses: Pelvic Inflammatory Disease, in Clindamycin 8:12.28.20.)

Although aminoglycosides are not usually recommended for the treatment of staphylococcal infections, the drugs have been used IM or IV in the treatment of serious infections caused by susceptible gram-positive bacteria when other less toxic anti-infectives are ineffective or contraindicated. The manufacturers state that amikacin, gentamicin, kanamycin, or tobramycin may be considered for the treatment of known or suspected staphylococcal infections in certain situations.1,2,3,4,5,6,7,8,13,15,19,20,21 This includes treatment of infections caused by susceptible staphylococci when other more appropriate anti-infectives are contraindicated (e.g., because of hypersensitivity) or would be ineffective because of resistance and for initial treatment of mixed infections that may involve both gram-negative bacteria and staphylococci.1,2,3,4,5,6,7,8,13,15,19,20,21 A regimen of vancomycin with or without gentamicin and with or without rifampin has been recommended for the treatment of oxacillin-resistant (methicillin-resistant) staphylococcal infections.329

Prior to and during parenteral aminoglycoside therapy, the causative organism should be cultured and in vitro susceptibility tests conducted.1,2,3,4,5,6,7,8,13,15,19,20,21 In patients in whom serious gram-negative bacterial infections are suspected, aminoglycoside therapy may be started pending results of susceptibility tests.1,2,3,4,5,6,7,8,13,15,19,20,21 In certain serious infections when the causative organism is unknown, concomitant therapy with another anti-infective (e.g., penicillin, cephalosporin) may be indicated pending results of susceptibility tests because of the possibility of infections due to aminoglycoside-resistant gram-positive organisms.1,2,3,4,5,6,7,8,13,15,19,20,21 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.1,2,3,4,5,6,7,8,13,15,19,20,21

Endocarditis

Enterococcal Endocarditis

Gentamicin† or streptomycin is used in conjunction with other appropriate anti-infectives (ampicillin, penicillin G sodium, vancomycin) for the treatment of endocarditis caused by Enterococcus (e.g., E. faecalis , E. faecium ).12,343,375,378 Enterococci usually are resistant to aminoglycosides alone and also are relatively resistant to ampicillin, penicillin G, or vancomycin.22,343,375,403 However, because antibacterial activity of the drugs may be additive or synergistic, regimens of gentamicin or streptomycin used concomitantly with ampicillin, penicillin G sodium, or vancomycin may be effective for the treatment of enterococcal endocarditis.22,343,375,403 Because enterococci generally exhibit high-level resistance to other aminoglycosides (amikacin, kanamycin, tobramycin), these aminoglycosides are not used in the treatment of enterococcal endocarditis.343,403

Enterococcal isolates should routinely be tested for in vitro susceptibility to penicillin and vancomycin and for high-level resistance to gentamicin and streptomycin.343,378 (See Spectrum: In Vitro Susceptibility Testing.) The most appropriate regimen for the treatment of enterococcal endocarditis is selected based on results of in vitro susceptibility testing; treatment duration depends on whether native or prosthetic valves are involved and how long symptoms have been present prior to initiation of treatment.343 Gentamicin usually is the preferred aminoglycoside for the treatment of enterococcal endocarditis,343,403,404,405 in part because IV gentamicin may be better tolerated than IM streptomycin and because laboratory monitoring of serum gentamicin concentrations may be more readily available than laboratory monitoring of streptomycin concentrations.343,405 Streptomycin may be effective for the treatment of enterococcal endocarditis caused by gentamicin-resistant strains since some, but not all, enterococci with high-level resistance to gentamicin are susceptible to streptomycin.22,343,375,403,404,441 Vancomycin should be used only in patients unable to tolerate ampicillin or penicillin G sodium since regimens that include vancomycin and an aminoglycoside may be associated with an increased risk of ototoxicity and nephrotoxicity and may be less effective compared with regimens that include one of the β-lactams and an aminoglycoside.343 (See Drug Interactions: Neurotoxic, Ototoxic, or Nephrotoxic Drugs.)

Studies evaluating efficacy of once-daily aminoglycoside regimens in animal models of enterococcal endocarditis have given conflicting results.399,343 Therefore, pending further accumulation of data regarding efficacy of once-daily gentamicin or streptomycin regimens in patients with enterococcal endocarditis, the American Heart Association (AHA) and Infectious Diseases Society of America (IDSA) state that once-daily gentamicin or streptomycin regimens should not be used for the treatment of enterococcal endocarditis.343

For the treatment of native or prosthetic valve endocarditis caused by enterococci susceptible to penicillin, vancomycin, and aminoglycosides, the AHA and IDSA recommend a regimen of IV ampicillin or IV penicillin G sodium given in conjunction with either IV or IM gentamicin or IM or IV streptomycin.343 An alternative regimen of IV vancomycin given in conjunction with IV or IM gentamicin should be used only in patients unable to tolerate penicillins.343 Streptomycin should be used instead of gentamicin if in vitro testing indicates the strain is gentamicin-resistant.343 In patients with native valve endocarditis, treatment with ampicillin or penicillin G sodium and gentamicin (or streptomycin) should be continued for 4-6 weeks;343 although a 4-week regimen may be used in those who have had symptoms of infection for 3 months or less prior to initiation of treatment, a 6-week regimen is recommended for those who have had symptoms for longer than 3 months.343 In patients with prosthetic valve or other prosthetic cardiac material, treatment should be continued for a minimum of 6 weeks.343 In addition, whenever a regimen of vancomycin and gentamicin (or streptomycin) is used, treatment should be continued for 6 weeks.343

For the treatment of native or prosthetic valve endocarditis caused by β-lactamase-producing enterococci resistant to penicillin and susceptible to aminoglycosides and vancomycin, the AHA and IDSA recommend a regimen of IV ampicillin sodium and sulbactam sodium and IV or IM gentamicin or, alternatively, a regimen of IV vancomycin and IV or IM gentamicin.343 Treatment should be continued for 6 weeks; however, if the strain is resistant to gentamicin, ampicillin-sulbactam should be continued for longer than 6 weeks.343 A 6-week regimen of IV vancomycin and IV or IM gentamicin is recommended when enterococci are intrinsically penicillin-resistant.343 Consultation with an infectious disease specialist is recommended when enterococci resistant to penicillin, aminoglycosides, or vancomycin are involved.343,378

Endocarditis Caused by Viridans Streptococci or S. bovis

Gentamicin is used in conjunction with other appropriate anti-infectives for the treatment of endocarditis caused by viridans streptococci (e.g., S. sanguis , S. oralis , S. salivarius , S. mutans , Gamella morbillorum ) or S. bovis (nonenterococcal group D streptococci).343 The AHA and IDSA state that once-daily gentamicin regimens can be used in conjunction with other appropriate anti-infectives for the treatment of endocarditis caused by viridans streptococci or S. bovis .343

For the treatment of native valve endocarditis caused by viridans streptococci or S. bovis highly susceptible to penicillin (i.e., penicillin MIC 0.12 mcg/mL or less), the AHA and IDSA recommend monotherapy with IV penicillin G sodium or IV or IM ceftriaxone given for 4 weeks.343 These monotherapy regimens avoid the use of gentamicin and are preferred in most patients older than 65 years of age and in those with impaired renal or eighth cranial nerve function.343 If necessary because of supply problems, monotherapy with ampicillin can be substituted for penicillin G sodium; if necessary in patients unable to tolerate penicillin or ceftriaxone, a 4-week regimen of IV vancomycin can be used.343 In selected patients only, the AHA and IDSA state that a 2-week regimen that consists of IV penicillin G sodium or IV or IM ceftriaxone in conjunction with once-daily IV or IM gentamicin can be used.343 The 2-week regimen should be used only in patients with uncomplicated native valve endocarditis caused by highly penicillin-susceptible viridans streptococci or S. bovis who are at low risk for gentamicin adverse effects; the 2-week regimen should not be used in those with known cardiac or extracardiac abscess, creatinine clearance less than 20 mL/minute, impaired eighth cranial nerve function, or infections caused by Abiotrophia , Granulicatella , or Gemella .343

For the treatment of native valve endocarditis caused by viridans streptococci or S. bovis relatively resistant to penicillin (i.e., penicillin MIC greater than 0.12 mcg/mL and less than or equal to 0.5 mcg/mL), the AHA and IDSA recommend a 4-week regimen of IV penicillin G sodium or IV or IM ceftriaxone in conjunction with IV or IM gentamicin given during the initial 2 weeks of treatment.343 Alternatively, in patients unable to tolerate penicillin G sodium or ceftriaxone, IV vancomycin can be used.343

In patients with prosthetic valves or other prosthetic material who have endocarditis caused by viridans streptococci or S. bovis highly susceptible to penicillin (i.e., penicillin MIC 0.12 mcg/mL or less), the AHA and IDSA recommend a 6-week regimen of IV penicillin G sodium or IV or IM ceftriaxone given with or without IV or IM gentamicin given during the initial 2 weeks of treatment.343 When highly penicillin-susceptible strains are involved, it is unclear whether the combination regimen that includes an aminoglycoside during the first 2 weeks is more effective than use of the β-lactam alone.343 If the strains involved are relatively or fully penicillin-resistant (i.e., penicillin MIC greater than 0.12 mcg/mL), the AHA and IDSA recommend a 6-week regimen of IV penicillin G sodium or IV or IM ceftriaxone given with a 6-week regimen of IV or IM gentamicin.343 Alternatively, in patients unable to tolerate penicillin G sodium or ceftriaxone, a 6-week regimen of IV vancomycin can be used.343

Endocarditis caused by viridans streptococci or S. bovis highly resistant to penicillin (i.e., penicillin MIC greater than 0.5 mcg/mL) or caused by Abiotrophia defectiva , Granulicatella , or Gamella should be treated with a regimen recommended for enterococcal endocarditis.343 (See Enterococcal Endocarditis under Parenteral: Endocarditis, in Uses.)

Staphylococcal Endocarditis

Gentamicin is used in conjunction with other appropriate anti-infectives for the treatment of staphylococcal endocarditis†, including infections caused by coagulase-positive strains ( S. aureus ) or coagulase-negative strains (e.g., S. epidermidis , S. lugdunensis ).343 Pending further accumulation of data, the AHA and IDSA state that once-daily gentamicin regimens should not be used for the treatment of staphylococcal endocarditis.343

For the treatment of native valve endocarditis caused by oxacillin-susceptible staphylococci, the AHA and IDSA recommend a regimen of IV nafcillin or oxacillin with or without IV or IM gentamicin.343 For penicillin-allergic patients (nonanaphylactoid type only), a regimen of IV cefazolin with or without IV or IM gentamicin is recommended.343 In patients with complicated right-sided staphylococcal endocarditis or with left-sided staphylococcal endocarditis, a 6-week regimen of the β-lactam should be used and gentamicin given concomitantly during the first 3-5 days of treatment.343 In those with uncomplicated right-sided staphylococcal endocarditis (i.e., patients with no evidence of renal failure, extrapulmonary metastatic infections, aortic or mitral valve involvement, meningitis, or oxacillin-resistant strains), a 2-week regimen that includes both the β-lactam and gentamicin can be considered.343

Staphylococcal endocarditis in patients with prosthetic valves or other prosthetic material usually is caused by oxacillin-resistant staphylococci, especially when endocarditis develops within 1 year after surgery, and is associated with high morbidity and mortality rates.343 Unless susceptibility to oxacillin has been demonstrated using in vitro susceptibility testing, it should be assumed that patients with staphylococcal prosthetic valve endocarditis have oxacillin-resistant strains.343 If prosthetic valve endocarditis is known to be caused by oxacillin-susceptible staphylococci, the AHA and IDSA recommend at least 6 weeks of IV nafcillin or oxacillin in conjunction with IV or oral rifampin and concomitant use of IV or IM gentamicin during the initial 2 weeks of treatment.343 If the strain is known to be penicillin susceptible (i.e., penicillin MIC 0.1 mcg/mL or less) and does not produce β-lactamase, IV penicillin G sodium can be substituted for nafcillin or oxacillin in this regimen; for penicillin-allergic patients (nonanaphylactoid type only), IV cefazolin can be substituted for nafcillin or oxacillin.343 If the strain is known or presumed to be oxacillin-resistant, the AHA and IDSA recommend at least 6 weeks of IV vancomycin in conjunction with IV or oral rifampin and concomitant use of IV or IM gentamicin during the initial 2 weeks of treatment.343

Prevention of Endocarditis

Gentamicin is used in conjunction with ampicillin or with vancomycin (in penicillin-allergic patients) for prevention of bacterial endocarditis† in patients undergoing certain genitourinary and GI tract (except esophageal) surgery or instrumentation who have cardiac conditions that put them at high risk.317,318 (See Prophylaxis of Bacterial Endocarditis under Uses: Prophylaxis in the Aminopenicillins General Statement 8:12.16.08)

The current recommendations published by the AHA should be consulted for specific information on which cardiac conditions are associated with high or moderate risk of endocarditis and which procedures require prophylaxis.318

Meningitis and Other CNS Infections

Amikacin, gentamicin, or tobramycin is used in the treatment of meningitis caused by susceptible bacteria.1,2,3,4,5,6,7,13,15,19,20,21,317,329,344,402 However, these drugs usually are used in conjunction with other appropriate anti-infectives (e.g., β-lactams, carbapenems, vancomycin) and should not be used alone for the treatment of meningitis since CSF concentrations attained following IM or IV administration are unpredictable and generally low.18,317,329,344 Amikacin, gentamicin, or tobramycin has been used intrathecally† or intraventricularly† to supplement IM or IV administration in the treatment of CNS infections (including meningitis and ventriculitis) caused by susceptible bacteria.18,22,53,84,89,92,114,144,155,384,385,387,433 Although concomitant parenteral and intrathecal or intraventricular therapy may result in higher anti-infective CSF concentrations, such therapy also may be associated with increased mortality in neonates.421

Mycobacterial Infections

Streptomycin, kanamycin†, or amikacin† is used in conjunction with other antituberculosis agents in the treatment of clinical tuberculosis.22,317,329,338,366

Streptomycin or amikacin have been used in conjunction with other antimycobacterial anti-infectives in the treatment of infections caused by some other mycobacteria, including Mycobacterium avium complex† (MAC),22,317,329,339,345,346,347,348,365 M. abscessus †,317,339 M. chelonae †,317,339 M. fortuitum †,317,329,339 and M. kansasii †.317,329,339,376

Although streptomycin and kanamycin have bactericidal activity against M. leprae in mice430 and streptomycin has been used in the past for the treatment of leprosy†,451 aminoglycosides are not currently recommended for the treatment of leprosy.22,317

For information on general principles in the treatment of tuberculosis and other mycobacterial diseases, see the Antituberculosis Agents General Statement 8:16.04.

Respiratory Tract Infections

Amikacin, gentamicin, or tobramycin is used in the treatment of respiratory tract infections, including community-acquired pneumonia (CAP) and nosocomial pneumonia, caused by susceptible bacteria.1,2,3,4,5,6,7,13,15,19,20,21,329,418,419,420 The drugs are used in conjunction with other appropriate anti-infectives and may be included in initial empiric combination regimens in severely ill patients and/or when multidrug-resistant gram-negative bacteria may be involved.329,418,419,420

Nosocomial Infections

The ATS, IDSA, and other clinicians recommend use of an antipseudomonal cephalosporin (cefepime, ceftazidime), antipseudomonal penicillin (piperacillin and tazobactam, ticarcillin and clavulanate), or an antipseudomonal carbapenem (imipenem or meropenem) for initial therapy of hospital-acquired pneumonia, ventilator-associated pneumonia, or health-care associated pneumonia because these drugs have a broad spectrum of activity against gram-positive, gram-negative, and anaerobic bacteria.329,418,419 In severely ill patients or in those with late-onset disease or risk factors for multidrug-resistant bacteria, the initial regimen should also include an aminoglycoside (amikacin, gentamicin, tobramycin) or antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin) to improve coverage against Pseudomonas .329,418 In hospitals where oxacillin-resistant (methicillin-resistant) Staphylococcus are common or if there are risk factors for these strains, the initial regimen also should include vancomycin or linezolid.329,418,419

Other Infections

Streptomycin or gentamicin† is used in the treatment of Brucellosis ( Brucella melitensis ),12,22,317,329,367,368,369,370,371,377 plague ( Yersinia pestis ),12,22,238,317,329,340,342,372,415,416,449 or tularemia ( Francisella tularensis ).12,22,317,329,341,342,373,374 Gentamicin, or to a lesser extent, streptomycin, also has been used in the treatment of Bartonella infections†.317,329,349,350,351,352

Amikacin is used in the treatment of Nocardia † infections22,317,329,417 and infections caused by Rhodococcus equi †.329

Streptomycin is used in the treatment of Burkholderia † infections (i.e., glanders)329 and for the treatment of rat-bite fever† caused by Streptobacillus moniliformis or Spirillum minus .329,364

Gentamicin† is used as an adjunct in the treatment of granuloma inguinale (Donovanosis) caused by Klebsiella granulomatis (formerly Calymmatobacterium granulomatis ).216,317 Streptomycin also has been used in the treatment of granuloma inguinale22 and in the treatment of chancroid caused by Haemophilus ducreyi ,12,22 but is not usually recommended for these infections.216

Empiric Therapy in Febrile Neutropenic Patients

Aminoglycosides (amikacin, gentamicin, tobramycin) are used in conjunction with an appropriate β-lactam (e.g., ceftazidime, ceftriaxone, cefepime), carbapenem (e.g., imipenem or meropenem), or extended-spectrum penicillin (e.g., piperacillin and tazobactam, ticarcillin and clavulanate) for empiric anti-infective therapy of presumed bacterial infections in febrile neutropenic patients†.203,206,207,236,237,259,308,316,329,337 An aminoglycoside should not be used alone for empiric therapy in febrile neutropenic patients.337 (For a more complete discussion of this therapy, see Uses: Empiric Therapy in Febrile Neutropenic Patients, in the Cephalosporins General Statement 8:12.06)

Perioperative Prophylaxis

Gentamicin is used in conjunction with clindamycin for perioperative prophylaxis† in patients undergoing head and neck surgery (incisions through oral or pharyngeal mucosa).330,363 A regimen of vancomycin with or without gentamicin has been recommended as an alternative for perioperative prophylaxis in patients undergoing vascular surgery and a regimen of clindamycin or metronidazole with gentamicin has been recommended as an alternative for perioperative prophylaxis in patients undergoing gynecologic and obstetric surgery who cannot receive β-lactams.353 Gentamicin also is used as an adjunct to cefoxitin in patients undergoing contaminated or dirty surgery†, such as that involving a perforated abdominal viscus.330 The fact that concurrent use of aminoglycosides and general anesthetics or neuromuscular blocking agents may potentiate neuromuscular blockade and cause respiratory paralysis should be considered.1,2,3,4,5,6,7,8,10,11,12,13,15,19,20,21 (See Drugs Interactions: General Anesthetics and Neuromuscular Blocking Agents.)

Oral

Oral neomycin or, less frequently, oral paromomycin, is used to inhibit ammonia-forming bacteria in the GI tract as an adjunct to protein restriction and supportive therapy in adults and children with hepatic encephalopathy.10,11,17,18,22,360,361 The subsequent decrease in blood ammonia may result in neurologic improvement.10,11,360,361 (See Uses: Hepatic Encephalopathy in Neomycin 8:12.02.)

Neomycin is used orally as an adjunct to mechanical cleansing of the large intestines for preoperative prophylaxis in patients undergoing colorectal surgery.11,18,22,127,330,353 For patients undergoing colorectal surgery, clinicians generally recommend a regimen of oral neomycin and oral erythromycin, oral neomycin and oral metronidazole, IV cefoxitin or IV cefotetan (no longer commercially available in the US), or IV cefazolin used in conjunction with IV metronidazole.330,331,353 It has been suggested that an oral regimen is as effective as a parenteral regimen in patients undergoing elective colorectal surgery.330 Although many clinicians use both an oral and a parenteral regimen in patients undergoing colorectal surgery,330,331,353 there is controversy over the benefits and risks of this strategy.330,354 (See Uses: Perioperative Prophylaxis in Neomycin 8:12.02.)

Although neomycin has been used orally as an adjunct to fluid and electrolyte replacement in the treatment of bacterial GI infections†, including diarrhea caused by enteropathogenic E. coli (EPEC),22,362 oral neomycin is no longer recommended for the treatment of any GI infection.22

Oral paromomycin is used in the treatment of various parasitic infections, including intestinal amebiasis caused by Entamoeba histolytica , infections caused by Dientamoeba fragilis †, and giardiasis†).17,317,332 (See Paromomycin 8:30.04.)

Oral neomycin has been used in the treatment of hypercholesterolemia†.22,70,128,358,359,414 (See Uses: Hypercholesterolemia in Neomycin 8:12.02.)

Oral Inhalation

Aminoglycosides have been administered by oral inhalation for the management of bronchopulmonary Ps. aeruginosa infections in cystic fibrosis patients.16,229,334,335,336 Tobramycin is commercially available as a preservative-free solution specifically formulated for oral inhalation via a nebulizer.16,335,336 Gentamicin,335,336 kanamycin,8 and tobramycin335,336 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, but are not routinely recommended for the treatment of acute exacerbations of these infections.335,336 (See Cystic Fibrosis Patients under Uses: Respiratory Tract Infections in Tobramycin 8:12.02.)

For topical uses of gentamicin, neomycin, and tobramycin, see 52:04.04 and 84:04.04.

Administration

Amikacin,1,2,3 gentamicin,4,5,6,7 kanamycin,8 and tobramycin13,15,19,20,21 are administered by IM injection or IV infusion. IV administration generally is recommended in patients with life-threatening infections, septicemia, shock, severe hypotension, congestive heart failure, hematologic disorders, severe burns, or reduced muscle mass.4,5,6,7 Streptomycin is administered by IM injection,12 but also has been given by IV infusion†.22,379,380,381,382

Neomycin10,11 and paromomycin17 are administered orally. Although kanamycin also has been administered orally,9 an oral dosage form is no longer commercially available in the US.

Tobramycin solution for oral inhalation is administered via a nebulizer.16 Tobramycin†,335,336 kanamycin,8 and gentamicin†335,336 also have been administered by oral inhalation as aerosols prepared extemporaneously from parenteral preparations of the drugs.

Amikacin, gentamicin, and tobramycin have been administered intrathecally† or intraventricularly† for the treatment of CNS infections.18,22,53,84,89,92,114,144,155,384,385,387,433 Intraventricular administration of aminoglycosides usually is preferred to intrathecal administration, especially in cases of ventriculitis, to ensure adequate drug concentrations throughout the CSF.89

Although some aminoglycosides (e.g., kanamycin, neomycin) have been administered by intraperitoneal instillation or local irrigation (abscess cavities, pleural space, peritoneal and ventricular cavities), there is an increased risk of toxicity with these routes.1,2,3,4,5,7,8,15,22,386 (See Other Precautions under Cautions: Precautions and Contraindications.)

Aminoglycosides should not be admixed with other drugs or infused simultaneously through the same tubing with other drugs.1,2,3,4,5,6,7,8,13,15,19,20,21

Dosage

Aminoglycoside dosage should be individualized taking into consideration the patient's pretreatment body weight, renal status, serum concentrations of the drug, severity of the infection, and susceptibility of the causative organism. Because of the potential toxicity of aminoglycosides, fixed-dosage recommendations that are not based on patient weight or serum drug concentrations are not advised.

Duration of Treatment

The usual duration of IM or IV aminoglycoside therapy for the treatment of many infections is 7-10 days.1,2,3,4,5,6,7,8,13,15,19,20,21 Although a longer duration may be necessary in complicated infections, toxicity is more likely to occur when aminoglycoside treatment is continued for longer than 10 days.4,5,6,7,13,15,19,20,21 Prolonged aminoglycoside therapy should be avoided1,2,3 and treatment duration should be limited to short term whenever feasible.1,2,3,10,11 Some aminoglycoside manufacturers (e.g., amikacin) state that safety of treatment for longer than 14 days has not been established.1,2,3 If use of an aminoglycoside for longer than 10 days is considered, serum concentrations and renal, auditory, and vestibular functions should be monitored.1,2,3,8,13,15,19,20,21 (See Cautions.)

Uncomplicated infections caused by susceptible organisms generally respond to usual dosages in 24-48 hours.1,2,3,8 If definitive clinical response has not occurred within 3-5 days, the susceptibility of the causative organism should be reevaluated.1,2,8 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.1,2,3,8

Once-Daily Dosing

Parenteral aminoglycosides historically have been administered in dosage regimens that include multiple daily doses (usually 2-4 doses daily),18 and these are the only dosage regimens included in current prescribing information for parenteral amikacin, gentamicin, kanamycin, and tobramycin.1,2,3,4,5,6,7,8,13,15,19,20,21 However, parenteral aminoglycosides are now administered in once-daily† (single-daily) dosing regimens in selected patients based on evidence that once-daily regimens can be at least as effective as, may provide superior pharmacokinetic-pharmacodynamic parameters (peak plasma concentration/MIC ratio), and may be less toxic than conventional dosage regimens employing multiple daily doses of the drugs.18,237,239,240,241,242,243,244,246,249,251,252,257,258,259,260,268,306,309,310,311,312,319,320,321,323,324,325,388,389,390,391,396,398,406,411,437,452 Once-daily (extended interval) dosage regimens may provide rapidly effective serum aminoglycoside concentrations that maximize bactericidal activity without increasing the risk of adverse effects.240,244,252,291,295,325,406,437,452 Such regimens also reduce time and expense associated with aminoglycoside monitoring and therapy (e.g., decreased number of IV infusions and associated administration costs).239,240,242,246,249,268,291,306,309,310,311,319,320,321,325,396,437,452 However, once-daily parenteral aminoglycoside regimens should not be used in all patients.18,406 It has been suggested that once-daily regimens have not been adequately studied to date in patients with creatinine clearance less than 25 mL/minute, pediatric patients, geriatric patients, pregnant women, obese patients, or patients with burns, ascites, or certain severe infections (e.g., meningitis, osteomyelitis, skin and skin structure infections, enterococcal endocarditis).18,406,411 In addition, the most appropriate methods for optimizing dosage selection for once-daily regimens and monitoring serum aminoglycoside concentrations in patients receiving such regimens have not been clearly established.18,306,396,406,410,411,435 (See Laboratory Monitoring of Therapy under Dosage and Administration: Dosage.)

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.309,310,311,319,320,321,322,325 However, various definitions of nephrotoxicity were used in these studies.237,239,241,243,244,245,246,248,257,289,307,309,310,311,312,319,321,322,324,325,406 In addition, only a few studies to date have included infants or children, pregnant women, or patients with renal dysfunction, or life-threatening infections (e.g., endocarditis, bacteremia).239,240,241,242,243,252,258,259,285,291,294,297,307,311,312,319,322,324,325,397,406 Results of at least one analysis of pooled data from randomized, controlled studies in pediatric patients indicate that once-daily administration of aminoglycosides is at least as safe and as effective as regimens that involve multiple daily doses.452 However, 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.239,240,241,242,243,252,258,259,285,291,294,297,307,311,312,319,322,324,325,397,406,411

Once-daily aminoglycoside regimens appear to offer several possible microbiologic advantages over multiple-daily dosing.239,240,241,242,243,244,245,250,251,253,258,287,294,295,298,299,300,301,309,310,311,312,320,321,325,326 Current pharmacodynamic data suggest that the use of larger, less frequent doses of aminoglycosides may enhance the antimicrobial efficacy of aminoglycosides.239,240,241,242,243,244,245,250,251,253,258,287,294,295,298,299,300,301,309,310,311,312,320,321,325,326 Unlike some other antibiotics (e.g., β-lactams), aminoglycosides have concentration-dependent bactericidal effects against many pathogens;239,240,241,242,243,244,245,248,250,251,258,294,295,296,299,300,302,320,321 higher serum concentrations are associated with increased bactericidal effects.239,240,241,242,245,253,294,295,296,299,300,303,320,321 The drugs also exhibit a prolonged, concentration-dependent postantibiotic effect (PAE) against a variety of gram-negative and gram-positive pathogens.239,240,241,242,244,245,250,253,258,294,295,297,299,300,302,320,321 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.239,241,245,250,285,294,295,297,321

Once-daily aminoglycoside regimens also appear to offer advantages in terms of the risk of toxicity reported with the drugs.239,240,241,242,246,248,254,256,295,296,299,303,304,309,310,311,319,320 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.239,240,241,242,246,248,254,256,295,296,299,303,304,309,310,311,319,320,452

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.239,240,241,245,246,254,255,256,294,295,304,320 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.239,240,241,243,244,245,256,294,304,320 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.243,244,246,249,254,255,257,277,291,296,305,320 In a study in patients undergoing nephrectomy who received identical single doses of gentamicin given by IV infusion over 30 minutes or 24 hours, gentamicin concentrations in renal cortical tissue were 50% higher with the 24-hour infusion.254 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.246

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.240,241,244,247,258,275,276,289,292,294,309,310,311,321

Once-daily aminoglycoside regimens have not been adequately studied to date in patients with renal impairment (e.g., creatinine clearance less than 25 mL/minute).18,245,248,268,287,295,312,313,319,325,397,406 It has been suggested that once-daily dosing regimens may be inappropriate in 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 and more prolonged dosing intervals or reduced dosage of the aminoglycoside should be used in such patients.18,245,248,268,287,295,312,313,319,325,406

Some clinicians also suggest that once-daily aminoglycoside regimens 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, ascites, severe sepsis, dialysis treatment)248,319,320,325,327,397,406 since such regimens could allow prolonged intervals of undetectable aminoglycoside concentrations that could outlast the PAE.239,248,312 Aminoglycosides usually are administered as adjunctive therapy with other anti-infective agents (e.g., β-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.241,242,259,285,291,295,307,310,320,323,324

Pending further accumulation of data, use of once-daily aminoglycoside dosing is not recommended in patients with enterococcal endocarditis.325,343

There now is some evidence from a few studies that once-daily tobramycin regimens may be as effective as multiple-daily doses in some cystic fibrosis patients.388,389,390,391

The optimum dosages for once-daily aminoglycoside regimens when the drugs are used alone or in conjunction with other anti-infectives have not been established.245,311,312,313,321,396,406,410 In most early studies, the once-daily dosage was simply the total daily dose that was given in 2 or more divided doses in the conventional regimen.245,246,255,257,261,264,265,266,267,269,270,271,272,273,274,275,287,292,293,309,311,319,320,323,452 In addition, other anti-infectives (e.g., β-lactam antibiotics) were administered concomitantly with the aminoglycosides in most studies of once-daily aminoglycoside therapy,237,246,257,260,261,262,263,264,265,266,268,269,270,273,274,285,287,292,293,307,309,311,319,320,323,452 confounding accurate determination of the efficacy of once-daily aminoglycoside therapy.239,241,242,285

Although early studies of once-daily aminoglycoside dosing generally consisted of administration of the usual total daily dosage as a single daily dose, various approaches have now been used in an attempt to optimize dosage for once-daily regimens.245,248,285,309,310,311,312,319,320,322,326,396,406,409,410,412,413,437 These approaches involve individualized pharmacokinetic parameters or microbiologic end points (e.g., peak plasma concentration/MIC ratio) and a variety of dosage nomograms and computer-assisted programs designed to achieve certain serum concentrations.245,248,285,309,310,311,312,319,320,322,326,396,406,409,410,412,413,437 Specialized references should be consulted for specific information.245,248,285,309,310,311,312,319,320,322,326,396,406,409,410,412,413,437

Laboratory Monitoring of Therapy

When aminoglycosides are administered in conventional dosage regimens that involve multiple daily doses, therapeutic drug monitoring of peak and trough concentrations is recommended to ensure potentially effective serum concentrations and avoid toxicity.1,2,3,4,5,6,7,8,13,15,19,20,21,18,22,34,53,239,245,247,258,277,279,280,282,283,284,285,287,393,394,395,396,437 For gentamicin or tobramycin administered in conventional dosage regimens (i.e., multiple daily doses), peak serum concentrations of 4-10 mcg/mL and trough concentrations that do not exceed 1-2 mcg/mL usually are recommended.18,22,34,53,239,245,247,258,277,278,279,280,282,283,284,285,287,393,394,395,396 For amikacin and kanamycin administered in conventional dosage regimens, peak serum concentrations of 15-30 and trough concentrations less than 5-10 mcg/mL have been suggested.22,53,258,278,280,281,282,284,286,287,395,396 Suggested desirable peak and trough serum concentrations of streptomycin are 5-35 mcg/mL and less than 5-10 mcg/mL, respectively.18,53,343

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.241,248,278 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 12.241,243,278,285 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.285,306 (See Dosage: Once-Daily Dosing.) 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.237,241,247,263,278,285

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.237,239,247,261,277,278,396 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.240,247 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.239,247,259,285,288,289,290,306

In patients receiving conventional aminoglycoside dosage regimens that involve multiple daily doses, blood specimens for peak serum aminoglycoside concentrations usually are obtained approximately 30-60 minutes following an IM and 15-30 minutes after completion of an IV infusion;18,34,278,395,437 specimens for trough drug concentrations are obtained immediately prior to the next IM or IV dose.18,34,278,395,437

Additional study is needed to determine the most appropriate use of therapeutic drug monitoring in patients receiving once-daily† regimens.306,309,311,313,396,397,399,400,406,408,409,410,412,413,435,437,439 It has been suggested that routine therapeutic drug monitoring may be unnecessary or that it may be adequate to measure only trough aminoglycoside concentrations in patients receiving once-daily aminoglycoside regimens.22,306,311,396,397,399,400,406,435,437 However, although a more favorable peak/MIC ratio may be possible with once-daily regimens and efficacy is presumed,399 there still is a need to monitor serum concentrations to ensure that accumulation does not occur in patients receiving once-daily regimens.399,400,435 The possibility that peak serum concentrations may be higher and trough concentrations lower with once-daily regimens than with conventional regimens should be considered.309,397,400,406,407,408,435,437 The ideal therapeutic ranges for once-daily dosing have not been established and the optimal time to obtain blood samples to monitor aminoglycoside concentrations in patients receiving once-daily aminoglycoside regimens is unclear, especially for critically ill patients and those with renal impairment.306,309,396,397,400,408,409,412,435 Specialized references should be consulted for specific information.245,248,285,306,309,310,311,312,319,320,322,326,396,397,400,406,409,410,412,413,437,439

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.1,2,3,4,5,6,7,8,13,15,19,20,21,436 Various formulae, tables, nomograms, and computer-assisted programs based on serum creatinine or creatinine clearance have been used to aid in dosage adjustment in patients with renal impairment.436 One frequently used method that has been recommended for determining dosage of amikacin, gentamicin, kanamycin, or tobramycin in patients with renal impairment is the method of Sarubbi and Hull, which is based on corrected creatinine clearance. (See Table.) 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.)

C(c)cr male = (140 - age)/serum creatinine

C(c)cr female = 0.85 × C(c)cr male

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.

Additional study is needed to determine whether the daily dose should be decreased or the dosage interval increased in patients with elevated trough concentrations.400

Ototoxicity and nephrotoxicity are the most serious adverse effects of aminoglycoside therapy and are most likely to occur in patients with past or present histories of renal impairment (especially if dialysis is required) and in patients who are severely dehydrated, receiving high aminoglycoside dosage or prolonged aminoglycoside therapy, or also are receiving or have received other ototoxic and/or nephrotoxic drugs.1,2,3,4,5,6,7,8,12,13,15,16,19,20,21,34,53 (See Drug Interactions: Neurotoxic, Ototoxic, or Nephrotoxic Drugs.)

Ototoxicity

Neurotoxicity manifested as auditory or vestibular ototoxicity has been reported with aminoglycosides administered by any route.1,2,3,4,5,6,7,8,12,13,15,16,19,20,21,34,53 Eighth cranial nerve damage may be manifested by vestibular manifestations 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.1,2,3,4,5,6,7,8,12,13,15,19,20,21 High-frequency deafness (detectable only by audiometric testing) usually occurs first.1,2,3,4,5,6,7,8,13 Patients developing cochlear damage may not have manifestations during aminoglycoside therapy to warn them of developing eighth-nerve toxicity, and total or partial irreversible bilateral deafness may occur after the drug has been discontinued.1,2,3,4,5,6,7,8,13,19,20,21 Ototoxicity usually is bilateral, may be partial or total, and usually is irreversible.1,2,3,4,5,6,7,8,12,13,15,19,20,21 The risk of aminoglycoside-associated hearing loss increases with the degree of exposure to either high peak or high trough serum concentrations.1,2,3,4,5,6,7,8,19,20,21

Although the distinctions are not absolute and either or both forms of ototoxicity may occur with any of the aminoglycosides, vestibular manifestations are more frequently associated with gentamicin, tobramycin, or streptomycin and auditory manifestations are more frequently associated with amikacin, kanamycin, neomycin, or paromomycin.22,53 The manufacturer of streptomycin states that vestibular dysfunction is cumulatively related to the total daily streptomycin dose and symptoms are likely to develop within 4 weeks in a large percentage of patients receiving a streptomycin dosage of 1.8-2 g daily, especially those who are elderly or have renal impairment.12 The ototoxic potential of gentamicin and tobramycin appears to be similar.13,19,20,21

Tinnitus and/or hearing loss has been reported in some patients receiving tobramycin by oral inhalation.16,445 In some reported cases, tobramycin administered by oral inhalation was used in patients who had previously received or were concurrently receiving a systemic aminoglycoside.16

Ototoxicity has been reported in patients receiving oral neomycin.10,11 Although relatively small amounts of neomycin usually are absorbed following oral administration, toxicity can occur even when recommended dosage is used.10,11 The risk of ototoxicity with oral neomycin is increased in patients with renal impairment and in those receiving high dosage and/or prolonged treatment.10,11

Renal and Electrolyte Effects

Aminoglycoside-induced nephrotoxicity may be evidenced by tubular necrosis; increased serum concentrations of BUN, nonprotein nitrogen (NPN), and creatinine; decreased urine specific gravity and creatinine clearance; proteinuria or albuminuria; or cells or casts in the urine.1,2,3,4,5,6,7,8,12,13,15,19,20,21 Azotemia, oliguria, toxic nephropathy, and acute renal failure have been reported.1,2,6,8,12 A Fanconi-like syndrome (proximal renal tubular dysfunction) characterized by aminoaciduria and metabolic acidosis also has occurred in patients receiving aminoglycosides (e.g., gentamicin).2,3,5,7

Hypocalcemia, hypomagnesemia, and hypokalemia have been reported with aminoglycosides.4,5,6,7,8,13,19,20,21 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 occurred.4,5,7,93,95 When this electrolyte wasting occurs in infants, tetany and muscle weakness appear to be the predominant manifestations.4,5,7 If renal effects and electrolyte abnormalities develop in patients receiving an aminoglycoside, appropriate therapy should be instituted to correct any electrolyte imbalance(s) associated with the syndrome.4,5,7

Rarely, nephrotoxicity may not become apparent until the first few days after cessation of aminoglycoside therapy.13,19 Aminoglycoside-induced renal toxicity usually is reversible following discontinuance of the drug;1,2,3,8,13,19,21 however, death secondary to uremia has occurred rarely.34

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. In some animal and clinical studies, tobramycin appeared to be less nephrotoxic than gentamicin; in other clinical studies, there was no difference in the incidence of nephrotoxicity reported with tobramycin or gentamicin.13,19,20,21 Amikacin and gentamicin appear to be approximately equal in nephrotoxic potential.

Transient increases in serum creatinine concentrations have been reported in clinical studies in patients receiving tobramycin by oral inhalation, but the incidence was similar to that reported in those receiving placebo.16

Although nephrotoxicity occurs most frequently in patients with a history of renal impairment who are treated for longer periods or with higher doses than recommended, adverse renal effects can occur in patients with initially normal renal function.13,19,20,21

Nervous System Effects

Neuromuscular blockade, apnea, respiratory depression, and respiratory paralysis have been reported when aminoglycosides were administered parenterally, orally, or by topical irrigation or instillation.1,2,3,4,5,6,7,8,13,15,19,22,53,71,386 Aminoglycosides produce varying degrees of neuromuscular blockade;22,53,383 neomycin probably is the most potent neuromuscular blocking agent of the currently available aminoglycosides followed by streptomycin, kanamycin, amikacin, gentamicin, and tobramycin.22,53 Although the blockade induced by an aminoglycoside is generally dose related and self-limiting, it rarely may result in respiratory paralysis.71 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 parkinsonism) or hypocalcemia or to patients who are receiving general anesthetics, neuromuscular blocking agents, or massive transfusions of citrated blood.1,2,3,4,5,8,13,15,19,20,21,22,53 Aminoglycoside-induced neuromuscular blockade may be partially or completely reversed by administration of calcium salts, but mechanically assisted respiration may be necessary.1,2,3,4,5,8,13,15,19,20,21,71

Peripheral neuropathy or encephalopathy, including numbness,1,2,3,4,5,7,13,19,20,21 skin tingling,1,2,3,4,5,7,13,19,20,21 muscle twitching,1,2,3,4,5,7,13,19,20,21 seizures,1,2,3,4,5,7,13,19,20,21 and a myasthenia gravis-like syndrome, has been reported during aminoglycoside therapy. Other nervous system effects that have been reported in patients receiving an aminoglycoside include headache,1,2,3,4,5,6,7,8,12,13,15,19,20,21,22 tremor,1,2,3 lethargy,4,5,6,7,13,15,19,20,21 confusion or disorientation,4,5,6,7,13,15,19,20,21 paresthesia,1,2,3,8,12,22 peripheral neuritis, arachnoiditis, encephalopathy, pseudotumor cerebri,5 and acute organic brain syndrome.4,5,6

CNS depression characterized by stupor and flaccidity, and in some cases, coma and respiratory depression, has been reported in very young infants receiving streptomycin dosage higher than recommended.12

Visual disturbances,4,5,6,7,22 optic neuritis with blurred vision, scotomas, and enlargement of the blind spot have been reported with aminoglycoside therapy.22

Dermatologic and Sensitivity Reactions

Serious sensitivity reactions, such as anaphylaxis1,2,3,4,5,6,7,8,12,13,15,19,21,68 and dermatologic reactions including exfoliative dermatitis,12,13,15,19,21 toxic epidermal necrolysis,13,15,19,21 erythema multiforme,13,15,19,21 angioedema,12 and Stevens-Johnson syndrome,13,15,19,21 have been reported rarely in patients receiving aminoglycosides; fatalities have occurred rarely.13,15,19,21 Cross-sensitivity occurs among the aminoglycosides.1,2,3,4,5,6,7,8,10,11,12,13,15,19,20,21

Other hypersensitivity reactions that have been reported with aminoglycosides include rash,1,2,3,4,5,6,7,8,12,13,19,20,21 pruritus,1,2,3,4,5,6,7,8,13,19,20,21 urticaria,1,2,3,4,5,6,7,8,12,13,19,20,21 stomatitis,1,2,3,4,5,6,7,8 generalized burning,1,2,3,4,5,6,7,8 fever,1,2,3,4,5,6,7,8,12 eosinophilia,1,2,3,4,5,6,7,8,12,13,19,20,21 and laryngeal edema.4,5,6,7

Some commercially available aminoglycoside preparations for IM or IV administration (e.g., amikacin, gentamicin, kanamycin, tobramycin) contain sodium metabisulfite, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.1,2,3,4,5,8,13,15,19 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.1,2,3,5,19,202

The manufacturer of streptomycin cautions that contact with streptomycin solutions during handling or preparation may cause sensitization to the drug.12

GI Effects

Adverse GI effects, including nausea, vomiting, diarrhea, increased salivation, stomatitis, weight loss, decreased appetite, or anorexia have been reported with parenteral aminoglycosides.1,2,3,4,5,6,7,8,12,13,19,20,21

The most frequent adverse reactions of orally administered aminoglycosides (neomycin, paromomycin) are nausea, vomiting, abdominal cramps, and diarrhea.10,11,17,22

A malabsorption syndrome that affects absorption of fat, nitrogen, cholesterol, carotene, glucose, disaccharides, xylose, lactose, sodium, calcium, cyanocobalamin (vitamin B₁₂), and iron has been reported with oral neomycin or paromomycin.10,11,22,53 The malabsorption syndrome usually is dose-related and reversible and occurs most frequently when oral neomycin therapy is prolonged or when high neomycin dosage (12 g daily) is used.10,11,22,53 A sprue-like syndrome with diarrhea, steatorrhea, and azotorrhea may occur with oral neomycin dosages of 4-6 g daily.18

Enterocolitis, possibly caused by neomycin-resistant staphylococci or Clostridium difficile , has been reported rarely with oral neomycin.22

Local Effects

Adverse local reactions, including pain at the injection site,4,5,6,7,8,13,19,20,21 local irritation,4,5,6,7,8 sterile abscess, subcutaneous atrophy,4,5,6,7 and fat necrosis4,5,6,7 have occurred with IM or IV administration of aminoglycosides. Infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation, and hypervolemia also have been reported.6,7 If an adverse local reaction occurs, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the infusion solution for examination if deemed necessary.6,7

Intrathecal† or intraventricular† administration of aminoglycosides has caused local inflammation and other complications such as nerve root pain, burning at the injection site, paraplegia, radiculitis, transverse myelitis, arachnoiditis, and other complications.22,84,154,155,433 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.

Intravitreous† and/or subconjunctival† administration of aminoglycosides (e.g., amikacin, tobramycin) has resulted in macular infarction or necrosis, sometimes leading to permanent loss of vision.1,13,19,20

Hematologic Effects

Adverse hematologic effects reported with aminoglycosides include anemia,1,2,3,4,5,6,7,13,19,20,21 leukopenia,4,5,6,7,13,19,20,21 granulocytopenia,4,5,6,7,13,19,20,21 transient agranulocytosis,4,5,6,7 thrombocytopenia,4,5,6,7,13,19,20,21 eosinophilia,4,5,6,7,13,19,20,21 and increased or decreased reticulocyte counts.4,5,6,7 Pancytopenia and hemolytic anemia have been reported with streptomycin.12

Other Adverse Effects

Other adverse effects that have been reported with aminoglycosides include tachycardia, arthralgia or joint pain,1,2,3,4,5,6,7 transient hepatomegaly4,5,6,7 or splenomegaly,4,5,6,7 hepatic necrosis, myocarditis, hypotension,1,2,3,4,5,6,7 hypertension,4,5,6,7 mental depression,4,5,6,7 alopecia,4,5,6,7,91 purpura,4,5,6,7 and pulmonary fibrosis.4,5,6,7 Transient increases in serum concentrations of AST (SGOT),4,5,6,7,13,19,20,21 ALT (SGPT),4,5,6,7,13,19,20,21 LDH,4,5,6,7,13,19,20,21 alkaline phosphatase, and bilirubin4,5,6,7,13,19,20,21 have been reported.

Precautions and Contraindications

Sensitivity Reactions

Aminoglycosides are contraindicated in patients with a history of hypersensitivity or serious toxic reactions to any aminoglycoside.1,2,3,4,5,6,7,8,10,11,12,13,15,16,17,19,20,21 Cross-sensitivity occurs among the aminoglycosides.1,2,3,4,5,6,7,8,10,11,12,13,15,19,20,21

Some commercially available IM or IV preparations of aminoglycosides contain sulfites which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.1,2,3,4,5,8,13,15,19 (See Cautions: Dermatologic and Sensitivity Reactions.)

The manufacturer states that individuals who handle or prepare streptomycin solutions should use care to avoid contact and resultant sensitization to the drug.12

If an allergic reaction to an aminoglycoside occurs, the drug should be discontinued and appropriate therapy instituted as indicated.13,15,19,21

Underlying GI Conditions

Oral neomycin and oral paromomycin are contraindicated in patients with intestinal obstruction.10,11,17 Oral neomycin is contraindicated in patients with inflammatory or ulcerative GI disease because of the potential for enhanced GI absorption of the drug.10,11 The manufacturer states that oral paromomycin should be used with caution in patients with ulcerative bowel lesions since inadvertent absorption could cause renal toxicity.17

Ototoxicity and Nephrotoxicity

Patients receiving an aminoglycoside (by any route of administration) should be under close medical supervision because of the risk of ototoxicity and nephrotoxicity.1,2,3,4,5,6,7,8,10,11,12,13,15,19,20,21 Patients should be well hydrated to minimize chemical irritation of the renal tubules.1,2,3,4,5,6,8,10,11,13,15,19

The risk of ototoxicity and nephrotoxicity is greatest in patients with past or present histories of renal impairment, dehydration, or previous exposure to ototoxic drugs and in those who receive high dosage or prolonged treatment.1,2,3,4,5,6,7,8,10,11,12,13,15,19,20,21 In addition, patients with preexisting tinnitus, vertigo, or subclinical high-frequency hearing loss are especially susceptible to ototoxicity and should be carefully observed for signs of eighth cranial nerve damage during aminoglycoside therapy.

Renal function should be assessed prior to initiation of aminoglycoside therapy.1,2,3,4,5,6,7,8,10 Renal and eighth-cranial nerve function should be monitored closely during aminoglycoside therapy, especially in patients with known or suspected renal impairment at the start of treatment and in those whose renal function deteriorates during treatment.1,2,3,4,5,6,8,10,12,13,15,19,20,21 When feasible, serial audiograms should be performed in patients old enough to be tested, particularly high-risk patients.1,2,3,4,5,6,7,8,12,13,20,21 Urine should be evaluated for decreased specific gravity, increased excretion of protein, and presence of cells or casts and serum BUN, serum creatinine, and creatinine clearance should be monitored.1,2,3,4,5,6,7,8,13,15,19,20,21 Serum calcium, magnesium, and sodium also should be monitored.19,20,21 (See Cautions: Renal and Electrolyte Effects and see Cautions: Ototoxicity.)

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. Prolonged peak serum concentrations of amikacin or kanamycin above 30-35 mcg/mL, gentamicin or tobramycin above 10-12 mcg/mL, or streptomycin above 40-50 mcg/mL may be associated with an increased risk of toxicity. Whenever possible, especially in patients with renal impairment, peak and trough serum concentrations of aminoglycosides should be determined periodically and dosage adjusted to maintain desired serum concentrations.1,2,3,4,5,6,7,8,13,15,19,20,21,18,22,34,53,239,245,247,258,277,279,280,282,283,284,285,287,393,394,395,396,437 (See Dosage and Administration: Dosage.)

If evidence of ototoxicity (e.g., dizziness, vertigo, tinnitus, roaring in the ears, hearing loss) occurs during aminoglycoside therapy, the drug should be discontinued or dosage reduced.1,2,3,4,5,6,7,8,12,13,19,20 The manufacturer of streptomycin states that baseline and periodic caloric stimulation tests and audiometric tests are advisable with extended streptomycin therapy and that tinnitus, roaring noises, or a sense of fullness in the ears indicates the need for audiometric examination and/or termination of streptomycin therapy.12 Tinnitus may be a sentinel symptom of ototoxicity and the onset of this symptom warrants caution.16

If signs of renal irritation (e.g., presence of white or red blood cells, casts, or albumin in urine) occur during aminoglycoside therapy, hydration should be increased.1,2,3 If other evidence of nephrotoxicity (e.g., decreased creatinine clearance or urine specific gravity, increased BUN and/or serum creatinine concentrations) occurs, the aminoglycoside should be discontinued or dosage reduced.1,2,3,4,5,6,7,8,10,11,12,13,19,20 If azotemia increases or if a progressive decrease in urinary output occurs, the drug should be discontinued.1,2,3

Because of an increased risk, aminoglycosides should not be used concomitantly and/or sequentially with other systemic, oral, or topical drugs that have neurotoxic, ototoxic, or nephrotoxic effects.1,2,3,4,5,6,7,8,10,11,12,13,15,16,19,20,21,34,53,57 (See Drug Interactions: Neurotoxic, Ototoxic, or Nephrotoxic Drugs.)

Neuromuscular Blockade

The possibility of neuromuscular blockade and respiratory paralysis should be considered when aminoglycosides are administered by any route, especially in patients receiving anesthetics or neuromuscular blocking agents (e.g., tubocurarine, rocuronium, succinylcholine) or in those receiving massive transfusions of citrate-anticoagulated blood.1,2,3,4,5,8,13,15,19,20,21,425 (See Drug Interactions: Neurotoxic, Ototoxic, and Nephrotoxic Drugs.) Neuromuscular blockade and respiratory paralysis have been reported when the drugs were administered parenterally, orally, or by topical irrigation or instillation.1,2,3,4,5,8,13,15,19,386

Aminoglycosides should be used with caution in patients with muscular disorders such as myasthenia gravis or parkinsonism, since the drugs may aggravate muscle weakness as a result of their potential to produce neuromuscular blockade.1,2,3,4,5,8,10,11,13,15,16,19,20,21 Calcium salts may reverse neuromuscular blockade, but mechanical respiratory assistance may be necessary.1,2,3,4,5,8,13,15,19,20,21,71 (See Cautions: Nervous System Effects.)

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of aminoglycosides and other antibacterials, the drugs should be used only for the treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.1,2,4,5,6,7,8,11,12,13,19,20,21 When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.1,2,4,5,6,7,8,11,12,13,19,20,21 In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.1,2,4,5,6,7,8,11,12,13,19,20,21

Patients should be advised that antibacterials (including aminoglycosides) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).1,2,4,5,6,7,8,11,12,13,19,20,21 Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with aminoglycosides or other antibacterials in the future.1,2,4,5,6,7,8,11,12,13,19,20,21

The use of aminoglycosides by any route may result in the overgrowth of nonsusceptible organisms, including fungi.1,2,3,4,5,6,7,8,10,11,12,13,15,17,19,20,21 If superinfection occurs, appropriate therapy should be instituted.1,2,3,4,5,6,7,8,10,11,12,13,15,19,20,21

Systemic Risks Associated with Local Administration

Administration of aminoglycosides by intraperitoneal instillation or local irrigation (abscess cavities, pleural space, peritoneal and ventricular cavities) is associated with an increased risk of systemic toxicity since the drugs are absorbed quickly and in substantial amounts when applied topically.1,2,3,4,5,7,8,15 (See Pharmacokinetics: Absorption.) Serious adverse systemic effects, including delayed-onset 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.1,2,3,4,5,7,8,10,11,15,386

Other Precautions

Parenteral aminoglycoside solutions containing sodium should be used with caution, if at all, in patients with congestive heart failure, severe renal insufficiency, or any clinical condition that involves edema with sodium retention.6,7 In patients with decreased renal function, administration of solutions containing sodium may result in sodium retention.6

The fact that oral neomycin may adversely affect GI absorption of some vitamins and drugs should be considered.10,11 (See Drug Interactions: Neomycin.)

In the event of aminoglycoside overdosage or toxic reactions, hemodialysis may aid in removal of aminoglycosides, especially if renal function is (or becomes) compromised.1,2,3,4,5,6,7,8,10,11,13,19,20,21 Peritoneal dialysis may be less effective than hemodialysis.4,5,6,7 In neonates, exchange transfusions may also be considered.1,2,3,4,5,8

Pediatric Precautions

Aminoglycosides should be used with caution and in reduced dosage in premature and full-term neonates because renal immaturity in these patients may result in prolonged serum half-lives of the drugs.1,2,3,4,5,6,7,8,12,13,19,20,21 A manufacturer of gentamicin states that the risk of toxic reactions is low in neonates, infants, and children with normal renal function provided they do not receive gentamicin dosages that are higher or continued longer than recommended.5

Safety and efficacy of oral neomycin have not been established in pediatric patients younger than 18 years of age.10,11 The manufacturers state that if use of oral neomycin is considered necessary in this age group, the drug should be used with caution and the duration of therapy should not exceed 3 weeks.10,11

Safety and efficacy of tobramycin solution for oral inhalation have not been established in pediatric patients younger than 6 years of age, in patients with forced expiratory volume in 1 second (FEV₁) less than 25% or exceeding 75% of the predicted value, or in patients colonized with Burkholderia cepacia (formerly Ps. cepacia ).16

Geriatric Precautions

Geriatric patients may be at higher risk of aminoglycoside-associated nephrotoxicity and ototoxicity than younger adults.1,2,3,4,8,10,11,13,15,19,20,21

Aminoglycosides are substantially eliminated in urine and the risk of toxicity may be increased in patients with impaired renal function.1,2,3,4,8,10,11,13,15,19,20,21 Because of age-related decreases in renal function, dosage should be selected with caution and renal function closely monitored whenever aminoglycosides are used in geriatric patients.1,2,3,4,8,10,11,13,15,19,20,21 Measuring creatinine clearance may be more useful than determining BUN or serum creatinine concentrations in this patient population since reduced renal function may not always be evident using the routine screening tests.1,2,3,4,8,10,11,13,15,19,20,21

Pregnancy, Fertility, and Lactation

Pregnancy

Aminoglycosides can cause fetal harm when administered to pregnant women.1,2,3,8,10,11,13,15,16,19,20,21 Aminoglycosides cross the placenta and there have been several reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy.1,2,3,4,5,6,7,8,10,11,12,13,15,19,20,21 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.1,2,3,4,5,6,7,8,10,11,12,13,15,19,20,21

If 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.1,2,3,4,5,6,7,8,10,11,12,13,15,16,19,20,21

Fertility

Reproduction studies in animals using subcutaneous amikacin or tobramycin have not revealed evidence of impaired fertility.1,2,16

Lactation

Small amounts of aminoglycosides are distributed into milk following IM or IV administration.1,2,3,4,5,6,7,8,10,11,12,13,15,19,20,21,422,423,424 Although it is not known whether neomycin is distributed into human milk following oral administration, it is distributed into cow milk following IM injection.10,11 It is not know whether tobramycin is distributed into milk following oral inhalation.16 Because of the potential for serious adverse reactions to aminoglycosides 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.1,2,3,4,5,6,7,8,10,11,12,13,15,16,19,20,21

Neurotoxic, Ototoxic, or Nephrotoxic Drugs

Concomitant and/or sequential use of an aminoglycoside and other systemic, oral, or topical drugs that have neurotoxic, ototoxic, or nephrotoxic effects (e.g., other aminoglycosides, acyclovir, amphotericin B, bacitracin, capreomycin, certain cephalosporins, colistin, cisplatin, methoxyflurane, polymyxin B, vancomycin) may result in additive toxicity and should be avoided, if possible.1,2,3,4,5,6,7,8,10,11,12,13,15,16,19,20,21,34,53,57

Because of the possibility of an increased risk of ototoxicity due to additive effects or altered serum and tissue aminoglycoside concentrations, aminoglycosides should not be given concomitantly with potent diuretics such as ethacrynic acid, furosemide, urea, or mannitol.1,2,3,4,5,6,7,8,10,11,12,13,15,16,19,20,21,53,54,56 It has been suggested that concomitant use of certain anti-emetics that suppress nausea and vomiting of vestibular origin and vertigo (e.g., dimenhydrinate, meclizine) may mask symptoms of aminoglycoside-associated vestibular ototoxicity.53

General Anesthetics and Neuromuscular Blocking Agents

Concurrent use of an aminoglycoside with general anesthetics or neuromuscular blocking agents (e.g., succinylcholine, rocuronium, tubocurarine) may potentiate neuromuscular blockade and cause respiratory paralysis.1,2,3,4,5,6,7,8,10,11,12,13,15,19,20,21,425 A single amikacin dose has potentiated the neuromuscular blocking effects of a single intubating dose of rocuronium.425

Aminoglycosides should be used with caution in patients receiving anesthetics or neuromuscular blocking agents, and patients should be closely observed for signs of respiratory depression.1,2,3,4,5,6,7,8,10,11,12,13,15,19,20,21

Neomycin

Oral neomycin may potentiate the effects of oral anticoagulants, possibly by interfering with GI absorption or synthesis of vitamin K.10,11 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,10,11,69 but apparently does not affect the terminal plasma half-life of digoxin.69 Serum digoxin concentrations should be monitored in patients receiving oral neomycin.10,11

Although the clinical importance is unclear, oral neomycin has been reported to decrease GI absorption of fluorouracil,10,11 methotrexate,10,11 cyanocobalamin (vitamin B₁₂),10,11 and penicillin V.11

Oral neomycin may decrease the rate but not the extent of absorption of oral spironolactone.150

Anti-infective Agents

-Lactams

In vitro studies indicate that the antibacterial activity of aminoglycosides and β-lactam antibiotics may be additive or synergistic against some organisms including Enterobacteriaceae, Pseudomonas aeruginosa , enterococci, and viridans streptococci.22,32,34,39,48,51,53,64 The synergistic effect of aminoglycosides and β-lactams is 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.34,53,64 Synergism between aminoglycosides and extended-spectrum penicillins generally is 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 t_½, 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.

Concomitant use of aminoglycosides and cephalosporins may result in increased nephrotoxicity1,2,3,4,6,7,8,13,15,19,20,21 since cephalosporins may spuriously elevate creatinine concentrations.1,2,3 (See Drug Interactions: Neurotoxic, Ototoxic, or Nephrotoxic Drugs.)

Penicillins are physically and/or chemically incompatible with aminoglycosides and can inactivate aminoglycosides in vitro. In vitro inactivation of aminoglycosides by penicillins can occur if the drugs are administered in the same syringe or IV infusion container. If concomitant therapy is indicted, the drugs should be administered separately and should not be admixed. Penicillins can inactivate aminoglycosides in vitro in serum samples obtained from patients receiving concomitant therapy with the drug and this may result in falsely decreased aminoglycoside concentrations. Amikacin appears to be the least susceptible and tobramycin the most susceptible to inactivation by β-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.

Carbapenems

The antibacterial activity of imipenem and aminoglycosides is additive or synergistic in vitro against some gram-positive bacteria including Enterococcus faecalis ,217,218,219,220,221,222 Staphylococcus aureus ,217,223 and Listeria monocytogenes .217,218,224 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.219,220,221,222

Other Anti-infectives

The antibacterial activity of streptomycin and vancomycin may be additive or synergistic against enterococci (e.g., E. faecalis ).22,343 However, vancomycin and aminoglycosides have similar neurotoxic, ototoxic, and nephrotoxic effects and concomitant and/or sequential use of the drugs may result in additive toxicity and should be avoided, if possible.1,2,3,4,5,6,7,8,10,11,12,13,15,16,19,20,21,343 (See Drug Interactions: Neurotoxic, Ototoxic, or Nephrotoxic Drugs.)

Chloramphenicol, clindamycin,63 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.

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.212,213,214,215 Increases in serum aminoglycoside concentrations appeared to be related to indomethacin-induced decreases in urine output.213,214 It also has been postulated that inhibitors of prostaglandin synthesis (e.g., aspirin) may increase nephrotoxicity of aminoglycosides.214,215 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.213,214

Laboratory Test Interferences

Tests for Urinary Glucose

Streptomycin reportedly causes false-positive results in urine glucose determinations using cupric sulfate solution (Benedict's reagent, Clinitest^®).

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.

In Vitro Susceptibility Testing

When in vitro susceptibility testing is performed according to the standards of the Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards [NCCLS]), clinical isolates identified as susceptible to an aminoglycoside are inhibited by drug concentrations usually achievable when the recommended dosage is used for the site of infection.392 Clinical isolates classified as intermediate have minimum inhibitory concentrations (MICs) that approach usually attainable blood and tissue concentrations and response rates may be lower than for strains identified as susceptible.392 Therefore, the intermediate category implies clinical applicability in body sites where the drug is physiologically concentrated or when a higher than usual dosage can be used.392 This intermediate category also includes a buffer zone which should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins.392 If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to an aminoglycoside, the strain is not inhibited by drug concentrations generally achievable with usual dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and clinical efficacy of the drug against the isolate has not been reliably demonstrated in clinical studies.392

Because there are differences in the spectra of activity of amikacin, gentamicin, kanamycin, tobramycin, and streptomycin, CLSI recommends that these drugs be tested individually to determine in vitro susceptibility.392

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test in vitro susceptibility of Enterobacteriaceae, Pseudomonas aeruginosa , Acinetobacter , or Staphylococcus , individual disks containing 30 mcg of amikacin, 10 mcg of gentamicin, 30 mcg of kanamycin, 10 mcg of tobramycin, or 10 mcg of streptomycin should be used.392 There is no class susceptibility disk that can be used to test susceptibility to all aminoglycosides.392

Susceptibility of enterococci to aminoglycosides cannot be predicted using standard disk-diffusion procedures.392 Although enterococci may appear susceptible to aminoglycosides in vitro, the drugs are not effective clinically when used alone in these infections.392 Therefore, CLSI recommends that enterococci be screened for high-level resistance to gentamicin and streptomycin and these results used to predict synergy between these aminoglycosides and ampicillin, penicillin G, or vancomycin for the treatment of enterococcal infections.392 In vitro susceptibility of enterococci to other aminoglycosides does not need to be evaluated since other aminoglycosides are inferior to gentamicin and streptomycin for the treatment of enterococcal infections.392 When the disk-diffusion screening test is used to test enterococci for high-level aminoglycoside resistance, a disk containing 120 mcg of gentamicin and a disk containing 300 mcg of streptomycin should be used.392 When the test is performed according to CLSI standardized procedures, a growth inhibition zone of 6 mm indicates the enterococcal strain is resistant and the aminoglycoside will not be synergistic with ampicillin, penicillin G, or vancomycin.392 If the growth inhibition zone is 7-9 mm, results are inconclusive and the agar or broth dilution screening test for high-level aminoglycoside resistance should be performed.392 If the growth inhibition zone is 10 mm or larger, the enterococcal strain is susceptible to the aminoglycoside and a synergistic effect will occur with ampicillin, penicillin G, or vancomycin provided the strain also is susceptible to that drug.392

Dilution Susceptibility Tests

When broth or agar dilution susceptibility tests are used to test in vitro susceptibility to aminoglycosides, each drug must be tested individually.392

Susceptibility of enterococci to aminoglycosides cannot be predicted using standard broth or agar dilution procedures.392 Although enterococci may appear susceptible to aminoglycosides in vitro, the drugs are not effective clinically when used alone in these infections.392 Therefore, CLSI recommends that enterococci be screened for high-level resistance to gentamicin and streptomycin and these results used to predict synergy between these aminoglycosides and ampicillin, penicillin G, or vancomycin for the treatment of enterococcal infections.392 In vitro susceptibility of enterococci to other aminoglycosides does not need to be evaluated since other aminoglycosides are inferior to gentamicin and streptomycin for the treatment of enterococcal infections.392 When the agar or broth screening test is used to test enterococci for high-level aminoglycoside resistance and is performed according to CLSI standardized procedures, the presence of more than one colony on the agar or any growth in the broth indicates the enterococcal strain is resistant and the aminoglycoside will not be synergistic with ampicillin, penicillin G, or vancomycin.392 The absence of growth indicates the enterococcal strain is susceptible to the aminoglycoside and a synergistic effect will occur with ampicillin, penicillin G, or vancomycin provided the strain also is susceptible to that drug.392

Gram-Negative Aerobic Bacteria

Aminoglycosides generally are 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 also are 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 .448 Although most strains of Y. pestis are susceptible to streptomycin,448 streptomycin-resistant strains have been reported rarely.447,450 Streptomycin, gentamicin, and tobramycin are active in vitro against Francisella tularensis .446

Streptomycin is active against Calymmatobacterium granulomatis , Haemophilus influenzae , H. ducreyi , and Pasteurella multocida .

Gram-Positive Bacteria

Aminoglycosides are active against some strains of Staphylococcus aureus and S. epidermidis. The drugs are only minimally active against streptococci; most strains of enterococci are resistant to the aminoglycosides alone.343,375,403 Streptomycin is active against Nocardia, Enterococcus faecalis , and Erysipelothrix .

Mycobacteria

Streptomycin is active in vitro against many strains of Mycobacterium tuberculosis and 22,338 M. bovis 22 and some strains of M. avium complex (MAC),22,339,365 M. kansasii ,22,339,427,444 M. malmoense ,339 M. marinum ,22,339 M. szulgai ,339 and M. ulcerans .22,426

Amikacin and kanamycin are active against many strains of M. tuberculosis 22,338 and may be active against multidrug-resistant strains.429 In vitro, amikacin is active against some strains of M. avium complex,339,428,431 M. abscessus ,339,442,443 M. chelonae ,22,339,443 M. fortuitum ,22,47,339 M. kansasii ,339,427 M. marinum ,22 and M. ulcerans . 426,432 Kanamycin is active in vitro against some strains of M. abscessus .442

Gentamicin and tobramycin usually are inactive against M. tuberculosis at clinically attainable concentrations.22

Streptomycin and kanamycin have activity against M. leprae in experimental leprosy in mice.22,430

Parasites

Paromomycin is active against protozoa, especially Entamoeba histolytica ,22 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 ,22 and that neomycin concentrations of 12.5 mcg/mL or paromomycin concentrations of 5 mcg/mL may be amebistatic against these organisms.200,201 Paromomycin also appears to have some activity against Cryptosporidium , but no anti-infective has been found to reliably eliminate Cryptosporidium .

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.

Streptomycin-resistant Y. pestis have been reported rarely;447,450 resistance is plasmid-mediated and transferable.447,450 Although a streptomycin-resistant Y. pestis strain isolated from a human case of bubonic plague in Madagascar was susceptible to spectinomycin, tetracyclines, sulfonamides, and chloramphenicol in vitro,450 a multidrug-resistant strain with high-level resistance to streptomycin, kanamycin, spectinomycin, tetracyclines, sulfonamides, chloramphenicol, and ampicillin also has been isolated in Madagascar.447

M. avium complex (MAC) with intermediate or high-level in vitro resistance to streptomycin has been reported.365 The importance of this in vitro resistance to streptomycin in terms of clinical response to treatment with multiple-drug regimens that include streptomycin and other drugs (e.g., clarithromycin, rifampin, ethambutol) is unclear.365

There is partial cross-resistance among the aminoglycosides. Mycobacterium tuberculosis generally demonstrate complete cross-resistance between amikacin and kanamycin22,338 and partial cross-resistance between kanamycin and capreomycin. Streptomycin-resistant M. tuberculosis may be susceptible to amikacin, kanamycin, and capreomycin.338 Resistant strains of initially susceptible M. tuberculosis develop rapidly if an aminoglycoside 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 serum 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 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 (t_½s) of aminoglycosides are usually 2-4 hours in adults with normal renal function. Plasma concentrations are higher and plasma elimination t_½s are more prolonged in patients with impaired renal function. Plasma concentrations and plasma elimination t_½s of the drugs are not usually affected by hepatic impairment; however, the plasma elimination t_½ 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 t_½s 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 t_½ 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 t_½s 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 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 .1,2,3,4,5,6,7,8,10,11,12,13,15,16,17,18,19,20,21,22,23,32 The drugs contain 1 or 2 amino sugars glycosidically linked to an aminocyclitol nucleus and are more accurately termed aminoglycosidic aminocyclitols.18,22,27 Streptidine is the aminocyclitol nucleus of streptomycin, and 2-deoxystreptamine is the aminocyclitol nucleus of amikacin, gentamicin, kanamycin, neomycin, paromomycin, and tobramycin.18,23,27

Neomycin B and paromomycin contain 3 amino sugars attached to the central 2-deoxystreptamine nucleus.18 The kanamycin family (kanamycins A and B, amikacin, tobramycin) contains 2 amino sugars attached to the central 2-deoxystreptamine nucleus.18 The gentamicin family (C₁, C₂, and C_1A) contains a different 3-amino sugar (garosamine).18 Amikacin is a semisynthetic derivative prepared from kanamycin A with a wider spectrum of activity than the parent drug.18,22,23

Amikacin,1,2,3 gentamicin,4,5,6,7 kanamycin,8 streptomycin,12 and tobramycin13,15,19,20,21 are commercially available for parenteral administration as sulfate salts; neomycin10,11 and paromomycin17 are commercially available for oral administration as sulfate salts; and tobramycin is commercially available as the base for oral inhalation via nebulization.16 Aminoglycosides are highly polar molecules and are relatively lipid insoluble.18,53

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 β-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).25 Specialized references should be consulted for specific compatibility information.25 (See also Drug Interactions: Anti-infective Agents.)

Only references cited for selected revisions after 1984 are available electronically.

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