Page 843 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 45 Aminoglycosides & Spectinomycin 829

This threshold is not precisely defined, but a trough concentration regimen, peak serum concentrations should be determined from
above 2 mcg/mL is predictive of toxicity. At clinically relevant a blood sample obtained 30–60 minutes after a dose, and trough
doses, the total time above this threshold is greater with multiple concentrations from a sample obtained just before the next dose.
smaller doses of drug than with a single large dose. Doses of gentamicin and tobramycin should be adjusted to main-
Numerous clinical studies demonstrate that a single daily dose tain peak levels between 5 and 10 mcg/mL (typically between
of aminoglycoside is just as effective—and probably less toxic— 8 and 10 mcg/mL in more serious infections) and trough levels
than multiple smaller doses. Therefore, many authorities recom- <2 mcg/mL (<1 mcg/mL is optimal).
mend that aminoglycosides be administered as a single daily dose
in most clinical situations. However, the efficacy of once-daily E. Adverse Effects
aminoglycoside dosing in combination therapy of enterococcal All aminoglycosides are ototoxic and nephrotoxic. Ototoxicity and
and staphylococcal endocarditis in patients with a prosthetic valve nephrotoxicity are more likely to be encountered when therapy is
remains to be defined, and administration of lower doses two or continued for more than 5 days, at higher doses, in the elderly,
three times daily is still recommended. In contrast, limited data do and in the setting of renal insufficiency. Concurrent use with loop
support once-daily dosing in streptococcal endocarditis. The role diuretics (eg, furosemide, ethacrynic acid) or other nephrotoxic
of once-daily dosing in pregnancy, obesity, and in neonates also is antimicrobial agents (eg, vancomycin or amphotericin) can poten-
not well defined. tiate nephrotoxicity and should be avoided if possible. Ototoxicity
Once-daily dosing has potential practical advantages. For can manifest either as auditory damage, resulting in tinnitus and
example, repeated determinations of serum concentrations are high-frequency hearing loss initially, or as vestibular damage with
unnecessary unless an aminoglycoside is given for more than 3 vertigo, ataxia, and loss of balance. Nephrotoxicity results in rising
days. A drug administered once a day rather than three times a serum creatinine levels or reduced creatinine clearance, although
day is less labor intensive. And once-a-day dosing is more feasible the earliest indication often is an increase in trough serum ami-
for outpatient therapy. noglycoside concentrations. Neomycin, kanamycin, and amikacin
Aminoglycosides are cleared by the kidney, and excretion is are the agents most likely to cause auditory damage. Streptomycin
directly proportional to creatinine clearance. To avoid accumu- and gentamicin are the most vestibulotoxic. Neomycin, tobramy-
lation and toxic levels, once-daily dosing of aminoglycosides is cin, and gentamicin are the most nephrotoxic.
generally avoided if renal function is impaired. Rapidly changing In very high doses, aminoglycosides can produce a curare-like
renal function, which may occur with acute kidney injury, must effect with neuromuscular blockade that results in respiratory
also be monitored to avoid overdosing or underdosing. Provided paralysis. This paralysis is usually reversible by calcium gluconate,
these pitfalls are avoided, once-daily aminoglycoside dosing is safe when given promptly, or neostigmine. Hypersensitivity occurs
and effective. If the creatinine clearance is >60 mL/min, then a infrequently.
single daily dose of 5–7 mg/kg of gentamicin or tobramycin is
recommended (15 mg/kg for amikacin). For patients with cre- F. Clinical Uses
atinine clearance <60 mL/min, traditional dosing as described Aminoglycosides are mostly used against aerobic Gram-negative
below is recommended. With once-daily dosing, serum concen- bacteria, especially when there is concern for drug-resistant patho-
trations need not be routinely checked until the second or third gens or in critically ill patients. They are almost always used in
day of therapy, depending on the stability of renal function and combination with a β-lactam antibiotic to extend empiric cover-
the anticipated duration of therapy. In most circumstances, it is age and to take advantage of the potential synergism between these
unnecessary to check peak concentrations; an exception may be two classes of drugs. Penicillin-aminoglycoside combinations have
when ensuring adequately high peak concentrations for treat- also been used to achieve bactericidal activity in treatment of
ing infections caused by drug-resistant pathogens. The goal is to enterococcal endocarditis and to shorten duration of therapy for
administer drug so that concentrations of <1 mcg/mL are present viridans streptococcal endocarditis. Due to toxicity, these com-
between 18 and 24 hours after dosing. This provides sufficient binations are used less frequently when alternate regimens are
time for washout of drug to occur before the next dose is given. available. For example, in the case of enterococcal endocarditis,
Several nomograms have been developed and validated to assist studies suggest that the combination of ampicillin and ceftriaxone
clinicians with once-daily dosing (eg, Freeman reference). is an effective regimen with less risk for nephrotoxicity. When
With traditional dosing, adjustments must be made to pre- aminoglycosides are used, the selection of agent and dose depends
vent accumulation of drug and toxicity in patients with renal on the infection being treated and the susceptibility of the isolate.
insufficiency. Either the dose of drug is kept constant and the
interval between doses is increased, or the interval is kept con-
stant and the dose is reduced. Nomograms and formulas have STREPTOMYCIN
been constructed relating serum creatinine levels to adjust-
ments in traditional treatment regimens. Because aminoglycoside Streptomycin (Figure 45–1) was isolated from a strain of Strepto-
clearance is directly proportional to the creatinine clearance, a myces griseus. The antimicrobial activity of streptomycin is typical
method for determining the aminoglycoside dose is to estimate of that of other aminoglycosides, as are the mechanisms of resis-
creatinine clearance using the Cockcroft-Gault formula described tance. Resistance has emerged in most species, restricting the cur-
in Chapter 60. For a traditional twice- or thrice-daily dosing rent usefulness of streptomycin, with the exceptions listed below.