Aminoglycosides clinical effectiveness

The clinical effectiveness of aminoglycosides and fluoroquinolones is influenced both by the height of the peak plasma concentration relative to the minimum inhibitory concentration (Cmax MIC ratio) and the area under the plasma concentration-time curve that is above the MIC during the dosage interval (AUIC = AUC/MIC). The former is relatively more important for fluoroquinolones maximum activity is achieved when Cmax is in the range 5-10 times the MIC. 

Aminoglycosides have short half-lives (2-3 h) and conventionally are given parenterally at 6- to 12-h intervals. Once-daily administration is becoming more common because it is clinically effective and causes less toxicity. 

Inhibition of bacterial growth that continues after antibiotic blood concentrations have fallen to low levels is called the postantibiotic effect (PAE). The mechanisms of PAE are unclear but may reflect the lag time required by bacteria to synthesize new enzymes and cellular components, the possible persistence of antibiotic at the target site, or an enhanced susceptibility of bacteria to phagocytic and other defense mechanisms. PAE may be another factor contributory to the clinical effectiveness of high-dose, once-daily administration of aminoglycosides. 

The scientific literature is replete with proposals for numerical values of these indices, for example, Cmax MIC90 > 10 1 for aminoglycosides, AUC MIC9o ratio > 125 h for fluoroquinolones, and T >MIC9o > 50% for P-lactams. In fact, these values provide no more than a guide to clinically effective dosage for several reasons ... 

Kanamycin, like neomycin, exerts prominent antibacterial activity against both gram positive and gram negative susceptible strains of bacteria. However, the clinical effectiveness of kanamycin has become obsolete due to the prevalence of aminoglycoside resistant bacteria. (33,34) As one of the antidotes... 

Patomomycin This oral aminoglycoside was first shown to be effective as a topical treatment for cutaneous leishmaniasis, and later as a parenteral drug against visceral leishmaniasis. Phase III clinical trials were completed in 2005 in India, 15 years after the potential of this component for treating viscer al leishmaniasis was discovered. It is currently not registered for this use. 

A major clinical distinction between the effects on the inner ear and the kidney is the fact that the renal effects are reversible while the effects on the inner ear are irreversible, leading to permanent loss of balance or auditory function. Furthermore, renal insults can more easily be monitored and thereby largely prevented, while monitoring of impending auditory or vestibular damage is not always possible. Ototoxic side effects frequently develop after cessation of aminoglycoside treatment, sometimes delayed by weeks. This review will therefore focus on the ototoxic side effects as a major unresolved issue in aminoglycoside toxicity. 

Van Lent-Evers, N.A., Mathot, R.A., Geus, W.P., van Hour, B.A., and Vinks, A.A. (1999) Impact of goal-oriented and model-based clinical pharmacokinetic dosing of aminoglycosides on clinical outcome a cost-effectiveness analysis. Ther Drug Monit 21 63-73. 

Adverse effects from aminoglycoside are both time- and concentration-dependent. Toxicity is unlikely to occur until a certain threshold concentration is reached, but once that concentration is achieved the time beyond this threshold becomes critical. This threshold is not precisely defined, but a trough concentration above 2 mcg/mL is predictive of toxicity. At clinically relevant doses, the total time above this threshold is greater with multiple smaller doses of drug than with a single large dose. 

Clinical Use. Paromomycin (Humatin) is an aminoglycoside antibacterial (see Chapter 33) that is used primarily to treat mild to moderate intestinal infections (amebiasis).51 This drug may also be used as an adjunct to other amebicides during the treatment of more severe protozoal infections. Paromomycin is also effective against some bacteria and tapeworms, and may be used as a secondary agent in certain bacterial or helminthic infections. This drug is administered orally. 

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