DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1372 Third, optimal microbial kill by the antibiotic may
be best achieved by maximizing certain shapes of the
concentration-time curve. Certain dose schedules maximize
antimicrobial effect. As an example, consider an
antibiotic with a serum t 1/2
of 3 hours that is being used to
treat a bloodstream infection by a pathogen with an MIC
of 0.5 mg/L, administered with a dosing interval of
24 hours (that is, a once-daily schedule). Figure 48–4A
depicts the concentration-time curve of the antibiotic, with
definitions of peak concentration (C Pmax
), area under the
curve (AUC), and the fraction of the dosing interval for
which the drug concentration remains above the MIC
(T > MIC), as shown. The AUC is a measure of the total
concentration of drug and is calculated by taking an integral
between two time points, 0-24 hours (AUC 0-24
) in this
case. Now, if one were to change the dosing schedule of
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Drug concentration (mg/L)
5
4
3
2
1
0
5
4
3
2
1
0
0
A
B
C max = maximum concentration
T>MIC
AUC 0-24h = 24h area under the
concentration-time curve
C max
Microbe’s MIC
AUC 0-8
AUC 8-16h AUC 16-24h
T 1
>MIC T 2 >MIC T 3
>MIC
MIC
3 6 9 12 15 18 21 24
Time in hours
Figure 48–4. Effect of different dose schedules on shape of concentration-time
curve. The total AUC for the fractionated dose in
curve B is determined by adding AUC 0-8h
, AUC 8-16h
and AUC 16-24h
,
which adds up to the same AUC 0-24h
in curve A. The time that the
drug concentration exceeds MIC in curve B is also determined by
adding up T 1
>MIC, T 2
>MIC, and T 3
>MIC, which results in a fraction
greater than that for curve A.
the same antibiotic amount by splitting it into three equal
doses administered at 0, 8, and 16 hours, the shape of the
concentration-time curves changes to that shown in
Figure 48–4B. Because the same cumulative dose has
been given for the dosing interval of 24 hours, the AUC 0-24
will be similar whether it was given once a day or three
times a day. For the same pathogen, therefore, the change
in dose schedule does not change the AUC 0-24
/MIC (or
AUC 0-24
/EC 90
). However, the C Pmax
will decrease by a
third when the total dose is split into thirds and administered
more frequently (Figure 48–4B). Thus, when a dose
is fractionated and administered more frequently, the
C Pmax
/MIC ratio decreases. In contrast, the time that the
drug concentration persists above MIC (T > MIC) will
increase with the more frequent dosing schedule, despite
the same cumulative dose being administered. Which
of the three indices (AUC/MIC, or C Pmax
/MIC or T>MIC)
is the most important to the outcome being assessed (i.e.,
microbial kill)? A common simple approach to the answer
is to determine which of these patterns best approximates
a perfect inhibitory sigmoid E max
curve (based on various
statistical assessments of goodness of fit).
Some classes of antimicrobial agents kill best when concentration
persists above MIC for longer durations of the dosing interval
while kill is decreased by reducing the time above MIC. Indeed,
increasing the drug concentration beyond 4-6 times the MIC does not
increase microbial kill. Two good examples are β-lactam antibacterials
(e.g., penicillin) and the antifungal agent 5-flourocytosine (5-FC)
(Ambrose et al., 2007; Andes and van Ogtrop, 2000). In fact, there are
usually good biochemical explanations for this pattern for the drugs.
The clinical implication, however, is that a drug optimized by T > MIC
should be dosed more frequently, or if possible should have its t 1/2
prolonged
by other drugs, so that drug concentrations persist above MIC
(or EC 95
) as long as possible. Thus the effectiveness of penicillin is
enhanced when it is given as a continuous infusion. HIV protease
inhibitors are often “boosted” with ritonavir. This “boosting” inhibits
the metabolism of the protease inhibitors by CYPs 3A4 and 2D6,
thereby prolonging time above EC 95
.
However, the peak concentration is what matters for some
antimicrobial agents. Persistence of concentration above MIC has
less relevance for these drugs, meaning that these drugs can be dosed
more intermittently. Aminoglycosides are a prime example of this
class as they used to be given three times a day but are highly effective
when given once a day. These C Pmax
/MIC-linked drugs are often
able to be administered less frequently due to their long duration of
post-antibiotic effect (PAE). In other words, effect continues long
after antibiotic concentrations decline below the MIC. An example
of such a drug is rifampin (Gumbo et al., 2007a). The entry of
rifampin into Mycobacterium tuberculosis increases with increased
concentration in the bacillus microenvironment, likely because of a
saturable transport process. Once inside the bacteria, the drug’s
macrocyclic ring binds the β-subunit of DNA-dependent RNA polymerase
(rpoB) to form a very stable drug-enzyme complex within
10 minutes, a process not enhanced by longer incubation of drug and