Læknablaðið - 15.01.1994, Blaðsíða 58

48
LÆKNABLAÐIÐ
penicillin against streptococci, in contrast to
the in vitro data.
The mechanism of the PAE is unknown.
Studies with 3H-thymidine incorporation
showed repression of DNA synthesis during
the PAE induced by most drugs with the
notable exception of ciprofloxacin, which
caused a dose dependent increase of DNA
synthesis during the PAE. Ultrastructural
electron microscopic studies during the PAE-
phase furthermore demonstrated species-
specific changes. These observations indicate
that the mechanism of the PAE probably is
variable and dependent on organism species
and antimicrobial class.
The PAE would only be a microbiological
curiosity, unless a biological significance
could be demonstrated. By in vitro
studies organisms in the PAE phase were
demonstrated to be less susceptible to the
bactericidal effect of a second antimicrobial
to which they were exposed during the PAE
phase.
More importantly, however, by employment
of the murine model mentioned above it
was demonstrated that for drugs inducing
a signitícant PAE serum levels needed not
be maintained constantly above the MIC
to achieve maximal efficacy. The major
pharmacokinetic parameter predicting efficacy
for such agents, e.g. aminoglycosides against
Gram-negative bacilli, is the area under the
concentration-vs-time curve (AUC) and the
optimal dosage interval is primarily dependent
on the duration of the PAE, thus indicating
that the optimal dosing in terms of efficacy,
cost and toxicity for these agents could be
with longer intervals than currently employed.
On the other hand, the ,0-Iactams do not
induce a PAE against Gram-negative bacilli
and furthermore exhibit a bactericidal activity
that is time- but not concentration-dependent.
For such drugs the major pharmacokinetic
parameter predicting efficacy and determining
the optimal dosage interval is the time drug
concentration exceeds the MIC, implicating
that the most eftícacious drug administration
in this case is by short dosage intervals or
even by continuous administration. In limited
human trials performed by other investigators
these concepts have been confirmed.
The determination of the PAE may thus
be of aid in clinical practice, similarly to
determinations of MIC/MBC and serum
bactericidal levels. To facilitate the usage of
the PAE in the clinical laboratory, two new
methods for quantitation of the PAE by use of
3H-thymidine uptake and COi generation have
been developed, standardized and shown to be
contparable to the standard method of viable
counts.
The study of PAE does provide information
about the action of antimicrobial agents that
cannot be derived from standard in vivo
sensitivity tests. However, additional animal
studies and human clinical trials are necessary
to substantiate these initial observations and to
determine the ultimate clinical significance of
the PAE.