Naber.qxp 16/7/08 2:10 pm Page 120
Bacterial Infections
well as anaerobic pathogens. Carbapenems maintain antibacterial doripenem and 83.4% for levofloxacin. The clinical cure rate in the test
efficacy against the vast majority of β-lactamase-producing organisms. of cure population was 95.1% for doripenem and 90.2% for
This stability against serine-β-lactamases is due to the trans-1- levofloxacin. Doripenem was microbiologically and clinically effective
hydroxyethyl substituent and its unique juxtaposition against the and therapeutically non-inferior to levofloxacin in this study of the
β-lactam carbonyl group.
20
The stability encompasses extended- treatment of complicated and uncomplicated UTIs, and was generally
spectrum β-lactamases and AmpC β-lactamases; however, it does not found to be safe and well-tolerated.
23
extend to metallo-β-lactamases.
Orally active 1β-methylcarbapenems have been undergoing pre-clinical
The group one parenteral carbapenem ertapenem has good or clinical trials for a number of years.
24
The substances CS-834, L-084
Gram-negative activity against most bacteria, excluding P. aeruginosa; and DZ-2640 have been selected for further investigation.
24
CS-834
it is also not active against methicillin-resistant S. aureus (MRSA) and from Sankyo is the orally active pro-drug of the substance R-95867.
enterococci. It contains a 1β-methyl substituent that reduces hydrolysis The substance is active against Gram-positive and Gram-negative
species, such as S. aureus, E. coli and K. pneumoniae, but is less active
against Pseudomonas spp. and Enterococcus spp.
25
The 24-hour
It has been convincingly demonstrated
cumulative renal excretion into the urine in healthy volunteers ranged
from 27 to 34%.
24
that severe infections have lower
mortality rates when the empirical
L-084 was developed by Wyeth and is the orally active pro-drug
of L-036. This substance exhibits excellent antibacterial activity against
therapy has initially covered all
Gram-positive and Gram-negative species, with the exception of
causative bacteria. P. aeruginosa. The accumulative urinary recoveries in volunteers
within 24 hours ranged from 54 to 73%.
24
DZ-2640 from the
Daiichi Group exhibits broad antibacterial activity except against
of the β-lactam group by the renal dihydropeptidase I. Furthermore, it P. aeruginosa. The cumulative renal recoveries in volunteers ranged
contains a meta-substituted benzoic acid substituent that increases the from 32 to 45%.
24
Urinary excretions of the oral carbapenems are
molecular weight and lipophilicity of the substance, and a carboxylic certainly not optimal, but are still in the intermediate range.
acid moiety resulting in a net negative charge. This results in high Nevertheless, exaggerated consumption of carbapenems in the future
protein binding that leads to a longer serum half-life.
20
Urinary will certainly also lead to the emergence of antibiotic resistance and
excretion is approximately 80%.
21
The lack of activity against multiresistant pathogens.
P. aeruginosa may sometimes be beneficial in circumstances where
extended-spectrum β-lactamase-producing bacteria are of great Future Strategies in the Treatment of
concern: with empirical treatment in situations where Pseudomonas Bacterial Urinary Tract Infections
spp. is not considered, the application of ertapenem would not Bacteria exhibit an enormous repertoire of different resistance
necessarily select for multiresistant Pseudomonas spp. mechanisms. Unspecific mechanisms such as reduced permeability
or efflux alter the tolerance to antibiotic substances less than
Group two parenteral carbapenems include imipenem and specific mechanisms such as inactivation of the antibiotic. However,
meropenem. They are active against many Gram-positive and Gram- the antibiotic spectrum targeted is much more extensive. On the
negative uropathogens excluding MRSA, vancomycin-resistant other hand, unspecific mechanisms can also be induced by
enterococci (VRE) and E. faecium. Imipenem is hydrolysed by the renal
dihydropeptidase I and combined with the specific inhibitor cilastatin.
Urinary excretion of the active imipenem is about 70% if combined
with cilastatin. Meropenem contains the 1β-methyl-substituent and is Known substances should be improved
stable against the renal dihydropeptidase I. Compared with imipenem,
in terms of higher bioavailability, longer
it is somewhat more active against P. aeruginosa, but less active
against Gram-positive uropathogens. The urinary excretion of the half-life and better pharmacodynamic
active substance is 70%.
21
and pharmacokinetic performance.
Doripenem is a new parenteral carbapenem and offers slightly more
activity than meropenem against selected pathogens, including some,
but not all, strains of P. aeruginosa not susceptible to imipenem or non-antibiotic substances such as salicylates. Thus, low-level resistance
meropenem. Doripenem is also active against Gram-positive pathogens can be conferred and give bacteria a selection advantage.
26
To
except MRSA, E. faecium and VRE. Urinary excretion is 75% and it is of counteract these factors, anti-infective substances are continuously
potential interest for the treatment of complicated UTIs.
22
A large, evaluated and investigated.
multinational phase III study evaluated the efficacy and safety of
doripenem for the treatment of complicated lower UTIs and The current research goals in medicinal chemistry include several
pyelonephritis (complicated and uncomplicated) and compared it with targets. Known substances should be improved in terms of higher
levofloxacin.
23
A total of 753 patients were randomised. The bioavailability, longer half-life and better pharmacodynamic
microbiological cure rate in the test of cure population was 82.1% for and pharmacokinetic performance. New derivatives of known
120 EUROPEAN INFECTIOUS DISEASE
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