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New Potent, Broad-spectrum Treatments for Serious Urinary Tract Infections
well as anaerobic pathogens. Carbapenems maintain antibacterial microbiological cure rate in the test of cure population was 82.1% for
efficacy against the vast majority of β-lactamase-producing organisms. doripenem and 83.4% for levofloxacin. The clinical cure rate in the test
This stability against serine-β-lactamases is due to the trans-1- of cure population was 95.1% for doripenem and 90.2% for
hydroxyethyl substituent and its unique juxtaposition against the
β-lactam carbonyl group.
The stability encompasses extended-
spectrum β-lactamases and AmpC β-lactamases; however, it does not
Known substances should be improved
extend to metallo-β-lactamases.
in terms of higher bioavailability, longer
The group one parenteral carbapenem ertapenem has good
half-life and better pharmacodynamic
Gram-negative activity against most bacteria, excluding P. aeruginosa;
it is also not active against methicillin-resistant S. aureus (MRSA) and
and pharmacokinetic performance.
enterococci. It contains a 1β-methyl substituent that reduces hydrolysis
of the β-lactam group by the renal dihydropeptidase I. Furthermore, it
contains a meta-substituted benzoic acid substituent that increases the levofloxacin. Doripenem was microbiologically and clinically effective
molecular weight and lipophilicity of the substance, and a carboxylic and therapeutically non-inferior to levofloxacin in this study of the
acid moiety resulting in a net negative charge. This results in a high treatment of complicated and uncomplicated UTIs, and was generally
protein binding that leads to a longer serum half-life.
Urinary found to be safe and well-tolerated.
excretion is approximately 80%.
The lack of activity against
P. aeruginosa may sometimes be beneficial in circumstances where Orally active 1β-methylcarbapenems have been undergoing pre-clinical
extended-spectrum β-lactamase-producing bacteria are of great or clinical trials for a number of years.
The substances CS-834, L-084
concern: with empirical treatment in situations where Pseudomonas and DZ-2640 have been selected for further investigation.
spp. is not considered, the application of ertapenem would not from Sankyo is the orally active pro-drug of the substance R-95867.
necessarily select for multiresistant Pseudomonas spp. The substance is active against Gram-positive and Gram-negative
species, such as S. aureus, E. coli and K. pneumoniae, but is less active
Group two parenteral carbapenems include imipenem and against Pseudomonas spp. and Enterococcus spp.
meropenem. They are active against many Gram-positive and Gram- cumulative renal excretion into the urine in healthy volunteers ranged
negative uropathogens excluding MRSA, vancomycin-resistant from 27 to 34%.
enterococci (VRE) and E. faecium. Imipenem is hydrolysed by the renal
dihydropeptidase I and combined with the specific inhibitor cilastatin. L-084 was developed by Wyeth and is the orally active pro-drug
Urinary excretion of the active imipenem is about 70% if combined of L-036. This substance exhibits excellent antibacterial activity against
with cilastatin. Meropenem contains the 1β-methyl-substituent and is Gram-positive and Gram-negative species, with the exception of
stable against the renal dihydropeptidase I. Compared with imipenem, P. aeruginosa. The accumulative urinary recoveries in volunteers
it is somewhat more active against P. aeruginosa, but less active within 24 hours ranged from 54 to 73%.
DZ-2640 from the
against Gram-positive uropathogens. The urinary excretion of the Daiichi Group exhibits broad antibacterial activity except against
active substance is 70%.
P. aeruginosa. The cumulative renal recoveries in volunteers ranged
from 32 to 45%.
Urinary excretions of the oral carbapenems are
Doripenem is a new parenteral carbapenem and offers slightly more certainly not optimal, but are still in the intermediate range.
activity than meropenem against selected pathogens, including some, Nevertheless, exaggerated consumption of carbapenems in the future
but not all, strains of P. aeruginosa not susceptible to imipenem or will certainly also lead to the emergence of antibiotic resistance and
meropenem. Doripenem is also active against Gram-positive pathogens multiresistant pathogens.
except MRSA, E. faecium and VRE. Urinary excretion is 75% and it is of
potential interest for the treatment of complicated UTI.
A large, Future Strategies in the Treatment of
Bacterial Urinary Tract Infections
Bacteria exhibit an enormous repertoire of different resistance
Urinary tract infections account for mechanisms. Unspecific mechanisms such as reduced permeability
more than 100,000 hospital admissions
or efflux alter the tolerance to antibiotic substances less than
specific mechanisms such as inactivation of the antibiotic. However,
each year … and they also account for the antibiotic spectrum targeted is much more extensive. On the
at least 40% of all hospital-acquired
other hand, unspecific mechanisms can also be induced by
non-antibiotic substances such as salicylates. Thus, low-level resistance
infections, which in the majority of
can be conferred and give bacteria a selection advantage.
cases are catheter-associated.
counteract these factors, anti-infective substances are continuously
evaluated and investigated.
multinational phase III study evaluated the efficacy and safety of The current research goals in medicinal chemistry include several
doripenem for the treatment of complicated lower UTIs and targets. Known substances should be improved in terms of higher
pyelonephritis (complicated and uncomplicated) and compared it with bioavailability, longer half-life and better pharmacodynamic
A total of 753 patients were randomised. The and pharmacokinetic performance. New derivatives of known
EUROPEAN GENITO-URINARY DISEASE 2007 49
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