Fluoroquinolone Enhances the Mutation Frequency for Meropenem-Selected Carbapenem Resistance in
            <i>Pseudomonas aeruginosa</i>
            , but Use of the High-Potency Drug Doripenem Inhibits Mutant Formation

Tanimoto, Koichi; Tomita, Haruyoshi; Fujimoto, Shuhei; Okuzumi, Katsuko; Ike, Yasuyoshi

doi:10.1128/aac.00464-08

Cited by 69 publications

(54 citation statements)

References 29 publications

(36 reference statements)

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“…everal bactericidal antibiotics have been reported to have low to moderate mutagenic activity when used at subinhibitory or sublethal concentrations (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), usually ranging from 3-to 8-fold over background levels of spontaneous mutations (with one exception [7]). In particular, ciprofloxacin (CPR) and its close derivative norfloxacin (NOR) display mutagenic activity in different detector systems (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14).…”

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confidence: 99%

Mutational Consequences of Ciprofloxacin in Escherichia coli

Song

Goff

Davidian

et al. 2016

Antimicrob Agents Chemother

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We examined the mutagenic specificity of the widely used antibiotic ciprofloxacin (CPR), which displays weak to moderate mutagenic activity in several bacteria and generates short in-frame deletions in rpoB in Staphylococcus aureus. To determine the spectrum of mutations in a system where any gene knockout would result in a recovered mutant, including frameshifts and both short and long deletions, we examined CPR-induced mutations in the thymidylate synthase-encoding thyA gene. Here, any mutation resulting in loss of thymidylate synthase activity generates trimethoprim (Trm) resistance. We found that deletions and insertions in all three reading frames predominated in the spectrum. They tend to be short deletions and cluster in two regions, one being a GC-rich region with potential extensive secondary structures. We also exploited the well-characterized rpoB-Rif r system in Escherichia coli to determine that cells grown in the presence of sublethal doses of CPR not only induced short inframe deletions in rpoB, but also generated base substitution mutations resulting from induction of the SOS system. Some of the specific point mutations prominent in the spectrum of a strain that overproduces the dinB-encoded Pol IV were also present after growth in CPR. However, these mutations disappeared in CPR-treated dinB mutants, whereas the deletions remained. Moreover, CPR-induced deletions also occurred in a strain lacking all three SOS-induced polymerases. We discuss the implications of these findings for the consequences of overuse of CPR and other antibiotics. Several bactericidal antibiotics have been reported to have low to moderate mutagenic activity when used at subinhibitory or sublethal concentrations (1-14), usually ranging from 3-to 8-fold over background levels of spontaneous mutations (with one exception [7]). In particular, ciprofloxacin (CPR) and its close derivative norfloxacin (NOR) display mutagenic activity in different detector systems (1-14). The mutagenic properties can result in an increase in the appearance of resistant mutants (1, 2, 4, 5). A previous study of CPR-induced mutations in the rpoB gene of Staphylococcus aureus detected short in-frame deletions (5). However, the rpoB system cannot detect out-of-frame deletions or insertions or in-frame deletions or insertions of more than 21 bp, since the integrity of the RNA polymerase must remain intact. Here, we have undertaken a study of the types of mutations resulting from treatment with CPR in Escherichia coli using the thyATrm r system, which detects trimethoprim (Trm)-resistant mutants that result from any mutations inactivating the thyA gene (15), including large or small deletions or additions, both in frame and out of frame. We also used the E. coli rpoB-Rif r system, which monitors mutations leading to rifampin (Rif) resistance (16-23), since the system is so extensively characterized that the spectra of different mutagenic pathways leave telltale fingerprints. This allows us to separate effects of CPR itself from those emanating from the ...

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confidence: 99%

Mutational Consequences of Ciprofloxacin in Escherichia coli

Song

Goff

Davidian

et al. 2016

Antimicrob Agents Chemother

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“…In vivo, the proliferative inhibitory effect and maximal bactericidal action correlate with the time for which the drug concentration exceeds its minimum inhibitory concentration MIC ; T MIC . In the present study, we chose DRPM as the antibiotic to be evaluated for the following reasons : 1 DRPM is highly effective against aerobic Gram-negative and Gram-positive bacteria, as well as anaerobic bacteria, and it suppresses the growth of antimicrobial-resistant Pseudomonas aeruginosa ; 2 DRPM, MEPM, and IPM exhibit potent activity, with an MIC 90 of 4, 16, and 32 µg / ml, respectively, and DRPM is clinically effective against P. aeruginosa infection ; 3 DRPM does not show any cross-resistance with MEPM and IPM against P. aeruginosa ; 4 incompatibility between DRPM and protease inhibitors is low ; and 5 DRPM is a drug with little effect on the central nervous system [30][31][32][33][34][35][36] .…”

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confidence: 99%

Usefulness of Continuous Regional Arterial Infusion with Doripenem and Protease Inhibitors for Severe Acute Pancreatitis

Yamamiya

Kitamura

Ishii

et al. 2015

Showa Univ J Med Sci

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: Doripenem DRPM is a relatively new drug belonging to the carbapenem antibiotic group. We hypothesized that the pharmacological characteristics of DRPM could make it useful in the treatment of severe acute pancreatitis SAP . We investigated the usefulness of continuous regional arterial infusion CRAI with DRPM and protease inhibitors for SAP. Two hundred and forty-two patients with SAP were admitted to Showa University Hospital between November 2002 and June 2013. Of these, 53 patients were treated with CRAI with carbapenem antibiotics and nafamostat mesilate NM , a serine protease inhibitor, via the celiac and superior mesenteric arteries. Clinical outcomes were evaluated retrospectively in 34 patients treated with DRPM and 19 patients undergoing non-DRPM therapy meropenem n 11, imipenem n 6 ; biapenem n 2 . The median time to commencement of oral intake was significantly shorter in the DRPM than non-DRPM group 9 vs 14 hospital days, respectively ; P 0.01 . In addition, the rate of walled-off necrosis in the DRPM group tended to be lower than in the non-DRPM group 37.5 vs 64.7 , respectively, P 0.069 . The results of the present study suggest that CRAI with DRPM and NM for SAP could have equivalent therapeutic effects to CRAI with other carbapenem antibiotics and NM.

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“…50 Response to the effect of fluoroquinolones may differ. Tanimoto et al 54 showed that fluoroquinolones enhanced the carbapenem resistance mutation rate in P. aeruginosa and that the highest mutation isolation frequency occurred during selection with meropenem, whereas doripenem inhibited mutant growth. However, in spite of the differences, the presence of common mechanisms leading to carbapenem resistance to include the emergence of new mechanisms such as the blaKPC-containing Klebsiella pneumo niae (KPC-Kp) isolates confirms that vigilance in monitoring bacterial resistance is warranted.…”

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confidence: 99%

“…53 In strains of P. aeruginosa passaged over the course of 7 days that had MICs near the expected break point for doripenem (#4 µg/mL), gentamicin maintained or prolonged doripenem potency. 53 Tanimoto et al 54 showed that fluoroquinolones enhance the carbapenem resistance mutation rate in P. aeruginosa and that the highest mutation isolation frequency occurred during selection with meropenem, whereas doripenem inhibited mutant growth.…”

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A Review of Doripenem for the Treatment of Serious Bacterial Infections

Redman

Flamm²,

Cirillo³

2010

Clinical Medicine Reviews in Therapeutics

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Doripenem is a carbapenem bactericidal agent that demonstrates in vitro activity against a wide variety of Gram-negative and Gram-positive pathogens. In vitro data show that doripenem combines the intrinsic activity of meropenem against Gram-negative pathogens with the intrinsic activity of imipenem against Gram-positive pathogens. The availability of doripenem is particularly welcome in the current setting of increased resistance among Gram-negative pathogens including Pseudomonas aeruginosa, Acinetobacter species, and extended-spectrum β-lactamase-producing Enterobacteriaceae. Characteristic of doripenem is its potent activity against P. aeruginosa with a minimum inhibitory concentration (MIC) necessary for the inhibition of 90% of all isolates (MIC 90 ) of 4 µg/mL, a value that is 2 to 4 times lower than the corresponding MIC 90 values of meropenem and imipenem. Doripenem was shown to be noninferior to other commonly used antibiotics in phase 3 clinical trials and is currently approved for the treatment of complicated intra-abdominal infection and complicated urinary tract infection, and in some countries for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia. Intravenous (IV) infusions of doripenem can be either 1 hour or for longer durations of 4 hours. Overall, IV doripenem is safe and well tolerated, with a limited propensity to induce seizures compared with other carbapenems. Doripenem may represent a valuable option when carbapenem therapy is warranted for the treatment of serious infection, particularly in cases in which the etiology is a drug-resistant, Gram-negative pathogen.

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Fluoroquinolone Enhances the Mutation Frequency for Meropenem-Selected Carbapenem Resistance in Pseudomonas aeruginosa , but Use of the High-Potency Drug Doripenem Inhibits Mutant Formation

Cited by 69 publications

References 29 publications

Mutational Consequences of Ciprofloxacin in Escherichia coli

Mutational Consequences of Ciprofloxacin in Escherichia coli

Usefulness of Continuous Regional Arterial Infusion with Doripenem and Protease Inhibitors for Severe Acute Pancreatitis

A Review of Doripenem for the Treatment of Serious Bacterial Infections

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