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Objectives: Combination therapy can be a strategy to ensure effective bacterial killing when treating Pseudomonas aeruginosa, a Gram-negative bacterium with high potential for developing resistance. The aim of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model that describes the in vitro bacterial time-kill curves of colistin and meropenem alone and in combination for one WT and one meropenem-resistant strain of P. aeruginosa.Methods: In vitro time-kill curve experiments were conducted with a P. aeruginosa WT (ATCC 27853) (MICs: meropenem 1 mg/L; colistin 1 mg/L) and a meropenem-resistant type (ARU552) (MICs: meropenem 16 mg/L; colistin 1.5 mg/L). PK/PD models characterizing resistance were fitted to the observed bacterial counts in NONMEM. The final model was applied to predict the bacterial killing of ARU552 for different combination dosages of colistin and meropenem.Results: A model with compartments for growing and resting bacteria, where the bacterial killing by colistin reduced with continued exposure and a small fraction (0.15%) of the start inoculum was resistant to meropenem, characterized the bactericidal effect and resistance development of the two antibiotics. For a typical patient, a loading dose of colistin combined with a high dose of meropenem (2000 mg q8h) was predicted to result in a pronounced kill of the meropenem-resistant strain over 24 h.Conclusions: The developed PK/PD model successfully described the time course of bacterial counts following exposures to colistin and meropenem, alone and in combination, for both strains, and identified a dynamic drug interaction. The study illustrates the application of a PK/PD model and supports high-dose combination therapy of colistin and meropenem to overcome meropenem resistance. [ABSTRACT FROM AUTHOR]

Objectives: The objectives of this study were to study the presence of mutators in a set of Acinetobacter baumannii isolates and to explore whether there is a correlation between mutation rates and antibiotic resistance.Methods: The variation in mutation rate was evaluated for 237 clinical A. baumannii isolates by determining the frequency of their mutation to rifampicin resistance. For each isolate, the antibiotic resistance profile was determined by disc diffusion and/or Etest. Isolates were divided into susceptible, resistant and MDR groups according to their resistance to five groups of different antibiotics. A comparison between differences in mutation frequency (f) and strain-specific factors was performed.Results: Of the 237 isolates 32%, 18% and 50% were classified as susceptible, resistant and MDR, respectively. The f of rifampicin resistance varied between 2.2 × 10(-10) and 1.2 × 10(-6). Of the strains under investigation, 16% had an ≥2.5- to 166-fold higher f. The presence of mutators (definition ≥2.5-fold increase in f compared with ATCC 19606) in the MDR group (22%) was significantly higher (P < 0.05) than that in the susceptible and resistant groups (11% and 7%, respectively). Furthermore, f was significantly higher in the MDR group compared with that in the susceptible and resistant groups.Conclusions: The facts that 26 of 37 mutator isolates (70%) in the population were MDR and that there was a significantly higher general f in isolates exhibiting an MDR profile suggest that hypermutability can be of advantage for the organism in a selective environment with extensive exposure to antimicrobials. [ABSTRACT FROM AUTHOR]

Objectives: In silico pharmacokinetic/pharmacodynamic (PK/PD) models can be developed based on data from in vitro time-kill experiments and can provide valuable information to guide dosing of antibiotics. The aim was to develop a mechanism-based in silico model that can describe in vitro time-kill experiments of Escherichia coli MG1655 WT and six isogenic mutants exposed to ciprofloxacin and to identify relationships that may be used to simplify future characterizations in a similar setting.Methods: In this study, we developed a mechanism-based PK/PD model describing killing kinetics for E. coli following exposure to ciprofloxacin. WT and six well-characterized mutants, with one to four clinically relevant resistance mutations each, were exposed to a wide range of static ciprofloxacin concentrations.Results: The developed model includes susceptible growing bacteria, less susceptible (pre-existing resistant) growing bacteria, non-susceptible non-growing bacteria and non-colony-forming non-growing bacteria. The non-colony-forming state was likely due to formation of filaments and was needed to describe data close to the MIC. A common model structure with different potency for bacterial killing (EC50) for each strain successfully characterized the time-kill curves for both WT and the six E. coli mutants.Conclusions: The model-derived mutant-specific EC50 estimates were highly correlated (r(2) = 0.99) with the experimentally determined MICs, implying that the in vitro time-kill profile of a mutant strain is reasonably well predictable by the MIC alone based on the model. [ABSTRACT FROM AUTHOR]

Objectives Ertapenem resistance is increasing in Enterobacteriaceae. The production of extended-spectrum β-lactamases (ESBLs) and reduced expression of outer membrane porins are major mechanisms of resistance in ertapenem-resistant Klebsiella pneumoniae. Less is known of ertapenem resistance in Escherichia coli. The aim of this study was to explore the impact of ESBL production in E. coli on the antibacterial activity of ertapenem. Methods Two E. coli strains, with and without ESBL production, were exposed to ertapenem in vitro for 48 h at concentrations simulating human pharmacokinetics with conventional and higher dosages. Results Isolates with non-susceptibility to ertapenem (MICs 0.75–1.5 mg/L) were detected after five of nine time–kill experiments with the ESBL-producing strain. All of these isolates had ompR mutations, which reduce the expression of outer membrane porins OmpF and OmpC. Higher dosage did not prevent selection of porin-deficient subpopulations. No mutants were detected after experiments with the non-ESBL-producing strain. Compared with other experiments, experiments with ompR mutants detected in endpoint samples showed significantly less bacterial killing after the second dose of ertapenem. Impaired antibacterial activity against E. coli with ESBL production and ompR mutation was also demonstrated in time–kill experiments with static antibiotic concentrations. Conclusions The combination of ESBL production and porin loss in E. coli can result in reduced susceptibility to ertapenem. Porin-deficient subpopulations frequently emerged in ESBL-producing E. coli during exposure to ertapenem at concentrations simulating human pharmacokinetics. Inappropriate use of ertapenem should be avoided to minimize the risk of selection of ESBL-producing bacteria with reduced susceptibility to carbapenems. [ABSTRACT FROM PUBLISHER]

Objectives During an outbreak of extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae at our hospital, we performed an educational antibiotic intervention aimed at reducing prescriptions of second- and third-generation cephalosporins and preventing increased use of fluoroquinolones and carbapenems. In this report, we describe the implementation strategy used and evaluate the intervention effect according to Cochrane recommendations. Methods New recommendations for empirical intravenous antibiotic treatment were communicated to prescribers throughout the hospital by infectious diseases physicians working with Strama (the Swedish strategic programme against antibiotic resistance). No restrictive measures were used. The intervention effect was analysed with interrupted time series (ITS) regression analysis of local and national monthly antibiotic sales data. Results A radical immediate and sustained reduction was demonstrated for the cephalosporins targeted in the intervention, whereas consumption of piperacillin/tazobactam and penicillin G increased substantially. Fluoroquinolone and carbapenem use was essentially unchanged. The ESBL outbreak subsided and no increased resistance to piperacillin/tazobactam was detected in K. pneumoniae, Escherichia coli or Pseudomonas aeruginosa blood isolates during the 2.5 year follow-up. Conclusions Our study clearly demonstrates that an educational intervention can have an immediate and profound effect on antibiotic prescription patterns at a large tertiary hospital. ITS regression analysis of local and national antibiotic sales data was valuable to readily assess the immediate and sustained effects of the intervention. [ABSTRACT FROM PUBLISHER]

The worldwide increase in antibiotic resistance is a concern for public health. The fact that the choice of dose and treatment duration can affect the selection of antibiotic-resistant mutants is becoming more evident, and an increased number of studies have used pharmacodynamic models to describe the drug exposure and pharmacodynamic breakpoints needed to minimize and predict the development of resistance. However, there remains a lack of sufficient data, and future work is needed to fully characterize these target drug concentrations. More knowledge is also needed of drug pharmacodynamics versus bacteria with different resistance mutations and susceptibility levels. The dosing regimens should exhibit high efficacy not only against susceptible wild-type bacteria but, preferably, also against mutated bacteria that may exist in low numbers in ‘susceptible’ populations. Thus, to prolong the life span of existing and new antibiotics, it is important that dosing regimens be carefully selected on the basis of pharmacokinetic and pharmacodynamic properties that prevent emergence of preexisting and newly formed mutants. [ABSTRACT FROM AUTHOR]

Objectives: To compare in an in vitro kinetic model the pharmacodynamics of moxifloxacin and levofloxacin with a concentration–time profile simulating the human free non-protein bound concentrations of 400 mg moxifloxacin intravenous (iv) once daily, 500 mg levofloxacin iv once daily and 750 mg levofloxacin iv once daily against strains of Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae and Escherichia coli with variable susceptibility to fluoroquinolones.Methods: The strains used in the study included S. pneumoniae ATCC 6306 (native strain), S. pneumoniae 19397 (double mutation; gyrA and parC), S. pneumoniae 4241 (single mutation; parC), S. aureus ATCC 13709 (native strain), S. aureus MB5 (single mutation; gyrA), E. coli M12 (single mutation; gyrA), E. coli ATCC 25922 (native strain) and K. pneumoniae ATCC 29655 (native strain). The strains were exposed to moxifloxacin and levofloxacin in an in vitro kinetic model simulating the free human serum concentration–time profile of moxifloxacin 400 mg once daily, levofloxacin 500 mg once daily and 750 mg once daily. Repeated samples were taken regularly during 24 h and viable counts were carried out.Results and conclusions: A correlation was seen between both the area under the serum concentration curve and MIC (AUC/MIC) and the peak concentration/MIC (Cmax/MIC) versus area under the bactericidal killing curve (AUBKC) or Δlog0–24 cfu/mL. Compiling all data, an AUC/MIC of ∼100 and a Cmax/MIC of 10 gave a maximal bactericidal effect for both levofloxacin and moxifloxacin. In accordance with the results from others, our study indicated that a lower AUC/MIC was needed for S. pneumoniae in comparison with the Gram-negative bacteria studied. Moxifloxacin yielded higher AUC/MIC and Cmax/MIC against the investigated Gram-positive bacteria in comparison with levofloxacin 500 mg once daily and 750 mg once daily. [ABSTRACT FROM PUBLISHER]

A microtechnique was developed for assay of dicloxacillin in small pieces of rabbit muscle. Muscle concentrations could be measured in repeated samples from the same animal. The muscle specimens (10–20 mg) were placed directly into agar wells without previous homogenization. After incubation, round and distinct zones of inhibition were formed. Freeze-dried muscle pieces with added known amounts of dicloxacillin were used as standards. Dicloxacillin concentrations in serum and muscle were followed for 3 h after a single intravenous injection at three dose levels (10, 20 and 40 mg/kg). Dicloxacillin was found to be rapidly distributed into muscle tissue. The highest muscle concentrations were usually found at the initial observation time of 15 mm and then declined. The elimination half-life in muscle was similar to that of serum. No dose-dependent pharmacokinetics was found. [ABSTRACT FROM PUBLISHER]

A microtechnique, requiring very small amounts of tissue material was developed for antibiotic assays in rabbit muscle. Without previous homogenization, small muscle pieces (10–20 mg) were placed into wells in agar plates, pre-inoculated with the test strain. Round and distinct zones of inhibition formed around the pieces. Standards for assay of ampicillin were prepared from freeze-dried muscle pieces with added known amount of the antibiotic. It was found that these standards could be substituted for by standards in 50% rabbit serum. Reproducibility was in the same range as that of a conventional homogenizing technique and results of ampicillin assays with both methods were comparable. The technique could be useful for pharmacokinetic studies of antibiotics in tissues. [ABSTRACT FROM PUBLISHER]

We studied the effect in vitro of azithromycin on the clinical strain Helicobacter pylori H:72 growing intracellularly in monolayers of HEp-2 epithelial cells. After using gentamicin to eradicate extracellular bacteria, different concentrations of azithromycin were added to the infected cells and samples were taken after 0, 4, 8 and 24 h. Infected cells not exposed to antibiotic were included as controls. The MIC of azithromycin to the H. pylori was 0.25 mg/L and the MBC 0.5 mg/L in a broth dilution plate count method. A bactericidal effect was observed on intracellular H. pylori, with inhibition increasing with increasing azithromycin concentrations. However, extracellular concentrations of 200 × MBC were necessary to achieve intracellular killing . Our results show that azithromycin is active against intracellular H. pylori suggesting that it might be possible to exploit this activity when treating infections due to the organism. [ABSTRACT FROM PUBLISHER]

The post-antibiotic effect (PAE) has been recognized as a pharmacodynamic parameter which may influence optimal dosage intervals. During the post-antibiotic phase, various bacteria have been shown to be very sensitive to a repeated exposure to the same antibiotic. A long period of growth suppression may be obtained when a low concentration (≤ 0.3 × MIC) is added to bacteria previously exposed to a supra-inhibitory concentration. This phenomenon has been named the post-antibiotic sub-MIC effect (PA SME). Since a period with sub-inhibitory concentrations will often exist between the doses when intermittent dosing of antibiotics is used, the PA SME probably reflects the in-vivo situation more closely than the PAE. The published literature on the PA SME is reviewed and its possible role in antibiotic dosing discussed. [ABSTRACT FROM PUBLISHER]

Neurotoxic reactions caused by -lactam antibiotics occur frequently following direct application of antibiotic to the brain surface or into the cerebral cisterns. Epileptogenic reactions have also been observed after administration of very high systemic doses. There seem to be considerable differences in the neurotoxic potential of the various -lactams; benzylpenicillin, cefazolin and, lately, imipenem/cilastatin appear to be drugs with higher neurotoxic potential than other compounds. There is now strong evidence that the concentration of /Mactam in the brain, and not that in the cerebrospinal fluid, is the decisive factor for the risk of neurotoxic reactions. Factors known to increase the risk of neurotoxicity are excessive doses, decreased renal function, damage to the blood-brain barrier, preexisting diseases of the central nervous system, old age and concurrent use of drugs that are nephrotoxic or that may lower the seizure threshold. Another factor that may be of importance is blockage of the transport system that is responsible for transport of /Mactams out of the central nervous system. [ABSTRACT FROM PUBLISHER]

A postantibiotic effect (PAE) was induced in group A streptococci established in a tissue cage model in rabbits. The bacteria were exposed to 10 × MIC of benzylpenicillin in tissue cage fluid (TCF) for 2 h. TCF was then aspirated, penicillin was eliminated by washing and the bacteria were transferred to tissue cages in other rabbits in order to study the in-vivo killing kinetics of streptococci in the postantibiotic phase. In these latter rabbits the concentration of benzylpenicillin in TCF corresponded to 10 or 0.3 × MIC. Bacteria not previously exposed to penicillin were used as controls. Streptococci in postantibiotic phase were killed as effectively after re-exposure to 10 × MIC as the growing controls. Although the concentration of penicillin fell below the MIC after 12 h, no regrowth was seen during the following 12 h in either culture. When only subinhibitory concentrations in TCF were used in the second phase, a killing of approximately 1 log cfu/ml was noted both in the previously exposed cultures and in controls. Both cultures started to multiply first after 6–7 h. [ABSTRACT FROM PUBLISHER]

A postantibiotic effect (PAE) for Ml2, PI800 was induced by 10 × MIC of benzylpenicillin for 2 h . The PAE was found to be 2·4 h (range 1·75–3.0 h). No incorporation of H-thymidine by the streptococci occurred during the first hours of the postantibiotic phase (PA-phase), indicating that bacterial cell division was inhibited during this period. However, these bacteria showed the same killing rate as previously unexposed control cultures when 10 × MIC of benzylpenicillin was added during the PA-phase. When bacteria in PA-phase were re-exposed to penicillin at a concentration of 0·2 × MIC multiplication of the bacteria was inhibited for 6–7 h, while at a concentration of 0·3 × MIC slow killing was induced. In contrast, previously untreated controls exposed to 0·2 × MIC and 0·3 × MIC showed a growth rate corresponding to that of bacteria grown in the absence of penicillin. The effects of subinhibitory concentrations on streptococci previously exposed to penicillin may therefore be a more important factor in determining dosage intervals than the PAE. [ABSTRACT FROM PUBLISHER]

The aim of the present investigation was to prospectively study the clinical and bacteriologic outcome of 15 consecutive patients with brain abscesses who were treated with surgical excision and cefotaxime (3 g every 8 hours) plus metronidazole (0.5 g every 8 hours) for at least 3 weeks. The patients were followed clinically and with computed tomographic (CT) examinations. All patients survived, and there were no recurrences within 1 year. CT scans showed an exponential decrease in the size of enhancement. Cultures of all six specimens obtained after <24 hours of treatment with cefotaxime and metronidazole were positive compared with cultures of three of nine specimens obtained later (P = .017). Anaerobic bacteria were isolated from 2 of 3 patients given two doses of metronidazole or less compared with none of 12 given three doses or more (P = .029). Reversible side effects occurred in nine patients. It is concluded that cefotaxime plus metronidazole is an alternative treatment for brain abscess in addition to surgical excision because of their good abscess penetration, their ability to eradicate bacteria, and a good clinical outcome. [ABSTRACT FROM PUBLISHER]

A letter to the editor is presented in response to the article which discusses the use of polymyxin antibiotic Colistin as the last line therapy against infections caused by the gram negative bacteria.

Doxycycline concentration in rabbit serum and muscle fluid were studied following a single iv infusion of 10 mg/kg. Maximal levels of doxycycline in muscle tissue fluid were found within 20 min after the end of infusion. Thereafter muscle fluid levels of doxycycline were similar to concurrent serum levels and were eliminated at a similar rate. [ABSTRACT FROM AUTHOR]