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Study objective: Comparison of efficacy and safety of sparfloxacin (Spfx) vs roxithromycin (ROXI) for treatment of community-acquired pneumonia (CAP). Design: Multicenter, double-blind, randomized study. Setting: Twenty-three university and community hospitals [...]

The essentials of control are already well known Until recently the medical community world wide has seemed incapable of reacting to the imminent crisis of antibiotic resistance. Several explanations exist [...]

There is an incoming tide of concern about the problems of antimicrobial resistance. For several years alarm has been expressed in the United States,[1] and the past 12 months have [...]

•We analysed patterns of antibiotic use in Chinese and Swedish public hospitals.•An interrupted time series design with segmented regression analysis was used.•Antibiotics were less frequently prescribed in Chinese public hospitals.•Huge gaps still exist between China and Sweden.•Policies are needed to guide quality use rather than simple restrictions in China.

Polymyxins (polymyxin B and colistin) are older bactericidal antibiotics that are increasingly used to treat infections caused by multidrug-resistant (MDR) Gram-negative bacteria. However, dosing and clinical use of these drugs vary widely. This survey was undertaken to reveal how polymyxins are used worldwide. Data were collected through a structured online questionnaire consisting of 24 questions regarding colistin usage patterns and indications as well as colistin dosage for adult patients. The questionnaire was disseminated in 2011 to relevant experts worldwide and was completed by 284 respondents from 56 different countries. Respondents from 11/56 countries (20%) had no access to colistin; 58/284 respondents (20.4%) reported that in 2010 they experienced that colistin was not available when needed. Formulations of polymyxins used were reported as: colistimethate sodium (48.6%); colistin sulfate (14.1%); both (1.4%); polymyxin B (1.4%); and unknown. Intravenous formulations were used by 84.2%, aerosolised or nebulised colistin by 44.4% and oral colistin for selective gut decontamination by 12.7%. Common indications for intravenous colistin were ventilator-associated pneumonia, sepsis and catheter-related infections with MDR Gram-negative bacteria. Only 21.2% of respondents used a colistin-loading dose, mainly in Europe and North America. This survey reveals that the majority of respondents use colistin and a few use polymyxin B. The survey results show that colistin is commonly underdosed. Clear guidance is needed on indications, dosing and antibiotic combinations to improve clinical outcomes and delay the emergence of resistance. Colistin should be considered a last-resort drug and its use should be controlled. International guidelines are urgently needed.

ABSTRACTThis report describes the pharmacokinetics of colistin methanesulfonate (CMS) and colistin in five intensive care unit patients receiving continuous venovenous hemodiafiltration. For CMS, the mean maximum concentration of drug in plasma (Cmax) after the fourth dose was 6.92 mg/liter and total clearance (CL) 8.23 liters/h. For colistin, the mean concentration was 0.92 mg/liter and CL/metabolized fraction (fm) 18.91 liters/h. Colistin concentrations were below the current MIC breakpoints, and the area under the concentration-time curve for the free, unbound fraction of the drug over 24 h in the steady state divided by the MIC (fAUC/MIC) was lower than recommended, suggesting that a dosage regimen of 160 mg CMS every 8 h (q8h) is inadequate.

ABSTRACTA previous pharmacokinetic study on dosing of colistin methanesulfonate (CMS) at 240 mg (3 million units [MU]) every 8 h indicated that colistin has a long half-life, resulting in insufficient concentrations for the first 12 to 48 h after initiation of treatment. A loading dose would therefore be beneficial. The aim of this study was to evaluate CMS and colistin pharmacokinetics following a 480-mg (6-MU) loading dose in critically ill patients and to explore the bacterial kill following the use of different dosing regimens obtained by predictions from a pharmacokinetic-pharmacodynamic model developed from an in vitrostudy on Pseudomonas aeruginosa. The unbound fractions of colistin A and colistin B were determined using equilibrium dialysis and considered in the predictions. Ten critically ill patients (6 males; mean age, 54 years; mean creatinine clearance, 82 ml/min) with infections caused by multidrug-resistant Gram-negative bacteria were enrolled in the study. The pharmacokinetic data collected after the first and eighth doses were analyzed simultaneously with the data from the previous study (total, 28 patients) in the NONMEM program. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.026 and 2.2 h, respectively. For colistin, a one-compartment model was sufficient and the estimated half-life was 18.5 h. The unbound fractions of colistin in the patients were 26 to 41% at clinical concentrations. Colistin A, but not colistin B, had a concentration-dependent binding. The predictions suggested that the time to 3-log-unit bacterial kill for a 480-mg loading dose was reduced to half of that for the dose of 240 mg.

ABSTRACTGentamicin is commonly used in the management of neonatal infections. Development of adaptive resistance is typical for aminoglycosides and reduces the antibacterial effect. There is, however, a lack of understanding of how this phenomenon influences the effect of different dosing schedules. The aim was to develop a pharmacokinetic-pharmacodynamic (PKPD) model that describes the time course of the bactericidal activity of gentamicin and its adaptive resistance and to investigate different dosing schedules in preterm and term newborn infants based on the developed model. In vitrotime-kill curve experiments were conducted on a strain of Escherichia coli(MIC of 2 mg/liter). The gentamicin exposure was either constant (0.125 to 16 mg/liter) or dynamic (simulated concentration-time profiles in a kinetic system with peak concentrations of 2.0, 3.9, 7.8, and 16 mg/liter given as single doses or as repeated doses every 6, 12, or 24 h). Semimechanistic PKPD models were fitted to the bacterial counts in the NONMEM (nonlinear mixed effects modeling) program. A model with compartments for growing and resting bacteria, with a function allowing the maximal bacterial killing of gentamicin to reduce with exposure, characterized both the fast bactericidal effect and the adaptive resistance. Despite a lower peak concentration, preterm neonates were predicted to have a higher bacterial killing effect than term neonates for the same per-kg dose because of gentamicin's longer half-life. The model supported an extended dosing interval of gentamicin in preterm neonates, and for all neonates, dosing intervals of 36 to 48 h were as effective as a 24-h dosing interval for the same total dose.

ABSTRACTA pharmacokinetic-pharmacodynamic (PKPD) model that characterizes the full time course of in vitrotime-kill curve experiments of antibacterial drugs was here evaluated in its capacity to predict the previously determined PK/PD indices. Six drugs (benzylpenicillin, cefuroxime, erythromycin, gentamicin, moxifloxacin, and vancomycin), representing a broad selection of mechanisms of action and PK and PD characteristics, were investigated. For each drug, a dose fractionation study was simulated, using a wide range of total daily doses given as intermittent doses (dosing intervals of 4, 8, 12, or 24 h) or as a constant drug exposure. The time course of the drug concentration (PK model) as well as the bacterial response to drug exposure (in vitroPKPD model) was predicted. Nonlinear least-squares regression analyses determined the PK/PD index (the maximal unbound drug concentration [fCmax]/MIC, the area under the unbound drug concentration-time curve [fAUC]/MIC, or the percentage of a 24-h time period that the unbound drug concentration exceeds the MIC [fT>MIC]) that was most predictive of the effect. The in silicopredictions based on the in vitroPKPD model identified the previously determined PK/PD indices, with fT>MICbeing the best predictor of the effect for β-lactams and fAUC/MIC being the best predictor for the four remaining evaluated drugs. The selection and magnitude of the PK/PD index were, however, shown to be sensitive to differences in PK in subpopulations, uncertainty in MICs, and investigated dosing intervals. In comparison with the use of the PK/PD indices, a model-based approach, where the full time course of effect can be predicted, has a lower sensitivity to study design and allows for PK differences in subpopulations to be considered directly. This study supports the use of PKPD models built from in vitrotime-kill curves in the development of optimal dosing regimens for antibacterial drugs.

ABSTRACTIt is generally accepted that only the unbound fraction of a drug is pharmacologically active. Posaconazole is an antifungal agent with a protein binding of 98 to 99%. Taking into account the degree of protein binding, plasma levels in patients, and MIC levels of susceptible strains, it can be assumed that the free concentration of posaconazole sometimes will be too low to exert the expected antifungal effect. The aim was therefore to test the activity of posaconazole in serum in comparison with that of the calculated unbound concentrations in protein-free media. Significant differences (P< 0.05) from the serum control were found at serum concentrations of posaconazole of 1.0 and 0.10 mg/liter, with calculated free concentrations corresponding to 1× MIC and 0.1× MIC, respectively, against one Candida lusitaniaestrain selected for proof of principle. In RPMI 1640, the corresponding calculated unbound concentration of 0.015 mg/liter resulted in a significant effect, whereas that of 0.0015 mg/liter did not. Also, against seven additional Candidastrains tested, there was an effect of the low posaconazole concentration in serum, in contrast to the results in RPMI 1640. Fluconazole, a low-grade-protein-bound antifungal, was used for comparison at corresponding concentrations in serum and RPMI 1640. No effect was observed at the serum concentration, resulting in a calculated unbound concentration of 0.1× MIC. In summary, there was a substantially greater pharmacodynamic effect of posaconazole in human serum than could be predicted by the non-protein-bound serum concentration. A flux from serum protein-bound to fungal lanosterol 14α-demethylase-bound posaconazole is suggested.

ABSTRACTAlthough the influence of protein binding (PB) on antibacterial activity has been reported for many antibiotics and over many years, there is currently no standardization for pharmacodynamic models that account for the impact of protein binding of antimicrobial agents in vitro. This might explain the somewhat contradictory results obtained from different studies. Simple in vitromodels which compare the MIC obtained in protein-free standard medium versus a protein-rich medium are prone to methodological pitfalls and may lead to flawed conclusions. Within in vitrotest systems, a range of test conditions, including source of protein, concentration of the tested antibiotic, temperature, pH, electrolytes, and supplements may influence the impact of protein binding. As new antibiotics with a high degree of protein binding are in clinical development, attention and action directed toward the optimization and standardization of testing the impact of protein binding on the activity of antibiotics in vitrobecome even more urgent. In addition, the quantitative relationship between the effects of protein binding in vitroand in vivoneeds to be established, since the physiological conditions differ. General recommendations for testing the impact of protein binding in vitroare suggested.

ABSTRACTWe have previously described a general semimechanistic pharmacokinetic-pharmacodynamic (PKPD) model that successfully characterized the time course of antibacterial effects seen in bacterial cultures when exposed to static concentrations of five antibacterial agents of different classes. In this PKPD model, the total bacterial population was divided into two subpopulations, one growing drug-susceptible population and one resting drug-insensitive population. The drug effect was included as an increase in the killing rate of the drug-susceptible bacteria with a maximum-effect (Emax) model. The aim of the present study was to evaluate the ability of this PKPD model to describe and predict data from in vitroexperiments with dynamic concentration-time profiles. Dynamic time-kill curve experiments were performed by using an in vitrokinetic system, where cultures of Streptococcus pyogeneswere exposed to benzylpenicillin, cefuroxime, erythromycin, moxifloxacin, or vancomycin using different starting concentrations (2 and 16 times the MIC) and elimination conditions (human half-life, reduced half-life, and constant concentrations). The PKPD model was applied, and the observations for the static as well as dynamic experiments were compared to model predictions based on parameter estimation using (i) static data, (ii) dynamic data, and (iii) combined static and dynamic data. Differences in experimental settings between static and dynamic experiments did not affect the growth kinetics of the bacteria significantly. With parameter reestimation, the structure of our previously proposed PKPD model could well characterize the bacterial growth and killing kinetics when exposed to dynamic concentrations with different elimination rates of all five investigated antibiotics. Furthermore, the model with parameter estimates based on data from only the static time-kill curve experiments could predict the majority of the time-kill curves from the dynamic experiments reasonably well. Adding data from dynamic experiments in the estimation improved the model fit for cefuroxime and vancomycin, indicating some differences in sensitivity to experimental conditions among the antibiotics studied.

ABSTRACTAn antagonistic effect of voriconazole on the fungicidal activity of sequential doses of amphotericin B has previously been demonstrated in Candida albicansstrains susceptible to voriconazole. Because treatment failure and the need to switch to other antifungals are expected to occur more often in infections that are caused by resistant strains, it was of interest to study whether the antagonistic effect was still seen in Candidastrains with reduced susceptibility to voriconazole. With the hypothesis that antagonism will not occur in voriconazole-resistant strains, C. albicansstrains with characterized mechanisms of resistance against voriconazole, as well as Candida glabrataand Candida kruseistrains with differences in their degrees of susceptibility to voriconazole were exposed to voriconazole or amphotericin B alone, to both drugs simultaneously, or to voriconazole followed by amphotericin B in an in vitrokinetic model. Amphotericin B administered alone or simultaneously with voriconazole resulted in fungicidal activity. When amphotericin B was administered after voriconazole, its activity was reduced (median reduction, 61%; range, 9 to 94%). Levels of voriconazole-dependent inhibition of amphotericin B activity differed significantly among the strains but were not correlated with the MIC values (correlation coefficient, −0.19; P= 0.65). Inhibition was found in C. albicansstrains with increases in CDR1and CDR2expression but not in the strain with an increase in MDR1expression. In summary, decreased susceptibility to voriconazole does not abolish voriconazole-dependent inhibition of the fungicidal activity of amphotericin B in voriconazole-resistant Candidastrains. The degree of interaction could not be predicted by the MIC value alone.

We have previously described a general semimechanistic pharmacokinetic-pharmacodynamic (PKPD) model that successfully characterized the time course of antibacterial effects seen in bacterial cultures when exposed to static concentrations of five antibacterial agents of different classes. In this PKPD model, the total bacterial population was divided into two subpopulations, one growing drug-susceptible population and one resting drug-insensitive population. The drug effect was included as an increase in the killing rate of the drug-susceptible bacteria with a maximum-effect (Emax) model. The aim of the present study was to evaluate the ability of this PKPD model to describe and predict data from in vitro experiments with dynamic concentration-time profiles. Dynamic time-kill curve experiments were performed by using an in vitro kinetic system, where cultures of Streptococcus pyogenes were exposed to benzylpenicillin, cefuroxime, erythromycin, moxifloxacin, or vancomycin using different starting concentrations (2 and 16 times the MIC) and elimination conditions (human half-life, reduced half-life, and constant concentrations). The PKPD model was applied, and the observations for the static as well as dynamic experiments were compared to model predictions based on parameter estimation using (i) static data, (ii) dynamic data, and (iii) combined static and dynamic data. Differences in experimental settings between static and dynamic experiments did not affect the growth kinetics of the bacteria significantly. With parameter reestimation, the structure of our previously proposed PKPD model could well characterize the bacterial growth and killing kinetics when exposed to dynamic concentrations with different elimination rates of all five investigated antibiotics. Furthermore, the model with parameter estimates based on data from only the static time-kill curve experiments could predict the majority of the time-kill curves from the dynamic experiments reasonably well. Adding data from dynamic experiments in the estimation improved the model fit for cefuroxime and vancomycin, indicating some differences in sensitivity to experimental conditions among the antibiotics studied.

ABSTRACTForeign travel has been suggested to be a risk factor for the acquisition of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. To our knowledge, this has not previously been demonstrated in a prospective study. Healthy volunteers traveling outside Northern Europe were enrolled. Rectal swabs and data on potential travel-associated risk factors were collected before and after traveling. A total of 105 volunteers were enrolled. Four of them did not complete the study, and one participant carried ESBL-producing Escherichia colibefore travel. Twenty-four of 100 participants with negative pretravel samples were colonized with ESBL-producing Escherichia coliafter the trip. All strains produced CTX-M enzymes, mostly CTX-M-15, and some coproduced TEM or SHV enzymes. Coresistance to several antibiotic subclasses was common. Travel to India was associated with the highest risk for the acquisition of ESBLs (88%; n= 7). Gastroenteritis during the trip was an additional risk factor (P= 0.003). Five of 21 volunteers who completed the follow-up after 6 months had persistent colonization with ESBLs. This is the first prospective study demonstrating that international travel is a major risk factor for colonization with ESBL-producing Enterobacteriaceae. Considering the high acquisition rate of 24%, it is obvious that global efforts are needed to meet the emergence and spread of CTX-M enzymes and other antimicrobial resistances.

ABSTRACTTelavancin is a novel bactericidal lipoglycopeptide with multiple mechanisms of action against gram-positive pathogens. The aim of this study was to describe the dynamics of the antimicrobial effect of telavancin against two strains of Staphylococcus aureus(methicillin susceptible and methicillin resistant) in an in vitro kinetic model with simulated human pharmacokinetics. Also, static experiments were performed to determine the rate and extent of killing by telavancin in the presence and absence of human albumin and human serum. Experiments in broth and in nutrient-depleted medium were performed to study the rate and extent of killing by telavancin of bacteria in different growth phases. In the in vitro kinetic model regrowth was noted at 24 h for both strains when exposed to initial concentrations below 5 mg/liter. There was a >3-log10killing at all concentrations from 0.5× MIC and above at 24 h both in broth and in the presence of 40-g/liter human albumin. In contrast to the methicillin-susceptible strain, the methicillin-resistant strain in 40-g/liter human albumin showed a regrowth at concentrations of 0.5× MIC and 1× MIC at 24 h. At all the other concentrations >3-log10killing was seen at 24 h. Concordant results were seen in 50% human serum. At a target area under the curve/MIC ratio of 50 (corresponding to the human dose of 10 mg/kg of body weight, administered intravenously), >3-log10killing was observed at 6 to 8 h. Unlike most antibiotics, telavancin was able to kill both strains in a nongrowing phase.

ABSTRACTDosing of antibacterial agents is generally based on point estimates of the effect, even though bacteria exposed to antibiotics show complex kinetic behaviors. The use of the whole time course of the observed effects would be more advantageous. The aim of the present study was to develop a semimechanistic pharmacokinetic (PK)/pharmacodynamic (PD) model characterizing the events seen in a bacterial system when it is exposed to antibacterial agents with different mechanisms of action. Time-kill curve experiments were performed with a strain of Streptococcus pyogenesexposed to a wide range of concentrations of the following antibiotics: benzylpenicillin, cefuroxime, erythromycin, moxifloxacin, and vancomycin. Bacterial counts were monitored with frequent sampling during the experiment. A simultaneous fit of all data was accomplished. The degradation of the drugs was monitored and corrected for in the model, and a link model was used to account for an effect delay. In the final PK/PD model, the total bacterial population was divided into two subpopulations: one growing drug-susceptible population and one resting insusceptible population. The drug effect was included as an increase of the killing rate of bacteria in the susceptible state, according to a maximum-effect (Emax) model. An internal model validation showed that the model was robust and had good predictability. In conclusion, for all drugs, the final PK/PD model successfully described bacterial growth and killing kinetics when the bacteria were exposed to different antibiotic concentrations. The semimechanistic model that was developed might, after further refinement, serve as a tool for the development of optimal dosing strategies for antibacterial agents.

Objectives: To evaluate the mutant prevention concentrations (MPCs) of ciprofloxacin for two susceptible and one first-step gyrA resistant mutant Escherichia coli strains in an in vitro kinetic model and to identify the pharmacodynamic index that best predicts prevention of resistance emergence.Methods: An in vitro kinetic model was used to measure MPC with static antibiotic concentrations and to test different dosing profiles to study pharmacokinetics/pharmacodynamics indices important to prevent the growth of resistant mutants. In one set of kinetic experiments the starting concentration was equal to the MPC and the T > MPC was varied before antibiotic dilution was begun. In a second set of kinetic experiments Cmax was varied and dilution of the antibiotic was started at time zero.Results: From the static experiments we calculated MPC values of 0.128 mg/L for both the susceptible strains (16× MIC) and 0.188 mg/L (4× MIC) for the first-step resistant (gyrA) strain. The kinetic experiments showed that the T > MPC needed to prevent the growth of resistant bacteria was shorter with an increased Cmax. When resistance was selected, several subpopulations with different levels of susceptibility to ciprofloxacin emerged.Conclusions: Neither T > MPC nor Cmax proved to be single correlates for preventing resistance development. For the two investigated wild-type strains, an AUC/MPC ratio of ≥22 was the single pharmacodynamic index that predicted prevention of resistant mutant development.

ABSTRACTAntibiotic dosing regimens may vary in their capacity to select mutants. Our hypothesis was that selection of a more resistant bacterial subpopulation would increase with the time within a selective window (SW), i.e., when drug concentrations fall between the MICs of two strains. An in vitro kinetic model was used to study the selection of two Escherichia colistrains with different susceptibilities to cefotaxime. The bacterial mixtures were exposed to cefotaxime for 24 h and SWs of 1, 2, 4, 8, and 12 h. A mathematical model was developed that described the selection of preexisting and newborn mutants and the post-MIC effect (PME) as functions of pharmacokinetic parameters. Our main conclusions were as follows: (i) the selection between preexisting mutants increased with the time within the SW; (ii) the emergence and selection of newborn mutants increased with the time within the SW (with a short time, only 4% of the preexisting mutants were replaced by newborn mutants, compared to the longest times, where 100% were replaced); and (iii) PME increased with the area under the concentration-time curve (AUC) and was slightly more pronounced with a long elimination half-life (T1/2) than with a short T1/2situation, when AUC is fixed. We showed that, in a dynamic competition between strains with different levels of resistance, the appearance of newborn high-level resistant mutants from the parental strains and the PME can strongly affect the outcome of the selection and that pharmacodynamic models can be used to predict the outcome of resistance development.

The aim of this study was to use detailed weekly data on outpatient antibiotic sales for pre-school children in Sweden to test for the significance of trends during 1992-2002. We also report on the special features found in weekly antibiotic data, and how the interrupted time series (ITS) design can adjust for this.

ABSTRACTPostantibiotic effects (PAEs), postantibiotic sub-MIC effects, and sub-MIC effects of the new nonfluoroquinolone PGE-9509924, ciprofloxacin, and levofloxacin against gram-positive and gram-negative strains were investigated. In comparison to ciprofloxacin and levofloxacin, PGE-9509924 exerted very similar PAEs against all strains except for both strains of Streptococcus pneumoniae, where longer PAEs were found for PGE-9509924. All three investigated quinolones showed no minimal PAEs against Pseudomonas aeruginosa.

ABSTRACTPharmacokinetic (PK) and pharmacodynamic (PD) properties for the selection of resistant pneumococci were studied by using three strains of the same serotype (6B) for mixed-culture infection in time-kill experiments in vitro and in three different animal models, the mouse peritonitis, the mouse thigh, and the rabbit tissue cage models. Treatment regimens with penicillin were designed to give a wide range of T>MICs, the amounts of time for which the drug concentrations in serum were above the MIC. The mixed culture of the three pneumococcal strains, 107CFU of strain A (MIC of penicillin, 0.016 μg/ml; erythromycin resistant)/ml, 106CFU of strain B (MIC of penicillin, 0.25 μg/ml)/ml, and 105CFU of strain C (MIC of penicillin, 4 μg/ml)/ml, was used in the two mouse models, and a mixture of 105CFU of strain A/ml, 104CFU of strain B/ml, and 103CFU of strain C/ml was used in the rabbit tissue cage model. During the different treatment regimens, the differences in numbers of CFU between treated and control animals were calculated to measure the efficacies of the regimens. Selective media with erythromycin or different penicillin concentrations were used to quantify the strains separately. The efficacies of penicillin in vitro were similar when individual strains or mixed cultures were studied. The eradication of the bacteria, independent of the susceptibility of the strain or strains or the presence of the strains in a mixture or on their own, followed the well-known PK and PD rules for treatment with β-lactams: a maximum efficacy was seen when the T>MICwas >40 to 50% of the observation time and the ratio of the maximum concentration of the drug in serum to the MIC was >10. It was possible in all three models to select for the less-susceptible strains by using insufficient treatments. In the rabbit tissue cage model, a regrowth of pneumococci was observed; in the mouse thigh model, the ratio between the different strains changed in favor of the less-susceptible strains; and in the mouse peritonitis model, the susceptible strain disappeared and was overgrown by the less-susceptible strains. These findings with the experimental infection models confirm the importance of eradicating all the bacteria taking part in the infectious process in order to avoid selection of resistant clones.

ABSTRACTOptimizing pharmacokinetic/pharmacodynamic indices of antibiotics to obtain clinical and microbiological efficacy is essential, but dosing regimens must also be tailored to minimize the risk for emergence of resistance. The aim of the present study was to investigate whether certain concentrations of benzylpenicillin are critical for the selection of resistant subpopulations. A mixed culture of Streptococcus pneumoniaecontaining ca. 90% susceptible (MIC = 0.031 mg/liter), 9% intermediate (MIC = 0.25 mg/liter), and 1% resistant (MIC = 8 mg/liter) was studied in an in vitro kinetic model. The time that concentrations exceeded the MIC (T>MIC) for the three strains in the culture was varied by different initial concentrations of benzylpenicillin. Samples for viable counts were withdrawn at different times during 24 h and seeded on blood agar plates and on selective antibiotic-containing plates. The T>MIC varied from 46 to 100% for the susceptible strain, from 6 to 100% for the intermediate strain, and from 0 to 48% for the resistant strain. Our study, which may mimic the clinical situation with carriage of a mixed population of S. pneumoniaewith different antibiotic susceptibilities, has shown that selection of resistant bacteria may easily occur if dosing regimens are only targeted toward fully susceptible strains.

ABSTRACTClinical and animal studies indicate that with optimal dosing, penicillin may still be effective against penicillin-nonsusceptible pneumococci (PNSP). The present study examined whether the same strains of penicillin-susceptible pneumococci (PSP) and PNSP differed in their pharmacodynamic responses to penicillin by using comparable penicillin dosing regimens in four animal models: peritonitis, pneumonia, and thigh infection in mice and tissue cage infection in rabbits. Two multidrug-resistant isolates ofStreptococcus pneumoniaetype 6B were used, one for which the penicillin MIC was 0.016 μg/ml and the other for which the penicillin MIC was 1.0 μg/ml. Two additional strains of PNSP were studied in the rabbit. The animals were treated with five different penicillin regimens resulting in different maximum concentrations of drugs in serum (Cmaxs) and times that the concentrations were greater than the MIC (T>MICs). The endpoints were bacterial viability counts after 6 h of treatment in the mice and 24 h of treatment in the rabbits. Similar pharmacodynamic effects were observed in all models. In the mouse models bactericidal activity depended on the T>MICand to a lesser extent on the Cmax/MIC and the generation time but not on the area under the concentration-time curve (AUC)/MIC. Maximal bactericidal activities were similar for both PSP and PNSP, being the highest in the peritoneum and blood (∼6 log10CFU/ml), followed by the thigh (∼3 log10CFU/thigh), and being the lowest in the lung (∼1 log10CFU/lung). In the rabbit model the maximal effect was ∼6 log10CFU/ml after 24 h. In the mouse models bactericidal activity became marked whenT>MICwas ≥65% of the experimental time andCmaxwas ≥15 times the MIC, and in the rabbit model bactericidal activity became marked whenT>MICwas ≥35%, Cmaxwas ≥5 times the MIC, and the AUC at 24 h/MIC exceeded 25. By optimization of the Cmax/MIC ratio andT>MIC, the MIC of penicillin for pneumococci can be used to guide therapy and maximize therapeutic efficacy in nonmeningeal infections caused by PNSP.

ABSTRACTTelithromycin (HMR 3647) is a new ketolide that belongs to a new class of semisynthetic 14-membered-ring macrolides which have expanded activity against multidrug-resistant gram-positive bacteria. The aim of the present study was to investigate different basic pharmacodynamic properties of this new compound. The following studies of telithromycin were performed: (i) studies of the rate and extent of killing of respiratory tract pathogens with different susceptibilities to erythromycin and penicillin exposed to a fixed concentration that corresponds to a dose of 800 mg in humans, (ii) studies of the rate and extent of killing of telithromycin at five different concentrations, (iii) studies of the rate and extent of killing of the same pathogens at three different inocula, (iv) studies of the postantibiotic effect and the postantibiotic sub-MIC effect of telithromycin, and (v) determination of the rate and extent of killing of telithromycin in an in vitro kinetic model. In conclusion, telithromycin exerted an extremely fast killing of all strains of Streptococcus pneumoniaeboth with static concentrations and in the in vitro kinetic model. A slower killing of the strains of Streptococcus pyogeneswas noted, with regrowth in the kinetic model of a macrolide-lincosamide-streptogramin B-inducible strain. The strains ofHaemophilus influenzaewere not killed at all at a concentration of 0.6 mg/liter due to high MICs. A time-dependent killing was seen for all strains. No inoculum effect was seen for the strains of S. pneumoniae, with a 99.9% reduction in the numbers of CFU for all inocula at both 8 h and 24 h. The killing of the strains of S. pyogeneswas reduced by 1 log10CFU at 8 h and 2 to 3 log10CFU at 24 h when the two lower inocula were used but not at all at 8 and 24 h when the highest inoculum was used. For both of the H. influenzaestrains there was an inoculum effect, with 1 to 2 log10CFU less killing for the inoculum of 108CFU/ml in comparison to that for the inoculum of 106CFU/ml. Overall, telithromycin exhibited long postantibiotic effects and postantibiotic sub-MIC effects for all strains investigated.

ABSTRACTRates of colonization with enterococci with acquired resistance to vancomycin (vancomycin-resistant enterococci [VRE]) and ampicillin (ampicillin-resistant enterococci [ARE]) were determined by using fecal samples from 670 nonhospitalized individuals and 841 patients in 27 major hospitals. Of the hospitalized patients, 181 (21.5%) were carriers of ARE and 9 (1.1%) were carriers of VRE. In univariate analyses, length of hospital stay (odds ratio [OR], 4.6; 95% confidence interval [CI], 2.5 to 8.9) and antimicrobial therapy (OR, 4.7; 95% CI, 3.3 to 6.7) were associated with ARE colonization, as were prior treatment with penicillins (OR, 3.1; 95% CI, 1.8 to 5.5), cephalosporins (OR, 2.9; 95% CI, 1.7 to 5.0), or quinolones (OR, 2.7; 95% CI, 1.5 to 4.7). In logistic regression analysis, antimicrobial therapy for at least 5 days was independently associated with ARE carriage (adjusted OR, 3.8; 95% CI, 2.6 to 5.4). Over 90% of the ARE isolates were fluoroquinolone resistant, whereas 14% of the ampicillin-susceptible Enterococcus faeciumisolates were fluoroquinolone resistant. ARE carriage rates correlated with the use of fluoroquinolones (P= 0.04) but not with the use of ampicillin (P= 0.68) or cephalosporins (P= 0.40). All nine VRE isolates were E. faecium vanBand were found in one hospital. Seven of these isolates were related according to their types as determined by pulsed-field gel electrophoresis. Among the nonhospitalized individuals, the ARE carriage rate was lower (6%; P< 0.05), and only one person, who had recently returned from Africa, harbored VRE (E. faecium vanA). The absence of VRE colonization in nonhospitalized individuals reflects an epidemiological situation in Sweden radically different from that in countries in continental Europe where glycopeptides have been widely used for nonmedical purposes.

216 patients aged >7 years with febrile group A streptococcal pharyngotonsillitis were randomly assigned to 3 treatment groups receiving either phenoxymethylpenicillin for 5 days followed by placebo for 5 days, phenoxymethylpenicillin for 10 days, or cefadroxil for 10 days. 209 patients completed treatment, 70 subjects in each phenoxymethylpenicillin group and 69 in the cefadroxil group. Within 1 week after completion of the antibiotic treatment significantly more recurrences with the same T-type as the initial streptococcal strain occurred in the 5-day treatment group (27%) as compared with the two 10-day groups (6% and 3%, respectively). The cumulative rate of recurrences (irrespective of T-type) within 2 months from the start of therapy was 55% among patients treated with phenoxymethylpenicillin for 5 days, 24% among those treated for 10 days with this drug and 19% among patients receiving cefadroxil. Obviously, one important factor to avoid recurrence of group A streptococcal pharyngotonsillitis is the length of antibiotic treatment and, in our opinion, it is not advisable to change the current recommendation of 10 days treatment.

To investigate and compare the in vitro activity of levofloxacin with the activities of ciprofloxacin and sparfloxacin.

Objective:To investigate and compare the in vitro pharmacodynamics of three carbapenems: imipenem, meropenem and BO-2727.

AbstractTissue distribution of ampicillin following a single intravenous injection was studied in normal and functionally nephrectomized rabbits. Serum concentrations of ampicillin were compared with those obtained in subcutaneous tissue cage fluid, muscle (measured by a direct agar diffusion method) and muscle tissue fluid (obtained from implanted cotton threads). Considerable differences were found. Penetration of ampicillin into rabbit muscle was rapid and the elimination half-life was similar to that of serum. Concentrations in tissue cage fluid were low as compared with muscle tissue fluid levels, and penetration and elimination was slower. Results from experiments in functionally nephrectomized rabbits showed that a steady state between serum and muscle seemed to be attained after 15–30 min. These results were used to estimate the degree of protein binding of ampicillin in muscle tissue fluid.

A new experimental model to evaluate the postantibiotic effect (PAE) in vivo was developed using subcutaneously implanted tissue cages in rabbits with normal host defence mechanisms. The rabbits received benzylpenicillin i.v. in a dose giving a free penicillin concentration of 10 × MIC in the tissue cage fluid (TCF). A log-phase suspension of group A streptococci was injected into the tissue cages exposing them to penicillin in vivo. After 2 h bacterial samples were withdrawn, treated with penicillinase and transferred to 2 tissue cages in untreated rabbits. Simultaneously, unexposed streptococci were implanted in 2 other cages in the same animals. By repeated sampling of TCF, growth curves of the streptococci exposed to penicillin and the controls could be compared and a PAE of 1.6-2.4 h demonstrated. The PAE was of the same magnitude as that found in vitro. The model has several advantages for the demonstration of PAE in vivo: repeated samplings are easy to perform percutaneously, the effect of subinhibitory antibiotic concentrations are avoided, interindividual variations are eliminated since each animal is its own control, and the experiments can be performed in animals with undisturbed host defence mechanisms.

AbstractDuring the months October to December of the years 1971–1974 the incidence of beta-haemolytic streptococci of the Lancefield groups, A, B, C and G from patients in the County of Uppsala was studied. The proportion of culture positive patients increased during the period studied from 7.2 to 13.7. The increase was not only due to group A. In cultures from the respiratory tract the finding of group A streptococci increased from 4.1 to 10.7 and group C from 0.1 to 1.6 , while group B and G streptococci remained constant. In cultures from wound infections the percentage of patients culture positive for group A streptococci increased from 6.2 to 8.7 , group B from 0.8 to 1.9 , and group G from 0.5 to 0.9 , while group C remained constant. During the same months of the years 1972 to 1974 the frequency of sera with an antistreptolysin O titre of more than 1000 Uml increased from 0.6 to 2.3 in the same region. A clinical study of scarlet fever and pharyngotonsillitis at the Department of Infectious Diseases showed a similar trend concerning group A streptococcal infections. These results stress the great importance of group A beta-haemolytic streptococci in human infections and indicate that the recent interest in non-group A infections should be continued.

An in vitro assay for measuring and comparing the efficacy of different antimicrobial agents against Chlamydia pneumoniae was developed. Azithromycin, a representative of the new azalide group of antibiotics, and doxycycline were evaluated with respect to their antibacterial effect and capacity for intracellular killing under different experimental conditions. For both study drugs, the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values increased significantly with longer bacterial preincubation time. The effect of different exposure times of antibiotics on the bacteria was also studied.

In a study of methods for the evaluation of clearing of wound infection, local treatment with Debrisan® (10 wounds) or saline (11 wounds) was examined clinically and bacteriologically. No correlation was found between clinical course and numbers of bacteria found in wound biopsies or swabs. Biopsy results varied greatly between sites in the same wound. In wounds with established infection, biopsies or wet swabs yielded little more information than conventional dry swabs. Debrisan seemed to offer no advantage over saline as regards clearing of infection in this small patient group.

Only a few years after the introduction of penicillin, resistant staphylococci were isolated in hospitals. This situation has led to the development of semisyn-thetic penicillins. Today, multiresistant Gram-positive bacteria have become an increasing problem in both hospitals and the community, frequently leaving the glycopeptides as the only therapeutic option. Notable problem pathogens are methicillin-resistant Staphylococcus aureus, coagulase-negative staphylococci and glycopeptide-resistant enterococci in the nosocomial environment, and penicillin-resistant Streptococcuspneumoniaein the community. In the hospital setting, as well as in the community and in animal husbandry, crowding and poor hygiene can facilitate the spread of resistant bacteria selected by antibiotic usage. However, the precise epidemiology and frequency of each drug-resistant pathogen depends on geographical location, the patient group involved and previous antibiotic use. Active measures need to be taken to reduce the spread of these pathogens and thus preserve the efficacy of available antibiotics.

A case of a 70-year-old woman with a history of gastric ulcer and several pneumonias is presented. She was found to have pulmonary emphysema, severe alpha-1-antitrypsin (αAT) deficiency and raised serum mitochondrial antibodies. Surgical liver biopsy showed portal liver cirrhosis, PAS-positive, diastaseresistant globules in the hepatocytes and changes interpreted as florid duct lesion of primary biliary cirrhosis. A brother had severe α1AT deficiency. Two daughters had raised mitochondrial antibodies. One of the latter had a granulomatous hepatitis, a common finding in primary biliary cirrhosis. The association of α1AT deficiency and primary biliary cirrhosis does not seem to have been described previously

The effect of ceftazidime in surgery of renal stones associated with urinary tract infection was investigated and its pharmacokinetics in serum and renal tissue was compared in 14 patients (15 kidneys) operated on for renal calculi associated with multiple urinary tract infection. Two to four days preoperatively ureteric catheterization was performed to localize the level of the infection and 2 g of ceftazidime was given intravenously twice daily for 10 days. Renal biopsy, serum samples and in one patient renal lymphatic fluid were taken simultaneously for antibiotic assay. Urine cultures were performed at regular intervals pre- and postoperatively. Ten patients had bacterial growth in the stone-carrying renal pelvis. The same strain was found in the bladder as in the pelvis. Nine patients had sterile urine after 3–5 days of treatment. One patient with bilateral stones did not get sterile urine until after seven days of treatment. Bacterial growth was found in two out of six cultured stones obtained from patients with bacterial growth in the pelvis. The decreases in concentration of ceftazidime in serum and renal tissue seemed to be parallel. Slight reversible elevation of liver transaminases was noted in 5/14 patients. It is concluded that the concentration of ceftazidime in serum parallels that in renal tissue. Ceftazidime seems to be an effective prophylactic in renal stone surgery and the preoperative dose should be given close to the operation.

A 34-year-old splenectomized man presented with fever, myalgia and dysuria. His condition rapidly deteriorated, he became anuric and developed severe haemolytic anaemia, thrombocy-topenia and fibrinolysis. Peripheral blood smears revealed intra-erythrocytic parasites consistent with Babesia divergens in 40% of the erythrocytes. The diagnosis was confirmed by gerbil inoculation and by a significant rise in antibody titer. Blood exchange transfusion reduced the number of babesia infected erythrocytes to 1%. Parenteral therapy with a combination of quinine and clindamycin eradicated parasitaemia after 10 days of treatment and the patient rapidly improved. Renal failure necessitated haemodialysis for one month, whereafter the patient made a full recovery. Human babesiosis is a rare disease, but with a potential fatal outcome and should be considered as a diagnostic alternative in splenectomized and otherwise immunocompromised individuals with severe febrile illnesses

In order to investigate the carrier rate of beta-hemolytic streptococci throat cultures were obtained every third month from 382 asymptomatic adults and schoolchildren during a 2-year period, altogether 2226 samples. In addition, 300 asymptomatic 4-year-olds were sampled once. The carrier rate of beta-hemolytic streptococci was 19.4%; group A streptococci alone 5.0%. There was no season-dependent variation. In the 3 age groups the carrier rates of group A streptococci were 0.8%, 5.9%, and 11.3%, respectively, with the highest rate among the 4-year-olds. Some of the individuals that were sampled repeatedly seemed to be pharyngeal carriers of group A streptococci, while others never became carriers. Group A streptococci were found significantly more often among 4-year-olds not attending day-care centres compared to those attending such institutions. For group C and G streptococci the influence of age on carrier rates was not similar to that found for group A streptococci. Throat carriership of beta-hemolytic streptococci does not result in clinical infections.

A review of the literature shows that antibiotic concentrations in tissues and tissue fluids are often quoted as being different in profile to concurrent serum levels. To study the relationship between serum and tissue concentrations we analysed published studies where different experimental models were tested simultaneously. In some models serum levels predicted tissue levels while in others they did not. The factors likely to be responsible for the differences were examined. The most important of these factors was tissue geometry (surface area to volume ratio; SA/V). Serum levels predicted tissue levels in models where the SA/V was high (>60) but not where the SA/V's were low (<10); here the antibiotic concentrations were lower and more prolonged than serum levels. These observations can be extrapolated to the clinical situation. In most situations involving prophylaxis or treatment of infections in non-specialised tissues (naturally high SA/V), serum levels will closely reflect levels in extracellular tissue fluid where most bacterial infections are located.

ABSTRACTL-749,345 is a new parenteral carbapenem with a very long half-life similar to that of ceftriaxone. The aim of the present study was to investigate different pharmacodynamic parameters of L-749,345 in comparison with those of ceftriaxone and imipenem. The following studies were performed: (i) comparative studies of the MICs of L-749,345, imipenem, and ceftriaxone for 70 strains of gram-positive and gram-negative bacteria; (ii) comparative studies of the rate of killing of gram-positive and gram-negative bacteria by L-749,345, imipenem, and ceftriaxone; (iii) studies of the postantibiotic effects of L-749,345, imipenem, and ceftriaxone; and (iv) studies of the postantibiotic sub-MIC effects of L-749,345, imipenem, and ceftriaxone. Significantly lower MICs of L-749,345 compared with those of ceftriaxone were found for all gram-negative organisms except Haemophilus influenzae. The MICs of L-749,345 were similar to those of imipenem for all organisms except Pseudomonas aeruginosaand methicillin-resistant Staphylococcus aureus, for which the MICs of L-749,345 were higher. A concentration-dependent killing of methicillin-resistant S. aureusbut not methicillin-susceptible strains was noted for both L-749,345 and imipenem. All three of the investigated drugs exhibited a postantibiotic effect against the gram-positive strains but exhibited no postantibiotic effect against the gram-negative strains.