Recent Updates on the Role of Pharmacokinetics-pharmacodynamics in Antimicrobial Susceptibility Testing as Applied to Clinical Practice.

Given current challenges in antimicrobial resistance and drug development, infectious diseases clinicians must rely on their own ingenuity to effectively treat infections while preserving the current antimicrobial armamentarium. An understanding of pharmacokinetics (PK), pharmacodynamics (PD), antimicrobial susceptibility testing (AST), and how these concepts relate, is essential to this task. In this review, we discuss how and why PK-PD impacts AST and the way infectious diseases are being treated, with a particular focus on vancomycin for methicillin-resistant Staphylococcus aureus, penicillin for Streptococcus pneumoniae, and an update on cephalosporins for Enterobacteriaceae. Finally, we address how new ideas to exploit PK-PD can promote innovative study design and bring about more rapid regulatory review of new antimicrobials.

[Treatment of community-acquired pneumonia--treatment]. / Samfundserhvervet pneumoni--behandling.

Penicillin is the drug of choice for treatment of community-acquired pneumonia (CAP) in Denmark. The primary determinant for therapeutic activity of penicillin is ''penicillin time'' (T>MIC), i.e. time with penicillin concentration above minimum inhibitory concentration. Eradication of S. pneumoniae requires T>MIC above 40-50%. The second determinant for therapeutic activity is the ratio between maximum penicillin concentration in serum and MIC (Cmax/MIC). Considering penicillin pharmacokinetics, intravenous penicillin 2 million units four times a day is recommended as empirical treatment of CAP.

Efficacy of beta-lactams against experimental pneumococcal endocarditis caused by strains with different susceptibilities to penicillin.

OBJECTIVES: To compare the in vitro and in vivo activity of penicillin, cefotaxime and ceftriaxone, using three strains of Streptococcus pneumoniae with different susceptibilities to penicillin (MICs of 0.015, 0.25 and 2 mg/L, respectively). METHODS: Time-kill curves and an experimental model of endocarditis in rabbits. RESULTS: Penicillin was efficacious in clearing bacteria from vegetations and blood irrespective of whether infections were caused by penicillin-susceptible or penicillin-resistant strains (P < 0.01 with respect to control groups). The same efficacy was shown with cefotaxime and ceftriaxone. Comparing the results of the in vivo model with those obtained in time-kill curves, penicillin showed the best results. CONCLUSIONS: These results confirm that penicillin is efficacious in the treatment of pneumococcal infections, including those produced by strains with MICs < or = 2 mg/L (with the exception of pneumococcal meningitis). These results also suggest that the breakpoints to define susceptibility and resistance of S. pneumoniae to penicillin must be reviewed, as has been done with amoxicillin and third-generation cephalosporins.

[Syphilis treatment. German and international guidelines--a comparison]. / Behandlung der Syphilis. Deutsche und internationale Leitlinien--ein Vergleich.

Guidelines are an important instrument for improving the quality of medical care. In 2001, the German STD Society (DSTDG) published guidelines for syphilis diagnostics and treatment. For two reasons, these guidelines had to be reviewed urgently: Firstly, there is an obvious "renaissance" of syphilis among men having sex with men, which is complicated by a frequent comorbidity with HIV infection. Secondly, the standard drug for syphilis treatment in Germany, clemizole penicillin, has no longer been available since July 2003. In this article, the new German guidelines for syphilis treatment 2004, published by the DSTDG, are compared with other syphilis guidelines, which are valid for the European countries, i.e., the CDC, UK, Russian, and European guidelines 2002.

Effect of sodium diclofenac on serum and tissue concentration of amoxicillin and on staphylococcal infection.

The effect of sodium diclofenac on serum and tissue amoxicillin concentration as well as their effect against staphylococcal infection was observed. Four polyurethane sponges were placed in the back of thirty rats. After 14 d, two granulomatous tissues received 0.5 ml of 10(8) cfu/ml (Staphylococcus aureus). Two days later, the rats were divided into five groups: group 1 received amoxicillin 50 mg/kg/p.o., group 2 received amoxicillin 25 mg/kg/p.o., group 3 received sodium diclofenac 2.5 mg/kg/i.m. and amoxicillin 50 mg/kg/p.o., group 4 received sodium diclofenac 2.5 mg/kg/i.m., and group 5 (control group) received NaCl 1 ml/p.o. After six hours of drug administration, blood serum (10 microl) and noninfected granulomatous tissues were placed on Mueller-Hinton agar inoculated with 10(8) cfu/ml (S. aureus). Infected tissues were dispersed in a sonic system and were spread (10 microl) on salt mannitol agar. Microorganisms were counted and the inhibition zones were measured after 18 h of incubation at 37 degrees C. Amoxicillin tissue concentration was 6.27 microg/g for group 1, 2.18 microg/g for group 2, and 0.72 microg/g for group 3. The serum concentrations were 11.56 microg/ml for group 1, 5.36 microg/ml for group 2, and 1.34 microg/ml for group 3. No differences were observed among group 1, 2, and 3 regarding staphylococci counts (Kruskall-Wallis test p>0.05). Group 4 reduced (p<0.05) staphylococci counts comparing to group 5. It was concluded that sodium diclofenac reduced serum and tissue amoxicillin concentration and, even in large doses, amoxicillin was not effective in eradicating the staphylococcal infection after 6 h of administration.

Efficacy of ampicillin combined with ceftriaxone and gentamicin in the treatment of experimental endocarditis due to Enterococcus faecalis with no high-level resistance to aminoglycosides.

OBJECTIVE: This study tests the usefulness of ceftriaxone combined with ampicillin as an alternative to ampicillin plus gentamicin for the treatment of experimental endocarditis due to Enterococcus faecalis without high-level resistance to aminoglycosides. It also determines whether adding ceftriaxone to ampicillin and gentamicin increases the effectiveness against experimental enterococcal endocarditis resulting from E. faecalis. METHODS: Animals with catheter-induced endocarditis were infected intravenously with 108 cfu of the EF91 strain of E. faecalis and were treated for 3 days with ampicillin 2 g every 4 h administered as 'human-like' (H-L) pharmacokinetics, plus gentamicin 1 mg/kg every 8 h H-L, or ceftriaxone 2 g every 12 h H-L alone or combined with gentamicin 6 mg/kg every 24 h administered subcutaneously. RESULTS: The results of therapy for experimental endocarditis resulting from EF91 showed that the combination of ampicillin plus ceftriaxone was as effective as ampicillin plus gentamicin. The triple combination did not improve on the overall efficacies of the two-drug combinations. CONCLUSIONS: Because of its lower nephrotoxicity, ampicillin plus ceftriaxone may be a useful alternative therapy for E. faecalis endocarditis in selected patients.

Selection of resistant Streptococcus pneumoniae during penicillin treatment in vitro and in three animal models.

Pharmacokinetic (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(>MIC)s, the amounts of time for which the drug concentrations in serum were above the MIC. The mixed culture of the three pneumococcal strains, 10(7) CFU of strain A (MIC of penicillin, 0.016 micro g/ml; erythromycin resistant)/ml, 10(6) CFU of strain B (MIC of penicillin, 0.25 micro g/ml)/ml, and 10(5) CFU of strain C (MIC of penicillin, 4 micro g/ml)/ml, was used in the two mouse models, and a mixture of 10(5) CFU of strain A/ml, 10(4) CFU of strain B/ml, and 10(3) CFU 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 beta-lactams: a maximum efficacy was seen when the T(>MIC) was >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.

Pharmacokinetic basis for oral perioperative prophylaxis with ofloxacin in general surgery.

BACKGROUND: Perioperative prophylaxis is recommended to be administered intravenously which, compared to oral prophylaxis, is more expensive. However, pharmacokinetic data on oral perioperative prophylaxis in patients with preoperative surgical and anesthesiological preparation are not available. PATIENTS AND METHODS: 40 patients with open hernial repair or cholecystectomy (low-risk group), colonic or pancreatic resection (high-risk group) received a standard single-dose perioperative prophylaxis with 4.5 g mezlocillin and 0.5 g metronidazole intravenously in addition to 400 mg ofloxacin orally 2 h prior to surgery. Antibiotic concentrations were measured perioperatively and pharmacokinetic data calculated. RESULTS: Serum and tissue concentrations of ofloxacin were above the MIC90 of the potential bacterial spectrum for surgical infection throughout the entire operation. Pharmacokinetic data were not influenced by preoperative surgical or anesthesiological preparation. CONCLUSION: Tissue and serum concentrations and the antibacterial spectrum of orally administered ofloxacin suggest effective protection against perioperative infection. Pharmacokinetic data confirm that oral ofloxacin may be used effectively as single-dose perioperative antibiotic prophylaxis. Since there are no clinical data comparing oral and intravenous singLe-dose prophylaxis, a prospective randomized clinical trial should be performed.

Efficacy of a novel tetracycline derivative, glycylcycline, against penicillin-resistant Streptococcus pneumoniae in a mouse model of pneumonia.

The MIC90 of glycylcycline (< or =0.06 mg/L) against 55 strains of Streptococcus pneumoniae was 100-fold lower than that of minocycline or tetracycline. In a mouse model of penicillin-resistant S. pneumoniae (PRSP) pneumonia, glycylcycline (10 mg/kg) decreased bacterial counts in the lungs from 10(6) cfu to <10(2) cfu, whereas no apparent reduction of bacterial numbers was observed with minocycline or penicillin G. Pharmacokinetic studies showed that the half-life and area under the curve of glycylcycline were superior to those of minocycline and penicillin G in the lungs. These results show a preferential distribution of glycylcycline in the lungs and potent in vivo bactericidal activity in PRSP pneumonia.

Streptococcus pneumoniae pneumonia in mice: optimal amoxicillin dosing predicted from a pharmacokinetic-pharmacodynamic model.

In an attempt to better understand the interaction of amoxicillin with Streptococcus pneumoniae in the lung, and to determine the parameters of therapeutic efficacy of the antimicrobial agent amoxicillin, we used a pharmacokinetic-pharmacodynamic model to describe the overall dose-effect relationship of amoxicillin against 12 strains of S. pneumoniae with penicillin minimum inhibitory concentrations ranging from <0.01 to 16 microg/ml in a neutropenic murine pneumonia model. We were able to correlate amoxicillin dosing, pharmacokinetics, and the temporal changes in bacterial count in lung. Moreover, survival rates measured in one strain at different dosing were significantly related to the number of bacteria in lung calculated from the pharmacokinetic-pharmacodynamic model. Disappearance of amoxicillin from the effect compartment appeared to be very slow and the rate constant (k(e0)) governing this process was significantly different between strains, ranging from 0.00131 to 0.03945 h(-1). These findings have two major implications: 1) after a single dose of amoxicillin, bacterial counts in lung rapidly decreased and the bacterial growth remained suppressed during a long period of time after cessation of exposure of microorganisms to amoxicillin; and 2) the duration of bacterial growth suppression was related to the intrinsic properties of S. pneumoniae strains rather than to host environment because k(e0) was significantly different between strains. These two premises clearly demonstrate that bacterial growth suppression is related to an in vivo postantibiotic effect. Furthermore, we have shown that the major determinant of amoxicillin in vivo bactericidal activity and therapeutic efficacy appeared to be the dose of amoxicillin because amoxicillin exhibits a rapid dose-dependent killing regardless of the S. pneumoniae strain. Our findings may have implications for the clinical use of amoxicillin. In view of our results, the guidance to increase the amoxicillin-loading dose in pneumococcal pneumonia appears to be immediately clinically relevant.

Development of a new experimental model of penicillin-resistant Streptococcus pneumoniae pneumonia and amoxicillin treatment by reproducing human pharmacokinetics.

The increase of penicillin-resistant Streptococcus pneumoniae (PRSP) pneumonia results in a greater risk of antibiotic treatment failure. In vitro data are not sufficient predictors of clinical efficacy, and animal models may be insufficiently contributive, since they often use immunocompromised animals and do not always respect the human pharmacokinetics of antibiotics. We developed an experimental PRSP pneumonia model in immunocompetent rabbits, by using intrabronchial instillation of PRSP (MIC = 4 mg/liter), without any adjuvant. This reproducible model was used to assess amoxicillin efficacy by reproducing human serum pharmacokinetics following 1-g oral or intravenous administrations of amoxicillin every 8 h. Evaluation was performed by using clinical, CT scan, macroscopic, histopathologic, and microbiological criteria. Experimental pneumonia in untreated rabbits was similar to untreated severe human bacteremic untreated pneumonia; in both rabbits and humans, (i) cumulative survival was close to 50%, (ii) red or gray lung congestion and pleuritis were observed, and (iii) lung and spleen concentrations reached 5 and 4 log(10) CFU/g. A 48-h treatment resulted in a significant bacterial clearance in the lungs (1.53 versus 5.07 log(10) CFU/ml, P < 0.001) and spleen (1.00 versus 4.40 log(10) CFU/ml, P < 10(-6)) and a significant decrease in mortality (0% versus 50%, P = 0.02) in treated versus untreated rabbits. No difference was observed on macroscopic and histopathologic lesions between treated and untreated rabbits (P = 0.36 and 0.78, respectively). Similar results were obtained by using a fully penicillin-susceptible S. pneumoniae strain (MIC = 0.01 mg/liter). Our findings suggest that (i) this new model can be contributive in the evaluation of antibacterial agents and (ii) 1 g of amoxicillin three times a day may be sufficient to treat PRSP pneumonia in immunocompetent humans.

Therapeutic effect of oral levofloxacin, ciprofloxacin, and ampicillin on experimental murine pneumonia caused by penicillin intermediate Streptococcus pneumoniae for which the minimum inhibitory concentrations of the quinolones are similar.

The therapeutic efficacy of oral treatment with levofloxacin, ciprofloxacin, and ampicillin on an experimental pneumonia caused by the penicillin-intermediate Streptococcus pneumoniae for which the minimum inhibitory concentrations (MICs) of the quinolones are similar was assessed in immunocompetent CBA/J mice. Levofloxacin exhibited a dose-dependent therapeutic effect, and achieved complete eradication of S. pneumoniae from the lungs at 120 mg/kg/day, whereas ciprofloxacin and ampicillin were hardly effective at all. A pharmacokinetic study in infected mice revealed good oral absorption and lung tissue penetration of levofloxacin (peak lung concentration: 5.95 microg/g of lung), low oral absorption of ciprofloxacin in spite of a good penetration into lung tissue (1.10 microg/g of lung), and low lung tissue penetration of ampicillin despite rather good oral absorption (1.71 microg/g of lung). In an in vitro time-kill study that simulated the peak concentration of drugs in the lungs of infected animals, the killing activity of levofloxacin was found to be greater than that of ciprofloxacin and ampicillin. These data suggest that the therapeutic efficacy of levofloxacin in this model is attributable to both its potent bactericidal activity and excellent pharmacokinetic profile.

Rationale behind high-dose amoxicillin therapy for acute otitis media due to penicillin-nonsusceptible pneumococci: support from in vitro pharmacodynamic studies.

To evaluate whether increased doses of amoxicillin should be used to treat acute pneumococcal otitis media, an in vitro pharmacokinetic model was used to evaluate the killing of pneumococci by amoxicillin when middle ear pharmacokinetics were simulated. Logarithmic-phase cultures were exposed to peak concentrations of 3, 6, and 9 microg of amoxicillin per ml every 12 h, and an elimination half-life of 1.6 h was simulated. Changes in viable bacterial counts were measured over 36 h. All three doses rapidly decreased the viable bacterial counts of penicillin-susceptible strains below the 10-CFU/ml limit of detection by 6 to 10 h and maintained counts below this limit through 36 h. The 3-microg/ml peak dose was much less effective against two of three strains with intermediate penicillin resistance and all three penicillin-resistant strains, with bacterial counts approaching those in drug-free control cultures by 12 h. The 6-microg/ml peak dose completely eliminated two of three strains with intermediate penicillin resistance and maintained viable counts of the other nonsusceptible strains at 1.5 to 2 logs below the initial inoculum through 36 h. The 9-microg/ml peak dose was most effective, completely eliminating all three strains with intermediate penicillin resistance and maintaining the viable counts of the resistant strains at 3 to 4 logs below the original inoculum. The pharmacodynamics observed in this study suggest that peak concentrations of amoxicillin of 6 to 9 microg/ml may be sufficient for the elimination of penicillin-nonsusceptible pneumococcal strains causing otitis media, especially those with intermediate resistance to amoxicillin. In vivo pharmacokinetic studies are needed to determine if these levels can be achieved in middle ear fluid with amoxicillin at 70 to 90 mg/kg/day divided into two daily doses. If these levels are reliably achieved, then clinical studies are warranted.

Treatment of experimental pneumonia due to penicillin-resistant Streptococcus pneumoniae in immunocompetent rats.

A model of pneumonia due to Streptococcus pneumoniae resistant to penicillin was developed in immunocompetent Wistar rats and was used to evaluate the efficacies of different doses of penicillin, cefotaxime, cefpirome, and vancomycin. Adult Wistar rats were challenged by intratracheal inoculation with 3 x 10(9) CFU of one strain of S. pneumoniae resistant to penicillin (MICs of penicillin, cefotaxime, cefpirome, and vancomycin, 2, 1, 0.5, and 0.5 microg/ml, respectively) suspended in brain heart broth supplemented with 0.7% agar. The rats experienced a fatal pneumonia, dying within 5 days and with peak mortality (70 to 80%) occurring 48 to 72 h after infection, and the bacterial counts in the lungs persisted from 8.87 +/- 0.3 log10 CFU/g of lung at 24 h of the infection to 9.1 +/- 0.3 log10 CFU/g at 72 h. Four hours after infection the animals were randomized into the following treatment groups: (i) control without treatment, (ii) penicillin G at 100,000 IU/kg of body weight every 2 h, (iii) penicillin G at 250,000 IU/kg every 2 h, (iv) cefotaxime at 100 mg/kg every 2 h, (v) cefpirome at 200 mg/kg every 2 h, and (vi) vancomycin at 50 mg/kg every 8 h. Two different protocols were used for the therapeutic efficacy studies: four doses of beta-lactams and one dose of vancomycin or eight doses of beta-lactams and two doses of vancomycin. Results of the therapy for experimental pneumonia caused by penicillin-resistant S. pneumoniae showed that initially, all the antimicrobial agents tested had similar efficacies, but when we prolonged the treatment, higher doses of penicillin, cefotaxime, and cefpirome were more effective than penicillin at lower doses in decreasing the residual bacterial titers in the lungs. Also, when we extended the treatment, vancomycin was more efficacious than penicillin at lower doses but was less efficacious than higher doses of penicillin or cefpirome. The model that we have developed is simple and amenable for inducing pneumonia in immunocompetent rats and could be used to explore the pathophysiology and to evaluate optimal therapy of this infection in the immunocompetent host.

The disposition of five therapeutically important antimicrobial agents in llamas.

The disposition of five therapeutic antimicrobial agents was studied in llamas (Lama glama) following intravenous bolus administration. Six llamas were each given ampicillin, tobramycin, trimethoprim, sulfamethoxazole, enrofloxacin and ceftiofur at a dose of 12 mg/kg, 1 mg/kg, 3 mg/kg, 15 mg/kg, 5 mg/kg, and 2.2 mg/kg of body weight, respectively, with a wash out period of at least 3 days between treatments. Plasma concentrations of these antimicrobial agents over 12 h following i.v. bolus dosing were determined by reverse phase HPLC. Disposition of the five antimicrobial agents was described by a two compartment open model with elimination from the central compartment, and also by non-compartmental methods. From compartmental analysis, the elimination rate constant, half-life, and apparent volume of distribution in the central compartment were determined. Statistical moment theory was used to determine noncompartmental pharmacokinetic parameters of mean residence time, clearance, and volume of distribution at steady state. Based on the disposition parameters determined, and stated assumptions of likely effective minimum inhibitory concentrations (MIC) a dose and dosing interval for each of five antimicrobial agents were suggested as 6 mg/kg every 12 h for ampicillin; 4 mg/kg once a day or 0.75 mg/kg every 8 h for tobramycin; 3.0 mg/kg/15 mg/kg every 12 h for trimethoprim/sulfamethoxazole; 5 mg/kg every 12 h for enrofloxacin; and 2.2 mg/kg every 12 h for ceftiofur sodium for llamas. Steady-state peak and trough plasma concentrations were also predicted for the drugs in this study for llamas.

Efficacies of cefotaxime and ceftriaxone in a mouse model of pneumonia induced by two penicillin- and cephalosporin-resistant strains of Streptococcus pneumoniae.

We previously demonstrated the efficacy of ceftriaxone (CRO), at 50 mg/kg of body weight every 12 h, against a highly penicillin-resistant (MIC, 4 micrograms/ml) Streptococcus pneumoniae strain with low-level resistance to CRO (MIC, 0.5 microgram/ml) in a leukopenic-mouse pneumonia model (P. Moine, E. Vallée, E. Azoulay-Dupuis, P. Bourget, J.-P. Bédos, J. Bauchet, and J.-J. Pocidalo, Antimicrob. Agents Chemother. 38:1953-1958, 1994). In the present study, we assessed the activity of CRO versus those of cefotaxime (CTX) and amoxicillin (AMO) against two highly penicillin- and cephalosporin-resistant S. pneumoniae strains (P40422 and P40984) (MICs of 2 and 8 for penicillin, 2 and 4 for AMO, and 4 and 8 for CRO or CTX, respectively). Against both strains, a greater than an 80% cumulative survival rate was observed with CRO at a dose of 100 or 200 mg/kg every 12 h (dose/MIC ratio, 25). With CTX, a high dosage of 400 mg/kg (dose/MIC ratio, 100 or 50) administered every 8 h (TID) was needed to protect 66 and 75% of the animals, respectively, with no statistically significant differences versus CRO. Against the P40422 strain, CRO (100 mg/kg) produced the greatest bactericidal effect, from the 8th to the 24th hour after a single injection (1.8-log-unit reduction over 24 h), and the fastest bacterial pulmonary clearance during treatment; with CTX, only multiple injections at a high dosage, i.e., 400 mg/kg TID, demonstrated a significant bactericidal effect. AMO in a high dosage, 400 mg/kg (dose/MIC ratio, 200) TID, showed good activity only against the P40422 strain. Despite the identical MICs of CTX and CRO, the longer time (3.6 to 4.6 h) that serum CRO concentrations remained above the MICs for the pathogens at a dose of 100 mg/kg resulted in greater efficacy versus CTX against highly penicillin- and cephalosporin-resistant S. pneumoniae strains.

Amoxicillin for the treatment of Helicobacter pylori infection.

Amoxicillin is one of the most active antimicrobials against Helicobacter pylori in vitro, with a minimum inhibitory concentration (MIC) of < or = 0.01-0.1 mg/l. Thus far, neither primary nor secondary resistant strains have been found. Amoxicillin, which has a bactericidal effect on H. pylori, but is less inhibitory in the stationary growth phase and against cell-adherent or slowly growing H. pylori, probably has both topical and systemic activity. It is fairly acid stable and is less affected by gastric acidity than macrolides. Nevertheless, its activity in vivo is considerably enhanced when it is given concomitantly with proton pump inhibitors. Several amoxicillin-containing treatment regimes have yielded H. pylori eradication rates of > or = 90%. Of particular interest are 1-week treatment regimens containing amoxicillin + clarithromycin + omeprazole, or amoxicillin + metronidazole + omeprazole, as well as a 1-h topical therapy developed in Japan.