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ACT-387042 and ACT-292706 are two novel bacterial topoisomerase inhibitors with broad-spectrum activity against Gram-positive and -negative bacteria, including methicillin-resistant Staphylococcus aureus and penicillin- and fluoroquinolone-resistant Streptococcus pneumoniae . We used the neutropenic murine thigh infection model to characterize the pharmacokinetics (PK)/pharmacodynamics (PD) of these investigational compounds against a group of 10 S. aureus and S. pneumoniae isolates with phenotypic resistance to beta-lactams and fluoroquinolones. The in vitro activities of the two compounds were very similar (MIC range, 0.03 to 0.125 mg/liter). Plasma pharmacokinetics were determined for each compound by using four escalating doses administered by the subcutaneous route. In treatment studies, mice had 10 7.4 to 10 8 CFU/thigh at the start of therapy with ACT-387042 and 10 6.7 to 10 8.3 CFU/thigh at the start of therapy with ACT-292706. A dose-response relationship was observed with all isolates over the dose range. Maximal kill approached 3 to 4 log 10 CFU/thigh compared to the burden at the start of therapy for the highest doses examined. There was a strong relationship between the PK/PD index AUC/MIC ratio (area under the concentration-time curve over 24 h in the steady state divided by the MIC) and therapeutic efficacy in the model ( R 2 , 0.63 to 0.82). The 24-h free-drug AUC/MIC ratios associated with net stasis for ACT-387042 against S. aureus and S. pneumoniae were 43 and 10, respectively. The 24-h free-drug AUC/MIC ratios associated with net stasis for ACT-292706 against S. aureus and S. pneumoniae were 69 and 25, respectively. The stasis PD targets were significantly lower for S. pneumoniae ( P < 0.05) for both compounds. The 1-log-kill AUC/MIC ratio targets were ∼2- to 4-fold higher than stasis targets. Methicillin, penicillin, or ciprofloxacin resistance did not alter the magnitude of the AUC/MIC ratio required for efficacy. These results should be helpful in the design of clinical trials for topoisomerase inhibitors.

Pharmacodynamic studies examine the relationship between drug pharmacokinetics and outcome. These investigations have been shown to be helpful for the design of dosing intervals, choice of optimal dose levels, and the development of susceptibility breakpoints. Pharmacodynamic studies with available antifungal agents have been useful in developing optimal dosing regimens to improve efficacy and reduce treatment-associated toxicities. This review summarizes accepted antifungal concepts and discusses recent advances in the field.

Dalbavancin is a novel lipoglycopeptide with activity against Staphylococcus aureus , including glycopeptide-resistant isolates. The in vivo investigation reported here tested the effects of this antibiotic against seven S. aureus isolates with higher MICs, including several vancomycin-intermediate strains. Results of 1-log kill and 2-log kill were achieved against seven and six of the isolates, respectively. The mean free-drug area under the concentration-time curve ( f AUC)/MIC values for net stasis, 1-log kill, and 2-log kill were 27.1, 53.3, and 111.1, respectively.

Inducible clindamycin resistance in beta-hemolytic streptococci remains an underrecognized phenomenon of unknown clinical significance. We performed an evaluation of inducible clindamycin resistance using an animal model as well as retrospectively reviewing the charts of patients treated with clindamycin monotherapy who were infected with beta-hemolytic streptococci inducibly resistant to clindamycin. The neutropenic mouse thigh model of infection was used to evaluate the in vivo activity of clindamycin against beta-hemolytic streptococci, including isolates susceptible, inducibly resistant, or constitutively resistant to clindamycin. The clinical microbiology laboratory information system and pharmacy databases were cross-referenced to identify patients with infections due to inducibly clindamycin-resistant beta-hemolytic streptococci who were treated with clindamycin monotherapy. Medical records of these patients were reviewed to evaluate microbiologic and clinical outcomes. Inducible clindamycin resistance resulted in impaired killing of beta-hemolytic streptococci in the animal model. Though suppressed initially, compared to those with constitutive resistance ( P = 0.0429), by 48 h, colony counts of inducibly clindamycin-resistant organisms were similar to those of constitutively resistant isolates ( P = 0.1142). In addition, we identified 8 patients infected with inducibly clindamycin-resistant beta-hemolytic streptococci who experienced clinical and microbiologic failure when treated with clindamycin monotherapy. These patients either improved initially and subsequently failed or never responded to clindamycin therapy. We have demonstrated in a murine model of infection and from human cases that inducible clindamycin resistance in beta-hemolytic streptococci is clinically significant. Routine testing and reporting by clinical laboratories should be encouraged and alternative antimicrobial agents considered when these organisms are encountered in clinical care.

As the populations of at-risk immunocompromised patients increases, the incidence of invasive mycosis has risen in parallel. Despite recent advances in antifungal pharmacology, the successful management of invasive fungal infections continues to pose a difficult challenge to clinicians. Numerous factors determine the outcome of these infections, including host immune status; pathogen-associated variables, including drug susceptibility; location of the infection; timing of the diagnosis relative to the initiation of antifungal therapy; and effective administration of the appropriate dose of the most potent and safest antifungal drug. The choices of antifungal drug and dosing regimen are among the few factors that the clinician can control. However, even if treatment with the appropriate drug and regimen is initiated, drug exposure at the site of infection may be inadequate because of pharmacokinetic variability and may contribute to treatment failure. Conversely, antifungal exposures may exceed anticipated concentrations and result in toxicity. The blood concentration of many antifungal drugs varies markedly because of inconsistent absorption, metabolism, elimination, or interaction with concomitant medications. Studies have demonstrated that an understanding of the pharmacokinetics and pharmacodynamics of these drugs plays an important role in optimizing drug choice and dosing regimen design. One tool for detecting drug exposures outside of the therapeutic window is monitoring the drug concentration in blood [1]. The usefulness of this tool in informing drug choice and dosing decisions is being increasingly explored. Several factors must be considered in determining whether therapeutic drug monitoring is appropriate for patient management. First, an accurate and cost-effective assay for measuring blood concentrations of the drug must be readily available to the clinician. Second