Pharmacokinetic and Pharmacodynamic Profiling of Minocycline for Injection following a Single Infusion in Critically Ill Adults in a Phase IV Open-Label Multicenter Study (ACUMIN).

Intravenous (i.v.) minocycline is increasingly used to treat infections caused by multidrug-resistant (MDR) Acinetobacter baumannii Despite its being approved nearly 50 years ago, published information on its pharmacokinetic (PK) profile is limited. This multicenter study examined the PK and probability of pharmacokinetic-pharmacodynamic (PK-PD) target attainment profile of i.v. minocycline in critically ill patients, with suspected or documented infection with Gram-negative bacteria. The PK study population included 55 patients who received a single 200-mg i.v. dose of minocycline. Plasma PK samples were collected predose and 1, 4, 12, 24, 36, and 48 h after initiation of minocycline. Total and unbound minocycline concentrations were determined at each time point. Probabilities of achieving the PK-PD targets associated with stasis and 1-log killing (free area under the curve above the MIC [fAUC:MIC] of 12 and 18, respectively) in an immunocompetent animal pneumonia infection model of A. baumannii were evaluated. A two-compartment population PK model with zero-order i.v. input and first-order elimination, which estimated a constant fraction unbound (fub) for minocycline, best characterized the total and unbound plasma minocycline concentration-time data. The only two covariates retained in the final PK model were body surface area (associated with central volume of distribution) and albumin (associated with fub). In the PK-PD probability of target attainment analyses, minocycline 200 mg i.v. every 12 h (Q12H) was predicted to result in a suboptimal PK-PD profile for patients with A. baumannii infections with MIC values of >1 mg/liter. Like all PK-PD profiling studies of this nature, these findings need clinical confirmation.

Telemonitoring in chronic obstructive airway disease and adult patients with cystic fibrosis.

We compared the use of telemonitoring in patients with chronic obstructive pulmonary disease (COPD) and adult patients with cystic fibrosis (CF). Seventy patients (51 CF and 19 COPD) were enrolled in two studies of six months' duration. Patients used a personal data assistant (PDA) attached to a spirometer to score symptoms and to perform daily spirometry. Criteria for diagnosis of exacerbations of COPD and CF were pre-defined. When exacerbations were detected, patients were offered treatment according to a pre-designed protocol. Thirty-two (63%) CF patients and one (5%) COPD patient withdrew from the studies due to lack of adherence to daily recording. For those who remained in the study, COPD patients recorded more study days (139) than CF patients (113), P = 0.03. The median number of exacerbations detected during the study was greater in COPD than in CF patients, although this was not significant. The median number of device-detected exacerbations in the COPD group was significantly greater than in the CF group, P = 0.024. When compared to a parallel period in the previous year, the number of hospitalisations for COPD exacerbations was reduced, whereas the number of intravenous antibiotics in CF patients did not differ. Adherence to telemonitoring was much greater for COPD than CF patients and the results appear to be more favourable for COPD patients than for CF patients.

PqsE functions independently of PqsR-Pseudomonas quinolone signal and enhances the rhl quorum-sensing system.

Pseudomonas aeruginosa is an opportunistic pathogen that causes both acute and chronic infections in immunocompromised individuals. This gram-negative bacterium produces a battery of virulence factors that allow it to infect and survive in many different hostile environments. The control of many of these virulence factors falls under the influence of one of three P. aeruginosa cell-to-cell signaling systems. The focus of this study, the quinolone signaling system, functions through the Pseudomonas quinolone signal (PQS), previously identified as 2-heptyl-3-hydroxy-4-quinolone. This signal binds to and activates the LysR-type transcriptional regulator PqsR (also known as MvfR), which in turn induces the expression of the pqsABCDE operon. The first four genes of this operon are required for PQS synthesis, but the fifth gene, pqsE, is not. The function of the pqsE gene is not known, but it is required for the production of multiple PQS-controlled virulence factors and for virulence in multiple models of infection. In this report, we show that PqsE can activate PQS-controlled genes in the absence of PqsR and PQS. Our data also suggest that the regulatory activity of PqsE requires RhlR and indicate that a pqsE mutant can be complemented for pyocyanin production by a large excess of exogenous N-butyryl homoserine lactone (C4-HSL). Finally, we show that PqsE enhances the ability of Escherichia coli expressing RhlR to respond to C4-HSL. Overall, our data lead us to conclude that PqsE functions as a regulator that is independent of PqsR and PQS but dependent on the rhl quorum-sensing system.