Reduction of virulence factor pyocyanin production in multidrug-resistant Pseudomonas aeruginosa.

Nosocomial infections caused by metallo-ß-lactamase (MBL)-producing multidrug-resistant (MDR) Pseudomonas aeruginosa have become a worldwide problem. Pyocyanin, a representative pigment produced by P. aeruginosa, is the major virulence factor of this organismThe aim of this study was to investigate the pyocyanin-producing ability of MBL-producing MDR P. aeruginosa. A total of 50 clinical isolates of P. aeruginosa, including 20 MDR strains, were collected at 18 general hospitals in Japan. The chromaticity and luminosity produced by pyocyanin in each isolate were measured. The quantity of pyocyanin and the expression of the phzM and phzS genes coding a pyocyanin synthesis enzyme were measured. MDR strains showed a bright yellow-green, while non-MDR strains tended to show a dark blue-green. The quantities of pyocyanin in MBL-producing strains and non-producing strains were 0.015 ± 0.002 and 0.41 ± 0.10 µg, respectively. The expression of the phzM and phzS genes in the MDR strains was 11 and 14 %, respectively, of the expression in the non-MDR strains. When the MBL gene was transduced into P. aeruginosa and it acquired multidrug resistance, it was shown that the pyocyanin-producing ability decreased. The pathogenicity of MBL-producing MDR P. aeruginosa may be lower than that of non-MDR strains. These MBL-producing MDR strains may be less pathogenic than non-MDR strains. This may explain why MDR-P. aeruginosa is unlikely to cause infection but, rather, causes subclinical colonization only.

Antibacterial activity of carbapenems against clinical isolates of respiratory bacterial pathogens in the northeastern region of Japan in 2007.

As the increasing prevalence of resistant strains of respiratory bacterial pathogens has recently been reported, continuous monitoring of the susceptibility of clinical isolates to antibacterial agents is important. We performed a surveillance study focusing on the susceptibility of major respiratory bacterial pathogens in the northeastern region of Japan to carbapenems and control drugs. A total of 168 bacterial strains isolated from patients with respiratory tract infections in 2007 were collected and the minimum inhibitory concentration (MIC) determined. MIC data were subjected to pharmacokinetic/pharmacodynamic analysis with Monte Carlo simulation to calculate the probability of achieving the target of time above MIC with each carbapenem. All Moraxella catarrhalis, Streptococcus pneumoniae, and methicillin-sensitive Staphylococcus aureus isolates were susceptible to carbapenems. Despite the increasing prevalence of ß-lactamase-nonproducing ampicillin-resistant strains, all Haemophilus influenzae isolates were susceptible to meropenem. For Pseudomonas aeruginosa, the susceptibility rates for meropenem and biapenem were 76.7%, and the highest probability of achieving pharmacodynamic target (40% of the time above MIC) was obtained with meropenem 0.5 g three times daily as a 4-h infusion (89.4%), followed by meropenem 0.5 g four times daily as a 1-h infusion (88.4%). Carbapenems have retained their position as key drugs for severe respiratory tract infections.

Antibacterial effects of brand-name teicoplanin and generic products against clinical isolates of methicillin-resistant Staphylococcus aureus.

Glycopeptide antibiotics, such as vancomycin and teicoplanin, have been used worldwide to treat infection caused by methicillin-resistant Staphylococcus aureus (MRSA). Generic teicoplanin products were manufactured by many companies in 2009. We investigated the susceptibility of 147 MRSA strains to brand-name teicoplanin (TEIC-1) and seven generic products (TEIC-2 to TEIC-8). The MIC(90) of generic TEIC-5 and TEIC-7 was 8 µg/ml whereas that of TEIC-1 and other generic products was 4 µg/ml. The potency equivalent of generic TEIC-5 and TEIC-7 was lower than that of TEIC-1, and TEIC content (%) per potency equivalent (200 mg) in a vial of these two generic products varied greatly compared with the other products. Although the potency equivalent of the TEIC used in this study was within the range stipulated in the Japanese Pharmacopeia, these results showed that the potency equivalent and susceptibility of two of the seven generic products differed from that of TEIC-1. The predicted AUC(0-72) value of those two generic products was 84-85% in comparison with that of TEIC-1. Among generic drugs, there may be products whose antimicrobial effect is not equal to that of the brand teicoplanin.

Evaluation of dosing designs of carbapenems for severe respiratory infection using Monte Carlo simulation.

Using the Monte Carlo simulation method, the influence of various doses and dosing frequencies of carbapenems on the antimicrobial activities against Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa, which are the main causative organisms of respiratory infections, was studied with the aim of identifying optimized effectiveness. Based on pharmacokinetic (PK) parameters of individual carbapenems in healthy adults, data on changes in the respective blood concentrations in 2000 cases were simulated by applying a lognormal distribution to probability distributions of their volume of distributions and half-life periods. Based on minimum inhibitory concentration (MIC) distribution data of the individual carbapenems against these strains, MICs in the 2000 cases were also simulated. Using these data in blood concentrations and MICs, the probabilities of attaining various percentages of the dosing interval during which drug concentrations remain above MIC (T > MIC) were calculated at several dosing regimens. Considering the probabilities of attaining the bactericidal effect (50% T>MIC) and daily drug costs, imipenem (IPM) at 500 mg i.v. BID, panipenem (PAPM) at 500 mg i.v. BID, and biapenem (BIPM) at 300 mg i.v. BID against Streptococcus pneumoniae; meropenem (MEPM) at 500 mg i.v. BID or TID against Haemophilus influenzae infections; and MEPM at 500 or 1000 mg i.v. TID against Pseudomonas aeruginosa, each over 30 min, were determined as appropriate empirical treatments. Selecting carbapenems with superior antimicrobial activities and optimizing their dose regimens are important to improve the efficacy. Application of Monte Carlo simulation to MIC distributions allows determination of appropriate empiric therapy even if drug susceptibility of a causative organism in individual patients is unknown.

Antibacterial activity of carbapenems against clinically isolated respiratory bacterial pathogens in Japan between 2005 and 2006.

The current status of the susceptibility of the main respiratory bacterial pathogens was evaluated by analysing the antibacterial activity of 21 drugs, including four carbapenems, against five species of the pathogens isolated between January 2005 and January 2006. A total of 157 strains were studied. Carbapenems inhibited the growth of all of the tested strains of Moraxella catarrhalis, Streptococcus pneumoniae and methicillin-susceptible Staphylococcus aureus strains at concentrations that were below the breakpoints set by the Japanese Society of Chemotherapy (2 and 1mug/mL for pneumonia and chronic respiratory tract infection, respectively). However, the majority of methicillin-resistant Staphylococcus aureus strains were resistant to carbapenems. Meropenem, but not the other carbapenems, inhibited the growth of all of the tested strains of Haemophilus influenzae isolates, including beta-lactamase-non-producing ampicillin-resistant strains, at concentrations of