Journal of Antimicrobial Chemotherapy

Published by Oxford University Press (OUP)
Online ISSN: 1460-2091
Publications
Article
One hundred and sixty-six patients with complicated and uncomplicated urinary tract infections were randomized to therapy with either 0.25, 0.50 or 1.00 g of ceftazidime im or iv twice daily for five days. Bacteriological data were complete in 138 patients. Escherichia coli caused 50% of all infections, Klebsiella and Enterobacter spp. caused 10.9%, Pseudomonas spp caused 10.9%, Proteus spp. caused 10.7%, and 8.7% were caused by other Gram-negative bacteria. Staphylococcus and Streptococcus spp. caused 9.4%. Cure rate was lowest in infections caused by Pseudomonas (53.3%) and Proteus spp. (64.3%); however, most of these infections were complicated. No significant dose-related difference in efficacy was observed, but the 0.25 g dose had the lowest cure rate in each category. Nausea was the only side effect. The most common laboratory abnormalities were elevated liver function tests. Minimal changes in haematological and renal function were seen.
 
Mean serum imipenem concentration–time data for eight healthy volunteers following administration of: 0.5 g, 0.5 h infusion (filled squares); 0.5 g, 2 h infusion (open circles); and 1 g, 2 h infusion (filled triangles). Table 1. Pharmacokinetic parameters (mean – SD) of imipenem administered by 2 h and 0.5 h infusion  
Article
The aim of this study was to demonstrate the t > MIC of 0.5 and 1 g of imipenem when administered by 2 h infusion every 6 h compared with 0.5 g of imipenem when administered by 0.5 h infusion every 6 h. The study was a randomized three-way crossover study with a 30 h wash-out period in eight healthy volunteers. Each subject received imipenem in three regimens: (i) a 0.5 h infusion of 0.5 g every 6 h for three doses; (ii) a 2 h infusion of 0.5 g every 6 h for three doses; and (iii) a 2 h infusion of 1 g every 6 h for three doses. Following 0.5 h infusion of 0.5 g, the percentages of time above four times an MIC of 4, 2 and 1 mg/L were 21.5 +/- 2.2%, 38.6 +/- 3.5% and 57.5 +/- 4% of a 6 h interval, respectively. For the 2 h infusion of 0.5 g, the percentages of time above four times an MIC of 4, 2 and 1 mg/L were 26.9 +/- 8.5%, 48.0 +/- 3.5% and 65.4 +/- 3.2% of a 6 h interval, respectively. For the 2 h infusion of 1 g, the percentages of time above four times an MIC of 4, 2 and 1 mg/L were 51.6 +/- 5.4%, 67.8 +/- 4.5% and 87.8 +/- 5.6% of a 6 h interval, respectively. A 2 h infusion resulted in a greater t > MIC than those after a 0.5 h infusion and intermittent infusion may be a useful mode of administration of imipenem in tropical countries.
 
Mean plasma imipenem concentration– time data for nine patients with VAP following administration of: 0.5 g, 0.5 h infusion (filled triangles); 0.5 g, 2 h infusion (filled diamonds); and 1 g, 2 h infusion (filled squares).  
PK parameters (mean+SD) of imipenem administered by 2 h and 0.5 h infusion
The percentages of the t .4ÂMIC at specific MICs of 4, 2 and 1 mg/L of imipenem after administration of: 0.5 g, 0.5 h infusion (filled triangles); 0.5 g, 2 h infusion (filled diamonds); and 1 g, 2 h infusion (filled squares).
Article
The aim of this study was to compare the t > MICs of imipenem between administration by a 2 h infusion with a 0.5 h infusion. The study was a randomized three-way crossover in nine patients with ventilator-associated pneumonia. Each subject received imipenem in three regimens consecutively: (i) a 0.5 h infusion of 0.5 g every 6 h for 24 h; (ii) a 2 h infusion of 0.5 g every 6 h for 24 h; and (iii) a 2 h infusion of 1 g every 6 h for 24 h. Following the 0.5 h infusion of 0.5 g of imipenem, the percentages of the t > 4 x MICs of 4, 2 and 1 mg/L were 20.32 +/- 9.32%, 44.11 +/- 16.40% and 64.67 +/- 20.56% of a 6 h interval, respectively. For the 2 h infusion of 0.5 g of imipenem, the percentages of the t > 4 x MICs of 4, 2 and 1 mg/L were 17.71 +/- 19.27%, 53.75 +/- 19.30% and 76.54 +/- 17.36% of a 6 h interval, respectively. For the 2 h infusion of 1 g of imipenem, the percentages of the t > 4 x MICs of 4, 2 and 1 mg/L were 60.26 +/- 23.96%, 77.78 +/- 20.11% and 93.35 +/- 8.26% of a 6 h interval, respectively. The 2 h infusions of imipenem resulted in greater t > MICs than the 0.5 h infusion. For infections caused by pathogens with high MICs, a 2 h infusion of 1 g of imipenem every 6 h can provide plasma concentrations above the MIC of 4 mg/L for 60% of a 6 h interval.
 
Article
BMS284756 is a novel des-F (6)-quinolone, which has a wide range of activity against many species of Gram-positive and -negative organisms. The potency of BMS284756 was compared with that of other quinolones, including ciprofloxacin, gatifloxacin and levofloxacin, and was tested against >10,000 bloodstream isolates from the year 2000 SENTRY antimicrobial surveillance programme. Twelve pathogens accounted for nearly all of the referred isolates and included Staphylococcus aureus, coagulase-negative staphylococci, Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Serratia spp., Pseudomonas aeruginosa, Acinetobacter spp., Enterococcus spp., Streptococcus pneumoniae and beta-haemolytic or viridans group streptococci. Of the four quinolones tested, BMS284756 was the most active overall against Staphylococcus spp. (MIC(50) < or = 0.03 mg/L) and Streptococcus spp. (MIC(50) 0.06 mg/L). In contrast, BMS284756 was less potent than the other quinolones against the enteric Gram-negative bacilli (MIC(50) < or = 0.03-1 mg/L). With a proposed breakpoint of < or =4 mg/L, BMS284756 may be a therapeutic alternative pending the results of clinical trials.
 
(a) Germination and toxin production by C. difficile PCR ribotype 001 in vessel 3 of the gut model, in response to clindamycin treatment. (b) Germination and toxin production by C. difficile PCR ribotype 027 in vessel 3 of the gut model, in response to clindamycin treatment.
continued. 
(a) Activity of metronidazole against C. difficile PCR ribotype 027 in vessel 2 of the gut model. (b) Activity of metronidazole against C. difficile PCR ribotype 001 in vessel 3 of the gut model. (c) Activity of metronidazole against C. difficile PCR ribotype 027 in vessel 3 of the gut model.
Article
We compared the behaviour of Clostridium difficile PCR ribotypes 001 and 027 in a human gut model, and compared the responses to metronidazole exposure. Using a human gut model primed with pooled human faeces, gut flora bacterial counts, C. difficile total viable counts, spore counts and cytotoxin titres were determined, following exposure to clindamycin, in the absence or presence of metronidazole. Duration of cytotoxin production by C. difficile ribotype 027 was markedly longer than that of ribotype 001 (23 versus 13 days, respectively), but peak toxin titres were similar. During toxin production, total C. difficile ribotype 027 populations had higher proportions of vegetative cells than did ribotype 001 (median 56.33 versus 23.54%). Similarly, total C. difficile ribotype 027 populations remained predominantly as vegetative cells for longer than did ribotype 001 (20 versus 9 days). The effects of metronidazole on C. difficile were markedly less than expected. Titres of C. difficile ribotype 001 cytotoxin were reduced but recurred following metronidazole administration. C. difficile ribotype 027 cytotoxin titres in the distal section of the gut model were unaffected by metronidazole. These observations correlated with poor metronidazole concentrations. Duration of cytotoxin production by C. difficile ribotype 027 markedly exceeds that of ribotype 001. Sub-optimal gut concentrations of metronidazole, possibly due to inactivation by components of normal gut flora, are associated with continued toxin production. These findings may help to explain the increased severity of symptoms and higher case-fatality ratio associated with infections due to C. difficile ribotype 027.
 
Model-fitted parameter estimates a for ABI-0043 versus S. aureus clinical isolates 
Time-kill experiments evaluating the bactericidal activity of ABI-0043 versus MRSA S285 (a), MRSA S293 (b), MSSA 288 (c) and MSSA 290 (d), and the pharmacodynamic relationship between concentration and log ratio change or log ratio area for MRSA S285 (e and i), MRSA S293 (f and j), MSSA 288 (g and k) and MSSA 290 (h and l). 
Article
ABI-0043 is a novel benzoxazinorifamycin derivative, which derives its potent bactericidal activity by the specific inhibition of bacterial RNA polymerase. We evaluated the in vitro pharmacodynamics and bactericidal activity of ABI-0043 against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S. aureus (MSSA). Using time-kill studies at a wide range of concentrations of ABI-0043, we evaluated the killing activity against four clinical isolates of S. aureus over 24 h. An integrated pharmacokinetic/pharmacodynamic area measure was applied to all cfu data and was fitted to a Hill-type mathematical model to evaluate pharmacodynamics. Bacterial killing for ABI-0043 occurred rapidly and in a concentration-dependent manner. Bactericidal activity was achieved within 4 h at > or =16 x MIC against all isolates. Bacterial reductions were greatest at > or =64 x MIC against MRSA and MSSA isolates, as a >4 log(10) cfu/mL reduction was observed as early as 2 h, and sustained throughout 24 h. The pharmacodynamics of ABI-0043 was well described by a Hill-type model, with a steep sigmoidicity constant and a low EC(50) against all isolates. ABI-0043 displayed rapid and sustained bactericidal activity against S. aureus clinical isolates. ABI-0043 represents a promising antistaphylococcal agent to combat serious S. aureus infections. Further, pharmacokinetic, pharmacodynamic and in vivo studies are warranted to determine its ultimate place in antibacterial therapy.
 
MIC range, MIC 50 , MIC 90 and distribution of susceptibility categories of the novel aminobenzimidazole compound VT12-008911 and antimicrobials currently or previously recommended for a large collection of clinical isolates of N. gonorrhoeae (n¼220) and international reference strains (n¼28) 
Article
Clinical resistance to the currently recommended extended-spectrum cephalosporins (ESCs), the last remaining options for empirical antimicrobial monotherapy of gonorrhoea globally, has been reported. New antimicrobials are essential to avoid the emergence of untreatable gonorrhoea. We have investigated the in vitro activity of a novel dual bacterial topoisomerase inhibitor of the ATPase activities of GyrB and ParE (Vertex aminobenzimidazole VT12-008911), compared with antimicrobials currently or previously recommended for gonorrhoea treatment. MICs were determined using agar dilution (VT12-008911) or Etest (seven antimicrobials) for international reference strains (n = 28) and clinical Neisseria gonorrhoeae isolates (n = 220). The latter included three extensively drug-resistant isolates with high-level ceftriaxone resistance, additional isolates with clinical ESC resistance and a high number of isolates with ciprofloxacin resistance and multidrug resistance. The MIC50, MIC90 and MIC range of VT12-008911 were 0.064, 0.125 and ≤0.002-0.25 mg/L, respectively. One-hundred and seventy (69%) isolates were ciprofloxacin resistant; however, only 54 of those isolates had a VT12-008911 MIC >0.064 mg/L (47 and 7 with MIC = 0.125 mg/L and MIC = 0.25 mg/L, respectively). The in vitro activity of VT12-008911 was superior to that of ciprofloxacin and all additional antimicrobials investigated. Time-kill curve analysis showed that VT12-008911 exhibited potent time-dependent bactericidal activity, at or very close to the MIC, against N. gonorrhoeae. In vitro results suggest that VT12-008911 might be an effective treatment option for gonorrhoea. However, it will be important to detail the pharmacokinetics/pharmacodynamics, toxicity, selection and mechanisms of VT12-008911 resistance in N. gonorrhoeae and, finally, to perform well-designed in vivo randomized clinical trials.
 
(a) Representative kidney histopathology of a mouse from the 20 mg/kg oral AMB group, which shows a normal pattern. (b) Representative kidney histopathology of a mouse from the 2 mg/kg iv Fungizone w group, which shows necrotic tubules that are interspersed with viable ones (an arrow indicates a necrotic tubule and arrowheads indicate some of the tubules with necrotic debris). (c) Representative jejunum histopathology of a mouse from the oral vehicle control group, which shows a normal villus pattern. (d) Representative jejunum histopathology of a mouse from the 20 mg/kg oral AMB group, which shows a normal villus pattern with no necrosis or inflammatory infiltrate. (e) Representative liver histopathology of a mouse from the 20 mg/kg oral AMB group, which shows normal morphology. (f) Representative liver histopathology of a mouse from the 2 mg/kg iv Fungizone w group, which shows a focal collection of necrotic hepatocytes with surrounding inflammatory cells (as indicated by arrows). This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.  
Article
The purpose of this study was to assess the biodistribution and toxicity of amphotericin B (AMB) following multiple dose administration of an oral lipid-based formulation (iCo-009). BALB/c female mice were used. ICo-009 was administered twice daily for 5 days at doses of 2.5-20 mg/kg. Untreated animals, oral vehicle or intravenous Fungizone® (1 or 2 mg/kg) served as control groups. The animals were sacrificed 12 h following the last administration of AMB, and blood and multiple tissues were harvested for drug analysis and histopathological evaluation. Plasma or tissue samples were analysed for concentrations of AMB or creatinine by means of HPLC-UV. A dose-dependent accumulation of AMB in liver, spleen, kidney and lung tissues was found. The concentration of the drug in all these organs exceeded the corresponding concentrations in plasma at the same dose. The concentrations of AMB in heart and brain were similar to the corresponding concentrations in plasma. Creatinine concentrations were elevated above normal concentrations in the 2 mg/kg Fungizone® group only. Histopathological analysis of kidney and liver tissues revealed a normal pattern in all treated groups, except the 2 mg/kg Fungizone® group. No gastrointestinal toxicity was found in this study. A multiple dose treatment regimen with iCo-009 in mice results in a gradual accumulation of AMB in tissues. Despite significant concentrations of AMB, no kidney or liver toxicity of orally administered AMB was detected in this study. Furthermore, multiple oral administration of iCo-009 or of vehicle control did not induce gastrointestinal toxicity.
 
Article
Serotype 012 Pseudomonas aeruginosa resistant to gentamicin (MIC greater than 4 mg/l) and carbenicillin (MIC greater than 128 mg/l) occur widely in Europe and are homogeneous in their phenotypic and genetic properties. It has been suggested that a single multiresistant strain of this serotype has become widespread. This study examined the resistance mechanisms present in multiresistant serotype 012 P. aeruginosa isolates from Austria, Belgium, France, Greece, Italy, Holland, West Germany and the UK. Disseminated isolates produced a PSE-1 type beta-lactamase, correlating with their resistance to the known substrates of this enzyme (carbenicillin, azlocillin and cefsulodin). These isolates also reacted with gene probes for the aminoglycoside modifying enzymes AAC(6')I and ANT(3'). The probe for AAC(6')I is known to cross-react with the gene for AAC(6')II. The fact that the organisms were resistant to netilmicin, gentamicin, sisomicin and tobramycin, but less so to amikacin, suggested that the latter enzyme was produced rather than AAC(6')I. PSE-1 beta-lactamase and the gene for AAC(6')I/AAC(6')II were absent from the International Antigenic Typing Scheme 012 reference strain, which was sensitive to beta-lactams and aminoglycosides, and also from a multiresistant serotype 012 strain isolated at a London burns unit in 1987. These organisms have been shown previously to be distinct from the disseminated multiresistant strain in their phenotypic properties. Two 012 isolates appeared to have additional resistance determinants to amikacin and isepamicin.
 
Article
The in vitro activity of S-013420, a novel bicyclolide, was investigated. All test strains for this study were isolated from Japanese medical facilities. MICs were determined by the microbroth dilution method or agar dilution method according to the CLSI guidelines. In time-kill kinetics, viable cells were measured at 1, 2.5, 4 and 6 h after exposure to antimicrobials. The frequencies of single-step resistance acquisition at 4x MIC and 8x MIC were determined using 10(7) cfu of bacterial cells. S-013420 showed MIC(90) values of 0.125, 0.125, 8 and 0.5 mg/L for Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae and Moraxella catarrhalis, respectively. S-013420 showed the most potent activity against erythromycin-intermediate and -resistant S. pneumoniae with an MIC(90) of 0.25 mg/L and inhibited the growth of all strains of S. pyogenes with macrolide resistance genes at 1 mg/L. The MICs of S-013420 for atypical pathogens such as erythromycin-susceptible Mycoplasma pneumoniae and Chlamydophila pneumoniae were 0.00049-0.001 and 0.0039 mg/L, respectively, although the activity of S-013420, as well as other macrolide agents, against erythromycin-resistant M. pneumoniae was significantly weak. S-013420 caused a 3 log(10) reduction in viable cells against all test strains of S. pneumoniae and H. influenzae. Acquisition of resistance to S-013420 was not observed for three strains of S. pneumoniae. S-013420 shows potent in vitro activity against respiratory tract pathogens. Against streptococci, including erythromycin-resistant strains, S-013420 demonstrated the most potent in vitro activity among the antimicrobials tested.
 
Number of viable bacteria in the lungs after 7 days of treatment with tomopenem or meropenem (100 mg/kg, twice daily) and control (saline, twice daily). Data are expressed as the mean + SEM for eight mice. Tomopenem and meropenem significantly reduced the number of viable bacteria compared with the control (P , 0.05).
MICs for Pseudomonas aeruginosa S10 strain
Histopathological examination of lung specimens. The control group showed the features of chronic bronchopneumonia; inflammatory cells had infiltrated around the bronchi and exudates had collected in the alveolar spaces. However, only few inflammatory cells were observed in both the tomopenem- and meropenem-treated groups. 
Selected PK parameters estimated for tomopenem and meropenem in serum and in the lung
Article
Tomopenem (CS-023) is a novel parenteral carbapenem with broad-spectrum activity against Gram-positive and -negative bacteria, as well as potent activity against drug-resistant pathogens, including penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. We compared the in vivo activity of tomopenem and that of meropenem in a chronic lower respiratory infection mouse model of P. aeruginosa. Mice with chronic airway infection by P. aeruginosa were treated with saline (as the control, twice daily), tomopenem (100 mg/kg, twice daily) or meropenem (100 mg/kg, twice daily) for 7 days. After treatment, the number of viable bacteria in lungs and histopathological findings were analysed. The pharmacokinetics of tomopenem and meropenem were also analysed after initial treatment. The number of viable bacteria in lungs treated with saline, tomopenem or meropenem was 4.21 +/- 1.28, 2.91 +/- 0.87 and 3.01 +/- 1.00 log(10) cfu/lung (mean +/- SEM), respectively (P < 0.05, control versus tomopenem- or meropenem-treated groups). In the histopathological examination of lung specimens, the control group had the features of chronic bronchial infection; however, tomopenem- and meropenem-treated groups had fewer inflammatory cells compared with the control group. The pharmacokinetic parameter of % time above MIC for tomopenem and meropenem was 16% and 17% in sera and 15% and 18% in lungs, respectively. Tomopenem significantly reduced the number of viable bacteria in a murine model of chronic airway infection by P. aeruginosa, compared with the control. Considering the longer half-life of tomopenem in humans compared with most other carbapenems, tomopenem treatment of chronic airway infection with P. aeruginosa is expected to be efficacious.
 
Article
To compare the in vitro activities of the carbapenem, CS-023, four representative beta-lactam antibiotics and levofloxacin, against 970 Gram-positive or Gram-negative US clinical isolates. Susceptibilities of bacteria chosen for their varying levels of resistance to the comparator agents were determined by NCCLS microdilution methodology. CS-023 exhibited activity comparable to that of imipenem against most Gram-positive isolates, but was approximately 8-fold more potent against oxacillin-resistant staphylococci. It was comparable to meropenem against most Gram-negative isolates, but was 4- to 8-fold more potent against five isolates of meropenem-resistant Pseudomonas aeruginosa. If tissue and body fluid concentrations >8 mg/L can safely be achieved, further studies of CS-023 are warranted to determine its clinical efficacy.
 
Mean (+SE) C. difficile PCR ribotype 027 total counts (log 10 cfu/mL), spore counts (log 10 cfu/mL), cytotoxin titres (RU) and antimicrobial concentrations (mg/L) in (a) oritavancin (ORI) and (b) vancomycin (VAN) experiments in vessel 3 of the gut model. Horizontal dashed lines indicate the limit of detection for bacterial culture. 
Article
To compare the efficacy of oritavancin and vancomycin in the treatment of Clostridium difficile infection (CDI) using an in vitro human gut model. We induced CDI by instilling clindamycin into an in vitro gut model primed with pooled human faeces and C. difficile ribotype 027 spores. Oritavancin and vancomycin were instilled in separate experiments at levels equivalent to those expected in the faeces (vancomycin) of patients or levels limited by the solubility of the drug (oritavancin). Clindamycin exposure elicited C. difficile proliferation and high-level cytotoxin production in both experiments. Vancomycin instillation reduced vegetative C. difficile numbers within 1 day but did not affect the numbers of C. difficile spores. Oritavancin instillation markedly reduced C. difficile vegetative numbers and spores to below the limits of detection within 2 days. Cytotoxin titres in both experiments declined to the limits of detection after instillation with oritavancin or vancomycin, but did so more quickly (within 5 days) in the vancomycin experiment. Cessation of vancomycin instillation was associated with further C. difficile proliferation and high-level cytotoxin production. Conversely, toxin recrudescence was not observed following cessation of oritavancin. Both oritavancin and vancomycin were effective in treating clindamycin-induced CDI in a human gut model, but only oritavancin appeared active against spore forms of C. difficile. Furthermore, recurrence of high-level cytotoxin production was observed following vancomycin instillation but not oritavancin. Oritavancin therapy may be more effective in treating CDI than vancomycin, possibly because it may prevent recrudescence of C. difficile spores.
 
Article
Co-amoxiclav is widely prescribed in hospitals. Although reports have suggested it may be linked to onset of Clostridium difficile infection (CDI), data on the risk of CDI associated with specific antibiotics is difficult to obtain, due to confounding clinical factors. We have examined the propensity of co-amoxiclav to induce CDI using a human gut model. We used a triple-stage chemostat human gut model to study the effects of co-amoxiclav on indigenous gut microorganisms and C. difficile PCR ribotype 027. C. difficile viable counts and spores were evaluated, and cytotoxin titres were assayed. Co-amoxiclav concentrations were measured using a large plate bioassay. Co-amoxiclav induced rapid C. difficile germination and high toxin production in the gut model, from 5 days after commencement of instillation. Cell proliferation and toxin production were prolonged and continued throughout the duration of the experiment. Only very low levels of co-amoxiclav antimicrobial activity could be detected within the gut model, despite having a marked effect on gut flora microorganisms. Co-amoxiclav induced CDI within the gut model, supporting clinical observations linking co-amoxiclav treatment with CDI onset. This reinforces the value of the gut model as a clinically relevant means of studying CDI. Caution should be exercised in the prescription of co-amoxiclav to patients in high CDI risk settings.
 
Article
The inhibitory (MIC) and bactericidal (MBQ activities of a new macrolide A-S6268 (TE-031) against 306 clinical aerobic bacterial isolates was compared with that of erythromycin. The MIC90/MBC90, ratios for A-56268 were: Campylobacter jejuni 4/16, Haemophitus influeniae 8/8–16, H. parabtfluenzae 8/8–16, Legionella pneumophila 0·06/0·5, methicillin-sensitive isolates of Staphylococcus aureus 0·5/1, and coagulase negative staphylococci 1/8, methkillin resistant isolates of Staph. aureus and coagulase negative staphylococci <16/<16, Streptococcus pneumoniae 0·06/0·125, streptococcus Group A 0·06/2·4, streptococcus Group B 0·06/8–< 16, streptococcus Groups C and G 0·125/8 and Str.faecalis 4/64. Compared with erythromycin, A-56268 had greater inhibitory and bactericidal activity against isolates of L. pneumophila, with an MIC90 16-fold less and an MBC90 eight-fold less than that of erythromycin. Except for cnterococd, A-56268 showed inhibitory activity equal to or greater than that of penicillin G against isolates of streptococci and an MIC two-fold less than that of erythromycin. For other strains tested, the inhibitory and bactericidal activities of A-56268 and erythromycin were similar. The dinical importance of the differences between these two macrolides will depend on the pharmacokinetk and tissue penetration properties of the new compound.
 
Article
The activity of a new macrolide, TE-031 (A-56268), against Legionella pneumophila in vitro was superior to the activities of roxithromycin, erythromycin and josamycin. The tissue concentrations of TE-031 in guinea pigs after oral administration (20 mg/kg) was much higher than those of roxithromycin, erythromycin and josamycin. The maximum concentration of TE-031 was 107.0 mg/kg in the lung, and 1.4 mg/l in the serum. The uptake of macrolides by cells collected by bronchoalveolar lavage in guinea pigs was measured by a radioisotopic method. The maximum ratios of intracellular to extracellular concentration of TE-031, roxithromycin, josamycin and erythromycin were 71.9, 24.8, 39.7 and 7.9, respectively. In infected guinea pigs, with the exception of erythromycin, the ratios were reduced to approximately half the values in normal animals. TE-031 showed greater therapeutic efficacy against experimental L. pneumophila pneumonia than roxithromycin, erythromycin and josamycin. TE-031 is a promising drug for treatment of legionella pneumonia and should be investigated in a clinical study on human Legionnaires' disease.
 
Article
The activity of A-56268 (TE-031), a new macrolide, was tested in a murine model of acute toxoplasmosis. All control animals died in 8 +/- 1 days, while all mice treated with nine daily doses of A-56268 at 300 mg/kg, administered by gavage, survived. Moreover, 41.6% of the surviving mice were free from cerebral infection with Toxoplasma gondii, as assessed by brain subpassage. A-56268 is active against T. gondii in vivo, but further studies are needed to determine its usefulness in the treatment of human toxoplasmosis.
 
Article
Erythromycin base and its 6-0-methyl derivative clarithromycin were actively accumulated 7.3 +/- 1.2-fold and 9.2 +/- 2-fold respectively by human neutrophils in vitro. The intraphagocytic bioactivities of the antimicrobial agents were investigated using the combination of a radioassay, colony counting method and a fluorescence microassay which facilitates the distinction between intracellular bacteriostatic and bactericidal mechanisms. Staphylococcus aureus, Listeria monocytogenes and Legionella micdadei were used as the test intraphagocytic microbial pathogens. Both agents were found to possess intracellular bioactivity for all three species of bacteria with clarithromycin being consistently more active than erythromycin. Under the assay conditions used both agents were bacteriostatic (intracellularly) for S. aureus and Leg. micdadei and bactericidal for List. monocytogenes. Clarithromycin is clearly a potent intraphagocytic antibiotic and potentially superior in this respect to erythromycin.
 
Article
The comparative in-vitro activity of A-56268 (TE-031), a new semisynthetic macrolide antibiotic, was assessed against approximately 400 bacterial isolates. The new drug demonstrated excellent activity against penicillin-susceptible streptococci (MIC90s less than or equal to 0.06 mg/l) and methicillin-susceptible staphylococci (MIC90 = 0.25 mg/l). Among other Gram-positive organisms tested, a significant number were resistant to A-56268 as well as to erythromycin and clindamycin. A-56268 was at least as active as erythromycin against Pasteurella multocida and Campylobacter jejuni, but was more active than erythromycin against Legionella spp. (MIC90 less than or equal to 0.06 mg/l), Bacteroides fragilis (MIC90 = 4 mg/l) and Bact. melaninogenicus (MIC90 less than or equal to 0.125 mg/l). Activity of A-56268 was pH dependent (more active at pH 7 than at pH 6) and was moderately affected by inoculum size. The drug was bactericidal against two strains of Streptococcus pyogenes tested, but exerted a bacteriostatic effect against Staphylococcus aureus and Str. faecalis.
 
Article
Norfloxacin (MK-0366) is a new antibacterial agent, closely related to nalidixic acid, with broad spectrum activity against Gram-positive and Gram-negative organisms, including Pseudomonas aeruginosa. A clinical study was conducted on forty hospitalized patients with bacteriologically proven urinary tract infections; 20 patients were given norfloxacin and 20 co-trimoxazole. Clinical results were excellent in both groups; norfloxacin was effective in infections due to Ps. aeruginosa and other multi-resistant pathogens. No side effects were reported.
 
Article
The in-vitro activity of the parenteral cephem FK-037 was compared to those of cefpirome, ceftazidime, cefuroxime, cefixime, amoxycillin and co-amoxiclav. Against the Enterobacteriaceae FK-037 was generally ≥ 16-fold more active than cefuroxime and two- to four-fold more active than ceftazidime and similar in activity to cefpirome. Pseudomonas aeruginosa displayed similar susceptibilities to ceftazidime and FK-037 (MIC90 4 and 8mg/L respectively). Methicillin-resistant Staphylococcus aureus were inhibited by ≤ 4 mg/L of FK-037. The MIC of FK-037 for 90% of Streptococcus pneumoniae was 0.5 mg/L. Haemophilus influenzae and Moraxella catarrhalis were inhibited by ≤2 mg/L FK-037.
 
Frequency of pneumococcal serotypes isolated from acute exacerbations throughout the 2001-12 period a 
Genotypes detected in three or more pneumococci isolated from acute exacerbations during the 2001-12 period 
Article
Pneumococci are an important cause of acute exacerbations in patients with chronic obstructive pulmonary disease (COPD). In the last decade, the pneumococcal population has changed, mainly due to the introduction of the 7-valent conjugate vaccine (PCV7). We analysed the antimicrobial susceptibility (microdilution), serotype (PCR) and genotype (PFGE/multilocus sequence typing) of pneumococci causing acute exacerbations during the period 2009-12. Results were compared with two previously published historic periods (2001-04 and 2005-08). A total of 206 pneumococci were collected from 162 COPD patients with acute exacerbations. Compared with previous periods, no significant changes in the rate of multidrug resistance were observed (36.2% in the 2001-04 period to 33.5% in the 2009-12 period, P = 0.644). The most frequent serotypes in the 2009-12 period were 15A (9.6%), 3 (8.1%), 19F (6.6%), 11A (6.1%) and 6C (5.6%), which accounted for 36.0%. A drastic decrease in PCV7 serotypes was observed throughout the study period (from 39.7% in 2001-04 to 10.9% in 2009-12, P < 0.001); non-PCV13 serotypes increased from 44.9% to 71.2%, especially 15A (from 2.2% to 9.6%) and 6C (from 0.0% to 5.6%) (P < 0.05). The most frequent genotypes (clonal complexes, CCs) in the 2009-12 period were CC63(15A,19F,15F) (9.1%), CC180(3) (4.5%), CC62(11A) (4.0%), CC97(10A) (4.0%), CC386(6C) (3.5%), CC260(3) (3.5%) and CC30(16F) (3.5%). Serotypes 19F, 19A, 6A and 6C were genetically diverse. PCV7 serotypes have decreased dramatically. In parallel, two non-PCV7 serotypes (15A and 6C) and their related genotypes (CC63 and CC386) showed a significant increase. Although resistance rates to β-lactams decreased over time, multidrug resistance remained stable.
 
Article
The antirhinovirus agent chalcone Ro 09–0410 was tested in double-blind place-controlled volunteer trials for its protective efficacy against experimental rhinovirus infection. Fifty volunteers received either drug (26 volunteers) or placebo (24 volunteers) both before and after challenge with 20–40 tissue culture infecting dose (TCID50) of human rhinovirus 2 (RV2). There was no evidence that medication significantly reduced the incidence of infection or illness, indeed there was some increase in the nasal secretion produced.
 
Article
Ro 09-0415, a phosphorylated ‘pro-drug’ of the potent antirhinovirus compound, 4′ ethoxy-2′-hydroxy-4, 6′ dimethoxy-chalcone (Ro 09-0410) was tested in a double-blind placebo-controlled trial for its protective effect against experimental rhinovirus infection. The maximum dose, 1200 mg bd, based on considerations of practicality and tolerance was given orally both before and after challenge with a sensitive rhinovirus, type 9. Plasma concentrations of active compound in excess of those required for the inhibition of rhinovirus type 9 in vitro were achieved, but there was no evidence to suggest that treatment with Ro 09-0415 had a beneficial effect. It is concluded that Ro 09-0415 given orally is unlikely to be of value in the prophylaxis or therapy of human rhinovirus infection.
 
Summary of in vivo mucosal toxicity studies in mice and rabbits 
Article
Compounds WHI-05 [5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-methoxyphenyl)-methoxyalaninyl phosphate] and WHI-07 [5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl)-methoxyalaninyl phosphate] are aryl phosphate derivatives of zidovudine (ZDV) with anti-HIV and contraceptive activity. WHI-05 and WHI-07 differ fundamentally from currently used surfactant microbicides that are cytotoxic to genital tract epithelial cells at spermicidal concentrations. These drugs were rationally designed to bypass the thymidine kinase dependency of ZDV activation in genital tract secretions, as well as to achieve spermicidal activity. WHI-05 and WHI-07 were formulated via a non-toxic gel-microemulsion for intravaginal use as potential anti-HIV spermicides. Pre-clinical safety studies of intravaginally administered WHI-05 and WHI-07 gel-microemulsions were performed in mice and rabbits to mimic closely the intravaginal application of a microbicidal preparation in women. In addition, systemic toxicity studies were performed in mice and non-human primates. The LD10 doses for WHI-05 and WHI-07 when administered intravenously or intraperitoneally were >500 mg/kg for mice. Female cynomolgus monkeys treated with 20 mg/kg WHI-05 and WHI-07 intravenously developed no grade 2-4 systemic toxicities. Repetitive intravaginal administration of 2% WHI-05 and WHI-07 via a gel-microemulsion to achieve concentrations as high as 6.1 x 10(4) and 5.7 x 10(6) times their respective in vitro anti-HIV IC50 values, and 1200 and 5700 times their spermicidal EC50 values, for up to 13 weeks, was not associated with mucosal, systemic or reproductive toxicity. Furthermore, long-term (2 years) intravaginal administration of 2% WHI-07 gel-microemulsion was not associated with systemic toxicity or increased carcinogenicity in mice. The improved potency, as well as the lack of mucosal, systemic and reproductive toxicity of WHI-05 and WHI-07, means that these compounds have clinical potential as safe, prophylactic contraceptives in addition to their microbicide activity to curb the sexual transmission of HIV.
 
Article
To assess whether methicillin-resistant Staphylococcus aureus (MRSA) vancomycin MIC shifts (MIC creep) at a tertiary care institution occurred that may have gone undetected using traditional susceptibility markers (percentage susceptible, MIC(50), MIC(90)) over a 5 year period. Additionally, MIC trends were evaluated for oxacillin, linezolid and daptomycin. Etest MICs were performed on MRSA blood culture isolates (January 2001-December 2005). Only one isolate per patient was studied. The reported Etest MIC result was used and not rounded upward. MIC(50), MIC(90), median and geometric mean MIC, percentage susceptible and percentage resistant were calculated for each drug in each year. Non-parametric methods (linear correlation and Mantel-Haenszel chi(2)) were used to assess MIC trends over time and the association of vancomycin, linezolid and daptomycin MICs with oxacillin MICs. All isolates were susceptible to vancomycin, linezolid and daptomycin and resistant to oxacillin. MICs increased for vancomycin, linezolid and oxacillin (P < 0.0001); however, daptomycin MICs decreased slightly (P = 0.0386). For vancomycin, linezolid and oxacillin, there were significant increases (P < 0.0001) in the percentage of isolates with MICs that were higher than the respective 2001 median MIC, but not for daptomycin (P = 0.1361). Oxacillin MICs were associated with MICs of linezolid (r = 0.364, P < 0.0001), vancomycin (r = 0.353, P < 0.0001) and daptomycin (r = 0.106, P = 0.0063). Oxacillin, vancomycin and linezolid MICs increased over time. For vancomycin and linezolid, these MIC increases were not reliably detected by percentage susceptibility as they occurred below the susceptibility breakpoint. Although the MICs of all agents appeared to be associated with increasing oxacillin MICs, the strongest associations were noted for vancomycin and linezolid.
 
Activity of telavancin against selected Gram-positive clinical isolates from Europe and Israel not susceptible to daptomycin and/or linezolid 
Article
Telavancin is a novel semi-synthetic lipoglycopeptide currently in late-stage clinical development for the treatment of serious infections due to Gram-positive bacteria. The objective of this study was to provide a baseline prospective assessment of its in vitro activity against a large and diverse collection of Gram-positive clinical isolates from Europe and Israel. Gram-positive clinical isolates, collected between October 2004 and December 2005 from 36 hospital laboratories in 15 countries, were tested by broth microdilution using CLSI methodology. In total, 3206 isolates were collected. Telavancin had potent activity against Staphylococcus aureus and coagulase-negative staphylococci (MIC range < or =0.015 to 2 mg/L), independent of resistance to methicillin or to multiple drugs. Telavancin had particularly strong activity against streptococcal isolates (MIC range < or =0.001 to 0.5 mg/L), including penicillin-resistant and multiple drug-resistant Streptococcus pneumoniae and erythromycin non-susceptible beta-haemolytic and viridans group streptococci. Telavancin also had excellent activity against vancomycin-susceptible enterococci (MIC(90) 0.5 mg/L), and although its MICs were elevated against VanA strains (Enterococcus faecalis MIC(90) 8 mg/L and Enterococcus faecium MIC(90) 4 mg/L), its MIC(90) was substantially lower than observed with available glycopeptides. Telavancin has potent in vitro activity against contemporary Gram-positive clinical isolates from diverse geographic areas in Europe and Israel.
 
Article
After a single iv bolus injection of 2 g ceftazidime, concentrations were measured in serum and urine in volunteers and in serum, bone, bile and tissue fluid in patients. The serum half-life was 171 min in volunteers (n = 6, average age 26 years) and 221 min in patients (n = 12, average age 58 years). The peripheral volumes of distribution were also different, being 7.81 in volunteers and 11.31 in patients. Urinary recovery from the volunteers averaged 92% of the dose. Bone samples free from blood and taken from the femoral head, the pelvis or the femoral shaft contained an average of 24.1 mg ceftazidime per litre of organic bone at 30 min after injection and 19.7 mg/l at 2 h. Samples of fluid from the periprosthetic space after hip replacement contained 25.6 mg/l at 2 h and were above 8 mg/l at 10 h. Bile concentrations reached 36.4mg/l at 90 min and were above 8 mg/l for over 8 h. Peritoneal fluid samples contained 27.6 mg/l at 1 h and 8.0 mg/l at 8 h. These concentrations are considered sufficient to treat most aerobic infections associated with surgery.
 
Article
A new VITEK 2 antibiotic susceptibility testing (AST) card, AST N-054, was introduced for aerobic gram-negative bacilli in 2007 and has been widely adopted for routine use in the UK. We evaluated its performance for detecting extended-spectrum beta-lactamase (ESBL) production in Escherichia coli. ESBL-producing faecal isolates of E. coli (n = 137) from residents in nursing homes were tested using the AST N-054 card on VITEK 2 and with MASTDISCS ID ESBL detection disc diffusion tests (Mast Diagnostics, Bootle, UK). The susceptibility result recommended by the VITEK 2 software was also recorded. The AST N-054 card detected ESBL production in 93 of the 137 isolates tested [test sensitivity 67.9% (95% CI, 59.7-75.1)]. E. coli strain A, a widespread lineage in the UK with a low-level CTX-M enzyme production, accounted for most of the detection failures, with 35/73 strain A isolates incorrectly reported versus 9/64 non-strain A isolates (P < 0.0001). The MASTDISCS correctly detected ESBL in 135/137 isolates [test sensitivity 98.5% (95% CI, 94.5-99.9)]. Of the 44 isolates found to be negative for ESBL production by VITEK 2, the Advanced Expert System misreported 29 as susceptible to cefotaxime and all as susceptible to ceftazidime and aztreonam. These data suggest that the AST N-054 card for the VITEK 2 system is less reliable than other previously reported cards for the detection of CTX-M beta-lactamase-producing E. coli circulating in the UK, particularly strain A isolates.
 
AMR patterns of Salmonella spp. isolated from pet dogs from volunteer households in Ontario, 2005-06 
Article
To compare the antimicrobial resistance (AMR) patterns of Salmonella spp. and Escherichia coli in the faeces of pet dogs from volunteer households in Southwestern Ontario, Canada. From October 2005 to May 2006, 138 dogs from 84 Ontario households were recruited to participate in a cross-sectional study. Five consecutive daily faecal samples were collected from each dog and cultured for Salmonella spp. and E. coli. A panel of 15 antimicrobials from seven antimicrobial classes was used for susceptibility testing. E. coli and Salmonella spp. were recovered from 96.4% and 23.2% of dogs, respectively. In total, 515 bacterial isolates from 136 dogs from 83 households were sent for antimicrobial susceptibility testing with 80.4% of isolates being pan-susceptible. The most common resistance pattern was to amoxicillin/clavulanic acid, ampicillin, cefoxitin, ceftiofur and ceftriaxone, present in 13.3% of Salmonella isolates and 1.3% of E. coli isolates. Fifty-eight of the isolates were resistant to two or more drug classes, with 70.7% and 29.3% being E. coli and Salmonella, respectively. Based on multilevel logistic regression, the odds of resistance were greater in E. coli than Salmonella [odds ratio = 3.2; 95% confidence interval (CI) = 1.22-8.43]. Agreement in resistance between E. coli and Salmonella isolates from the same dog was low [prevalence-adjusted, bias-adjusted kappa (PABAK) = 0.38; 95% CI = 0.30-0.46]. Pet dogs are a potential household source of antimicrobial-resistant Salmonella spp. and E. coli. However, extrapolating the epidemiology of antimicrobial resistance in pathogens, like Salmonella, from E. coli should be done with caution.
 
Non-susceptibility trends among non-fermenters (% intermediate plus % resistant) 
Non-susceptibility rates among ICU and non-ICU isolates of P. aeruginosa 
P. aeruginosa surveys compared 
Article
Pseudomonas and Acinetobacter spp. are important opportunists, notorious for resistance. Pseudomonas spp. are collected in the British Society for Antimicrobial Chemotherapy (BSAC) bacteraemia surveillance, with Acinetobacter spp. and Stenotrophomonas maltophilia well represented in the 'other Gram-negatives' group. Data for collected isolates were reviewed together with LabBase bacteraemia reports to the Health Protection Agency (HPA). Isolates with unusual resistances were subjected to molecular investigation. From 2001 to 2006, the BSAC surveillance collected 1226 Pseudomonas aeruginosa, 240 Acinetobacter spp.-125 of them Acinetobacter calcoaceticus/baumannii (Acb) complex-and 165 S. maltophilia. Among P. aeruginosa, non-susceptibility rates to beta-lactams and gentamicin fluctuated, without trend, below 10%; those to ciprofloxacin ranged from 16% to 22%. One P. aeruginosa isolate from 2001 had VIM-2 metallo-beta-lactamase. For Acb, the BSAC data indicated frequent non-susceptibility, except to imipenem, where only five non-susceptible isolates were collected, all after 2003, four of them belonging to the OXA-23 clone 1 lineage which is prevalent in Southeast England. Reports to the HPA indicated rising imipenem non-susceptibility in Acb (P < 0.0001). Co-trimoxazole retained near-universal activity against S. maltophilia. Among new antibiotics, doripenem MICs were </=4 mg/L for most imipenem-resistant P. aeruginosa but >/=16 mg/L for Acb OXA-23 clone 1. Ceftobiprole had higher MICs than ceftazidime for P. aeruginosa, but 81% of the isolates were inhibited at </=4 mg/L. Tigecycline had activity against most Acb, including OXA-23 clone 1, and also against S. maltophilia. Most P. aeruginosa from bacteraemias in the UK and Ireland remain relatively susceptible by international standards; in contrast, multiresistance is widespread in Acb, with imipenem non-susceptibility emerging.
 
Article
To assess potential risk factors among socioeconomic variables and the rate of influenza for the use of different fluoroquinolone antimicrobials in Canada, and to evaluate modelling fluoroquinolone-use data by two different outcome measures. Fluoroquinolone use was described monthly from 2000 to 2006 by two outcome measurements: defined daily doses and prescription counts. Multivariable linear and negative binomial models were produced with socioeconomic and influenza rate data. Significant socioeconomic predictors varied among the individual fluoroquinolone models, which may reflect the range of infections that are treated with fluoroquinolones. However, socioeconomic variables within the ciprofloxacin and levofloxacin models were similar, and indicated that use was highest in advantaged populations, depending on the measures being assessed. The rate of influenza was a significant predictor within models describing levofloxacin use and the defined daily dose model for ciprofloxacin use, after accounting for season. Influenza significantly interacted with the education variable in the levofloxacin defined daily dose model. Significant associations between levofloxacin use and influenza rates, after accounting for season, may suggest that levofloxacin was used to treat secondary bacterial infections or was prescribed inappropriately for seasonal viral respiratory tract infections. Yearly patterns of ciprofloxacin use show that prescribing practices changed; more ciprofloxacin prescriptions were dispensed towards the end of the study period, but for smaller doses or shorter treatment times. Associations with socioeconomic variables suggest that the fluoroquinolones ciprofloxacin and levofloxacin were more likely to be used in advantaged populations, probably due to the high cost of fluoroquinolone antimicrobials in comparison to the penicillin and macrolide groups.
 
Article
Investigation of the antibiotic susceptibilities and trends for staphylococci collected from bacteraemia cases in the UK and Ireland, from 2001 to 2006, as part of the British Society for Antimicrobial Chemotherapy's Bacteraemia Surveillance Programme. Twenty-five hospitals from the UK and Ireland each collected up to 10 consecutive isolates of both Staphylococcus aureus and coagulase-negative staphylococci (CoNS) per year from 2001 to 2006. MIC determination and identification to species level were carried out centrally. mecA and also mupA alleles were sought by PCR in S. aureus and CoNS from 2005 and 2006, respectively. One thousand four hundred and forty-eight S. aureus and 1214 CoNS were collected. The overall prevalence of methicillin resistance was 42% (with </=6% annual fluctuation) for S. aureus and 67% (range 54% to 80%) for CoNS. Resistance to aminoglycosides, macrolides, quinolones and tetracyclines was strongly associated with methicillin resistance in both species groups. Many (20.8%) CoNS and three (0.2%) S. aureus isolates were non-susceptible to teicoplanin, but there was no vancomycin non-susceptibility found in S. aureus and only one vancomycin-intermediate CoNS isolate. There was little evidence of susceptibility trends over time for any antibiotic, with the surveillance period preceding the recent fall in methicillin-resistant S. aureus (MRSA) prevalence indicated by the mandatory surveillance of MRSA bacteraemia in England. The newer antibiotics, ceftobiprole, daptomycin, linezolid, telavancin and tigecycline, all had excellent activity against staphylococci. Multiresistant staphylococci remain abundant in the UK and Ireland but many new antimicrobials are becoming available and these may prove effective alternatives to glycopeptides.
 
Article
To describe the current patterns and trends in antimicrobial susceptibility in enterococci and streptococci (excepting pneumococci) from bacteraemia in the UK and Ireland from 2001 to 2006. In each year 2001-06, blood culture isolates were collected by 25 laboratories distributed across the UK and Ireland. In total, there were 1408 isolates of enterococci, 1332 of beta-haemolytic streptococci and 1012 of alpha- and non-haemolytic streptococci. A single central laboratory re-identified the isolates and measured MICs by the BSAC agar dilution method. The prevalence of reduced susceptibility in streptococci and enterococci did not change significantly for most antibiotics, but trends were noted to increased ampicillin, imipenem and vancomycin resistance in Enterococcus faecium. The prevalence of reduced susceptibility to macrolides and tetracycline in streptococci, to tetracycline and gentamicin (high level) in enterococci and to beta-lactams and glycopeptides in E. faecium were all high, with some differences in the prevalence among species or groups. Reduced susceptibility to some antimicrobial agents among streptococci and enterococci remains common and continued surveillance is warranted.
 
Article
Enterobacteriaceae are common agents of bacteraemia, with Escherichia coli accounting for 20% of the cases. Reflecting this importance, members of the family constitute 4 of the 12 collection groups in the British Society for Antimicrobial Chemotherapy (BSAC) Bacteraemia Surveillance Programme. MICs from the BSAC surveillance programme were reviewed, along with bacteraemia reports received by the Health Protection Agency (HPA) via its CoSurv/LabBase system. Isolates with unusual resistances were subjected to molecular analysis. The BSAC and HPA systems both revealed dramatically increasing resistance to cephalosporins, ciprofloxacin and gentamicin among E. coli and Klebsiella spp., with cephalosporin resistance largely contingent on the spread of CTX-M extended-spectrum beta-lactamases (ESBLs); fluoroquinolone resistance also increased among Proteus mirabilis and ESBL-negative E. coli. Carbapenem resistance remained extremely rare, but two Enterobacter spp., from the same patient in different years, had KPC carbapenemases, while a few isolates had carbapenem resistance contingent upon combinations of beta-lactamase and impermeability, and ertapenem MICs for AmpC-derepressed Enterobacter spp. rose over time. Three new agents-ceftobiprole, doripenem and tigecycline-were tested. Ceftobiprole was broadly active, except against ESBL producers and Klebsiella oxytoca hyperproducing K1 enzyme, and was variable against AmpC-derepressed Enterobacter spp. and against Proteus vulgaris. Doripenem was more potent than imipenem. Tigecycline was almost universally active against E. coli, but low-level non-susceptibility (MIC 2 mg/L) was frequent among Klebsiella spp. E. coli and Klebsiella spp. showed dramatic shifts, with sharply rising non-susceptibility to cephalosporins, ciprofloxacin and gentamicin. The rise in cephalosporin resistance reflected dissemination of CTX-M ESBLs. Carbapenems remain broadly active and new agents offer potential.
 
Demographic, clinical and treatment outcome information for 16 patients given linezolid as a part of MDR TB treatment regimens 
Drug resistance profile of M. tuberculosis isolates obtained from 16 patients with MDR TB before linezolid was added to individualized treatment regimens. Grey, susceptible; black, resistant; white, not tested. INH, isoniazid; RIF, rifampicin; EMB, ethambutol; PZA, pyrazinamide; STR, streptomycin; CAP, capreomycin; KAN, kanamycin; AMK, amikacin; ETH, ethionamide; CYC, cycloserine; FQ, fluoroquinolone; RFB, rifabutin; PAS, para-aminosalicylic acid; AMC, amoxicillin/clavulanate; CLO, clofazimine; LZD, linezolid. 
Mycobacterial culture status before and after starting linezolid among 15 patients with pulmonary MDR TB. Time 0 ¼time linezolid was added to the regimen. Patient 9 omitted due to extrapulmonary (spinal) TB disease with only one positive culture. 
Summary measures of the occurrence and management of adverse effects after starting linezolid among 16 patients with MDR TB 
Article
Rationale Linezolid may be effective for the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB); however, serious adverse events are common and there is little information on the management of these toxicities. We retrospectively reviewed public health and medical records of 16 MDR TB patients, including 10 patients with XDR TB, who were treated with linezolid in New York City between January 2000 and December 2006, to determine treatment outcomes and describe the incidence, management and predictors of adverse events. Linezolid was added to MDR TB regimens for a median duration of 16 months (range: 1-29). Eleven patients (69%) completed treatment, four (25%) died and one (6%) discontinued treatment without relapse. Myelosuppression occurred in 13 (81%) patients a median of 5 weeks (range: 1-11) after starting linezolid, gastrointestinal adverse events occurred in 13 (81%) patients after a median of 8 weeks (range: 1-57) and neurotoxicity occurred in seven (44%) patients after a median of 16 weeks (range: 10-111). Adverse events were managed by combinations of temporary suspension of linezolid, linezolid dose reduction and symptom management. Five (31%) patients required eventual discontinuation of linezolid. Myelosuppression was more responsive to clinical management strategies than was neurotoxicity. Leucopenia and neuropathy occurred more often in males and older age was associated with thrombocytopenia (P < 0.05). The majority of MDR TB patients on linezolid had favourable treatment outcomes, although treatment was complicated by adverse events that required extensive clinical management.
 
Article
Our objective was to develop and test standardized methods for collection and statistical analysis of longitudinal data on hospital antibacterial use from different countries. We collected data on monthly supply of antibiotics from pharmacies in one hospital from each of 18 European countries. We applied a standardized method to classify drugs, measure use in defined daily doses and compare the effect of using occupied bed-days (OBDs) or admissions as denominators for longitudinal analysis. Antibiotic use increased in 14 (78%) hospitals and decreased in 4 hospitals. For 16 (89%) hospitals, adjustment of antibiotic use with OBDs resulted in larger changes over time than adjustment with admissions. Inclusion of all hospital clinical activity variables (admissions, length of stay and OBDs) in multivariate time series analysis identified distinct hospital groups. Nine (50%) hospitals had statistically significant changes in antibiotic use (six increasing and three decreasing) that were not explained (n = 3) or only partially explained (n = 6) by change in clinical activity. Three (17%) hospitals had no significant change in antibiotic use. In the remaining six hospitals, apparent changes in antibiotic use were largely explained by changes in clinical activity. This is the first study to use a standardized method for data collection and longitudinal analysis of antibiotic use in different hospitals. These data suggest that determination of changes in antibiotic exposure of hospital patients over a period of time is unreliable if only one clinical activity variable (such as OBDs) is used as the denominator. We recommend inclusion of admissions, OBDs and length of stay in statistical, time series analysis of antibiotic use. This model is also relevant to longitudinal analysis of infections in hospitals.
 
Characteristics of bla CMY-2 plasmids from S. enterica analysed 
Article
Resistance to extended-spectrum cephalosporins has increased in Salmonella worldwide, and is a concern in both hospital and community settings. The aim of this report was to investigate cefoxitin-resistant Salmonella isolates identified from human clinical cases across Canada. Cefoxitin-resistant isolates, defined as having an MIC > or = 32 mg/L, were screened for the ampC classes DHA, FOX, ENT and CIT in a multiplex PCR followed by sequence analysis. Plasmid analysis by restriction fragment length polymorphism (RFLP) and replicon typing was performed on a convenience sample of cefoxitin-resistant Salmonella. In 2005, 5.3% (181/3442) and in 2006, 3.1% (102/3250) of Salmonella isolates collected from all provinces across Canada displayed cefoxitin resistance. Seventy-one out of 283 (25.1%) were multidrug resistant (MDR), as defined by resistance to at least three different antibiotic classes. The bla(CMY-2) gene was harboured by 96.8% (274/283) of the cefoxitin-resistant isolates. Analysis of CMY-2 plasmids revealed that 19.7% contained genes conferring resistance to multiple antimicrobials. Replicon typing of transformant CMY-2 plasmid DNA revealed the predominance of I1-Igamma and A/C. Of the MDR CMY-2 plasmids, 75% contained replicon type A/C. RFLP patterns of CMY-2 plasmids revealed clusters corresponding to the I1-Igamma and A/C replicon types. Incompatibility group I1-Igamma is the most prevalent of the Salmonella CMY-2 plasmids, while A/C is associated with MDR CMY-2 plasmids.
 
Distribution of HIV-RNA (a), PBMC HIV-DNA (b) and CD4 cell count (c) in 674 patients at the time of diagnosis of primary HIV infection, according to estimated time since infection. HIV-RNA is expressed in log 10 copies/mL, HIV-DNA in log 10 copies/10 6 PBMCs and CD4 count in cells/mm 3 .  
HIV-RNA (a), PBMC HIV-DNA (b) and CD4 cell count (c) values according to the number of antibodies (Abs) on the western blot at enrolment and on the clinical status at enrolment. n, number of patients.  
Article
To analyse immunovirological status during primary HIV-1 infection (PHI) according to contemporary clinical status and time since infection. Plasma HIV-RNA and peripheral blood mononuclear cell (PBMC) HIV-DNA levels and CD4 cell counts were determined at enrolment in the ANRS PRIMO cohort. Time since infection was estimated based on both the number of antibodies on western blot at enrolment (0-1, 2-4 or > or =5 specific antibodies) and the estimated interval between infection and enrolment based on clinical and epidemiological features. Patients were classified according to the presence or absence of clinical symptoms at enrolment. Between 1996 and 2006, 674 patients were enrolled an estimated median of 47 days after infection. Median marker values were as follows: HIV-RNA 5.10 log(10) copies/mL (range <1.70-8.33); HIV-DNA 3.30 log(10) copies/10(6) PBMCs (<1.84-4.93); and 506 CD4 cells/mm(3) (40-1542). Median HIV-RNA and PBMC HIV-DNA levels were significantly higher in patients with 0 or 1 specific antibody (n = 71) than in patients with 2-4 (n = 228) or > or =5 antibodies (n = 375). Symptomatic patients had significantly higher HIV-RNA and PBMC HIV-DNA levels and lower CD4 cell counts. However, 10% of symptomatic patients recruited shortly after infection had favourable immunovirological status. Plasma HIV-RNA, PBMC HIV-DNA and CD4 cell count values were highly diverse and correlated strongly with clinical status during PHI. Early diagnosis was not always associated with severe PHI. Combining PBMC HIV-DNA with HIV-RNA, CD4 cell count and clinical symptoms would have allowed identification of 179 patients (26.5%) at high risk of rapid disease progression who did not meet current guidelines for early treatment initiation.
 
Article
Detection and characterization of extended-spectrum beta-lactamases (ESBLs) and AmpC-encoding genes was conducted in German Salmonella isolated from different sources from 2003 to 2007. Non-duplicate German isolates from the National Salmonella Reference Laboratory Collection (2003-07) with ceftiofur MICs of > or =4 mg/L were tested for beta-lactam/beta-lactamase inhibitor susceptibility, presence of ESBLs or AmpC-encoding genes, class 1 and 2 integrons, other resistance genes, and IS26 and ISEcp1 sequences by PCR/sequencing. The isoelectric point of the beta-lactamase was determined. Strains were analysed by PFGE and plasmid profiling. The bla genes were mapped by Southern-blot hybridization. Plasmids were characterized by rep-PCR typing. Sixteen isolates (10 Salmonella Typhimurium, 2 Salmonella Anatum, 2 Salmonella Paratyphi B dT + , 1 Salmonella Infantis and 1 Salmonella London) carried bla(CTX-M) (15 bla(CTX-M-1) and one bla(CTX-M-15)) genes located on self-transferable IncB/O, IncI1 and/or IncN plasmids. Seven of the Salmonella Typhimurium isolates carried the SGI1-M variant. Six isolates (five Salmonella Agona and one Salmonella Kentucky) carried the bla(CMY-2) gene on IncI1 conjugative plasmids. bla(TEM-20) genes were detected in two Salmonella Paratyphi B dT+ isolates, and bla(TEM-52) in one Salmonella Paratyphi B dT+ and one Salmonella Virchow, located on IncI1 plasmids. All Salmonella Paratyphi isolates harboured a 2300 bp/dfrA1-sat2-aadA1 class 2 integron. Among the 22 679 German Salmonella isolates investigated, the ESBL and AmpC beta-lactamase prevalence was still low; however, it is slowly increasing. Various beta-lactamase genes are linked to a variety of genetic elements capable of horizontal DNA transfer. Consequently, their dissemination is likely and demands adequate risk management strategies.
 
Top-cited authors
Neil Woodford
  • Public Health England
Stefan Schwarz
  • Freie Universität Berlin
Henrik Hasman
  • Statens Serum Institut
Ea Zankari
  • Technical University of Denmark
Laurent Poirel
  • Université de Fribourg