International Journal of Antimicrobial Agents - Articles in Press

Trends in approval of new antimicrobial agents in India compared with the USA - Corrected Proof

Bhaven C. Kataria, Dimple S. Mehta, Sanjay J. Mehta — 2012-05-17

Infectious diseases remain the second leading cause of death in India . Antibiotic use has been increasing in India . The large multinational pharmaceutical companies primarily target markets such as the USA and Europe for sales of their new drugs. However, antimicrobial resistance, a global problem, is particularly pressing in developing countries where the infectious disease burden is high . The need for new antimicrobial agents is equally essential for India as it is in the developed markets. Therefore, a study was undertaken to compare the trends in approval of new antimicrobial agents in India and the USA.

Impact of an antimicrobial stewardship programme on patient safety in Singapore General Hospital - Corrected Proof

2012-05-16

Abstract: Whilst studies have shown that antimicrobial stewardship programmes (ASPs) can effectively reduce antibiotic utilisation, cost of care and even antimicrobial resistance rates, ASPs should avoid the perception that the goal is primarily to reduce antibiotic purchases and costs, instead of focusing on improving the quality of care. In addition, to address the concern of primary physicians who deemed that ASPs’ choices of antibiotics were often inadequate, the impact of ASPs on patient safety should be monitored and evaluated. The aim of this study was to analyse the impact of ASP interventions on patient safety in Singapore General Hospital (SGH), a 1559-bed, large, acute, tertiary-care hospital in Singapore. A retrospective database review of data on ASP interventions issued between October 2008 and September 2010 was performed. The database maintained by the ASP team detailed patients’ demographic data as well as outcomes of issued interventions. The ASP recommended 1256 interventions in a total of 1249 admissions in six departments. Shorter average length of stay (mean±standard deviation 19.4±19.9 days vs. 24.2±24.2 days) was observed among patients of physicians who accepted ASP suggestions compared with patients of physicians who rejected ASP interventions (P<0.01). ASP interventions did not alter all-cause mortality (P=0.191). In addition, the number of infection-related re-admissions (P<0.001) and the 14-day re-infection rate (P=0.009) were higher among patients whose physicians rejected ASP interventions. In conclusion, interventions recommended by the ASP in SGH were safe and were associated with a reduction in the duration of hospital stay, 14-day re-infection rate and infection-related re-admissions.

Effects of amiodarone and posaconazole on the growth and ultrastructure of Trypanosoma cruzi - Corrected Proof

2012-05-16

Abstract: The antifungal posaconazole (PCZ) is the most advanced candidate for the treatment of Chagas disease, having potent anti-Trypanosoma cruzi activity in vitro and in animal models of the disease as well as an excellent safety profile in humans. Amiodarone (AMD) is the antiarrhythmic drug most frequently used for the symptomatic treatment of chronic Chagas disease patients, but it also has specific anti-T. cruzi activity. When used in combination, these drugs exhibit potent synergistic activity against the parasite. In the present work, electron microscopy was used to analyse the effects of both compounds, acting individually or in combination, against T. cruzi. The 50% inhibitory concentration (IC50) against epimastigote and amastigote forms was 25nM and 1.0nM for PCZ and 8μM and 5.6μM for AMD, respectively. The antiproliferative synergism of the drugs (fractional inhibitory concentration<0.5) was confirmed and the ultrastructural alterations in the parasite induced by them, leading to cell death, were characterised using electron microscopy. These alterations include intense wrinkling of the protozoan surface, swelling of the mitochondrion, shedding of plasma membrane vesicles, the appearance of vesicles in the flagellar pocket, alterations in the kinetoplast, disorganisation of the Golgi complex, accumulation of lipid inclusions in the cytoplasm, and the formation of autophagic vacuoles, the latter confirmed by immunofluorescence microscopy. These findings indicate that the association of PCZ and AMD may constitute an effective anti-T. cruzi therapy with low side effects.

Oseltamivir-resistant influenza A(H1N1) 2009 virus in Greece during the post-pandemic 2010–2011 season - Corrected Proof

2012-05-16

Abstract: Information on the drug susceptibility of influenza epidemic strains is important for antiviral resistance monitoring. In Greece, the 2009–2010 pandemic waves were very mild and seroprevalence rates remained low after this influenza season, resulting in exclusive detection of the pandemic strain during the 2010–2011 influenza season. In the present study during the post-pandemic 2010–2011 season, 50 consecutive influenza A(H1N1) 2009 virus-positive samples from patients hospitalised in Greek hospitals were analysed for resistance to the neuraminidase inhibitor oseltamivir. All patients were hospitalised with severe influenza complications and had previously received oseltamivir. Influenza A(H1N1) 2009 virus detection and testing for oseltamivir resistance were performed with real-time PCR amplification assays. The H275Y substitution associated with resistance to oseltamivir was identified in two immunocompetent patients who received oseltamivir treatment for 3 days and 5 days, respectively. In both cases, patients were discharged in good condition despite development of resistance to antiviral treatment.

Variations in serotypes and susceptibility of adult non-invasive Streptococcus pneumoniae isolates between the periods before (May 2000–May 2001) and 10 years after (May 2010–May 2011) introduction of conjugate vaccines for child immunisation in Spain - Corrected Proof

2012-05-14

Abstract: This study explored the serotype distribution and antibiotic susceptibility of adult non-invasive Streptococcus pneumoniae isolates received in the Spanish Reference Laboratory for Pneumococci immediately prior to introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in June 2001 (May 2000–May 2001) and 10 years afterwards (May 2010–May 2011). Serotyping was performed by Quellung reaction and/or dot-blot assay, and minimum inhibitory concentrations (MICs) were determined by agar dilution. Clinical and Laboratory Standards Institute (CLSI) breakpoints were used for susceptibility interpretation. A total of 1274 isolates were identified (650 in the first period and 624 in the second period). PCV7 serotypes (as a group) showed a decrease (P<0.001) from 43.2% in the first period to 13.9% in the second period, with MIC90 values (MIC for 90% of the organisms) of levofloxacin for the remaining PCV7 serotypes of 16μg/mL. Inversely, non-PCV7 serotypes (as a group) increased from 56.8% to 86.1% (P<0.001), mainly due to increases in serotypes 19A (294.1% increase; P<0.001) and 15A (180.0% increase; P=0.005). Globally, non-susceptibility to penicillin decreased from 54.2% in the first period to 36.9% in the second period (P<0.001). Serotype 19A became the most worrisome, with an increase (at least five dilutions) in MIC90 for all β-lactams in the second period, with non-susceptibility increasing from 18.2% to 71.4% (P=0.003) for penicillin and from 0.0% to 38.1% (P=0.022) for amoxicillin. Cefditoren showed the highest intrinsic activity (lowest MIC50/MIC90) overall and also against serotype 19A. Continuous surveillance of serotype distribution and antibiotic susceptibility among adult non-invasive isolates is necessary to detect emerging serotypes and to continuously assess the intrinsic activity of highly active oral antibiotics such as levofloxacin and cefditoren and of parenteral antibiotics such as cefotaxime.

Skin and soft tissue concentrations of tedizolid (formerly torezolid), a novel oxazolidinone, following a single oral dose in healthy volunteers - Corrected Proof

2012-05-14

Abstract: Plasma concentrations of antimicrobial drugs have long been used to correlate exposure with effect, yet one cannot always assume that unbound plasma and tissue concentrations are similar. Knowledge about unbound tissue concentrations is important in the development of antimicrobial drugs, since most infections are localised in tissues. Therefore, a clinical microdialysis study was conducted to evaluate the distribution of tedizolid (TR-700), the active moiety of the antimicrobial prodrug tedizolid phosphate (TR-701), into interstitial fluid (ISF) of subcutaneous adipose and skeletal muscle tissues following a single oral 600mg dose of tedizolid phosphate in fasting conditions. Twelve healthy adult subjects were enrolled. Two microdialysis probes were implanted into the thigh of each subject, one into the vastus medialis muscle and one into subcutaneous adipose tissue. Probes were calibrated using retrodialysis. Dialysate samples were collected every 20min for 12h following a single oral dose of 600mg tedizolid phosphate, and blood samples were drawn over 24h. Unbound tedizolid levels in plasma were similar to those in muscle and adipose tissue. The ratios of unbound (free) AUC in tissues over unbound AUC in plasma (fAUCtissue/fAUCplasma) were 1.1±0.2 and 1.2±0.2 for adipose and muscle tissue, respectively. The median half-life was 8.1, 9.2 and 9.6h for plasma, adipose tissue and muscle tissue, respectively. Mean protein binding was 87.2±1.8%. The study drug was very well tolerated. The results of this study show that tedizolid distributes well into ISF of adipose and muscle tissues. Unbound levels of tedizolid in plasma, adipose tissue and muscle tissue were well correlated. Free plasma levels are indicative of unbound levels in the ISF of muscle and adipose tissues.

Increasing consumption of antimicrobial agents in Denmark parallels increasing resistance in Escherichia coli bloodstream isolates - Corrected Proof

2012-05-14

Escherichia coli is one of the most important causes of nosocomial infections. In hospitals, E. coli bloodstream infections (BSIs) are often treated with β-lactams (mainly cephalosporins and carbapenems) and fluoroquinolones. However, resistance to these compounds has been reported with increasing frequency in Europe in recent years. Until 2006, the occurrence of third-generation cephalosporin (3GC)-resistant E. coli from BSIs in Denmark was low . In 2009, we reported on the consequences of increased antibacterial consumption in Danish hospitals (2001–2007) . In the present study, we report the development of antimicrobial consumption in Danish hospitals (2007–2010) and resistance among E. coli from BSIs (2008–2010).

Susceptibility of Campylobacter isolates from river water in Brittany, France - Corrected Proof

Martine Denis, Gwenaëlle Mourand, Bérangère Chidaine, Isabelle Kempf — 2012-05-14

Campylobacter is the major source of bacterial gastroenteritis in developed countries. The main risk factors include consumption of contaminated foods of animal origin, but contaminated water may also be involved. Campylobacter can be isolated from environmental samples such as waste samples, surface water treatment plants or rivers. Consuming or swimming in contaminated water are demonstrated causes of human campylobacteriosis. Severe cases of campylobacteriosis may require antimicrobial administration, but very few data exist on the antimicrobial susceptibility of isolates collected from environmental water samples. It was therefore decided to take advantage of a collection of environmental Campylobacter isolates obtained in 2006 during a previous study to explore their susceptibility.

Specific non-peroxide antibacterial effect of manuka honey on the Staphylococcus aureus proteome - Corrected Proof

2012-05-14

Abstract: Manuka honey, derived from the New Zealand flowering plant Leptospermum scoparium, shows promise as a topical antibacterial agent and effective chronic wound dressing. The aim of this study was to determine the non-peroxide antibacterial effects of this honey on the proteome of the common wound pathogen Staphylococcus aureus. Proteomic analysis was performed on cells treated for a short time with manuka honey compared with the proteome of untreated cells as well as cells treated with a Leptospermum honey sample without antibacterial activity. Treatment with manuka honey resulted in a significant decrease in the bacterial cell growth rate as well as downregulation of ten and upregulation of two proteins. Nine of these proteins were also differentially expressed by cells treated with the inactive Leptospermum honey, but to a lesser degree, and the rate of bacterial growth was not affected. The differentially expressed proteins have roles in ribosomal function, protein synthesis, metabolic processes and transcription. Manuka honey uniquely caused downregulation of two proteins [dihydrolipoamide dehydrogenase (DLD) and elongation factor Tu (EF-Tu)] associated with two of these pathways as well as upregulation of one stress-related protein [cold shock protein C (CspC)]. The proteomic profile following treatment with manuka honey differed from the profiles of other antibacterial agents, indicating a unique mode of action and its potential value as a novel antimicrobial agent.

Investigating the antimicrobial peptide ‘window of activity’ using cationic lipopeptides with hydrocarbon and fluorinated tails - Corrected Proof

Brandon Findlay, George G. Zhanel, Frank Schweizer — 2012-05-14

Abstract: To probe the effect of carbon–fluorine bonds on antimicrobial peptide–membrane interactions, 24 cationic lipopeptides were created. The collection of lipopeptides was built from two different peptide sequences, KGK and KKK, with a variety of different lipids selected to probe the effectiveness of both hydrocarbon and fluorinated tails. The antimicrobial activity of each peptide was tested against a mixture of pathogenic and reference bacterial strains, with the cationic disinfectant benzalkonium chloride as a positive control. Non-specific interactions with hydrophobic proteins were assessed by repeating antimicrobial testing in the presence of bovine serum albumin (BSA), and the toxicity of the lipopeptides was assessed by measuring lysis of ovine erythrocytes. Peptide sequence had a moderate effect on activity, with the most active peptide (C16-KGK) inhibiting the growth of two Staphylococcus epidermidis strains at ≤0.25μg/mL. Tail composition was less important than the overall hydrophobicity, with the most active fluorinated tails equivalent to moderately active hydrocarbon tails. The activity of all peptides was significantly reduced by the presence of BSA, and haemolysis was closely correlated with antimicrobial activity.

Susceptibility to manuka honey of Staphylococcus aureus with varying sensitivities to vancomycin - Corrected Proof

Rowena Jenkins, Mandy Wootton, Robin Howe, Rose Cooper — 2012-05-14

Staphylococcus aureus is an important human pathogen capable of causing life-threatening infections. It is the most frequent isolate recovered from wounds, and multidrug-resistant strains are common place. Since the emergence of meticillin-resistant S. aureus (MRSA), glycopeptides have been the first-choice interventions. Initially vancomycin and teicoplanin proved clinically effective, but homogeneous and heterogeneous vancomycin-intermediate S. aureus (VISA and hVISA, respectively) strains have been detected since 1997. Although vancomycin-resistant S. aureus (VRSA) and VISA are rare, hVISA occurs at a prevalence of 0.5–1% in isolated cultures of MRSA, and strains can be found worldwide . The rise of VRSA resistant to multiple antibiotics has made treatment of infections increasingly difficult.

Association between PCR ribotypes and antimicrobial susceptibility among Clostridium difficile isolates from healthcare-associated infections in South Korea - Corrected Proof

Jieun Kim, Jung Oak Kang, Hyunjoo Pai, Tae Yeal Choi — 2012-05-14

Abstract: In this study, the association between antimicrobial susceptibility, PCR ribotype and presence of the ermB gene in clinical isolates of Clostridium difficile was investigated. PCR ribotyping and ermB gene PCR were performed on 131 C. difficile isolates. The susceptibility of these isolates to metronidazole, vancomycin, piperacillin/tazobactam (TZP), clindamycin, moxifloxacin and rifaximin was also determined. Use of antibiotics within the previous 2 months was documented. Resistance rates to clindamycin, moxifloxacin and rifaximin were 67.9%, 62.6% and 19.1%, respectively. No metronidazole, vancomycin or TZP resistance was detected. Previous exposure to moxifloxacin was significantly correlated with resistance to this antibiotic, but prior use of clindamycin was not significantly correlated with clindamycin resistance. Sixty-four strains (48.9%) carried the ermB gene, of which all but one (98.5%) were resistant to clindamycin. The clindamycin resistance rates of the common PCR ribotypes (018, 017 and 001) were 91.4%, 100% and 84.2%, respectively, and their moxifloxacin resistance rates were 91.4%, 95.0% and 78.9%, respectively. Resistance rates to rifaximin were 5.7% and 95.0% in ribotype 018 and 017 strains, whilst none of the 001 strains were resistant to rifaximin. In conclusion, the common ribotypes 018, 017 and 001 of C. difficile have high rates of resistance to clindamycin and moxifloxacin, but differ greatly in the frequency of rifaximin resistance.

Use of the quorum sensing inhibitor furanone C-30 to interfere with biofilm formation by Streptococcus mutans and its luxS mutant strain - Corrected Proof

2012-05-14

Abstract: Streptococcus mutans is recognised as a major aetiological agent of dental caries. One of its important virulence factors is its ability to form biofilms on tooth surfaces. The aim of this study was to evaluate the effects of the quorum sensing inhibitor furanone C-30 on biofilm formation by S. mutans and its luxS mutant strain. The effects of furanone C-30 on biofilms of both strains formed on 96-well microtitre plates at 37°C were determined by a colorimetric technique (MTT assay). Different concentrations of furanone C-30 (0.0, 2.0 and 4.0μg/mL) and different time points of biofilm formation (4, 14 and 24h) were investigated. The structures and thickness of the biofilms were observed by confocal laser scanning microscopy (CLSM). Quorum sensing-related gene expression (ftf, smu630, brpA, gbpB, gtfB, vicR, comDE and relA) was investigated by real-time polymerase chain reaction (RT-PCR). The results showed that synthetic furanone C-30 can inhibit biofilm formation by S. mutans and its luxS mutant strain, although it does not affect the bacterial growth rate itself. The quantities of biofilm formed by both strains significantly decreased (P<0.05) and the biofilms became thinner and looser as revealed by CLSM with increasing concentrations of furanone C-30. Expression of the genes tested was downregulated in the biofilms by the addition of furanone C-30. These results revealed that synthetic furanone C-30 can effectively inhibit biofilm formation by S. mutans and its luxS mutant strain.

Emergence of blaOXA-23 and blaOXA-58 carbapenemase-encoding genes in multidrug-resistant Acinetobacter baumannii isolates from University Hospital of Annaba, Algeria - Corrected Proof

2012-05-14

Acinetobacter baumannii is an important opportunistic pathogen that is rapidly evolving towards multidrug resistance and is responsible for nosocomial infections, especially in Intensive Care Units (ICUs) . Extensive use of antimicrobial agents within hospitals has contributed to the emergence of multidrug-resistant (MDR) A. baumannii strains that exhibit resistance to a wide range of antibiotics. Carbapenems have potent activity against A. baumannii and, until recently, were often used to treat infections caused by MDR A. baumannii isolates .

Long-term triple-antibiotic treatment against brucellar vertebral osteomyelitis - Corrected Proof

2012-05-14

We retrospectively analysed prospectively defined therapeutic modalities in patients with vertebral brucellosis fulfilling the World Health Organization (WHO) clinical and laboratory diagnostic criteria at the reference outpatient Clinic for Bone and Joint Infections in ATTIKON University Hospital (Athens, Greece) from 1999 to 2009. Diagnosis of vertebral brucellosis was based on: (a) core temperature >38°C; (b) detection of Brucella spp. in blood and/or spinal tissue cultures taken by percutaneous transpedicular biopsy of the affected spinal segments under fluoroscopy; (c) standard agglutination titre for Brucella spp. ≥1:160; and (d) relevant clinical features (backache unrelieved by rest) and magnetic resonance imaging (MRI) signs compatible with vertebral osteomyelitis.

A novel thermotolerant and acidotolerant peptide produced by a Bacillus strain newly isolated from a fermented food (kimchi) shows activity against multidrug-resistant bacteria - Corrected Proof

Yun Hee Choi, Seung Sik Cho, Jaya Ram Simkhada, Jin Cheol Yoo — 2012-05-14

Abstract: In an attempt to isolate effective antimicrobial peptides (AMPs) from a microbial source for the treatment of multidrug-resistant (MDR) bacteria, BCP61 was purified from Bacillus sp. CS61 newly isolated from the traditional fermented food kimchi. BCP61 (ca. 1100Da) was purified to homogeneity using sequential chromatographic steps. It was found to be stable at pH 2.0–10.0 and up to 80°C. BCP61 displayed antimicrobial activity against MDR bacteria such as meticillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant S. aureus (VRSA) and vancomycin-resistant enterococci (VRE). Minimal inhibitory concentrations of BCP61 for MRSA, VRSA and VRE were in the range 0.625–20μg/mL. The N-terminal amino acid sequence of BCP61 was A-I-N-X-D-A-A-Y-L, which differed from reported AMPs. The fourth unidentified amino acid was replaced and several peptides were synthesised. Among them, only cysteine replacement displayed antimicrobial activity. BCP61 from a food-borne strain may be useful in therapeutic applications.

Corrigendum to “Potential protective role of linezolid against Clostridium difficile infection” [Int. J. Antimicrob. Agents. 39(5) (2012) 414–419] - Corrected Proof

2012-05-14

The authors regret the following error that was published in the abstract of the above paper. In the sentence that reads:

Human β-defensin-3 alters, but does not inhibit, the binding of Porphyromonas gingivalis haemagglutinin B to the surface of human dendritic cells - Corrected Proof

2012-05-11

Abstract: Human β-defensin-3 (HBD3) is a small, cationic, host defence peptide with broad antimicrobial activities and diverse innate immune functions. HBD3 binds to many microbial antigens and, in this study, we hypothesised that the known binding of HBD3 to Porphyromonas gingivalis recombinant haemagglutinin B (rHagB) alters, but does not inhibit, the binding of rHagB to human dendritic cells. To test this, human myeloid dendritic cells were incubated for 5min with rHagB, HBD3+rHagB (10:1 molar ratio), HBD3 or 0.1M phosphate-buffered saline (PBS) (pH 7.2) and were then rapidly fixed and processed for confocal microscopy and ultramicrotomy. rHagB and HBD3 could be detected with primary monoclonal mouse antibody to rHagB (MoAb 1858) or polyclonal rabbit antibody to HBD3 (P241) and secondary fluorescent-labelled anti-mouse or anti-rabbit antibodies (confocal microscopy) or protein A–colloidal gold (immunoelectron microscopy). In cells incubated with rHagB only, fluorescence and protein A–colloidal gold were seen at the cell surface and throughout the cytoplasm. In cells incubated with HBD3+rHagB, fluorescence was observed only at the cell surface in a ‘string of pearls’ configuration. Overall, these results suggest that HBD3 binding to rHagB alters, but does not inhibit, the binding of rHagB to human myeloid dendritic cells.

Comparison of the prevalence and changing resistance to nalidixic acid and ciprofloxacin of Shigella between Europe–America and Asia–Africa from 1998 to 2009 - Corrected Proof

2012-04-06

Abstract: Shigella is becoming an increasing public health problem due to development of multiple antimicrobial resistance, frequently resulting in treatment failure. A systematic review was conducted based on a literature search of computerised databases. Random or fixed-effects models were used, based on the P-value considering the possibility of heterogeneity between studies, for meta-analysis. Statistical analyses were performed using STATA 10.0. In the area of Asia–Africa, resistance rates to nalidixic acid and ciprofloxacin were 33.6% [95% confidence interval (CI) 21.8–46.6%] and 5.0% (95% CI 2.8–7.8%), respectively, 10.5 and 16.7 times those of Europe–America. Moreover, resistance to nalidixic acid and ciprofloxacin in Asia–Africa progressively increased each year, reaching 64.5% (95% CI 13.8–99.3%) and 29.1% (95% CI 0.9–74.8%), respectively, in 2007–2009, whilst isolates in Europe–America remained at low levels of resistance (<5.0% and <1.0%, respectively). All Shigella flexneri strains showed higher resistance than Shigella sonnei in Europe–America: overall, 3.5% (95% CI 1.4–6.4%) vs. 2.6% (95% CI 1.0–5.0%) resistant to nalidixic acid and 1.0% (95% CI 0.3–2.2%) vs. 0.1% (95% CI 0.0–0.3%) resistant to ciprofloxacin. In Asia–Africa, a similar trend was found for ciprofloxacin [3.0% (95% CI 1.4–5.3%) vs. 0.5% (95% CI 0.2–0.8%)], whereas the trend was reversed for nalidixic acid [32.6% (95% CI 14.5–53.9%) vs. 44.3% (95% CI 26.9–62.5%). In conclusion, quinolone resistance in Shigella has increased at an alarming speed, reinforcing the importance of continuous monitoring of antimicrobial resistance in Shigella.

Treatment failure and recurrence of Clostridium difficile infection following treatment with vancomycin or metronidazole: a systematic review of the evidence - Corrected Proof

2012-03-07

Abstract: The objective of this review was to evaluate the frequency of treatment failure and recurrence of Clostridium difficile infection (CDI) following treatment with vancomycin or metronidazole in recently performed studies (last 10 years). Searches in PubMed and Scopus were performed by two reviewers independently. Data regarding treatment failure and recurrence following metronidazole and vancomycin treatment were extracted and analysed. In total, 39 articles (7005 patients) were selected for inclusion in the systematic review. The reported treatment failure was 22.4% with metronidazole (16 studies) and 14.2% with vancomycin (8 studies). Recurrence of CDI occurred in 27.1% of patients following metronidazole treatment (18 studies) and 24.0% of patients following vancomycin treatment (8 studies). Mean treatment failure and recurrence in the selected studies was 22.3% (24 studies) and 22.1% (37 studies). The reported outcomes depended on the study design (higher in prospective and retrospective cohort studies than in randomised controlled trials), geographic location of the study (higher in North America than in Europe and Asia), funding (higher in studies funded by non-profit organisations than pharmaceutical companies), mean age of the studied population (higher in older patients) and duration of follow-up (higher in studies with follow-up >1 month). In conclusion, infection with C. difficile is associated with 22.4% and 14.2% treatment failure and 27.1% and 24.0% recurrence after treatment with metronidazole and vancomycin, respectively. The variation in the reported outcomes amongst studies depends on the study design, location, funding, age and follow-up period.

WITHDRAWN: Synergistic interaction of aciclovir and a helicase-primase inhibitor, BAY 57-1293, against herpes simplex virus type 1 - Corrected Proof

Manish Kumar, Hilary W. Thompson, Emily D. Varnell, Herbert E. Kaufman — 2009-01-27

This article has been withdrawn at the request of the author(s). The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

WITHDRAWN: High frequency of mutations in the rpoB gene in rifampicin-resistant clinical isolates of Mycobacterium tuberculosis from Iran - Corrected Proof

Farahnoosh Doustdar, Azar Dokht Khosravi, Parissa Farnia, Ahmad Reza Bahremand — 2007-10-16

This article has been withdrawn consistent with Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The Publisher apologizes for any inconvenience this may cause.