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Mark H Wilcox

Publications and source records attributed to Mark H Wilcox.

At least 19 recordsLinked to original sources
PubMed2006

Tigecycline does not induce proliferation or cytotoxin production by epidemic Clostridium difficile strains in a human gut model.

OBJECTIVES: Data on the risk of Clostridium difficile infection (CDI) associated with specific antibiotics are difficult to obtain because of confounding clinical factors. It is particularly important to evaluate the propensity of new antibiotics to induce CDI. We have examined the propensity of tigecycline to induce CDI using a human gut model. METHODS: We used a three-stage chemostat human gut model to study the effects of tigecycline on indigenous gut microflora and C. difficile. Two epidemic C. difficile were studied in separate experiments: PCR ribotype 001 (UK, CD001) and PCR ribotype 027 (North America, CD027). Tigecycline MICs for 39 C. difficile representing 19 distinct PCR ribotypes were also determined. RESULTS: Tigecycline MICs were 0.06 mg/L for all the C. difficile strains. Peak tigecycline concentrations in the gut model were 10.9 and 11.7 mg/L in CD027 and CD001 experiments, respectively. Tigecycline instillation invoked marked decreases in numbers of bacteroides and bifidobacteria (10(7)-10(8) cfu/mL) and lesser reductions in facultative anaerobes. Despite markedly altered gut microflora, CD001 and CD027 remained as spores for the duration of the experiment, with no evidence of proliferation or cytotoxin production. CONCLUSIONS: Tigecycline exposure did not induce C. difficile proliferation or cytotoxin production despite reduced competing microflora. The potency of tigecycline against C. difficile may contribute to the low risk of CDI induction. Factors other than gut microflora colonization resistance may be important in preventing C. difficile spore germination, proliferation and cytotoxin production.

Anti-Bacterial Agents↗
PubMed2006

Measurement of ampicillin, vancomycin, linezolid and gentamicin activity against enterococcal biofilms.

BACKGROUND: Enterococci frequently cause biofilm infections but susceptibility of clinical isolates growing in biofilms has not been investigated. The minimum biofilm eradicating concentration (MBEC) has been suggested as a guide to treatment of biofilm infections. We measured an alternative endpoint, the minimum biofilm inhibitory concentration (MBIC) and compared the results with MIC and MBC. OBJECTIVES: To compare the MIC, MBC and MBIC of ampicillin, vancomycin and linezolid against enterococcal biofilms, to assess the impact of additional gentamicin and correlate findings with clinical outcome. METHODS: MIC and MBC were measured using standard techniques. MBICs were measured using a modification of the Calgary biofilm device method. Fifty-eight enterococcal isolates from episodes of intravascular catheter-related bloodstream infection were tested. RESULTS: Tolerance to ampicillin, vancomycin and linezolid was seen in 93%, 100% and 93% of isolates, respectively. MIC(90)s of ampicillin, vancomycin and linezolid were all 4 mg/L for Enterococcus faecalis isolates. MBC(90)s of ampicillin, vancomycin and linezolid for E. faecalis isolates were 1024, >128 and 2048 mg/L, respectively. MBIC(90)s of ampicillin, vancomycin and linezolid for E. faecalis isolates were 8192, 4096 and 4096 mg/L, respectively. Results for Enterococcus faecium were similar for vancomycin and linezolid but this species was generally more resistant to ampicillin. Adding 10 mg/L gentamicin had a variable effect on MIC, MBC or MBIC, which was not predictable by gentamicin susceptibility on disc testing. CONCLUSIONS: Very high concentrations of ampicillin, vancomycin and linezolid are required to inhibit enterococcal biofilms in vitro. Combining these agents with gentamicin significantly reduced MIC, MBC and MBIC against only a proportion of enterococcal isolates. No correlation between MBIC and outcome was found.

Acetamides↗
PubMed2006

Tigecycline and the need for a new broad-spectrum antibiotic class.

BACKGROUND: Lack of progress in developing new antimicrobials, particularly new classes, as opposed to variants of existing agents, has contributed to the emergence of antibiotic-resistant pathogens. METHODS: Data synthesis after review of pertinent English-language literature. RESULTS: The development of new classes of antimicrobial agents is crucial, considering the increasing prevalence of nosocomial pathogens resistant to empiric as well as second- and third-line antibiotic choices. Tigecycline has recently been approved for the treatment of complicated skin and skin structure as well as intra-abdominal infections. Published data on the in vitro and in vivo properties of tigecycline, the first-in-class glycylcycline, are reviewed. CONCLUSION: It is plausible that tigecycline could to some extent replace available broadspectrum agents for approved indications and thereby reduce the selective pressure for some currently prevalent multi-resistant pathogens in the hospital setting.

Anti-Bacterial Agents↗
PubMed2005

Comparison of the efficacy of ramoplanin and vancomycin in both in vitro and in vivo models of clindamycin-induced Clostridium difficile infection.

OBJECTIVES: Treatment of Clostridium difficile infection (CDI) is limited primarily to either metronidazole or vancomycin. We compared vancomycin and a novel glycolipodepsipeptide, ramoplanin, in both hamster and in vitro gut models of clindamycin-induced CDI. METHODS: We used an in vitro triple-stage chemostat model that simulates the human gut, and an in vivo hamster model, both primed with clindamycin. RESULTS: Clindamycin exposure elicited symptomatic disease in the hamster model, and promoted C. difficile germination and toxin production in the gut model. C. difficile germination and toxin production were not associated with depletion of gut microflora in the gut model, but were temporarily associated with subinhibitory concentrations of clindamycin. Both ramoplanin and vancomycin were associated with rapid symptom resolution in the hamster model, and rapid toxin titre decrease in the in vitro gut model. In both models of CDI, vancomycin was associated with greater persistence of C. difficile spores. C. difficile spores were recovered significantly more often from the caecal contents of vancomycin-treated (n = 19/23) compared with ramoplanin-treated (n = 6/23) hamsters (P < 0.05). CONCLUSIONS: Results from the in vitro gut and hamster models were concordant. Ramoplanin and vancomycin were similarly effective at reducing cytotoxin production in the gut CDI model and in resolving symptoms in the hamster model. Ramoplanin may be more effective than vancomycin at killing spores and preventing spore recrudescence. These findings suggest a potential therapeutic role for ramoplanin in CDI that requires further clinical investigation.

Animals↗
PubMed2005

Effects of piperacillin/tazobactam on Clostridium difficile growth and toxin production in a human gut model.

OBJECTIVES: Clostridium difficile infection (CDI) is a major cause of morbidity in the nosocomial environment. Antimicrobial agents such as the third-generation cephalosporins, lincosamides and aminopenicillins are well known for their propensity to induce CDI, but the definitive reasons why remain to be elucidated. Despite their broad spectrum of activity against both aerobic and anaerobic bacteria, the ureidopenicillins remain a class of antimicrobials infrequently associated with the development of CDI. METHODS: We used a triple-stage chemostat model that simulates the human gut to study the effects of the ureidopenicillin/beta-lactamase inhibitor combination piperacillin/tazobactam on gut bacterial populations and C. difficile. RESULTS: Piperacillin/tazobactam rapidly reduced all enumerated gut bacterial populations (including bacteroides, bifidobacteria and lactobacilli) below the limits of detection by the end of the piperacillin/tazobactam instillation period. Despite such widespread disruption of gut bacterial populations, C. difficile populations remained principally as spores, with no sustained proliferation or high-level cytotoxin production observed. CONCLUSIONS: Factors other than reduced colonization resistance must be responsible for determining whether CDI develops following antimicrobial administration. We believe the gut model is a promising approach for the study of C. difficile pathogenesis reflecting in vivo events likely to occur in CDI.

Anti-Bacterial Agents↗
PubMed2005

In situ diagnosis of intravascular catheter-related bloodstream infection: a comparison of quantitative culture, differential time to positivity, and endoluminal brushing.

OBJECTIVE: To compare the accuracy of three techniques that do not require central venous catheter removal to diagnose catheter-related bloodstream infection. DESIGN: Prospective cohort study of central venous catheters from suspected cases of catheter-related bloodstream infection. SETTING: University teaching hospital. PATIENTS: One hundred and twenty-five central venous catheters from patients with suspected catheter-related bloodstream infection (a raised peripheral white blood cell count, temperature >37 degrees C, and/or local signs of infection at the catheter skin entry site) in intensive care and surgical patients in a large teaching hospital were assessed. INTERVENTIONS: None. MEASUREMENTS: Three techniques were compared: the differential time to positivity of central venous catheter vs. peripheral-blood cultures, quantitative culture of central venous catheter vs. peripheral blood, and the endoluminal brush with peripheral blood culture. MAIN RESULTS: Central venous catheters with a median dwell time of 11 days were examined. There were 36 episodes of catheter-related bloodstream infection, defined as a positive result from at least two of the three tests in the presence of a peripheral blood culture growing the same microorganism and without an identifiable alternative source of sepsis. The sensitivities of the endoluminal brush, quantitative culture, and differential time to positivity techniques were 100%, 89%, and 72%, respectively, with corresponding specificities of 89%, 97%, and 95%. Blood could be directly aspirated from only 231 of 312 (74%) lumens. In the 20 cases of catheter-related bloodstream infection associated with multiple-lumen central venous catheters, endoluminal brushing was positive for one, two, and three lumens in nine (45%), six (30%), and five (25%) cases, respectively. CONCLUSIONS: All three techniques had relatively high sensitivity. However, inability to obtain samples via central venous catheters is a major drawback of the differential time to positivity and quantitative blood culture approaches. Differential time to positivity is simple to perform and has high specificity and therefore could be used as a first line approach, with the endoluminal brush reserved for cases where blood cannot be obtained. All lumens of multiple-lumen central venous catheters must be sampled to ensure maximal sensitivity.

Bacteremia↗
PubMed2005

Molecular epidemiology of endemic Clostridium difficile infection and the significance of subtypes of the United Kingdom epidemic strain (PCR ribotype 1).

We previously identified two subtypes of the epidemic strain Clostridium difficile PCR ribotype 1, one clindamycin-sensitive strain (arbitrarily primed PCR [AP-PCR] type Ia) and a closely related clindamycin-resistant strain (AP-PCR type Ib) in our institution. We have now carried out prospective epidemiological surveillance for 4 years, immediately following the relocation of two acute medicine wards for elderly patients (wards A and B), to determine the clinical epidemiology of subtypes of the epidemic C. difficile PCR ribotype 1 group. To maximize the chance of strain discrimination, we used three DNA fingerprinting methods, AP-PCR, ribospacer PCR (RS-PCR), and pulsed-field gel electrophoresis (PFGE), to analyze C. difficile isolates recovered from symptomatic patients and from repeated environmental samplings. On ward B the incidence of C. difficile infection correlated significantly with the prevalence of environmental C. difficile both in ward areas closely associated with patients and health care personnel (r = 0.53; P < 0.05) and in high-reach sites (r = 0.85; P < 0.05). No such relationships were found on ward A. Seventeen distinct C. difficile genotypes were identified, 17 by AP-PCR, 12 by PFGE, and 11 by RS-PCR, but only 4 of 17 genotypes caused patient infection. Isolates recovered from the hospital ward environment were much more diverse (14 genotypes). AP-PCR type Ia represented >90% of the C. difficile isolates. In addition to this genotype, only two others were isolated from both patient feces and environmental surfaces. AP-PCR type Ib (clindamycin-resistant PCR ribotype 1 clone) was not associated with any cases of C. difficile infection and was isolated from the environment on only two occasions, after having been implicated in a cluster of six C. difficile infections 5 months before this study. The disappearance of this strain implies that differences in virulence and/or selective pressures may exist for this strain and the closely related, widespread C. difficile AP-PCR type Ia strain. Our findings emphasize the need to understand the epidemiology and virulence of clinically significant strains to determine successful control measures for C. difficile infections.

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PubMed2005

Antibiotic prescribing as a risk factor for MRSA.

There is accumulating evidence to support the role of specific antibiotic classes as risk factors for selecting meticillin-resistant Staphylococcus aureus (MRSA). Crucially, however, controlled studies of antimicrobial prescribing interventions are lacking. The evidence for the association between antimicrobial prescribing and expansion of MRSA is reviewed here.

Anti-Bacterial Agents↗
PubMed2005

Update on linezolid: the first oxazolidinone antibiotic.

Linezolid is the first of an entirely new class of antibiotics, the oxazolidinones, in decades. It has a spectrum of activity against virtually all important Gram-positive pathogens. The unique mechanism of action of linezolid makes cross-resistance with other antimicrobial agents unlikely. Linezolid has both intravenous and oral formulations and the latter is 100% bioavailable. Since its first approval and marketing in March 2000 in the US, linezolid has gained approval for use in many other countries for the treatment of community-acquired and nosocomial pneumonia, complicated and uncomplicated skin and soft-tissue infections, and infections caused by methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, including cases with concurrent bacteraemia. Several earlier comprehensive reviews summarised the chemistry, mechanism of action, pharmacokinetics, clinical efficacy and safety profile of linezolid. The present review provides an update on the latest data regarding the antimicrobial activity of linezolid versus other commonly used agents, the clinical and health-economic outcomes of linezolid versus vancomycin and teicoplanin, and safety issues.

Acetamides↗
PubMed2004

Long-term surveillance of cefotaxime and piperacillin-tazobactam prescribing and incidence of Clostridium difficile diarrhoea.

OBJECTIVES: We followed the effects of changes to a new antibiotic policy favouring a ureidopenicillin as opposed to a third-generation cephalosporin on the long-term incidence of Clostridium difficile diarrhoea (CDD) and antibiotic utilization in a large Elderly Medicine Unit. PATIENTS AND METHODS: In 1999, piperacillin-tazobactam was added to the formulary in Elderly Medicine and its use promoted in preference to cefotaxime. Following review and feedback to clinicians of surveillance data, cefotaxime prescribing was actively restricted during 2000-2001. An audit of prescriber adherence to antibiotic policy was carried out by reviewing the records of 159 patients during February-April 2001. In December 2001, due to manufacturer production problems, supply of piperacillin-tazobactam was stopped. We performed standardized period prevalence surveillance (February-April) allowing comparisons of antibiotic utilization and CDD incidence during the 5 year study period (1998-2002). RESULTS: CDD incidence did not change significantly (P>0.1) during 1998-1999 despite a marked increase in piperacillin-tazobactam prescribing. However, when cefotaxime prescribing was curtailed in 2001, CDD rates decreased (in four of five wards) and overall by 52% (P=0.008). When piperacillin-tazobactam became unavailable in 2002, despite advice to the contrary cefotaxime prescribing rose five-fold, and CDD rates increased in four of five wards and by 232% (P<0.01) overall. Adherence to antibiotic policy introduced in 2000 was good (81% accordance); 94%, 88% and 73% of patients with cellulitis, urinary tract and respiratory tract infection, respectively, received appropriate antibiotics. CONCLUSIONS: Long-term prescribing of piperacillin-tazobactam in Elderly Medicine in preference to cefotaxime is associated with reduced rates of CDD. However, unless cephalosporin prescribing is curtailed, the beneficial effects on CDD rates may be missed. This is one of few studies to document adverse effects due to loss of antibiotic supply.

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PubMed2004

Descriptive study of intravenous immunoglobulin for the treatment of recurrent Clostridium difficile diarrhoea.

OBJECTIVES: Clostridium difficile diarrhoea (CDD) cases treated with intravenous immunoglobulin during a 2 year period were reviewed to determine disease severity and response to treatment. PATIENTS AND METHODS: Of 580 CD cytotoxin-positive patients, five received intravenous immunoglobulin because of protracted and/or recurrent CDD (median duration 50 days, range 45-64); two had biopsy- proven pseudomembranous colitis. The five patients received a median three non-CDD antibiotic courses (range 2-8). Indices of CDD severity included hypoalbuminaemia (n = 5, median 27 g/L, range 11-29), marked hypokalaemia (n = 3, range 1.9-2.7 mM), markedly raised peripheral white cell count (n = 3, 18-34 x 10(9) cells/L), abdominal signs (n = 3) and pyrexia (n = 1). The five cases received metronidazole for median 17 days (range 0-63) plus vancomycin for median 14 days (range 10-42) before intravenous immunoglobulin. One also received rifampicin plus vancomycin and one was given Saccharomyces boulardii. RESULTS: Intravenous immunoglobulin was given at a dosage of 300-500 mg/kg (most commonly 400 mg/kg) for one dose (two patients), two doses (two patients) and in one case for six doses. The latter patient died of intractable CDD, three had a good therapeutic response to intravenous immunoglobulin and CDD recurred within 6 weeks in one case. In the three successfully treated cases, CDD resolved within 11 days. CONCLUSIONS: Intravenous immunoglobulin is useful for the treatment of intractable and severe CDD. Controlled studies are needed to assess the true value of this and other forms of passive immunotherapy.

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PubMed2004

Health-care-associated infection: morbidity, mortality and costs.

Health-care-associated infection is rightly an area of increasing attention, not least because of considerable resource issues. Not all infection is preventable. However, much is possible and is indeed obligatory to avoid unnecessary infection, and attendant morbidity, mortality and, increasingly, litigation.

Costs and Cost Analysis↗
PubMed2003

Effects of cefotaxime and desacetylcefotaxime upon Clostridium difficile proliferation and toxin production in a triple-stage chemostat model of the human gut.

Clostridium difficile is recognized as an important nosocomial pathogen. C. difficile infection (CDI) is thought to arise as a result of depletion of the normal gut flora by antimicrobial agents. Cefotaxime (CTX) is well-known for its propensity to cause CDI, but the reasons behind its particular predisposition to the disease remain unclear. Previous investigations have so far relied upon the hamster model of CDI or human volunteers. We have used a triple-stage chemostat model of the human gut to investigate the behaviour of C. difficile and components of the normal gut flora, in response to exposure to CTX alone, and in combination with its active metabolite desacetylcefotaxime (dCTX). C. difficile remained in a steady state during non-antibiotic exposed periods, with no detectable cytotoxin. During both antibiotic exposure regimens, proliferation of C. difficile and elevated cytotoxin levels were observed. Cessation of antibiotic instillation produced a reduction in cytotoxin levels and viable counts. Decreases in bacterial counts were observed in response to both antibiotic exposure regimens, notably for bifidobacteria and bacteroides. Numbers of bacteroides were profoundly affected by exposure to the CTX/dCTX combination, and this may indicate a possible role for bacteroides in colonization resistance. We believe that the gut model is a promising method for studying C. difficile pathogenesis in conditions analogous to the in vivo situation.

Bacterial Toxins↗
PubMed2003

Gastrointestinal disorders and the critically ill. Clostridium difficile infection and pseudomembranous colitis.

Clostridium difficile causes a spectrum of diseases ranging from diarrhoea to pseudomembranous colitis, primarily in the hospitalized elderly, although community-acquired infection is probably under-documented. Host factors are increasingly recognized as critical determinants of disease expression. Exposure to antibiotics, particularly those adversely affecting anaerobic gut flora, appears to create a niche which is exploited by C. difficile. Several retrospective and intervention studies have indicated that third-generation cephalosporins have a high propensity to induce C. difficile diarrhoea. Conversely, some broad-spectrum antibiotics, including ureidopenicillins (e.g. piperacillin-tazobactam) and ciprofloxacin, are less likely to induce C. difficile infection. Effective control of C. difficile in the hospital requires both antibiotic control and prevention of environmental seeding and bacterial spread. Epidemic C. difficile strains are widely distributed in the hospital environment, both as a cause and result of nosocomial diarrhoea. Current treatment options are antibiotic-based, which is less than ideal. Although many biotherapeutic approaches have been tried few have shown real benefit.

Clostridioides difficile↗
PubMed2003

Efficacy of linezolid versus comparator therapies in Gram-positive infections.

Treatment of Gram-positive bacterial infections is currently a therapeutic challenge because many of these pathogens are now resistant to standard antimicrobial agents. The emergence of multidrug-resistant, Gram-positive pathogens emphasizes the need for new antimicrobial therapy. Linezolid is an oxazolidinone antibiotic with a novel mechanism of action that works by inhibiting bacterial protein synthesis by blocking formation of the initiation complex. It is active against Gram-positive organisms resistant to other antibiotics, including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae and vancomycin-resistant enterococci (VRE). Results are encouraging from several large-scale, randomized, Phase III trials comparing the efficacy and safety of linezolid with standard comparator agents for the treatment of nosocomial pneumonia, community-acquired pneumonia, skin and skin structure infections, and infections due to MRSA and VRE. Intravenous/oral linezolid is a promising antimicrobial agent and provides the clinician with an additional treatment option, particularly among the limited therapies for resistant Gram-positive bacterial infections.

Acetamides↗
PubMed2003

Each lumen is a potential source of central venous catheter-related bloodstream infection.

OBJECTIVE: To determine the relative rates of microbial colonization of individual lumens in triple-lumen central venous catheters (CVCs) and calculate the chance of detecting catheter-related blood stream infection (CRBSI) if only one lumen is sampled. DESIGN: Prospective evaluation of CVCs from suspected and nonsuspected CRBSI cases. SETTING: University teaching hospital. PATIENTS: Triple-lumen CVCs from 50 cases of suspected CRBSI (a raised peripheral white blood cell count, temperature >37 degrees C, and/or local signs of infection at the catheter skin entry site) were evaluated. For comparison, 50 triple-lumen CVCs routinely removed at the end of use were evaluated. MEASUREMENTS: In both groups, peripheral blood cultures were taken before CVC removal. After CVC removal, each lumen was sampled in vitro using the endoluminal brush, and the tip was then cultured using the Maki roll technique. MAIN RESULTS: CVCs causing CRBSI had significant microbial colonization in one, two, or three lumens in ten (40%), ten (40%), or five (20%) cases, respectively. Overall, random sampling of only one lumen in CVCs causing CRBSI had a 60% chance of detecting significant colonization. CONCLUSIONS: If only one CVC lumen is sampled, a negative result does not reliably rule out infection. Each lumen of multiple-lumen CVCs should be considered as a potential source of CRBSI.

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