A. M. Lovering

Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis

Objective To systematically review the literature and, where appropriate, meta-analyse studies investigating subsequent antibiotic resistance in individuals prescribed antibiotics in primary care. Design Systematic review with meta-analysis. Data sources Observational and experimental studies identified through Medline, Embase, and Cochrane searches. Review methods Electronic searches using MeSH terms and text words identified 4373 papers. Two independent reviewers assessed quality of eligible studies and extracted data. Meta-analyses were conducted for studies presenting similar outcomes. Results The review included 24 studies; 22 involved patients with symptomatic infection and two involved healthy volunteers; 19 were observational studies (of which two were prospective) and five were randomised trials. In five studies of urinary tract bacteria (14 348 participants), the pooled odds ratio (OR) for resistance was 2.5 (95% confidence interval 2.1 to 2.9) within 2 months of antibiotic treatment and 1.33 (1.2 to 1.5) within 12 months. In seven studies of respiratory tract bacteria (2605 participants), pooled ORs were 2.4 (1.4 to 3.9) and 2.4 (1.3 to 4.5) for the same periods, respectively. Studies reporting the quantity of antibiotic prescribed found that longer duration and multiple courses were associated with higher rates of resistance. Studies comparing the potential for different antibiotics to induce resistance showed no consistent effects. Only one prospective study reported changes in resistance over a long period; pooled ORs fell from 12.2 (6.8 to 22.1) at 1 week to 6.1 (2.8 to 13.4) at 1 month, 3.6 (2.2 to 6.0) at 2 months, and 2.2 (1.3 to 3.6) at 6 months. Conclusions Individuals prescribed an antibiotic in primary care for a respiratory or urinary infection develop bacterial resistance to that antibiotic. The effect is greatest in the month immediately after treatment but may persist for up to 12 months. This effect not only increases the population carriage of organisms resistant to first line antibiotics, but also creates the conditions for increased use of second line antibiotics in the community.

Linezolid-induced inhibition of mitochondrial protein synthesis.

BACKGROUND Linezolid is an oxazolidinone antibiotic that is increasingly used to treat drug-resistant, gram-positive pathogens. The mechanism of action is inhibition of bacterial protein synthesis. Optic and/or peripheral neuropathy and lactic acidosis are reported side effects, but the underlying pathophysiological mechanism has not been unravelled. METHODS We studied mitochondrial ultrastructure, mitochondrial respiratory chain enzyme activity, and mitochondrial DNA (mtDNA) in muscle, liver, and kidney samples obtained from a patient who developed optic neuropathy, encephalopathy, skeletal myopathy, lactic acidosis, and renal failure after prolonged use of linezolid. In addition, we evaluated mtDNA, respiratory chain enzyme activity, and protein amount in muscle and liver samples obtained from experimental animals that received linezolid or placebo. RESULTS In the patient, mitochondrial respiratory chain enzyme activity was decreased in affected tissues, without ultrastructural mitochondrial abnormalities and without mutations or depletion of mtDNA. In the experimental animals, linezolid induced a dose- and time-dependent decrease of the activity of respiratory chain complexes containing mtDNA-encoded subunits and a decreased amount of protein of these complexes, whereas the amount of mtDNA was normal. CONCLUSION These results provide direct evidence that linezolid inhibits mitochondrial protein synthesis with potentially severe clinical consequences. Prolonged courses of linezolid should be avoided if alternative treatment options are available.

What is the evidence base to guide surgical treatment of infected hip prostheses? systematic review of longitudinal studies in unselected patients

BackgroundProsthetic joint infection is an uncommon but serious complication of hip replacement. There are two main surgical treatment options, with the choice largely based on the preference of the surgeon. Evidence is required regarding the comparative effectiveness of one-stage and two-stage revision to prevent reinfection after prosthetic joint infection.MethodsWe conducted a systematic review to identify randomised controlled trials, systematic reviews and longitudinal studies in unselected patients with infection treated exclusively by one- or two-stage methods or by any method. The Embase, MEDLINE and Cochrane databases were searched up to March 2011. Reference lists were checked, and citations of key articles were identified by using the ISI Web of Science portal. Classification of studies and data extraction were performed independently by two reviewers. The outcome measure studied was reinfection within 2 years. Data were combined to produce pooled random-effects estimates using the Freeman-Tukey arc-sine transformation.ResultsWe identified 62 relevant studies comprising 4,197 patients. Regardless of treatment, the overall rate of reinfection after any treatment was 10.1% (95% CI = 8.2 to 12.0). In 11 studies comprising 1,225 patients with infected hip prostheses who underwent exclusively one-stage revision, the rate of reinfection was 8.6% (95% CI = 4.5 to 13.9). After two-stage revision exclusively in 28 studies comprising 1,188 patients, the rate of reinfection was 10.2% (95% CI = 7.7 to 12.9).ConclusionEvidence of the relative effectiveness of one- and two-stage revision in preventing reinfection of hip prostheses is largely based on interpretation of longitudinal studies. There is no suggestion in the published studies that one- or two stage methods have different reinfection outcomes. Randomised trials are needed to establish optimum management strategies.

The role of microbial biofilms in prosthetic joint infections

Abstract — Prosthetic joint infection (PJI) still remains a significant problem. In line with the forecasted rise in joint replacement procedures, the number of cases of PJI is also anticipated to rise. The formation of biofilm by causative pathogens is central to the occurrence and the recalcitrance of PJI. The subject of microbial biofilms is receiving increasing attention, probably as a result of the wide acknowledgement of the ubiquity of biofilms in the natural, industrial, and clinical contexts, as well as the notorious difficulty in eradicating them. In this review, we discuss the pertinent issues surrounding PJI and the challenges posed by biofilms regarding diagnosis and treatment. In addition, we discuss novel strategies of prevention and treatment of biofilm-related PJI.

The effect of surgical approach on blood flow to the femoral head during resurfacing

We determined the effect of the surgical approach on perfusion of the femoral head during hip resurfacing arthroplasty by measuring the concentration of cefuroxime in bone samples from the femoral head. A total of 20 operations were performed through either a transgluteal or an extended posterolateral approach. The concentration of cefuroxime in bone was significantly greater when using the transgluteal approach (mean 15.7 mg/kg; 95% confidence interval 12.3 to 19.1) compared with that using the posterolateral approach (mean 5.6 mg/kg; 95% confidence interval 3.5 to 7.8; p < 0.001). In one patient, who had the operation through a posterolateral approach, cefuroxime was undetectable. Using cefuroxime as an indirect measure of blood flow, the posterolateral approach was found to be associated with a significant reduction in the blood supply to the femoral head during resurfacing arthroplasty compared with the transgluteal approach.

Development and evaluation of vancomycin dosage guidelines designed to achieve new target concentrations

OBJECTIVES The aims of this study were to develop a population pharmacokinetic model of vancomycin in adult patients, to use this model to develop dosage guidelines targeting vancomycin trough concentrations of 10-15 mg/L and to evaluate the performance of these new guidelines. METHODS All data analyses were performed using NONMEM. A population pharmacokinetic model was first developed from vancomycin dosage and concentration data collected during routine therapeutic drug monitoring in 398 patients, then new vancomycin dosage guidelines were devised by using the model to predict vancomycin trough concentrations in a simulated dataset. Individual estimates of CL and V1 were then obtained in an independent group of 100 patients using the population model and the POSTHOC option. These individual estimates were used to predict vancomycin trough concentrations and steady-state AUC(24)/MIC ratios using the current and new dosage guidelines. RESULTS The population analysis found that the vancomycin data were best described using a bi-exponential elimination model with a typical CL of 3.0 L/h that changed by 15.4% for every 10 mL/min difference from a CL(CR) of 66 mL/min. V(ss) was 1.4 L/kg. The proposed dosage guidelines were predicted to achieve 55% of vancomycin troughs within 10-15 mg/L and 71% within 10-20 mg/L, which is significantly higher than current guidelines (19% and 22%, respectively). The proportion of AUC(24)/MIC ratios above 400 was also higher, 87% compared with 58%. CONCLUSIONS New vancomycin dosage guidelines have been developed that achieve trough concentrations of 10-15 mg/L earlier and more consistently than current guidelines.

Does laboratory antibiotic susceptibility reporting influence primary care prescribing in urinary tract infection and other infections

OBJECTIVES Using a prospective interrupted time series design, our goal was to determine whether a change in urine antibiotic susceptibility reporting from co-amoxiclav to cefalexin to community clinicians served by Southmead General Hospital led to a change in antibiotic prescribing. METHODS We used longitudinal data on antibiotic prescribing using a clinician questionnaire to identify prescribing for urinary tract infections (UTIs) when a urine specimen was submitted to microbiology; MIQUEST computer search in general practices for prescribing for all UTIs in the community; and Prescribing Analysis and Cost (PACT) data to determine antibiotic prescribing for all infections. RESULTS Cefalexin and cephalosporin prescribing increased when cefalexin was reported and co-amoxiclav prescribing decreased when co-amoxiclav was not reported by the laboratory. This was seen for episodes of UTI in which a general practitioner (GP) sent a specimen as determined with: the questionnaire results (9-fold rise in cephalosporins, 70% fall in co-amoxiclav); episodes of UTI identified by MIQUEST searches in the practice (50% increase in cefalexin, 25% reduction in co-amoxiclav); and overall antibiotic prescribing in the practice determined with PACT data (20% increase in cefalexin, 8% reduction in co-amoxiclav). MIQUEST data indicated that prescribing reverted to pre-intervention levels once the change in antibiotic reporting had stopped. CONCLUSIONS Our data provide more evidence that changing laboratory antibiotic susceptibility reporting has a direct effect on antibiotic prescribing by GPs. Our data indicate that much of the change in prescribing was attributable to the use of cefalexin and co-amoxiclav for persistent or recurrent infections. Microbiology laboratories can influence antibiotic use by selectively reporting antibiotics they would prefer GPs to prescribe.

Pharmacokinetic evaluation of linezolid in patients with major thermal injuries

AIMS To evaluate the pharmacokinetics of linezolid following its administration in patients with major thermal injuries and in a group of healthy volunteers. METHODS In an open-label, multicentre design with two parallel groups, a group of patients with major thermal injuries (>20% body area) and a group of age-, sex- and weight-matched healthy volunteers, subjects received a single 600 mg intravenous dose of linezolid. Serial blood and urine collections were made and the concentrations of linezolid in these samples were determined by HPLC. Non-compartmental analyses were used to describe the pharmacokinetic disposition of linezolid. RESULTS C(max) concentrations and the volume of distribution at steady state (V(ss)) were not statistically different (P > 0.05) between the two groups of subjects. In contrast, values describing clearance [elimination rate constant (k(el)), t(1/2) and mean residence time (MRT)] were significantly different (P < 0.05) in patients with thermal injuries compared with volunteers, which lead to an approximate reduction by half in AUC(0-infinity) from 98.1 mg.h/L (volunteers) to 42.5 mg.h/L (patients). Although renal clearance was similar in the two groups (24.7 +/- 23 versus 30.6 +/- 14.3 mL/min; P = 0.156), non-renal clearance was substantially increased (323 +/- 191 versus 80.4 +/- 27.5 mL/min) in the patients with thermal injuries, though this difference did not achieve statistical significance (P = 0.063). CONCLUSIONS The pharmacokinetics of linezolid are altered in patients with major thermal injuries, mainly as a result of increased non-renal clearance. These changes are of sufficient magnitude that linezolid concentrations may be sub-therapeutic in some patients and we suggest that the dosage interval may need to be decreased in this patient population.

Evaluation of linezolid for the treatment of Clostridium difficile infection caused by epidemic strains using an in vitro human gut model

OBJECTIVES Therapeutic options in Clostridium difficile infection (CDI) are limited. We examined linezolid activity in vitro and potential therapeutic efficacy using a gut model of CDI. METHODS MICs were determined by agar incorporation for 118 diverse C. difficile faecal isolates, including epidemic strains and strains with reduced susceptibility to metronidazole. CDI was established in two gut model experiments using C. difficile epidemic strains (ribotypes 027 and 106) and linezolid was dosed to achieve human gut concentrations. RESULTS Linezolid demonstrated good in vitro activity against 98% of the isolates. Two isolates (PCR ribotypes 023 and 067) demonstrated resistance to linezolid, although supplementary susceptibility testing of ribotype 023 isolates did not detect further resistance. In a gut model that simulates CDI, linezolid reduced the duration of cytotoxin production by C. difficile PCR ribotype 027 without influencing viable counts of vegetative forms of the organism. C. difficile PCR ribotype 106 viable counts declined at a faster rate than those of PCR ribotype 027 following dosing with linezolid, but cytotoxin titres declined at a similar rate to an untreated control. Gut flora perturbation occurring on linezolid exposure reversed after drug cessation. Recrudescence of spore germination with subsequent cytotoxin was seen with the C. difficile ribotype 106 strain. Resistance to linezolid was not detected either during linezolid instillation or post-dosing. CONCLUSIONS Linezolid may reduce toxin levels, as reported in staphylococci and streptococci. Further evaluation is warranted of the effect of linezolid on expression of C. difficile toxin, and to investigate potential recurrence of CDI following cessation of linezolid.

Effect of antibiotic prescribing in primary care on meticillin-resistant Staphylococcus aureus carriage in community-resident adults: a controlled observational study

The objectives of this study were to investigate the relationship between primary care antibiotics prescribed within 2 months and 12 months and the carriage of meticillin-resistant Staphylococcus aureus (MRSA) in nasal flora from a large representative sample of community-resident adults. S. aureus isolates were obtained from nasal samples submitted by UK resident adults aged ≥ 16 years registered with 12 general practices in the former Avon and Gloucestershire health authority areas. Individual-level antibiotic exposure data during the 12 months prior to providing the samples were collected from the primary care electronic records. MRSA status was determined by measuring resistance to cefoxitin. In total, 6937 adults were invited to take part, of whom 5917 returned a nasal sample. S. aureus was identified in 946 samples and a total of 761 participants consented to primary care record review and had complete data for the analyses. There was no evidence of an association between any antibiotic in the previous 2 months and MRSA isolation, with an adjusted odds ratio (aOR) of 1.33 [95% confidence interval (CI) 0.12-15; P=0.8]. There was a suggestion of an association between any antibiotic use in the previous 12 months and MRSA, with an aOR of 2.45 (95% CI 0.95-6.3; P=0.06). In conclusion, there is a suggestion that antibiotics prescribed within 12 months is associated with the carriage of MRSA, but not within 2 months, although the 2-month analysis had fewer data subjects and was therefore underpowered to detect this association. A larger study would be able to clarify these associations further.