Xenorhabdus antibiotics: a comparative analysis and potential utility for controlling mastitis caused by bacteria

Xenorhabdus antibiotics: a comparative analysis and potential utility for controlling mastitis caused by bacteria

J Appl Microbiol. 2007 Nov 1

Furgani G, Böszörményi E, Fodor A, Máthé-Fodor A, Forst S, Hogan JS, Katona Z, Klein MG, Stackebrandt E, Szentirmai A, Sztaricskai F, Wolf SL.

Department of Genetics, Faculty of Natural Sciences, Eötvös University, Budapest, Hungary.

Aims: The role of antibiotics produced by bacterial symbionts of entomopathogenic nematodes is to suppress growth of microbes in the soil environment. These antibiotics are active against Gram-positive and Gram-negative bacteria, and were tested against mastitis isolates from dairy cows.

Methods and Results: Two bioassays were adapted for Xenorhabdus antibiotics; an overlay method on agar plates, and serially diluted, cell-free, Xenorhabdus cultures. The antimicrobial activities of the liquid cultures of 13 strains from five Xenorhabdus species were further evaluated. Antimicrobial activities of the type strains of X. nematophila, X. budapestensis and X. szentirmaii were tested on mastitis isolates of Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae with both bioassays. A previously reported antibiotic from X. nematophila, nematophin, was synthesized in three steps from tryptamine and 4-methyl-2-oxovaleric acid sodium salt.

Conclusions: The antibiotics of all three Xenorhabdus strains were powerful in either bioassay, but the sensitivity of the isolates differed from each other. While Kl. pneumoniae was the least susceptible, Staph. aureus had the highest sensitivity to each Xenorhabdus strain. Xenorhabdus szentirmaii and X. budapestensis were more potent antibiotic producers than X. nematophila, and raceme nematophin was ineffective against all mastitis isolates.

Significance and Impact of the Study: These results indicate that Xenorhabdus antibiotics are effective against mastitis isolates and should be further evaluated for their potential in mastitis control or prevention.

PMID: 17976177 [PubMed - as supplied by publisher]

Antibiotic resistant Staphylococcus aureus: a paradigm of adaptive power.

Antibiotic resistant Staphylococcus aureus: a paradigm of adaptive power.

Curr Opin Microbiol. 2007 Oct 5

de Lencastre H, Oliveira D, Tomasz A.

Laboratory of Microbiology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA; Laboratory of Molecular Genetics, Instituto de Tecnologia Química e Biológica (ITQB) da Universidade Nova de Lisboa (UNL), 2780 Oeiras, Portugal.

Nothing documents better the spectacular adaptive capacity of Staphylococcus aureus than the response of this important human and animal pathogen to the introduction of antimicrobial agents into the clinical environment. The effectiveness of penicillin introduced in the early 1940s was virtually annulled within a decade because of the plasmid epidemics that spread the ss-lactamase gene through the entire species of S. aureus. In 1960 within one to two years of the introduction of penicillinase resistant ss-lactams (methicillin), methicillin resistant S. aureus (MRSA) strains were identified in clinical specimens. By the 1980s, epidemic clones of MRSA acquired multidrug resistant traits and spread worldwide to become one of the most important causative agents of hospital acquired infections. In the early 2000s, MRSA strains carrying the Tn1546 transposon-based enterococcal vancomycin resistant mechanism were identified in clinical specimens, bringing the specter of a totally resistant bacterial pathogen closer to reality. Then, in the late 1990s, just as effective hygienic and antibiotic use policies managed to bring down the frequency of MRSA in hospitals of several countries, MRSA strains began to show up in the community.

PMID: 17921044 [PubMed - as supplied by publisher]

Reducing antibiotic overuse: a call for a national performance measure for not treating asymptomatic bacteriuria.

Reducing antibiotic overuse: a call for a national performance measure for not treating asymptomatic bacteriuria.

Clin Infect Dis. 2007 Nov

Gross PA, Patel B.
Department of Medicine, Hackensack University Medical Center, Hackensack, NJ 07601, USA. pgross@humed.com

Positive urinary tract culture results often represent asymptomatic bacteriuria, which does not need to be treated with antimicrobial agents. Avoiding treatment of asymptomatic bacteriuria in adults should reduce the risk of development of antibiotic resistance and is consistent with the Infectious Diseases Society of America and US Preventive Services Task Force guidelines on bacteriuria. A similar approach for not treating upper respiratory illnesses with antibiotics was initiated by the Centers for Disease Control and Prevention. We propose that a hospital and ambulatory performance measure should be developed for not treating asymptomatic bacteriuria in adults. In addition, such an effort would aid hospitals in confronting the proposal of the Centers for Medicare and Medicaid Services (to be implemented in 2009) to not pay the expenses associated with catheter-associated urinary tract infection.

University of Chicago Press

Protective effect of antibiotics against serious complications of common respiratory tract infections: retrospective cohort study with the UK General

Protective effect of antibiotics against serious complications of common respiratory tract infections: retrospective cohort study with the UK General Practice Research Database.

BMJ. 2007 Oct 18

Petersen I, Johnson AM, Islam A, Duckworth G, Livermore DM, Hayward AC.
UCL Centre for Infectious Disease Epidemiology, Department of Primary Care and Population Sciences, University College London, London NW3 2PQ.

OBJECTIVE: To determine the extent to which antibiotics reduce the risk of serious complications after common respiratory tract infections.

DESIGN: Retrospective cohort study.

SETTING: UK primary care practices contributing to the general practice research database. Data source 3.36 million episodes of respiratory tract infection.

MAIN OUTCOME MEASURES: Risk of serious complications in treated and untreated patients in the month after diagnosis: mastoiditis after otitis media, quinsy after sore throat, and pneumonia after upper respiratory tract infection and chest infection. Number of patients needed to treat to prevent one complication.

RESULTS: Serious complications were rare after upper respiratory tract infections, sore throat, and otitis media, and the number needed to treat was over 4000. The risk of pneumonia after chest infection was high, particularly in elderly people, and was substantially reduced by antibiotic use, with a number needed to treat of 39 for those aged >/=65 and 96-119 in younger age groups.

CONCLUSION: Antibiotics are not justified to reduce the risk of serious complications for upper respiratory tract infection, sore throat, or otitis media. Antibiotics substantially reduce the risk of pneumonia after chest infection, particularly in elderly people in whom the risk is highest.

Full text available:

British Medical Journal

Effects of tigecycline, linezolid and vancomycin on biofilms of viridans streptococci isolates from patients with endocarditis.

Effects of tigecycline, linezolid and vancomycin on biofilms of viridans streptococci isolates from patients with endocarditis.

Int J Artif Organs. 2007 Sep

Presterl E, Lassnigg A, Eder M, Reichmann S, Hirschl AM, Graninger W.
Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna - Austria and Institute of Hygiene and Medical Microbiology, Division of Clinical Microbiology, Medical University of Vienna, Vienna - Austria.

Background: Endocarditis, and prosthetic valve endocarditis in particular, is a serious disease with high morbidity and mortality. We investigate the effects of tigecycline, linezolid and vancomycin on biofilms of viridans group streptococci (VGS) isolated from patients with definite native or prosthetic valve endocarditis.

Methods and Results: Ten of 20 VGS blood stream isolates from patients with endocarditis formed biofilms in the microtiter plate biofilm model. The minimal inhibitory concentrations (MIC) for tigecycline, linezolid and vancomycin were determined using the microdilution broth method. Biofilms were grown for 24 hours and were incubated with tigecycline, linezolid and vancomycin at increasing concentrations from 1-128x MIC of the isolate being tested. Biofilm thickness was quantified by measuring the optical density (OD) after dyeing it with crystal violet. The incubation of the biofilms with tigecycline, linezolid or vancomycin resulted in a significant reduction of OD compared to the control biofilm without antibiotic (p<0.05).>

Conclusions: In the present study on viridans streptococci isolated from patients with endocarditis, tigecycline and linezolid reduced the density of the biofilms as effectively as vancomycin. However, linezolid and vancomycin were bactericidal at higher concentrations. Linezolid and vancomycin at very high doses may be useful in the treatment of biofilm-associated diseases caused by VGS infections.

PMID: 17918125 [PubMed - as supplied by publisher]

Antibiotic prescription and prevalence rate in the outpatient paediatric population: analysis of surveys published during 2000-2005.

Antibiotic prescription and prevalence rate in the outpatient paediatric population: analysis of surveys published during 2000-2005.
Eur J Clin Pharmacol. 2007 Sep 21
Rossignoli A, Clavenna A, Bonati M.
Laboratory for Mother and Child Health, Mario Negri Institute for Pharmacological Research, via G. La Masa 19, 20156, Milan, Italy, clavenna@marionegri.it.

OBJECTIVE: To evaluate antibiotic paediatric consumption data in the community setting using data from studies published between 2000 and 2005 and to compare inter- and intra-country antibiotic prescribing patterns.

METHODS: A literature search was performed in EMBASE and MEDLINE to identify pharmacoepidemiological studies published between 2000 and 2005.

RESULTS: Large differences between studies were found, with significant heterogeneity in epidemiological indicators. Only 20 studies reporting comparable drug prescription data were considered in the analysis, all of which were from the USA, Canada, North-Central Europe and Italy. Pre-school children were reported as comprising the most exposed age group to antibiotic therapy (prevalence 72%; prescription rate 2.2 prescriptions/person per year). In the overall child and adolescent population (less or equal to 19 years), prevalence varied from 14 to 57% (mean 34%), and the prescription rate from 0.2 to 1.3 prescriptions/person per year. Relevant inter-country qualitative and quantitative differences in antibiotic prescribing were apparent, although these were observed in only a few countries: prevalence was higher in Italy and Canada (prevalence range 42-57%) and lower in the Netherlands and the United Kingdom (prevalence range 14-21%). Penicillins were the most prescribed antibiotics in all cases (40-70% of antibiotic prescriptions), followed by macrolides (16-45%), while cephalosporins accounted for a large proportion of the prescriptions in Italy (30-40%) and Canada, but were practically absent in North European prescriptions.

CONCLUSION: Comparative drug utilisation studies on antibiotic use in children are needed, as are improvements in regulatory and educational programmes aimed at limiting the number prescriptions given for antibiotics. Both approaches would address public health problems, such as bacterial resistance and safety and elevated costs, related to the use and misuse of these drugs.

PMID: 17891535 [PubMed - as supplied by publisher]

Evaluation of phenoxymethylpenicillin treatment of acute otitis media in children aged 2-16.

Evaluation of phenoxymethylpenicillin treatment of acute otitis media in children aged 2-16.

Scand J Prim Health Care. 2007 Sep

Neumark T, Mölstad S, Rosén C, Persson LG, Törngren A, Brudin L, Eliasson I.

Lindsdal Primary Health Centre, Kalmar, Sweden.

Keywords: Acute otitis media; antibiotics; AOM; children; family practice; general practice; PcV; phenoxymethylpenicillin; primary healthcare

Objective. To study the clinical recovery from acute otitis media (AOM) in children, 2-16 years of age, managed with or without treatment with phenoxymethylpenicillin (PcV). Design. An open, prospective randomized trial. Children aged between 2 and 16 years, presenting with one- or double-sided AOM (without perforation) with symptom duration of less than four days, were included. The children were randomized to PcV for five days or to no primary antibiotic treatment. A health score and compliance were registered on a daily basis for seven days.

Setting. A total of 32 health centres and 72 GPs in south-east Sweden. Subjects. Children aged 2-16 presenting with earache. Main outcome measures. Recovery time, symptom duration, frequency of complications (up to three months) and consumption of healthcare services independent of treatment with or without antibiotics.

Results. A total of 179 patients carried out the trial; 92 were randomized to PcV, 87 to no primary antibiotic treatment. The median recovery time was four days in both groups. Patients who received PcV had less pain (p <0.001)>

Conclusions. Our investigation supports that PcV treatment of AOM does not affect the recovery time or complication rates. PcV provided some symptomatic benefit in the treatment of AOM in otherwise healthy children, aged 2-16 years.

Informaworld

Efficacy of azithromycin in the treatment of childhood typhoid Fever.

Efficacy of azithromycin in the treatment of childhood typhoid Fever.
Mymensingh Med J. 2007 Jul
Islam MN, Rahman ME, Rouf MA, Islam MN, Khaleque MA, Siddika M, Hossain MA.
Dr Md Nazrul Islam, Assistant Registrar, Department of Paediatrics, Mymensingh Medical College Hospital, Mymensingh.

An intervention study was carried out in Paediatric wards for a period of one year from January 2003 to December 2003 to determine the efficacy and safety of azithromycin in the treatment of uncomplicated childhood typhoid fever.

A total of 50 cases were enrolled in the study. The inclusion criteria of the cases were: documented fever for more than 7 days plus two or more of the following clinical features: toxic appearance, abdominal tenderness, hepatomegaly, splenomegaly, diarrhoea, constipation and coated tongue plus positive Widal test and/or blood culture positivity.

Patients who had complication like gastrointestinal tract (GIT) haemorrhage; intestinal perforation and/or shock were excluded from the study. Data were collected in a structured questionnaire. Azithromycin was given at a dose of 10mg/kg /day for a period of 07 days. The time to defervescence was 3.82+/-1.49 days. The minimum defervescence time was 02 days and maximum was 07 days. Clinical cure rate was 94%. No serious adverse effect was noted related to azithromycin therapy except nausea, vomiting, and jaundice. Prior treatment with antibiotics did not affect defervescence time (P>0.05).

Pre-treatment febrile period has got positive and linear correlation with clinical response (r = +0.593). It was found that once daily administration of oral azithromycin for seven days in the treatment of uncomplicated typhoid fever was effective and reasonably safe.

PubMed

The future of natural products as a source of new antibiotics

The future of natural products as a source of new antibiotics
Curr Opin Investig Drugs. 2007 Aug

Luzhetskyy A, Pelzer S, Bechthold A.
Albert-Ludwigs-Universität Freiburg, Institut für Pharmazeutische Wissenschaften, Pharmazeutische Biologie und Biotechnologie, Stefan-Meier-Straße 19, D-79194 Freiburg, Germany. andreas.bechthold@pharmazie.uni-freiburg.de.

One reason for the current crisis in antibiotic development is the low return on investment, which is intrinsic to anti-infective drug development. Despite this, smaller pharmaceutical companies are attempting to address the medical need for new antibiotics. Natural products have played a major role in antibiotic drug discovery since 1941 when penicillin was introduced to the market, and currently natural products are again the most important source for promising drug candidates. This review discusses novel methods and technologies that will increase the success rate for identifying novel antibiotics from natural sources.

PMID: 17668363 [PubMed - as supplied by publisher]

New aspects of natural products in drug discovery
Trends Microbiol. 2007 Jun

Lam KS.
Nereus Pharmaceuticals Inc., 10480 Wateridge Circle, San Diego, CA 92121, USA. rlam@nereuspharm.com

During the past 15 years, most large pharmaceutical companies have decreased the screening of natural products for drug discovery in favor of synthetic compound libraries. Main reasons for this include the incompatibility of natural product libraries with high-throughput screening and the marginal improvement in core technologies for natural product screening in the late 1980s and early 1990 s. Recently, the development of new technologies has revolutionized the screening of natural products. Applying these technologies compensates for the inherent limitations of natural products and offers a unique opportunity to re-establish natural products as a major source for drug discovery. Examples of these new advances and technologies are described in this review.

Science Direct

Selection and use of anti-infective agents for intra-abdominal infections

Selection and use of anti-infective agents for intra-abdominal infections

Arq Gastroenterol. 2007

Coelho JC, Baretta GA, Okawa L.
Serviço de Cirurgia do Aparelho Digestivo, Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, PR.

Correspondence:

Dr. Júlio C. U. Coelho Rua Bento Viana, 1140 – apt.2202 80240-110 – Curitiba, PR E-mail: juliocoelho@bbs2.sul.com.br

Headings: Abdomen. Infection. Cross infection. Anti-bacterial agents.

BACKGROUND: Intra-abdominal infections are common and are associated with elevated morbidity and mortality. The microorganisms that cause intra-abdominal infections are usually from the gastrointestinal flora, mainly E. coli and Bacteroides fragilis.

AIM: To present a review of the selection and use of antibiotics in intra-abdominal infections.

CONCLUSIONS: Appropriate use of antibiotics is essential to control infection and to reduce treatment failure. Antibiotics are initiated whenever intra-abdominal infection is suspected and the antimicrobial agents are selected based on the most common microorganisms involved. In addition, efficacy, cost, safety, and posologic regimen are considered for an appropriated selection. Antibiotic regimen is different whether the infection is acquired in the community or at hospital due to the more resistant flora in the latter.

SciFlo Brazil

Successful treatment of vancomycin-resistant enterococcus ventriculitis in a child.

Successful treatment of vancomycin-resistant enterococcus ventriculitis in a child.

Braz J Infect Dis. 2007 Apr

Silva PS, Monteiro Neto H, Sejas LM.
Pediatric Intensive Care Unit, Department of Pediatrics, State Hospital of Diadema, Federal University of São Paulo, São Paulo, SP, Brazil.

Key-Words: Vancomycin, resistance, treatment

Abstract

Enterococci are an uncommon cause of CNS infection. A 20 month-old boy, diagnosed with hydrocephalus with ventriculoperitoneal shunt and history of lengthy hospitalization and use of wide spectrum antibiotics, was admitted to the pediatric intensive care unit diagnosed with ventriculitis. On the 14th day of empirical antibiotic therapy (vancomycin and meropenem) the child presented fever while the CSF sample culture evidenced vancomycin-resistant Enterococcus faecium.

The patient received intravenous linezolid achieving cerebrospinal fluid sterilization.

Conclusion: Intravenous linezolid appears to be a safe and effective therapy for vancomycin-resistant enterococcus ventriculoperitoneal shunt infection.

Case Report
A 20 month-old boy, with underlying diagnosis of neurodevelopmental delay and hydrocephalus with ventriculoperitoneal shunt (VPS) secondary to Pneumococcus meningitis at 6 months of life, presented a cardiorespiratory arrest on his arrival in hospital, and was then resuscitated over 23 minutes. The infant remained hospitalized for 10 days within the pediatric intensive care unit (PICU), diagnosed with aspirative pneumonia and cardiogenic shock, receiving oxacillin and ceftriaxone.
On the 18th day, the patient was readmitted to the PICU with a diagnosis of septic shock due to central venous catheter-related infection, being discharged from the PICU on the 7th day, having received vancomycin and cefepime for a total of 3 weeks. On the 39th day he was readmitted to the PICU diagnosed with ventriculitis. The cerebrospinal fluid (CSF) sample obtained by reservoir puncture revealed 71 cells/mm3 (72% neutrophils; glucose 13 mg/dL and protein 69 mg/dL). Cultures were negative. The patient received external ventricular drain associated with vancomycin and meropenem empirically for 4 weeks, undergoing a VPS on the 30th PICU day. On the 14th postoperative (PO) day, the patient developed perivalvular abscess, the CSF obtained from the shunt reservoir presented 74 cells/mm3 (79% neutrophils), upon which the patient was submitted to external ventricular shunt (EVS) whilst vancomycin and meropenem were resumed. On the 6th PO day after EVS, fluconazole was associated due to the presence of yeast in a routine CSF sample. Cultures for fungus were negative. On the 14th day of antibiotic therapy, the patient evolved with fever (39ºC), presenting the following laboratorial exams: white blood cells (WBC) 23,000/mm3, platelets 156,000/mm3, C-reactive protein 20 mg/dL, CSF with 15 cells (90% neutrophils), glucose 45 g/dL, protein 910 g/dL, Gram stain showed Gram-positive cocci in chains, and 2 serial CSF cultures yielded Enterococcus faecium resistant to vancomycin, ampicillin, streptomycin, ciprofloxacin, chloramphenicol and susceptible to gentamicin. The vancomycin minimum inhibitory concentration (MIC) of this isolate was > 32 µg/mL (using an E-test method with an inoculum density of 0.5 McFarland standard). Based on this information, he was switched to linezolid monotherapy, dosed at 10 mg/kg intravenously every 8 hours.
Following the 2nd day of linezolid, the patient became afebrile, and after the 3rd day had sterile CSF. Following 4-week treatment with linezolid, the patient had a new VPS in place (CSF: 1 cell/mm3, glucose 54 g/dL and protein 90 g/dL) and C-reactive protein of 1.78 mg/dL. Treatment continued for a further 2 weeks, during which time CSF samples remained sterile. Concentrations of linezolid in CSF were not recorded. The patient tolerated the 6-week treatment without showing evidence of bone marrow suppression. Fecal cultures obtained during treatment with linezolid were negative. The patient evolved requiring ventilation assistance due to neurologic compromise, and was cared for in an intermediate care unit.

Discussion
The emergence of nosocomially acquired vancomycin-resistant enterococci has become a significant concern and a treatment challenge to physicians [3]. Approximately 12% to 18% of enterococci in the United States exhibit vancomycin resistance [3].

Risk factors for vancomycin-resistant enterococcus (VRE) colonization in children include young age, use of invasive devices, antimicrobial drug administration, immunosuppression, low birth weight, and underlying malignancy [10]. Such patients have commonly been treated with vancomycin or broad-spectrum antibiotics before VRE isolation [11]. Two important factors predisposing patients to VRE infection are the percentage of hospital days receiving antimicrobial therapy of any type and the number of days receiving intravenous vancomycin [7]. Our patient had received several weeks of broad-spectrum antibiotics before developing VRE meningitis; this prolonged use of antibiotics, associated with the long stay in hospital were likely contributory factors in both colonization and subsequent infection with VRE. However, treatment with lengthy courses of broad-spectrum antibiotics is often unavoidable in critically ill patients.

The National Nosocomial Infections Surveillance system of the Centers for Disease Control and Prevention reported vancomycin resistance in 28.5% of nosocomial enterococcal intensive care unit infections in 2003 [12]. In a recent study, 14% of VRE-colonized patients progressed to infection within 15 days of a positive surveillance culture [13]. A recent review noted that, although Enterococcus faecalis is responsible for 80% of enterococcal infections, E. faecium strains account for 98% of vancomycin-resistant cases [14].

There are no established guidelines for the treatment of central nervous system infection caused by VRE. Therapeutic options for vancomycin-resistant enterococci are limited because these organisms are usually resistant to multiple antimicrobial agents. Treatment often has to include investigational drugs or less tested new drugs. In our patient the therapy included intravenous linezolid. To the best of our knowledge, there has only been 1 previous case report of ventriculitis due to enterococcus in a child treated successfully with linezolid [4].

Linezolid, the first member of the oxazolidinones class of antibiotics licensed by the U.S. Food and Drug Administration (FDA), inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit. It is approved for use in adults and children for serious infections caused by Enterococcus faecium or Enterococcus faecalis including vancomycin-resistant strains (VRE), Staphylococcus aureus including methicilllin-resistant strains (MRSA), coagulate-negative staphylococci and streptococci including penicillin-resistant Streptococcus pneumoniae [15]. Linezolid is essentially bacteriostatic. In vitro time-kill experiments against multidrug-resistant (including vancomycin-resistant) enterococci, linezolid was not bactericidal but had greater bacteriostatic activity against these organisms [16].

CSF penetration of linezolid suggests utility in treatment of meningitis and intracranial prosthetic device infections. In individuals with noninflamed meninges, linezolid concentrations in CSF were 70% of plasma concentrations [17]. In adults, reversible thrombocytopenia is the major hematologic consequence of linezolid use, generally occurring after > 2 weeks of treatment and thought to be due to transient bone marrow suppression. In children, thrombocytopenia is less common; however, a complete blood count should be monitored weekly while children are receiving linezolid [17]. In adults, linezolid-induced neuropathy has been reported among patients receiving the drug for > 6 months.

Vancomycin and aminoglycosides with variable penetration of the blood-brain barrier and monitoring CSF levels is recommended. Intraventricular administration of antimicrobials with irregular penetration of blood-brain barrier makes theoretical sense but is controversial [18]. Problems with intraventricular antibiotics include allergic reactions, drug-induced inflammation and toxic or inadequate concentrations [18]. Even though our case presented gentamycin-susceptible enterococcus, the patient was successfully treated without needing intraventricular administration of drugs.

Optimal management of ventricular shunt infection requires removal of the shunt, placement of a temporary external ventricular drain (EVD), followed by reinternalization after CSF sterilization. A recent analysis strongly confirmed this as the most effective treatment method [19].

Length of time on antibiotic therapy in patients with ventriculoperitoneal shunt infection remains controversial. Studies employing linezolid for the treatment of VPS infections range from 3 to 12 weeks in length [4,8,20,21]. Despite receiving prolonged treatment, our patient presented no bone marrow compromise according to serial hemograms. However, peripheral neuropathic signs could not be assessed in this case because the patient presented severe neurologic compromise due to the underlying disease and comorbidity.

In conclusion, intravenous linezolid appears to be a safe and effective therapy for vancomycin-resistant enterococcus ventriculitis. Our success with linezolid in this instance is encouraging for the future role of this class of drugs for the treatment of shunt infections.

ScieFLO Brazil

Pharmacokinetics and pharmacodynamics of antimicrobials

Pharmacokinetics and pharmacodynamics of antimicrobials

Clin Infect Dis. 2007 Jul

Drusano GL.
Ordway Research Institute, Albany, NY 12208, USA. gdrusano@ordwayresearch.org

Antibiotics are some of our most commonly used drugs. Until recently, little has been known about how to optimize administration of these agents. Unfortunately, the rate of discovery of new antibiotics has been declining, coincident with the explosion in the number of multidrug-resistant organisms in both the community and hospital environments. This development makes the identification of optimal regimens that will result in good clinical and microbiological outcomes important, but it also makes clear the necessity of identifying regimens that will suppress the emergence of resistant organisms. Given that new agents for multidrug-resistant pathogens will take nearly a decade to become available to physicians, keeping organisms susceptible to drugs that are already available is even more critical. Pharmacodynamics allows identification of the drug exposure measure that is closely associated with the ability to kill organisms and, also, to suppress the emergence of resistant subpopulations of organisms. Use of Monte Carlo simulation allows identification of drug doses in the clinical arena to accomplish these ends. Such approaches should be applied to all old and new antibacterial agents.

Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial.

Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial.
BMJ. 2007 Jun 29

Hickson M, D'Souza AL, Muthu N, Rogers TR, Want S, Rajkumar C, Bulpitt CJ.
Nutrition and Dietetic Research Group, Faculty of Medicine, Imperial College, London W12 0HS.

OBJECTIVE: To determine the efficacy of a probiotic drink containing Lactobacillus for the prevention of any diarrhoea associated with antibiotic use and that caused by Clostridium difficile. DESIGN: Randomised double blind placebo controlled study.

PARTICIPANTS: 135 hospital patients (mean age 74) taking antibiotics. Exclusions included diarrhoea on admission, bowel pathology that could result in diarrhoea, antibiotic use in the previous four weeks, severe illness, immunosuppression, bowel surgery, artificial heart valves, and history of rheumatic heart disease or infective endocarditis.

INTERVENTION: Consumption of a 100 g (97 ml) drink containing Lactobacillus casei, L bulgaricus, and Streptococcus thermophilus twice a day during a course of antibiotics and for one week after the course finished. The placebo group received a longlife sterile milkshake.

MAIN OUTCOME MEASURES: Primary outcome: occurrence of antibiotic associated diarrhoea. Secondary outcome: presence of C difficile toxin and diarrhoea.

RESULTS: 7/57 (12%) of the probiotic group developed diarrhoea associated with antibiotic use compared with 19/56 (34%) in the placebo group (P=0.007). Logistic regression to control for other factors gave an odds ratio 0.25 (95% confidence interval 0.07 to 0.85) for use of the probiotic, with low albumin and sodium also increasing the risk of diarrhoea. The absolute risk reduction was 21.6% (6.6% to 36.6%), and the number needed to treat was 5 (3 to 15). No one in the probiotic group and 9/53 (17%) in the placebo group had diarrhoea caused by C difficile (P=0.001). The absolute risk reduction was 17% (7% to 27%), and the number needed to treat was 6 (4 to 14).

CONCLUSION: Consumption of a probiotic drink containing L casei, L bulgaricus, and S thermophilus can reduce the incidence of antibiotic associated diarrhoea and C difficile associated diarrhoea. This has the potential to decrease morbidity, healthcare costs, and mortality if used routinely in patients aged over 50. Trial registration National Research Register N0016106821.

PMID: 17604300 [PubMed - as supplied by publisher]

Tetracyclines and Methicillin-Resistant Staphylococcus Aureus MRSA

Tetracyclines as an Oral Treatment Option for Patients with Community-Onset Methicillin-Resistant Staphylococcus aureus Skin and Soft-Tissue Infections.

Antimicrob Agents Chemother. 2007 Jun 18

Ruhe JJ, Menon A.

Division of Infectious Diseases, Department of Medicine, University of Arkansas for Medical Sciences; and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, U.S.A.

Few data exist on the clinical utility of the second-generation tetracyclines doxycycline and minocycline for the treatment of community-associated methicillin-resistant Staphylococcus aureus (MRSA) skin and soft-tissue infections (SSTI). We performed a retrospective cohort study on 282 patients who presented with MRSA SSTI to the emergency room or outpatient clinic at two tertiary medical centers between October 2002 and February 2007. Median MRSA susceptibility to tetracycline was 95%. Time zero was defined as the time of the first incision and drainage procedure or, if none was performed, the time of the first positive wound culture. The median patient age was 48 years.

Abscesses constituted the majority of clinical presentations (75%), followed by furuncles or carbuncles (13%), and cellulitis originating from a purulent focus of infection (12%). 225 (80%) patients underwent incision and drainage. Doxycycline or minocycline was administered in 90 (32%) episodes; the other 192 SSTI were treated with beta-lactams. Treatment failure, defined as the need for a second incision and drainage procedure and/or admission to the hospital by at least two days after time zero, was diagnosed in 28 (10%) episodes at a median of three days after time zero. On logistic regression analysis, receipt of a beta-lactam agent was the only clinical characteristic associated with treatment failure (adjusted OR 3.94; 95% CI, 1.28-12.15; P=0.02).

The second-generation tetracyclines appear to be a reasonable oral treatment option for patients with community-onset MRSA SSTI in areas where MRSA are susceptible to the tetracyclines.

Antimicrobial Agents and Chemotherapy

The effect of the timing of antibiotics and surgical treatment on infection rates in open long-bone fractures: A 9-year prospective study from a distr

The effect of the timing of antibiotics and surgical treatment on infection rates in open long-bone fractures: A 9-year prospective study from a district general hospital.

Injury. 2007 Jun 19
Al-Arabi YB, Nader M, Hamidian-Jahromi AR, Woods DA.
The Great Western Hospital, Marlborough Road, Swindon SN3 6BB, United Kingdom.

AIMS: To determine whether a delay of greater than 6h from injury to initial surgical debridement and the timing of antibiotic administration affect infection rates in open long-bone fractures.

METHODS: We studied 248 consecutive open long-bone fractures in 237 patients over a 9-year period. The patients were followed until clinical or radiological union occurred or until a secondary procedure for non-union or infection was performed.

RESULTS: Surgical debridement was performed within 6h of injury in 62% of cases and after 6h in 38% of cases. Infection rates were 7.8% and 9.6%, respectively, and the difference was not statistically significant (p=0.6438). The timing of antibiotic administration was not significantly related to the infection rate.

CONCLUSION: Whilst open long-bone fractures should be treated expeditiously, we suggest that adherence to a 6h window has not been shown to affect infection rates nor has the timing of antibiotic administration during the acute phase.

Elsevier

Comparative activities of antibiotics against intracellular non-typeable Haemophilus influenzae.

Comparative activities of antibiotics against intracellular non-typeable Haemophilus influenzae.
Wien Klin Wochenschr. 2007 Jun

Kratzer C, Graninger W, Macfelda K, Buxbaum A, Georgopoulos A.
Department of Internal Medicine I, Division of Infectious Diseases and Tropical Diseases, Medical University of Vienna, Vienna, Austria, apostolos.georgopoulos@meduniwien.ac.at.

INTRODUCTION: Non-typeable Haemophilus influenzae (NTHi) is a major bacterial pathogen of community-acquired respiratory tract infection and is usually found extracellularly, although studies have revealed that NTHi may possess the ability to invade human epithelial cells where it is then protected against attack by the local immune system and partly against the effect of antibiotics. The aim of the present study was to assess the ability of ampicillin, azithromycin, telithromycin, ciprofloxacin and moxifloxacin, five antibiotics in common clinical use, to kill NTHi within bronchial epithelial cells.

METHODS: Confluent human bronchial epithelial cells were infected with NTHi 77, a particularly invasive clinical strain. Extracellular bacterial cells were killed with gentamicin and the intracellular bacteria were incubated with antibiotics at concentrations of 1 mg/l or 10 mg/l for 4 h or 8 h. Viable intracellular bacteria were counted after lysis of the epithelial cells.

RESULTS: With the exception of ampicillin, all the antibiotics caused significant reduction of intracellular bacteria at concentrations of 10 mg/l and exposure for 4 h or at 1 mg/l for 8 h. At 1 mg/l, moxifloxacin eliminated 94% of intracellular NTHi after 4 h and 98% after 8 h; ciprofloxacin, azithromycin and telithromycin only achieved killing indices below 75 after 4 h but 86-90% killing after 8 h. At 10 mg/l, moxifloxacin, ciprofloxacin, telithromycin and azithromycin were able to achieve 99.7%, 96.3%, 86.7% and 74.7% eradication of intracellular bacteria, respectively, after exposure for 4 h.

CONCLUSION: These results demonstrate the rapid antibacterial efficacy of moxifloxacin against intracellular NTHi in vitro. Moxifloxacin, which combines high extracellular and intracellular activities, could be an important tool in the treatment of recurrent respiratory tract infections.

PMID: 17571234 [PubMed - as supplied by publisher]

Emergence and maintenance of resistance to fluoroquinolones and coumarins in Staphylococcus aureus: predictions from in vitro studies.

Emergence and maintenance of resistance to fluoroquinolones and coumarins in Staphylococcus aureus: predictions from in vitro studies.

J Antimicrob Chemother. 2007 Jun 7

Vickers AA, O'neill AJ, Chopra I.
Antimicrobial Research Centre and Research Institute of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.

Objectives: Fluoroquinolones and coumarins interfere with the activity of bacterial type II topoisomerase enzymes. We examined the development of resistance to these agents in Staphylococcus aureus and determined the effect of simultaneous topoisomerase IV and DNA gyrase mutations on the biological fitness of the organism.

This work aimed to gain insight into how such mutants might arise and survive in the clinical environment. Methods Spontaneous mutants resistant to fluoroquinolones and coumarins were selected in S. aureus. Resistance mutations were identified by DNA sequencing of PCR amplicons corresponding to the genes encoding topoisomerase IV and DNA gyrase. In vitro fitness of resistant mutants was compared with the antibiotic-susceptible progenitor strain using pair-wise competition assays.

Results: Mutants simultaneously resistant to both a fluoroquinolone and either of the coumarins, novobiocin or coumermycin A1, could not be recovered following a single-step selection. However, mutants concurrently resistant to both classes of antimicrobial could be generated by step-wise selections. These mutants demonstrated reductions in competitive fitness of up to 36%.

Conclusions: Dual-targeting of topoisomerase IV and DNA gyrase enzymes, for example with the combination of a fluoroquinolone and a coumarin agent, could minimize the emergence of resistance to these drugs in S. aureus. However, resistance-associated fitness costs may not be sufficient to limit the survival of mutants with dual resistance, if they arose in the clinical setting.

Antimicrobial Chemotherapy

Antibiotics, Physician outcome judgements, inappropriate treatment

Do physician outcome judgments and judgment biases contribute to inappropriate use of treatments? Study Protocol.

Implement Sci. 2007 Jun 7

Brehaut JC, Poses R, Shojania KG, Lott A, Man-Son-Hing M, Bassin E, Grimshaw J.

ABSTRACT: BACKGROUND: There are many examples of physicians using treatments inappropriately, despite clear evidence about the circumstances under which the benefits of such treatments outweigh their harms. When such over- or under- use of treatments occurs for common diseases, the burden to the healthcare system and risks to patients can be substantial. We propose that a major contributor to inappropriate treatment may be how clinicians judge the likelihood of important treatment outcomes, and how these judgments influence their treatment decisions. The current study will examine the role of judged outcome probabilities and other cognitive factors in the context of two clinical treatment decisions: 1) prescription of antibiotics for sore throat, where we hypothesize overestimation of benefit and underestimation of harm leads to over-prescription of antibiotics; and 2) initiation of anticoagulation for patients with atrial fibrillation (AF), where we hypothesize that underestimation of benefit and overestimation of harm leads to under-prescription of warfarin.

METHODS: For each of the two conditions, we will administer surveys of two types (Type 1 and Type 2) to different samples of Canadian physicians. The primary goal of the Type 1 survey is to assess physicians' perceived outcome probabilities (both good and bad outcomes) for the target treatment. Type 1 surveys will assess judged outcome probabilities in the context of a representative patient, and include questions about how physicians currently treat such cases, the recollection of rare or vivid outcomes, as well as practice and demographic details. The primary goal of the Type 2 surveys is to measure the specific factors that drive individual clinical judgments and treatment decisions, using a 'clinical judgment analysis' or 'lens modeling' approach. This survey will manipulate eight clinical variables across a series of sixteen realistic case vignettes. Based on the survey responses, we will be able to identify which variables have the greatest effect on physician judgments, and whether judgments are affected by inappropriate cues or incorrect weighting of appropriate cues. We will send antibiotics surveys to family physicians (300 per survey), and warfarin surveys to both family physicians and internal medicine specialists (300 per group per survey), for a total of 1,800 physicians. Each Type 1 survey will be two to four pages in length and take about fifteen minutes to complete, while each Type 2 survey will be eight to ten pages in length and take about thirty minutes to complete.

DISCUSSION: This work will provide insight into the extent to which clinicians' judgments about the likelihood of important treatment outcomes explain inappropriate treatment decisions. This work will also provide information necessary for the development of an individualized feedback tool designed to improve treatment decisions. The techniques developed here have the potential to be applicable to a wide range of clinical areas where inappropriate utilization stems from biased judgments.

PMID: 17555586 [PubMed - as supplied by publisher]

Appropriate usage of antibiotics by therapeutic drug monitoring

Appropriate usage of antibiotics by therapeutic drug monitoring

Yakugaku Zasshi. 2007 Jun

Kokubun H, Kimura T, Yago K.
Department of Pharmacy, Kitasato University Hospital.

Aminoglycosides are mainly distributed in the extracellular fluid, so when they are given to neonates who have a large amount of extracellular fluid, their distribution is increased. In our data, the volume of distribution (Vd) of Arbekacin in the neonates was twice that of the adults, 0.54 l/kg. Therefore, the dose per weight of aminoglycosides to the neonates should be increased more than to the adults. In the renal function of the neonates, differentiation of the nephron is completed within 36 weeks after conception, but it is functionally immature. In our data, renal drug excretion increased rapidly in the post-conceptional ages (PCAs) of 34-35 weeks. Consequently, we based the Arbekacin administration schedule for the neonates on the PCAs. There is excellent correlation between serum level of vancomicin (VCM) and dosexserum creatinine (Scr)/weight in the haemodialysis patients, suggesting that we can use weight and Scr to set the VCM administration schedule for these patients. We also established on administration schedule of Teicoplanin for the haemodialysis patients. In this article, we present the TDM analysis result of the antibiotics in our hospital.

PMID: 17541241

[PubMed - in process]