Novel Beta-lactam antibiotics derivatives: their new applications as gene reporters, antitumor prodrugs and enzyme inhibitors.

Novel Beta-lactam antibiotics derivatives: their new applications as gene reporters, antitumor prodrugs and enzyme inhibitors.

Xing B, Rao J, Liu R.

Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, 637616. Bengang@ntu.edu.sg.

Since the antibiotic properties of penicillin were first noticed in the beginning of last century, beta-lactam based antibiotics have been well developed as miracle drugs for the therapy of bacterial infectious diseases in clinics. Recently, these "old" antibiotics and their relevant derivatives have also found new applications as gene reporters, anti-cancer prodrugs and enzyme inhibitors.

In this review, we will introduce the latest developments in the study of these new applications based on literatures reported over the last decade. The first section covers the recent developments of beta-lactam antibiotics as drugs against bacteria, the second section briefly discusses the occurrence of bacterial resistance and mechanistic studies of beta-lactam resistance in bacteria, the third section presents the current development of fluorogenic cephalosporin based beta-lactam probes for real-time imaging of gene expression, and the fourth section describes relevant studies on beta-lactam based substrates as anti-tumor prodrugs.

Beta-lactam substrates as protease inhibitors will be also described in the fifth section. The final section summarizes future perspectives for beta-lactam antibiotic derivatives as scaffolds in the fields of molecular imaging, drug delivery and enzymatic assays.

PMID: 18473935 [PubMed - in process]

Antibiotics to reduce post-tonsillectomy morbidity

Antibiotics to reduce post-tonsillectomy morbidity

Cochrane Database Syst Rev. 2008 Apr

Dhiwakar M, Clement W, Supriya M, McKerrow W.

BACKGROUND: Tonsillectomy continues to be one of the most common surgical procedures performed in children and adults. Despite improvements in surgical and anaesthetic techniques, postoperative morbidity, mainly in the form of pain, remains a significant clinical problem. Postoperative bacterial infection of the tonsillar fossa has been proposed as an important factor causing pain and associated morbidity, and some studies have found a reduction in morbid outcomes following the administration of perioperative antibiotics.

OBJECTIVES: To determine whether perioperative antibiotics reduce pain and other morbid outcomes following tonsillectomy.

SEARCH STRATEGY: Cochrane ENT Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1 2007), MEDLINE (1950 to 2007) and EMBASE (1974 to 2007) were searched. The date of the last search was March 2007.

SELECTION CRITERIA: All randomised controlled trials examining the impact of perioperative administration of systemic antibiotics on post-tonsillectomy morbidity in children or adults.

DATA COLLECTION AND ANALYSIS: Two authors independently collected data. Primary outcomes were pain, consumption of analgesia and secondary haemorrhage (defined as significant if patient re-admitted, transfused blood products or returned to theatre, and total if any documented haemorrhage). Secondary outcomes were fever, time taken to resume normal diet and activities and adverse events. Where possible, summary measures were generated using random-effects models.

MAIN RESULTS: Nine trials met the eligibility criteria. Most did not find a significant reduction in pain with antibiotics. Similarly, antibiotics were not shown to be effective in reducing the need for analgesics. Antibiotics were not associated with a reduction in significant secondary haemorrhage rates (Relative Risk (RR) 0.49, 95% CI 0.08 to 3.11, P = 0.45) or total secondary haemorrhage rates (RR 0.92, 95% CI 0.45 to 1.87, P = 0.81). With regard to secondary outcomes, antibiotics reduced the proportion of subjects with fever (RR 0.63, 95% CI 0.46 to 0.85, P = 0.002).

AUTHORS' CONCLUSIONS: The present review suggests that there is little or no evidence that antibiotics reduce the main morbid outcomes following tonsillectomy (i.e. pain, the need for analgesia or secondary haemorrhage rates). They do however appear to reduce fever. Some important methodological shortcomings exist in the included trials which are likely to have produced bias favouring antibiotics. We therefore advocate caution when prescribing antibiotics routinely to all patients undergoing tonsillectomy. Whether a subgroup of patients who might benefit from selective administration of antibiotics exists is unknown and needs to be explored in future trials.

PubMed

Emergence of Tetracycline-Resistant Vibrio cholerae O1 Serotype Inaba, in Kolkata, India.

Emergence of Tetracycline-Resistant Vibrio cholerae O1 Serotype Inaba, in Kolkata, India.

Jpn J Infect Dis. 2008 Mar

Roychowdhury A, Pan A, Dutta D, Mukhopadhyay AK, Ramamurthy T, Nandy RK, Bhattacharya SK, Bhattacharya MK.
National Institute of Cholera and Enteric Diseases, Kolkata, India. mkbidh@gmail.com.

Out of 2,235 diarrheal stool samples collected from patients admitted to the Infectious Diseases Hospital, Kolkata, 343 cases were positive for Vibrio cholerae (341, V. cholerae O1 and 2, O139). During the year 2004, infections caused by V. cholerae serotype Ogawa and Inaba were 93 and 7%, respectively, while in 2005, the Inaba isolation rate rose to 88% as compared to 12% for Ogawa. Susceptibility to antimicrobial agents revealed that the O1 strains were resistant to multiple antibiotics (ampicillin, co-trimoxazole, furazolidone, nalidixic acid and streptomycin) with reduced susceptibility to ciprofloxacin. Increased isolation of tetracycline-resistant strains (27.3% for Ogawa and 15% for Inaba) was noted in 2005. It appears that the population might be at risk of infection by the Inaba serotype and that tetracycline may not be useful for the treatment.

Japanese Journal of Infectious Disease

Emergence of Vibrio cholerae O1 biotype El Tor serotype Inaba causing outbreaks of cholera in Orissa, India.

Jpn J Infect Dis. 2006 Aug

Pal BB, Khuntia HK, Samal SK, Das SS, Chhotray GP.
Pathology and Microbiology Division, Regional Medical Research Centre, Orissa, India.

A total of 431 rectal swabs, collected from acute diarrheal cases at a surveillance site and at different diarrheal outbreak areas of Orissa from May to October 2005, were bacteriologically analyzed. Out of 265 culture-positive samples, Vibrio cholerae O1 was isolated in 56 samples (20.8%), of which 37 were the Inaba serotype and 19 were the Ogawa. The antibiogram profile revealed that all the V. cholerae O1 Ogawa and Inaba serotypes were uniformly sensitive to ampicillin, chloramphenicol, gentamicin, ciprofloxacin, norfloxacin and tetracycline. The V. cholerae O1 Inaba serotypes were resistant to furazolidone and nalidixic acid, while the Ogawa strains were resistant to furazolidone, nalidixic acid and neomycin. The multiplex polymerase chain reaction (PCR) assay on some selected strains of both serotypes revealed that all the strains were positive for ctxA and tcpA genes showing biotype El Tor. The present study revealed the emergence of V. cholerae O1 biotype El Tor serotype Inaba, which caused sporadic outbreaks of cholera in 2005. The outbreaks of diarrheal disorders in one geographical area of the state (in the Pattamundai area, Kendrapara district) in 2005 were due to V. cholerae O1 Ogawa, whereas the other outbreaks in other areas (Puri, Khurda and Dhenkanal districts) from August to October 2005 were due to V. cholerae O1 serotype Inaba. This is the first report that an emergence of V. cholerae O1 serotype Inaba caused sporadic outbreaks of cholera in different parts of Orissa. Switching over of V. cholerae O1 Ogawa strains to Inaba, causing diarrheal outbreaks in Orissa, needs close monitoring.

Japanese Journal of Infectious Disease

Antibiotics for adults with clinically diagnosed acute rhinosinusitis: a meta-analysis of individual patient data.

Antibiotics for adults with clinically diagnosed acute rhinosinusitis: a meta-analysis of individual patient data.

Lancet. 2008 Mar

Young J, De Sutter A, Merenstein D, van Essen GA, Kaiser L, Varonen H, Williamson I, Bucher HC.

Correspondence to: Jim Young, Basel Institute for Clinical Epidemiology, Hebelstrasse 10, University Hospital Basel, CH-4031 Basel, Switzerland

Basel Institute for Clinical Epidemiology, University Hospital Basel, Basel, Switzerland. jyoung@uhbs.ch

BACKGROUND: Primary-care physicians continue to overprescribe antibiotics for acute rhinosinusitis because distinction between viral and bacterial sinus infection is difficult. We undertook a meta-analysis of randomised trials based on individual patients' data to assess whether common signs and symptoms can be used to identify a subgroup of patients who benefit from antibiotics.

METHODS: We identified suitable trials--in which adult patients with rhinosinusitis-like complaints were randomly assigned to treatment with an antibiotic or a placebo--by searching the Cochrane Central Register of Controlled Trials, Medline, and Embase, and reference lists of reports describing such trials. Individual patients' data from 2547 adults in nine trials were checked and re-analysed. We assessed the overall effect of antibiotic treatment and the prognostic value of common signs and symptoms by the number needed to treat (NNT) with antibiotics to cure one additional patient.

FINDINGS: 15 patients with rhinosinusitis-like complaints would have to be given antibiotics before an additional patient was cured (95% CI NNT[benefit] 7 to NNT[harm] 190). Patients with purulent discharge in the pharynx took longer to cure than those without this sign; the NNT was 8 patients with this sign before one additional patient was cured (95% CI NNT[benefit] 4 to NNT[harm] 47). Patients who were older, reported symptoms for longer, or reported more severe symptoms also took longer to cure but were no more likely to benefit from antibiotics than other patients.

INTERPRETATION: Common clinical signs and symptoms cannot identify patients with rhinosinusitis for whom treatment is clearly justified. Antibiotics are not justified even if a patient reports symptoms for longer than 7-10 days.

The Lancet

Antibiotic treatment for Clostridium difficile-associated diarrhea in adults

Antibiotic treatment for Clostridium difficile-associated diarrhea in adults

Cochrane Database Syst Rev. 2007 Jul

Nelson R.
Northern General Hospital, Department of General Surgery, Herries Road, Sheffield, Yorkshire, UK, S5 7AU. altohorn@btinternet.com

BACKGROUND: Clostridium difficile (C. difficile) is recognized as a frequent cause of antibiotic-associated diarrhea and colitis.

OBJECTIVES: The aim of this review is to establish the efficacy of antibiotic therapy for C. difficile-associated diarrhea (CDAD), to identify the most effective antibiotic treatment for CDAD in adults and to determine the need for stopping the causative antibiotic during therapy.

SEARCH STRATEGY: MEDLINE (1966 to 2006), EMBASE (1980 to 2006), Cochrane Central Database of Controlled Trials and the Cochrane IBD Review Group Specialized Trials Register were searched using the following search terms: "pseudomembranous colitis and randomized trial"; "Clostridium difficile and randomized trial"; "antibiotic associated diarrhea and randomized trial".

SELECTION CRITERIA: Only randomized, controlled trials assessing antibiotic treatment for CDAD were included in the review. Probiotic trials are excluded. The following outcomes were sought: initial resolution of diarrhea; initial conversion of stool to C. difficile cytotoxin and/or stool culture negative; recurrence of diarrhea; recurrence of fecal C. difficile cytotoxin and/or positive stool culture; patient response to cessation of prior antibiotic therapy; sepsis; emergent surgery: fecal diversion or colectomy; and death.

DATA COLLECTION AND ANALYSIS: Data were analyzed using the MetaView statistical package in Review Manager. For dichotomous outcomes, relative risks (RR) and 95% confidence intervals (CI) were derived from each study. When appropriate, the results of included studies were combined for each outcome. For dichotomous outcomes, pooled RR and 95% CI were calculated using a fixed effect model, except where significant heterogeneity was detected, at which time the random effects model was used. Data heterogeneity was calculated using MetaView.

MAIN RESULTS: Twelve studies (total of 1157 participants) involving patients with diarrhea who recently received antibiotics for an infection other than C. difficile were included. The definition of diarrhea ranged from at least two loose stools per day with an associated symptom such as rectal temperature > 38 (o)C, to at least six loose stools in 36 hours. Eight different antibiotics were investigated: vancomycin, metronidazole, fusidic acid, nitazoxanide, teicoplanin, rifampin, rifaximin and bacitracin. In paired comparisons, no single antibiotic was clearly superior to others, though teicoplanin, an antibiotic of limited availability and great cost, showed in some outcomes significant benefit over vancomycin and fusidic acid, and a trend towards benefit compared to metronidazole. Only one placebo controlled trial was done and no conclusions can be drawn from it due to small size and classification error. Only one study investigated synergistic antibiotic combination, metronidazole and rifampin, and there was no advantage to the drug combination.

AUTHORS' CONCLUSIONS: Current evidence leads to uncertainty whether mild CDAD needs to be treated. Patients with mild CDAD may resolve their symptoms as quickly without treatment. The only placebo-controlled study shows vancomycin's superior efficacy. However, this result should be treated with caution due to the small number of patients enrolled and the poor methodological quality of the trial. The Johnson study of asymptomatic carriers also shows that placebo is better than vancomycin or metronidazole for eliminating C. difficile in stool during follow-up. If one does decide to treat, then two goals of therapy need to be kept in mind: improvement of the patient's clinical condition and prevention of spread of C. difficile infection to other patients. Given these two considerations, one should choose the antibiotic that brings both symptomatic cure and bacteriologic cure.

In this regard, teicoplanin appears to be the best choice because the available evidence suggests that it is better than vancomycin for bacteriologic cure and has borderline superior effectiveness in terms of symptomatic cure. Teicoplanin is not readily available in the United States, which must be taken into account when making treatment decisions in that country.

Plain language summary

Antibiotic therapy for Clostridium difficile-associated diarrhea (CDAD) needs further investigation.Diarrhea may be a side effect of many commonly used antibiotics, and this is in some cases due to overgrowth of a bacterium called Clostridium difficile (C. difficile) in the colon after other bacteria have been killed. The seriousness of C. difficile-associated diarrhea can range from being a nuisance to a life threatening or even fatal disease. The treatment of CDAD is usually cessation of the initiating antibiotic and immediate administration of a new antibiotic. However each of these three strategies, cessation of the original antibiotic, immediate retreatment, and the choice of a new antibiotic are poorly supported by currently available evidence. The antibiotic that is most tested, vancomycin, is the one most prone to serious side effects. Seven other antibiotics are included in this review and within the limitations of the included studies, they each seem to be as effective as vancomycin.

The Cochrane Library

Pediatric fingertip injuries: do prophylactic antibiotics alter infection rates?

Pediatric fingertip injuries: do prophylactic antibiotics alter infection rates?

Pediatr Emerg Care. 2008 Mar

Altergott C, Garcia FJ, Nager AL.
Department of Pediatrics, Division of Emergency Medicine, Childrens Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USA. caltergott@chla.usc.edu

STUDY OBJECTIVE: Fingertip injuries are common in the pediatric population. Considerable controversy exists as to whether prophylactic antibiotics are necessary after repair of these injuries. Our goal was to compare the rate of bacterial infections among subgroups treated with and without prophylactic antibiotics. The study hypothesis was that infection rates were similar in the 2 groups.

METHODS: This was a prospective randomized control trial of pediatric patients presenting to an urban children's hospital with trauma to the distal fingertip, requiring repair. Patients were randomized to 2 groups: group 1 received no antibiotics, and group 2 received antibiotics (cephalexin). Repairs were performed in a standardized fashion, and all patients were reevaluated in the same emergency department in 48 hours and again by phone 7 days after repair. The primary outcome measure was the rate of infection at 7 days after repair.

RESULTS: One hundred forty-six patients were initially enrolled in the study, 11 patients were withdrawn before study completion, 69 subjects were randomized to the no-antibiotic group, and 66 subjects were randomized to the antibiotic group. There was 1 infection in each group at 7 days after repair. The infection rate was 1.45% (95% confidence interval, 0.04%-7.81%) for the no-antibiotic group and was 1.52% (95% confidence interval, 0.04%-8.16%) for the antibiotic group, not statistically significant (P = 1.00).

CONCLUSIONS: This study suggests that routine prophylactic antibiotics do not reduce the rate of infection after repair of distal fingertip injuries.

Lippincott, Williams & Wilkins

Trends in Resistance to Ciprofloxacin, Cefazolin, and Gentamicin in the Treatment of Bacterial Keratitis

Trends in Resistance to Ciprofloxacin, Cefazolin, and Gentamicin in the Treatment of Bacterial Keratitis

J Ocul Pharmacol Ther. 2008 Mar 10

Afshari NA, Ma JJ, Duncan SM, Pineda R, Starr CE, Decroos FC, Johnson CS, Adelman RA.
Duke University Eye Center, Duke University Medical Center, Durham, NC.

Purpose: The aim of this study was to evaluate the microbial profile, resistance patterns, and antibiotic sensitivity of bacterial keratitis to three commonly used ocular antibiotics.

Methods: All cases of bacterial keratitis referred to the Massachusetts Eye and Ear Infirmary Microbiology Laboratory from two consecutive annual 10-month periods were reviewed. The bacterial profile and resistance to ciprofloxacin, cefazolin, and gentamicin was evaluated within the two intervals.

Results: Of the 485 cultures analyzed, 66.4% (322) were positive for bacterial isolates. Of these, 19.2% were polymicrobial, 87.5% were gram-positive, and 12.5% were gram-negative. The most prevalent isolate was coagulase-negative Staphylococcus (45.5%), followed by S. aureus (15.2%).

The resistance patterns for gram-positive bacteria for ciprofloxacin for the first versus second time interval were 12% and 22% (P = 0.04) respectively, for cefazolin 13% and 23% (P = 0.04), and for gentamicin 4% and 7% (P = 0.36). The resistance patterns for gram-negative bacteria for ciprofloxacin, cefazolin, and gentamicin were not significantly different in the two tested time periods (all P greater then 0.05).

Conclusions: There was increased resistance of gram-positive organisms to ciprofloxacin and cefazolin, but not gentamicin, in the two examined time periods. Increased resistance to these commonly used antibiotics emphasizes the need for close follow-up after initial empiric treatment, and maintaining a low threshold for selecting alternative therapy.

Liebert

Ciprofloxacin in primary prophylaxis of spontaneous bacterial peritonitis: A randomized, placebo-controlled study.

Ciprofloxacin in primary prophylaxis of spontaneous bacterial peritonitis: A randomized, placebo-controlled study.

J Hepatol. 2008 Feb

Terg R, Fassio E, Guevara M, Cartier M, Longo C, Lucero R, Landeira C, Romero G, Dominguez N, Muñoz A, Levi D, Miguez C, Abecasis R.
Unidad de Hígado, Hospital de Gastroenterología “Dr. Bonorino Udaondo”, Sección Hepatología, Av. Caseros 2061, 1264 Buenos Aires, Argentina.

BACKGROUND/AIMS: Low protein concentration in ascitic fluid has been identified as a risk factor for spontaneous bacterial peritonitis (SBP). Until now, primary prophylaxis has not been recommended in these patients. The aim was to investigate the efficacy of long-term administration of ciprofloxacin to prevent SBP.

METHODS: One hundred cirrhotic patients with (less then) 1.5g/dl of total protein in ascitic fluid were randomized prospectively, in a double blind fashion to receive ciprofloxacin 500mg/day (n=50) or placebo (n=50) for 12 months.

RESULTS: Baseline data were similar in both groups. In the ciprofloxacin group, SBP occurred almost four times less frequently than in the placebo group but it was not statistically significant. The probability of survival at 12 months was significantly higher in patients receiving ciprofloxacin (86% versus 66%) (p<0.04). p="0.05).">

CONCLUSIONS: Patients with cirrhosis and low protein concentration in ascitic fluid are candidates to receive long-term prophylaxis to reduce the risk of infections and improve survival.

Elsevier