Development of the semi-synthetic penicillins and cephalosporins.

Semi-synthetic penicillins and cephalosporins both derive from their respective chemical nuclei, 6-aminopenicillanic acid (6-APA) and 7-aminocephalosporanic acid (7-ACA). Work leading to their isolation was being carried out in parallel, but following very different pathways, during the last half of the 1950s. The development of 6-APA was reviewed recently in this journal, and in the present article I take a closer look at early work on 'penicillin amidase' and revisit the steps that led to 7-ACA.

Probiotics and prebiotics in the elderly.

Probiotics (usually lactobacilli and bifidobacteria) and prebiotics (non-digestible oligosaccharides) have been shown to be useful in preventing certain disease conditions as well as possibly promoting specific aspects of health. In the present review, the evidence from clinical trials for benefits from probiotics and prebiotics to elderly populations is presented and discussed, specifically in respect of three common conditions found in the elderly. Both probiotics and prebiotics may be helpful in malnutrition, particularly in lactose intolerance and calcium absorption, and in constipation. Probiotics have been shown clearly to boost immunity in the elderly, but the clinical significance of this remains to be clarified. These results are encouraging, and further large scale studies seem justified to establish the place of probiotic and prebiotic supplements in elderly subjects.

Antibiotic resistance from two perspectives: man and microbe.

Despite much effort, antibiotic resistance continues to increase. Looking back, it is clear that this was an inevitable consequence of antibiotic use. From a bacterial viewpoint, the introduction of antibiotics was a tremendous stimulus to evolution. As a survival reaction to stress (selection pressure) bacteria, by means of their extreme biochemical and genetic versatility, have adapted to 21st Century conditions. Resistance can be to some extent contained by less and better use of antibiotics, but ultimately novel approaches to the treatment and prevention of infectious diseases will have to be forthcoming. This will only be achieved if best use is made of alternative resources presently available and most importantly, man's ingenuity must be fully engaged.

The role of probiotics in the treatment and prevention of Helicobacter pylori infection.

Literature reporting activity of probiotics in infections due to Helicobacter pylori has been reviewed to assess their value in combating such infections. Several in vitro studies show that lactobacilli or their cell-free cultures inhibit or kill H. pylori, prevent its adhesion to mammalian epithelial cells and prevent IL8 release. In vivo models demonstrate that pre-treatment with a probiotic can prevent H. pylori infections and/or that administration of probiotics markedly reduced an existing infection. Thirteen clinical trials have been published. In six (180 patients), a probiotic was used alone; five of these had an encouraging result-in three there were significantly reduced breath test readings and in two others some patients were cleared of infection. In seven further trials (682 patients), probiotics were added to a therapeutic regimen of antibiotics, resulting in an increased cure rate in two studies, and reduced side-effects in four. Trials in which fermented milk products or whole cultures of lactobacilli were used tended to show better results than when the probiotic was taken in the form of bacteria alone. Not all the studies were randomised, double-blind and placebo controlled, and some involved only small numbers of patients. The results suggest that probiotics may have a place as adjunctive treatment in H. pylori infections and possibly in prophylaxis. Future trials should address in particular the type of patient (asymptomatic volunteers, symptomatic patients), choice of probiotic strain(s), a wide range of probiotic strains (Lactobacillus acidophilus, L. johnsonii, L. gasseri, lactobacillus GG, Bifidobacterium longum, and bioyoghurts) have been used-some non-viable, regimens (doses and duration) and criteria of success (breath test, histology, culture, serology).

Activity of ketolide ABT-773 (cethromycin) against erythromycin-resistant Streptococcus pneumoniae: correlation with extended MLSK phenotypes.

OBJECTIVES: (i) To determine the inhibitory and bactericidal activities of ABT-773, a novel ketolide, against sensitive and erythromycin-resistant pneumococci; (ii) to subdivide erythromycin-resistant pneumococci into resistance phenotypes, more extensive than the conventional M and MLS(B) groups, by assessing susceptibilities to, and interactions between, erythromycin (14-membered macrolide), clindamycin (lincosamide), rokitamycin (16-membered macrolide), ABT-773 (ketolide), quinupristin (streptogramin B) and dalfopristin (streptogramin A). METHODS: MICs and MBCs of ABT-773 were determined for 165 strains of pneumococci (113 resistant to erythromycin). Extended phenotypes for the erythromycin-resistant strains were described in terms of intrinsic susceptibility to, and induction of resistance by, the antibiotics listed above. RESULTS: Erythromycin-resistant strains could be divided into 10 extended phenotypes (designated II-XI), two of which (II and IX) predominated. ABT-773 at 0.12 mg/L inhibited 109 strains (median 0.03 mg/L). MICs for the other four strains (of phenotypes X and XI) were 0.25-1 mg/L. MICs were only slighter higher when measured on agar in CO(2) than by the NCCLS method (in broth in air). MBCs were usually < or = 2 x MIC, but for 10 strains (eight of phenotype X, one each of types IX and XI) MBCs were > 1 mg/L, and three of the latter (all type X) were tolerant. Clones of reduced susceptibility (MICs 1-8 mg/L, increased by up to 32-fold) could be isolated from some strains of phenotypes VII, IX and X, but not from those of type II (efflux mechanism) or from erythromycin-sensitive strains. CONCLUSIONS: ABT-773 was active against all 113 erythromycin-resistant pneumococci tested, which belonged to 10 phenotypes. Extended phenotyping of pneumococci revealed interesting and potentially useful subdivisions of the classical phenotypes.

Nisin, alone and combined with peptidoglycan-modulating antibiotics: activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci.

OBJECTIVE: We have sought ways to circumvent resistance, by combining nisin with other antibiotics known to target bacterial cell wall biosynthesis. METHODS: Twenty strains each of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) were tested in vitro by standardized methods against nisin alone and combined with bacitracin, ramoplanin and chloramphenicol. RESULTS: Ramoplanin was the most potent compound, and bacitracin had the least activity. Two-way synergy was observed with nisin and ramoplanin. However, chloramphenicol was clearly antagonistic to the activity of nisin. CONCLUSIONS: Observations of synergy between nisin and ramoplanin against MRSA and VRE offer a promising approach to the concept of combining nisin with inhibitors of cell wall peptidoglycan. Further investigations are needed in order to develop this approach as a clinical possibility.

Vancomycin-resistant Staphylococcus aureus: a real and present danger?

The glycopeptide antibiotics, vancomycin and teicoplanin, are the mainstay of therapy for infections involving strains of Staphylococcus aureus that are resistant to methicillin and gentamicin. Durng the last 5 years, clinical isolates of S. aureus showing reduced susceptibility to glycopeptides have been reported from many countries around the world, often associated with prolonged glycopeptide therapy. Detection and monitoring of such strains has been hindered by the fact that vancomycin (or glycopeptide)-intermediate S. aureus (VISA) isolates may be missed on conventional disk sensitivity tests. Effective control measures are required to prevent the increasing occurrence and spread of such strains in both the hospital and community settings. An important aspect of control is promoting the judicious use of glycopeptides. The recent introduction of the alternative antibiotics quinupristin/dalfopristin and linezolid, which are active against S. aureus strains resistant to many other classes of agent, should facilitate this process.

Identity and antibiotic susceptibility of enterobacterial flora of salad vegetables.

The enterobacterial flora from carrots (organic and non-organic) and salad vegetables has been identified and antibiotic susceptibilities determined. Pseudomonas fluorescens and Pantoea (formerly Enterobacter) agglomerans were the species most commonly found; the former was usually resistant to at least six of the antibiotics under test. Rahnella aquatilis (often producing beta-lactamase) was also found in carrots. There were no clear differences in flora from organic and non-organic carrots. Thus, uncooked vegetables are a potential source of highly resistant opportunistic pathogens.

Immunopharmacology of antibiotics: direct and indirect immunomodulation of defence mechanisms.

Antibiotics can alter the host's reaction to an infection (itself an immunomodulating event) in various ways. Indirect actions involve killing of bacteria, changing the intestinal flora, intrinsic antigenicity and preventing bacteria making virulence factors. Direct actions are upon phagocytic function, chemotaxis and lymphocyte activities. Immunomodulation can be positive ("pro-host") or negative, and can be quantitated by means of the parameter "immune index". Among the cephalosporins, cefodizime shows the greatest positive immunomodulating activity, due to the unique nature of the 3-sidechain. Cefotaxime has an immunodepressing effect in vitro. The oral cephalosporin cefaclor appears to have a beneficial effect on polymorph function. While immunomodulation by antibiotics may appear marked in in vitro and ex vivo experiments, and in animal models, this phenomenon does not appear to have decisive effects therapeutically.

Anti-cariogenic properties of tea (Camellia sinensis).

Various components in green and black tea, the beverages made by infusing appropriately processed dried leaves of Camellia sinensis, notably simple catechins, have properties in vitro that suggest an anti-cariogenic activity. These include: a direct bactericidal effect against Streptococcus mutans and S. sobrinus; prevention of bacterial adherence to teeth; inhibition of glucosyl transferase, thus limiting the biosynthesis of sticky glucan; inhibition of human and bacterial amylases. Studies in animal models show that these in-vitro effects can translate into caries prevention. A limited number of clinical trials in man suggest that regular tea drinking may reduce the incidence and severity of caries. If substantiated, this could offer a very economical public health intervention.

Patterns of phenotypic resistance to the macrolide-lincosamide-ketolide-streptogramin group of antibiotics in staphylococci.

Phenotypes of resistance to the macrolide-lincosamide-ketolide-streptogramin (MLKS) group of antibiotics have been determined in 540 clinical isolates of staphylococci (210 Staphylococcus aureus and 330 coagulase-negative species). Results of disc diffusion tests using erythromycin A, oleandomycin, rokitamycin, clindamycin, telithromycin, quinupristin and dalfopristin delineated four main groups corresponding to those defined classically using erythromycin and clindamycin only, but with sub-divisions. Resistance to erythromycin was more common in coagulase-negative strains (56%) than in S. aureus (16%); telithromycin, clindamycin, quinupristin-dalfopristin and rokitamycin were active against >97% of S. aureus strains and >88% of the coagulase-negative strains. The commonest resistance phenotype was 'inducible MLS(B)' (12% in S. aureus, 31% in coagulase-negative strains); this group could be divided in terms of the different inducing abilities of erythromycin and oleandomycin. 'Constitutive MLS(B)' and 'MS' phenotypes were more often found in coagulase-negative strains (11 and 13%, respectively) than in S. aureus (2 and 1%). Novel phenotypes were found during the isolation of constitutively resistant mutants from inducible strains, and of resistant mutants from 'MS' strains. This extended phenotyping scheme has revealed further complexities and evolutionary possibilities in patterns of resistance to this group of antibiotics.

Sir Edward Abraham's contribution to the development of the cephalosporins: a reassessment.

This paper is based on an invited lecture given at the 21st International Congress of Chemotherapy in July 1999, as part of a Symposium entitled '50 years of cephalosporins: their use the next 50 years', (Hamilton-Miller JMT, Cephalosporins: from mould to drug. Sardinia to Oxford and beyond, J Antimicr Chemother 1999;44(A):26). Celebration of this Golden Anniversary was made more poignant by the death of the last major participant, Sir Edward Abraham, in May 1999. This history has been told before, but mainly by Sir Edward, who being a very modest man (to which his obituaries graphically attest) consistently underplayed the role that he and Newton had in the discovery of cephalosporin C, that led to all the cephalosporins now in use. I had the privilege of working at the Dunn School from 1967 to 1970, with Abraham and Newton, where I met Brotzu, Florey and Dorothy Hodgkin, all of whom had important roles in this story. Other workers at the Dunn School at that time, e.g. Heatley, Sanders and Jennings (who became Lady Florey), helped develop penicillin. Such a galaxy of stars of the antibiotic firmament will never again be assembled. "Let us now praise famous men... these were honoured in their generation, and were the glory of their times" - Ecclesiasticus XLIV. vv 1.7.