Promising Antimicrobials Research Articles

New drugs to treat skin and soft tissue infections

Due to increasing antimicrobial resistance, a pressing need exists for new antibiotics to treat skin and soft tissue infections. Several newer agents such as tigecycline, daptomycin, and linezolid have been important additions for the treatment of multidrug-resistant pathogens. New drugs in development such as dalbavancin and ceftobiprole will further enhance our ability to treat mixed infections and improve patient compliance. These promising new antimicrobials will likely grow in importance as resistant bacterial strains increase in community-acquired infections.

Pyrrolidine bis-cyclic guanidines with antimicrobial activity against drug-resistant Gram-positive pathogens identified from a mixture-based combinatorial library

The rapid rise in antibiotic-resistant Gram-positive bacterial infections prompted us to explore the development of novel strategies for synthesis of large chemical libraries amenable to high-throughput screening for antimicrobial activities. Here we report the solid-phase synthesis of a 738,192 member pyrrolidine bis-cyclic guanidine chemical library with 26 different amino acids at three positions of diversity and 42 carboxylic acids at the fourth position. This synthetic combinatorial library was developed for positional scanning and screened for bacteriostatic and bactericidal activities against the important human pathogen methicillin-resistant Staphylococcus aureus (MRSA). The eight compound mixtures exhibiting bactericidal activity (10 μg/mL) against MRSA were used to direct the synthesis of 36 individual compounds that were then screened for activity against MRSA, vancomycin-resistant Enterococcus faecalis (VRE), and two Gram-negative bacterial species. At least 20 individual compounds were bactericidal for MRSA at ⩽2.5 μg/mL, with a subset of these compounds showing bactericidal activities (⩽10 μg/mL) against the other species tested. This approach demonstrates the capability to synthesize and screen a complex library to yield promising antimicrobials that address a critical need for novel infectious disease therapeutics.

Straightforward representation of antimicrobial chemotherapeutics susceptibility profiles in a private tertiary care hospital

Culture-based values for antimicrobial susceptibility of 28 antimicrobials against different bacteria isolated from clinical material in a tertiary care hospital were used to pick the most promising antimicrobials. Isolates originating from urinary tract, blood and pyogenic foci, enteric fever and enteritis were grouped. Antimicrobials, systemic or oral, exhibiting a 75% or more susceptibility were compartmentalized in relation to divergent clinical disorders. Retrospective categorized culture-based susceptibility values should help a rational prospective chemotherapeutic intervention against infectious syndromes encountered in hospital practice.

Present Status and Future Prospects of Chemotherapeutics for Intractable Infections due to Mycobacterium avium Complex

Mycobacterium avium-intracellulare complex (MAC) infections are frequently encountered in immunocompromised hosts, especially AIDS patients, although nodular-bronchiectasis type MAC infections without predisposing conditions are steadily increasing, particularly in Japan. Clinical control of MAC infection is difficult, since it responds poorly to available antimycobacterial regimens because of the intrinsic resistance of MAC organisms to common antituberculosis drugs, although some antimycobacterial drugs, such as macrolides (clarithromycin, azithromycin), ethambutol, clofazimine and rifamycins (especially rifabutin), are fairly or modestly effective in controlling AIDS-associated MAC bacteremia. In addition, treatment of pulmonary MAC infections is also difficult, even with available antimycobacterial multi-drug therapies. The insufficient efficacy of the majority of ordinary antimycobacterial drugs in treating MAC diseases is principally due to the low susceptibility of MAC to the majority of ordinary antimycobacterial drugs, the extremely wide range of susceptibilities of MAC isolates to most antimicrobial drugs, and the fact that polyclonal MAC infections are occasionally seen in AIDS patients. Therefore, the development of new antimicrobials and administration protocols that are safe and potently effective against MAC infections is urgently needed. However, despite the gradual but steady increase in the incidence of MAC infections, and thereby the urgent call for new drug development, new drugs that are truly useful for the treatment of refractory MAC diseases continue to elude us. In this review article, the following topics will be described: (1) the present status of the existing anti-MAC drugs, with special reference to the recent findings of the in vitro and in vivo anti-MAC activities of macrolides and other moderately useful drugs, such as new rifamycins, clofazimine and some fluoroquinolones, and (2) the present status and future prospects of the development of new promising antimicrobials with anti-MAC activity.

Use of the Quinolones in Paediatrics

For many years, quinolone-induced cartilage toxicity observed in experiments involving immature animals has represented an indisputable contraindication for the use of these promising antimicrobials in prepubertal patients. Clinical, magnetic resonance imaging and histopathological monitoring of patients receiving ciprofloxacin at the University of Berne, together with published data, suggest that the quinolones do not cause arthropathy in humans. Conditions that potentially qualify for quinolone use (especially ciprofloxacin) in children include oral antipseudomonal (or antistaphylococcal) therapy for pulmonary exacerbations in cystic fibrosis, and complicated urinary tract, skeletal, aural and shunt infections. In addition to these rarer indications, there is an urgent need for the quinolones in developing countries for children with endemic and epidemic shigellosis and invasive salmonellosis. At present, these compounds are not approved for paediatric use and therefore must be administered as part of a controlled study or on a compassionate use basis in individual patients.