Biomedical subjects
P Ball
Publications and source records attributed to P Ball.
Meet the spin doctors...
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Storming the Tower of Babel.
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New antibiotics for community-acquired lower respiratory tract infections: improved activity at a cost?
Opinions are changing as to the continued validity of traditional beta-lactam and macrolide therapy of community acquired LRTI, partly because of resistance and partly because of early evidence that suggests that some new agents may be more effective. Guidelines are altering to reflect this view, although there is conflicting evidence on their effects on outcome. Fluoroquinolones are becoming accepted in the treatment of community acquired pneumonia and are established choices for acute exacerbations of chronic bronchitis. The 8-methoxy fluoroquinolones, moxifloxacin and gatifloxacin, have excellent anti-pneumococcal activity and may become drugs of choice for penicillin/macrolide resistant infections. They appear free of the serious idiosyncratic reaction profiles, possibly related to the immunologically reactive 1-difluorophenyl substituent, which characterised the recently withdrawn temafloxacin, trovafloxacin and tosufloxacin. All quinolones so far tested appear to prolong the QTc interval, but only sparfloxacin and grepafloxacin caused clinical effects. Nevertheless, caution is required until this effect is fully investigated.
Future antibiotic trials.
The true value of antibiotics in acute exacerbations of chronic bronchitis remains to be defined. Although short-term benefits are generally accepted, if prescription volume is an indicator, there is little evidence to support their use in mild exacerbations.Thus, most therapeutic episodes are probably unnecessary and certainly encourage bacterial resistance. In more severe exacerbations, trials must be designed to validate the potential benefits-if they exist-of pharmacologically-improved antibiotics by demonstration of both short- and longer-term benefits. The relevance of standard bacteriological and short-term clinical outcome assessments must be questioned. Alternative outcome measures, e.g., quality of life, may allow differentiation of antibiotic classes. Long-term assessment of symptom-free intervals, related to baseline status, might open pathways to the prevention of progressive, bacteria-initiated inflammatory damage to small airways. There is little excuse for continued ignorance of the nature of bacterial involvement in chronic bronchitis and the potential for more effective therapy.
Safety of the new fluoroquinolones compared with ciprofloxacin.
Significant safety issues that have arisen with fluoroquinolones include phototoxicity, cardiotoxicity, tendinitis, CNS effects and drug interactions. Ciprofloxacin is well tolerated; the incidence of adverse events is low and serious adverse events are rare. Levofloxacin has a reduced CNS adverse event rate compared with ofloxacin. Sparfloxacin has significant phototoxicity and potential cardiac toxicity. Grepafloxacin has significantly increased adverse event rates, particularly gastrointestinal intolerance. Taste perversion and nausea are common. Trovafloxacin has an increased potential for CNS adverse reactions, notably dizziness. Post-marketing surveillance data indicate the possibility of serious hepatic reactions and pancreatitis. Interactions between fluoroquinolones and drugs metabolised by the hepatic cytochrome P450 system affect the clearance of theophylline and caffeine. Quinolone absorption is significantly reduced by co-administration of antacids. Hospitalised patients are likely to be receiving multiple-drug therapy, but drug interactions are avoidable. The interactions of specific fluoroquinolones should be checked prior to prescription.
Quinolone-induced QT interval prolongation: a not-so-unexpected class effect.
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Quinolone generations: natural history or natural selection?
The quinolones have evolved from antibacterial agents with a limited spectrum of predominantly anti-gram-negative antimicrobial activity and a restricted number of indications to a class of widely used oral (and, in some cases, intravenous) antibiotics with extensive indications for infections caused by many bacterial pathogens in most body tissues and fluids. This evolutionary pattern has arisen through the development of new core and side-chain structures, with associated improvements in activity, pharmacokinetics and tolerability, and through the selection of molecules that remain useful and well tolerated. This review describes the progress of the quinolones from the first to the third (IIIa and IIIb) generations. Special attention is given to gemifloxacin, currently the most developmentally advanced third-generation quinolone, which has enhanced in vitro gram-positive antimicrobial activity and no troublesome adverse drug reactions. Preliminary data indicate that gemifloxacin should prove to be an important addition to the fluoroquinolone class. Further clinical trial data are awaited with interest.
Moxifloxacin (Avelox): an 8-methoxyquinolone antibacterial with enhanced potency.
Moxifloxacin is a novel 8-methoxyquinolone with enhanced potency against important Gram-positive pathogens, notably Streptococcus pneumoniae. It retains class activity against Gram-negative bacteria. Currently available for oral use, it has a prolonged half-life, enabling once-daily administration and reflecting balanced renal and hepatic elimination. Clinical trials have demonstrated an excellent safety record with minor class effects in the skin and gastrointestinal systems. Potential for phototoxicity is minimal and moxifloxacin is free of clinically significant neurological, hepatic or cardiac effects. Investigated primarily in respiratory infections, moxifloxacin has shown excellent performance in community-acquired pneumonia (both pneumococcal and atypical), acute exacerbations of chronic bronchitis and acute maxillary sinusitis. It is available in many European countries and in the US where it is rapidly establishing clinical acceptance and formulary inclusion.
Split-second chemistry is rewarded.
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Therapy for pneumococcal infection at the millennium: doubts and certainties.
Rapidly burgeoning worldwide multiple drug-resistant pneumococcal serotypes pose an urgent demand for new management approaches. Perhaps modern intensive care methods may have alternatives to offer. Indeed, standard assessments such as the admission APACHE II score may overestimate individual risk of death in severe CAP, and mortality can be reduced. However, among those at highest risk for mortality in the early phase of invasive disease, the conclusions reached 2-3 decades ago, that it is questionable whether a more effective drug than penicillin can be developed, and that a reduction in the number of deaths consequent to this infection can be accomplished only by widespread immunoprophylactic measures, remain inescapable. Clearly, as discussed elsewhere in this supplement, the continuing validity of these 20-year-old conclusions and the global prevalence of DRSP demand the development and marketing of new conjugate vaccines, although more widespread use of the existing 23-valent polysaccharide vaccine among high-risk populations is essential in the interim. With respect to resistance selection pressures, antibiotic prescription control may provide the answer. However, patient expectations of antibiotic therapy for trivial respiratory infection is high and, in the United Kingdom, 75% of previously healthy adults will receive it; those who do not will usually consult another physician in an effort to secure such therapy. Thus, without the intervention of government or managed care organizations, self-regulation in prescribing is unlikely. The evidence for beta-lactam treatment failure in meningitis has led to alternative approaches, with vancomycin as the primary agent. Penicillins may remain effective for otitis media, but oral cephalosporins are suspect. Data on pediatric pneumococcal pneumonia continue to suggest use of beta-lactams, at least for disease caused by strains with intermediate penicillin sensitivity. Pallares et al concluded that penicillins and cephalosporins remain the drugs of choice for severe pneumococcal pneumonia in adults. Others who share this conclusion often cite that study as evidence. However, in the case of penicillins, the mortality rate was 6% higher in a subgroup selected for monomicrobial infection and reduced risk factors for mortality when penicillin-resistant infection was present, and the overall mortality was 14% higher with penicillin-resistant strains (taking into account "all comers"). Those who depend on the findings of evidence-based medicine may accept the premise that penicillins and cephalosporins remain the drugs of choice, and agree with Goldstein and Garau that it would indeed be a mistake to adopt alternative therapies. Others may consider the deaths of 6 of 100 patients who were not in the highest-risk group too high a price to pay for statistical significance and may be skeptical of the continued use of beta-lactam therapy on higher-risk patients. In addition, the persistent selection pressure applied by continued use of beta-lactams offers a powerful population-based argument for alternatives. As DRSP continues to spread and resistant strains with penicillin MIC >2 mg/L become more prevalent, new agents such as the azabicyclo-methoxyquinolone, moxifloxacin, and perhaps grepafloxacin, but not the more toxic sparfloxacin and trovafloxacin, will undoubtedly flourish as treatments for CAP. By that time, the results of clinical studies on ketolides and oxazolidinones could offer further choices.
New Fluoroquinolones: Real and Potential Roles.
The second-generation fluoroquinolones have enjoyed successful clinical use for more than 10 years in many countries, and they have a valued and proven record of safety and efficacy. However, deficiencies with respect to gram-positive and anaerobic organisms limit the use of these agents in respiratory, intra-abdominal, and pelvic infections. New, third-generation agents with dramatically increased activity against gram-positive and anaerobic bacteria--notably, Streptococcus pneumoniae and Bacteroides fragilis--have shown high rates of efficacy in pneumonia, bronchitis, and surgical and gynecologic infections. Although most of these new drugs produce similar clinical results, adverse reaction profiles differ and may influence therapeutic choices.
Principles for formulating parenteral nutrition for neonates.
Total parenteral nutrition in humans began with work on neonates, and every year since then there have been important new discoveries. In the past 12 months there have been important new preliminary findings in parenteral nutrition cholestasis, and in bone mineralization. There has been further work on clinical pathways and other aspects of quality assurance, and scientists continue to find new aspects.
Comparative tolerability of the newer fluoroquinolone antibacterials.
The most common adverse effects of the fluoroquinolones involve the gastrointestinal tract, skin and CNS, and are mainly mild and reversible. Of the gastrointestinal events, nausea and vomiting are the most common. Mild hepatic reactions are a class effect, usually presenting as mild transaminase level increases without clinical symptoms. However, postmarketing surveillance has revealed significant hepatotoxicity with trovafloxacin. It is not currently known whether the severe reactions to trovafloxacin are specific to that agent or simply represent an extreme of an emerging class effect. The enormous worldwide usage of, and extensive published adverse effect data on the other fluoroquinolones and naphthyridones suggests the former. In perspective, rare but serious hepatotoxicity has been reported with other fluoroquinolones and the overall incidence of trovafloxacin hepatotoxicity is not dissimilar to that reported with flucloxacillin and amoxicillin-clavulanic acid. CNS reactions vary in severity and include dizziness, convulsions (notably with lomefloxacin) and psychoses. Fluoroquinolones differ in their pro-convulsive activity, relating to their differing potential as gamma-aminobutyric acid antagonists and binding to the N-methyl-D-aspartate receptor. The basis for the increased seizure potential following the coadministration of nonsteroidal anti-inflammatory drugs with certain fluoroquinolones is not fully understood. Fluoroquinolone phototoxicity, caused by the generation of toxic free oxygen species under exposure to UVA radiation, is significantly more common with 8-halogenated compounds. Certain patient groups, e.g. patients with cystic fibrosis, are predisposed to this adverse effect. Murine photocarcinogenicity has been demonstrated with lomefloxacin, but no such effects have been reported in humans. Prolongation of the QTc interval is also a class effect, although cardiac arrhythmias have only been linked with sparfloxacin. Among the newer fluoroquinolones, clinically significant cardiac events are rare or absent but possible interactions in patients receiving other drugs capable of causi ng QT prolongation should be anticipated. Tendinitis and rupture, usually of the Achilles tendon, are rare, class-effects of fluoroquinolones, most frequently reported with pefloxacin. Predisposing factors include aging, corticosteroid use, renal disease, haemodialysis and transplantation. Use of fluoroquinolones in paediatric patients remains contentious. However, accruing human data suggest that restrictions on paediatric use imposed because of fluoroquinolone-induced cartilage damage in juvenile animals, may soon be relaxed. Data from over 1700 children in the UK failed to disclose arthropathy and extensive paediatric use of norfloxacin in Japan and ciprofloxacin in developing countries has been free of articular effects.
Four-level cervical corpectomy.
STUDY DESIGN: Retrospective analysis of 31 cases of cervical spondylotic myelopathy treated by four-level subaxial cervical corpectomy. OBJECTIVE: To determine whether extremes of anterior decompression and fusion have inordinate or unique levels of morbidity. SUMMARY OF BACKGROUND DATA: There is a paucity of data on experience with four-level corpectomy. However, counsel against such surgery can be found. MATERIALS AND METHODS: The records and studies of 31 consecutive cases of cervical spondylotic myelopathy, treated by four-level corpectomy, were retrospectively analyzed. Patients in 26 cases were observed longer than 2 years. No hardware was used in the procedures. External orthosis, worn for 6 months, was a Philadelphia-type collar in 25 patients and a halo vest in 6. RESULTS: Three patients died within 3 weeks of surgery (9.7%). Delayed radiculopathy occurred in four patients after surgery, three had acute graft complications, and one had pseudomeningocele, for a morbidity rate of 25.8%. There was no infection or worsened myelopathy. CONCLUSIONS: No unique morbidity is associated with extremes of subaxial decompression when compared with surgery of lesser extent.
Artificial tissues. Liver spots.
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Particle retention efficiency of filters in respiratory devices.
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