The recently launched document, ‘Burden of Respiratory Infectious Disease in Australia’ is a timely reminder of the full impact of respiratory infection on the health of Australians, both as multiple specific disease entities that are significant in their own right and as an important complicating factor that cuts across all areas of respiratory health. The document outlines the dramatic mismatch between the enormity of total disease burden and the relative paucity of effective management strategies. In the first instance this mismatch may seem surprising, but on further reflection, this should not be the case.

Where did the idea of using macrolides in cystic fibrosis (CF) come from? The majority of adolescents and adults with CF are colonized with Pseudomonas aeruginosa (P. aeruginosa) against which macrolides have no antibacterial activity. An anti-inflammatory role for this class of antibiotics in asthma was postulated in 19701. More recently, erythromycin has been shown to improve survival in diffuse pan bronchiolitis2. This is a mostly Japanese chronic condition, characterized by upper and lower respiratory tract sepsis, airways obstruction and P. aeruginosa colonization. Following an anecdotal experience with one adolescent in the UK, an open label uncontrolled study of azithromycin was carried out in seven children with CF. A significant improvement in lung function was observed following at least 3 months of therapy3. There are now three placebo-controlled randomized trials on the use of azithromycin in CF: from Australia4, UK5 and USA6. These have been the subject of a Cochrane Library metanalysis7. These three studies involved 604, 415 and 1856 patients, respectively. The Australian study involved adults only, the UK study involved children only and the USA study involved both. Treatment periods were 3 months (Australia) or 6 months (UK and USA). Dosing was either daily (Australia and UK) or three times per week (USA). All patients had CF; in the majority P. aeruginosa colonization was documented and was an inclusion criterion for the USA study. In each of the studies, there was a significant improvement in lung function during the treatment period as measured by forced expiratory volume in 1 second. A decrease in hospital stay and intravenous antibiotic use was observed in the Australian and USA studies. Improvement in bodyweight was also observed in the USA study. Improvement in quality of life indices was documented in the two studies in which this was measured4,6. In general terms, the azithromycin was well tolerated and adverse effects, especially nausea and diarrhoea, were no more than would have been expected for a drug of this class. Adherence to therapy, as measured by returned tablet counts, was satisfactory, for example, greater than 85% in the USA study. There was no evidence of emergence of resistant bacteria during the studies, although this is an obvious concern. There was no evidence to suggest that response to therapy was related to eradication of azithromycin-susceptible organisms. So how can this be? How might azithromycin or other macrolides have a favourable impact in CF patients? There are two possible mechanisms: (i) anti-inflammatory and (ii) anti-infective. Macrolides have been shown to inhibit neutrophil oxidative burst, chemotaxis and elastase production, although these effects are variable8. Macrolides have often also been shown to reduce production and release of pro-inflammatory cytokines including tumour necrosis factor-α (TNF-α), interleukins-6 and -8 and gamma interferon8. In our randomized control trial4, we demonstrated a reduction in C-reactive protein over the 3 month treatment period with azithromycin. We have also demonstrated a reduction in TNF-α production by peripheral blood mononuclear cells in vitro9 and in vivo10. Macrolides have no inherent antibacterial activity against P. aeruginosa or other Gram-negative bacilli, however, there are some potential mechanisms whereby inhibition of such organisms may occur. Subinhibitory concentrations of azithromycin have been shown to inhibit synthesis of the bacterial enzymes elastase and protease11, and pyocyanin synthesis12. This drug may also inhibit type 4 pili induced twitching motility13. Inhibition of P. aeruginosa alginate production, biofilm production and quorum sensing ability have also been demonstrated for azithromycin12–14. The half-life of macrolides is very long (azithromycin persists for approximately 12 days in neutrophils15) and they have excellent intracellular and tissue penetration16. Are the clinical effects of azithromycin in CF patients applicable to other macrolides? Azithromycin is the sole member of the 15 membered macrolides currently licensed for use in a clinical setting; all the others are 14 or 16 membered drugs. These differences are not only structural, but also apply to some antimicrobial and immunomodulatory effects, drug interactions and toxicity16,17. Some of the immunomodulatory effects of azithromycin have not been observed for other macrolides, although studies in this area are limited. Clinical experience with the use of macrolides other than azithromycin is limited, but anecdotally they may be inferior in this respect. One small open study showed no benefit from clarithromycin18. Obviously, further clinical studies need to be carried out on macrolide use in CF patients. Further analysis has taken place in the USA cohort (L Saiman, pers. Commun.), and our group is conducting a randomized controlled trial on daily versus weekly azithromycin. Many questions remain unanswered and many issues require resolution. We do not know the optimal dose or frequency of azithromycin use. We do not know if the beneficial effects of azithromycin are maintained or if therapy has to be life long. In these early days there is no consensus on when treatment should be started; in particular the currently available data in children are very limited. Perhaps there are clinical or other features that could identify who are most likely to respond to this therapy; our anecdotal experience suggests that there may be responders and non-responders. We do not really know if azithromycin is the optimal drug for this scenario, perhaps other macrolides, other antimicrobials or other anti-inflammatory drugs have a role to play. Antimicrobial resistance has not been comprehensively studied in the three randomized controlled trials and we must keep this possibility in mind. Macrolide resistance to streptococci and pneumococci has been increasing in many countries, and there is a clear correlation between macrolide use and the level of resistance19. For patients with CF, these studies represent a potential for improved quantity and quality of life. The prospect of fewer sick days and hospital admissions, and a greater feeling of well-being, is very attractive to those with this chronic debilitating condition. Many patients from our trial have continued to take azithromycin, sometimes at their own expense. Further studies will help us refine our knowledge in this area so we can prescribe more effectively and wisely.

Macrolide antibiotics have been licensed since the 1950s and have an important role in the treatment of a diverse range of infectious diseases. Macrolide antibiotics have antibacterial activity against gram-positive bacteria, some gram-negative bacteria and intracellular pathogens. The spectrum of antibacterial activity combined with excellent intracellular and tissue penetration has led to the extensive use of this class of drugs in respiratory disease. Macrolide antibiotics also have demonstrated anti-inflammatory properties in various in vitro and in vivo model systems. Novel antimicrobial and anti-inflammatory properties of macrolide may result in clinical benefits, particularly in conditions where the infectious agent is inherently resistant to macrolides. Three randomized control trials have demonstrated improved lung function in patients treated with the macrolide antibiotic, azithromycin. Azithromycin was generally well tolerated and resulted in reduction in the inflammatory response which may be due to an immunomodulatory role. Short term studies (three to six months) have not demonstrated the development of increased bacterial resistance or the emergence of new pathogens following azithromycin.

Objective. Despite widespread adoption of home care services, few randomised trials have compared health outcomes in the hospital and at home. We report a prospective, randomised trial of home versus hospital therapy in adults receiving intravenous (IV) antibiotics. Our objective was to show that home care is a feasible alternative to hospitalisation over a broad range of infections, without compromise to quality of life (QOL) or clinical outcomes.Methods. Consenting adults requiring IV antibiotics were randomised to complete therapy at home or in hospital. Short Form 36 and Perceived Health Competence Scale (PHCS) were used for assessment of QOL. Statistical analysis used unpaired t-tests, Mann-Whitney tests and ANOVA.Results. One hundred and twenty-nine admissions were referred. Recruitment was hampered by patient preference for one therapy over another. 82 (62%) were included and randomised: 44 to home, 38 to hospital; the two groups had comparable characteristics. There were no differences in improvements in QOL and PHCS scores between the two groups after treatment. Treatment duration was median 11.5 days (range 3 - 57) and 11 days (range 4 - 126) for home and hospital groups, respectively. Home therapy costs, approximately, half that of hospital therapy. Time to readmission was longer after hospital therapy.Conclusion. Out study showed that home IV therapy is welt tolerated, is less costly, is not associated with any major disadvantage to QOL or clinical outcomes compared to hospital therapy, and is an appropriate treatment option for selected patients. (C) 2003 The British Infection Society. Published by Elsevier Ltd. All rights reserved.

Aim: To further characterize the properties of 1,4-dideoxy-1,4-imino-d-arabinitol (DAB), a recently described novel and potent inhibitor of glycogen phosphorylase and potential anti-diabetic agent, we have determined its pharmacokinetic properties in rats, dogs and mice and compared these to its pharmacodynamic anti-hyperglycaemic efficacy.Methods: Male Sprague Dawley rats, beagle dogs and diabetic Umea ob/ob mice were administered DAB or C-14-DAB at various doses and by different routes and in either the conscious or the unconscious state and with or without glucagon, as appropriate. At different time points thereafter, blood, tissue and urine samples were withdrawn for analyses of DAB or C-14-DAB, and blood samples were taken for glucose concentration.Results: DAB suppressed the blood glucose excursion in glucagon-challenged rats with an ID100 of 1-2 mg/kg per orally and intravenously and had a pharmacodynamic t(50) for 1.6 mg/kg intravenously and for 1.2 mg/kg per orally of 50 and 60 min respectively. The pharmacokinetics of c. 2 mg/kg DAB in rats revealed elimination half-lives of 25 min after intravenous (i.v.) and 49 min after per oral (p.o.) administration; the oral bioavailability was 89%. In rats, DAB was distributed preferentially in liver vs. skeletal muscle and was eliminated predominantly through urine as parent compound. The pharmacokinetics of 4 mg/kg DAB in dogs showed elimination half-lives of 107 min after i.v. and 129 min after p.o. administration with an estimated oral availability of 78%. At 4 mg/kg DAB p.o., glucagon-induced hyperglycaemia in dogs was reduced in a time-dependent manner with an estimated t(50) of 4 h. DAB was very rapidly cleared in mice; nevertheless, a dose-dependent reduction of blood glucose of up to 9 mmol/l was seen in diabetic ob/ob mice dosed subcutaneously, with statistically significant effects evident from 30 to 120 min.Conclusions: These data show that DAB is nearly completely orally available in rats and dogs and that it can reduce glucagon-induced and spontaneous hyperglycaemia. Inhibition of hepatic glycogen phosphorylase may benefit glycaemic control in patients with type 2 diabetes.

Infection frequently causes exacerbations of chronic obstructive pulmonary disease (COPD). Mannose-binding lectin (MBL) is a pattern-recognition receptor that assists in clearing microorganisms. Polymorphisms in the MBL2 gene reduce serum MBL levels and are associated with risk of infection. We studied whether the MBL2 codon 54 B allele affected serum MBL levels, admissions for infective exacerbation in COPD and disease susceptibility. Polymorphism frequency was determined by PCR-RFLP in 200 COPD patients and 104 smokers with normal lung function. Serum MBL was measured as mannan-binding activity in a subgroup of 82 stable COPD patients. Frequency of COPD admissions for infective exacerbation was ascertained for a 2-year period. The MBL2 codon 54 B allele reduced serum MBL in COPD patients. In keeping, patients carrying the low MBL-producing B allele had increased risk of admission for infective exacerbation (OR 4.9, P(corrected)=0.011). No association of MBL2 genotype with susceptibility to COPD was detected. In COPD, serum MBL is regulated by polymorphism at codon 54 in its encoding gene. Low MBL-producing genotypes were associated with more frequent admissions to hospital with respiratory infection, suggesting that the MBL2 gene is disease-modifying in COPD. MBL2 genotype should be explored prospectively as a prognostic marker for infection risk in COPD.

Conference Abstract| June 01 2001 Regulation of Pyruvate Dehydrogenase in Human Muscle Cells E. L. Abbot; E. L. Abbot 1School of Biochemistry and Genetics, Medical School, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom Search for other works by this author on: This Site PubMed Google Scholar J. G. McCormack; J. G. McCormack 1School of Biochemistry and Genetics, Medical School, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom Search for other works by this author on: This Site PubMed Google Scholar S. J. Yeaman S. J. Yeaman 1School of Biochemistry and Genetics, Medical School, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (2001) 29 (3): A69. https://doi.org/10.1042/bst029a069b Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation E. L. Abbot, J. G. McCormack, S. J. Yeaman; Regulation of Pyruvate Dehydrogenase in Human Muscle Cells. Biochem Soc Trans 1 June 2001; 29 (3): A69. doi: https://doi.org/10.1042/bst029a069b Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search This content is only available as a PDF. © 2001 Biochemical Society2001 Article PDF first page preview Close Modal You do not currently have access to this content.

A key feature of type 2 diabetes is impairment in the stimulation of glycogen synthesis in skeletal muscle by insulin. Glycogen synthesis and the activity of the enzyme glycogen synthase (GS) have been studied in human myoblasts in culture under a variety of experimental conditions. Incubation in the absence of glucose for up to 6 h caused an approximately 50% decrease in glycogen content, which was associated with a small decrease in the fractional activity of GS. Subsequent reincubation with physiological concentrations of glucose led to a dramatic increase in the rate of glycogen synthesis and in the fractional activity of GS, an effect which was both time- and glucose concentration-dependent and essentially additive with the effects of insulin. This effect was seen only after glycogen depletion. Inhibitors of signaling pathways involved in the stimulation of glycogen synthesis by insulin were without significant effect on the stimulatory action of glucose. These results indicate that at least two distinct mechanisms exist to stimulate glycogen synthesis in human muscle: one acting in response to insulin and the other acting in response to glucose after glycogen depletion, such as that which results from exercise or starvation.

This is an interesting, broadly based textbook of infectious diseases, now into its second edition. The three authors combine expertise and experience in infectious and tropical diseases, epidemiology and microbiology. Being 500 pages long, it is not a large reference textbook such as Mandell's Principles and Practice of Infectious Diseases, but it is concise and readable as a result.

ABSTRACT Various treatment regimens and difficulties with research design are encountered with cystic fibrosis (CF) because no standard diagnostic criteria exist for defining acute respiratory exacerbations. This study evaluated the role of serial monitoring of concentrations of selected cytokines and inflammatory mediators in serum and sputum as predictors of respiratory exacerbation, as useful outcome measures for CF, and to guide therapy. Interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-α), neutrophil elastase-α-1-protease inhibitor complex (NE complex), protein, and α-1-protease inhibitor (α-1-PI) were measured in serum and sputum collected from CF patients during respiratory exacerbations and periods of well-being. Levels of NE complex, protein, and α-1-PI in sputum rose during respiratory exacerbations and fell after institution of antibiotic therapy (P = 0.078, 0.001, and 0.002, respectively). Mean (± standard error of the mean) levels of IL-8 and TNF-α were extremely high in sputum (13,780 ± 916 and 249.4 ± 23.5 ng/liter, respectively) but did not change significantly with clinical deterioration of the patient (P > 0.23). IL-8 and TNF-α were generally undetectable in serum, and therefore these measures were unhelpful. Drop in forced expiratory volume in 1 s was the only clinical or laboratory parameter that was close to being a determinant of respiratory exacerbation (P = 0.055). This study provides evidence of intense immunological activity occurring continually within the lungs of adult CF patients. Measurement of cytokines and inflammatory mediators in CF sputum is not helpful for identifying acute respiratory exacerbations.

The case of a 9-year-old girl with cat-scratch disease (CSD) complicated by development of a paravertebral mass and osteomyelitis is presented. Following multiple scratches and inguinal lymphadenopathy, she developed back pain, and imaging demonstrated a paravertebral mass with evidence of osteomyelitis involving vertebra T9. The diagnosis was made on the basis of detection of Bartonella henselae by use of molecular techniques on an aspirate from the vertebral column and supportive serology for infection with B. henselae. Eleven other cases of this unusual manifestation associated with CSD have been reported in the literature and are reviewed. The patient was treated with gentamicin, followed by rifampicin and trimethoprim-sulfamethoxazole, orally and made a favorable recovery over 7 months. This is comparable with other case reports, regardless of the choice of antibiotic therapy. CSD in immunocompetent hosts is not always self-limiting, and tissues beyond the lymph nodes can be involved.

Australian and New Zealand Journal of MedicineVolume 29, Issue 4 p. 601-625 THE AUSTRALASIAN SOCIETY FOR INFECTIOUS DISEASES First published: 25 March 2008 https://doi.org/10.1111/j.1445-5994.1999.tb00773.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume29, Issue4August 1999Pages 601-625 RelatedInformation

The regulation of glycogen synthesis and associated enzymes was studied in human myoblasts and myotubes maintained in culture. Both epidermal growth factor (EGF) and insulin stimulated glycogen synthesis approximately 2-fold, this stimulation being accompanied by a rapid and stable activation of the controlling enzyme glycogen synthase (GS). EGF also caused inhibition of glycogen synthase kinase 3 (GSK-3) and activation of the alpha isoform of protein kinase B (PKB) with the time-course and magnitude of its effects being similar to those induced by insulin. An inhibitor of the mitogen-activated protein (MAP) kinase pathway did not prevent stimulation of GS by EGF, suggesting that this pathway is not essential for the effect. A partial decrease in the fold activation of GS was, however, observed when p70(S6k) activation was blocked with rapamycin, suggesting a contribution of this pathway to the control of GS by either hormone. Wortmannin, a selective inhibitor of phosphatidylinositol 3'-kinase (PI-3 kinase) completely blocked the effects of both EGF and insulin in these cells. These results demonstrate that EGF, like insulin, activates glycogen synthesis in muscle, acting principally via the PKB/GSK-3 pathway but with a contribution from a rapamycin-sensitive component that lies downstream of PI-3 kinase.

We describe a 46-year-old man in whom retinitis was diagnosed as his initial HIV and AIDS defining illness, A diagnosis of CMV infection was made based on the clinical appearance of the fundus and confirmed by DNA polymerase chain reaction (PCR) on his vitreous biopsy, His CD4+ T lymphocyte count at the time was 580 x 10(6)/l (16%) with a CD4:CD8 ration of 0.28. He had a splenectomy following trauma more than 20 years earlier. He responded very well to intravenous and oral ganciclovir and remains recurrence-free almost 2 years later.This case and others highlight two issues: (i) CMV retinitis in HIV positive patients is not confined to those with very low CD4+ T lymphocyte counts; (ii) previous splenectomy may have an impact on CD4+ cell numbers and function.

Australian and New Zealand Journal of MedicineVolume 28, Issue 6 p. 845-846 Saksenaea vasiformis breast abscess related to gardening injury M. WILSON, M. WILSON Registrar in Infectious Diseases, Townsville General Hospital, TownsvilleSearch for more papers by this authorJ. ROBSON, J. ROBSON Consultant Microbiologist, Sullivan and Nicholaides Pathology, TaringaSearch for more papers by this authorC. M. PYKE, C. M. PYKE Senior Lecturer, University Department of Surgery, Mater Misericordiae Hospital, South BrisbaneSearch for more papers by this authorJ. G. McCORMACK, J. G. McCORMACK Associate Professor of Medicine and Director of Infectious Diseases, University of Queensland, Department of Medicine, Mater Misericordiae Hospital, Brisbane, Qld.Search for more papers by this author M. WILSON, M. WILSON Registrar in Infectious Diseases, Townsville General Hospital, TownsvilleSearch for more papers by this authorJ. ROBSON, J. ROBSON Consultant Microbiologist, Sullivan and Nicholaides Pathology, TaringaSearch for more papers by this authorC. M. PYKE, C. M. PYKE Senior Lecturer, University Department of Surgery, Mater Misericordiae Hospital, South BrisbaneSearch for more papers by this authorJ. G. McCORMACK, J. G. McCORMACK Associate Professor of Medicine and Director of Infectious Diseases, University of Queensland, Department of Medicine, Mater Misericordiae Hospital, Brisbane, Qld.Search for more papers by this author First published: 25 March 2008 https://doi.org/10.1111/j.1445-5994.1998.tb01573.xCitations: 17AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. References 1 Holland J. Emerging zygomycoses of humans: Saksenaea vasiformis and Apophomyces elegans. Curr Top Med Mycol 1997; 8: 27– 34. 2 Sugar AM. Agents of Mucormycosis and related species. In: GL Mandell, JE Bennett, R Dolin (Eds). Principles and practice of infectious diseases, 4th edn. New York Wiley, 1995; 2003– 6. 3 Chakrabarti A, Kumar P, Padhye AA et al. Primary cutaneous zygomycoses due to Saksenaea vasiformis and Apophomyces elegans. Clin Infect Dis 1997; 24: 580– 3. 4 Torell J, Cooper BH, Helgeson NGP. Disseminated Suksenuea vasiformis infection. Am J Clin Pathol 1981; 76: 116– 21. Citing Literature Volume28, Issue6December 1998Pages 845-846 ReferencesRelatedInformation