Infectious disease emergencies: role of the infectious disease specialist.

The importance of infections for public health has become obvious during the last decades. Examples are emerging infections such as HIV/AIDS and severe acute respiratory syndrome, deliberate release of microorganisms, such as the anthrax episode in the USA, the increasing problems with organisms resistant to antimicrobial treatment, such as methicillin-resistant Staphylococcus aureus, and the threat of a new influenza pandemic with a case fatality rate similar to that in the 1918 outbreak. An effective response to infectious disease emergencies requires careful planning and establishment of resources in advance. The medical specialties involved are clinical microbiology, clinical infectious diseases and epidemiology. Clinical microbiology should include bacteriology, virology, and parasitology; the technical developments during the last 15 years have clearly erased most of the methodological differences between these branches of microbiology. New techniques such as new generations of Polymerase Chain Reaction (PCR), rapid methods for nucleic acid sequence analyses and microarrays have enabled more rapid identification of organisms and provide powerful tools in the epidemiological analysis of an outbreak. The infectious disease specialists are necessary for rapid and adequate clinical diagnoses, optimal use of antimicrobial agents and provision of facilities for containment of patients who may spread the infections. The need for isolation units became acute when many countries prepared themselves for a possible severe acute respiratory syndrome outbreak in Europe. With few exceptions, Europe still lacks epidemiological field forces, and it has been embarrassing to be obliged to call upon the Centers for Disease Control for European outbreaks. Hopefully, this will be corrected with the creation of the European Centre for Disease Prevention and Control (ECDC).

Report of working group 3: specialist training and continuing medical education/professional development in the infection disciplines.

The European Union of Medical Specialists (UEMS) core curricula for training in infectious diseases and medical microbiology are adequate with the exception of one deficiency which is the absence of training in epidemiology, public health and infection control. Infectious disease curricula should include training in HIV, tuberculosis, hepatitis and sexually transmitted diseases. There is a need for a core curriculum in infection control. Infection control should have a basis in both medical microbiology and infectious diseases, and should become a specialty dealing with healthcare hygiene in hospitals, in outpatient clinics and also in institutions for the elderly. In the UK, a specialty training in infection is offered and includes internal medicine, clinical infectious diseases and medical microbiology for a total of 9 years. The UEMS should be contacted about the creation of a single specialty of infection, allowing for various degrees of sub-specialisation in infectious diseases or medical microbiology. It is unlikely that a European board examination validating the training of specialists will become a reality soon. Meanwhile, national systems should be created, documenting the content of the training and evaluating the quality of the training institutions. A medical specialist has a constant need for further education. This is generally a national matter, with requirements varying throughout Europe. It should be possible to accumulate continuing medical education/continuing professional development merits on a European level as well as on a national one. With the expansion of the European Union, it is important that the quality and content of specialist training can be verified and training curricula be harmonised. The UEMS should assist in this, in collaboration with scientific societies such as the ESCMID.

Lack of development of new antimicrobial drugs: a potential serious threat to public health.

Antimicrobial resistance is threatening the management of infections such as pneumonia, tuberculosis, malaria, and AIDS. In the past, resistance could be handled by development of new drugs active against resistant microbes. However, the pharmaceutical industry has reduced its research efforts in infections; genomics has not delivered the anticipated novel therapeutics; new regulatory requirements have increased costs; antibiotic use in common infections-eg, bronchitis and sinusitis-is questioned; and, compared with other drugs, return on investments is lower for antimicrobials. To avoid a serious threat to public health, academia, biotechnology and pharmaceutical industry, regulators, and healthcare providers must find solutions to this problem. Academia should concentrate on technologies to unlock new drug targets, and industry on drug candidates. In addition, regulators and pharmaceutical companies should agree on new clinical-trial designs so that information on therapeutic efficacy is generated in fewer patients-eg, by studying pharmacodynamics of antimicrobials in patients with defined infections.

Evaluation of 5-day therapy with telithromycin, a novel ketolide antibacterial, for the treatment of tonsillopharyngitis.

A pooled analysis of two double-blind, multicentre, Phase III studies compared oral telithromycin 800 mg once-daily for 5 days with penicillin V 500 mg three-times-daily or clarithromycin 250 mg twice-daily for 10 days in the treatment of Streptococcus pyogenes (group A beta-haemolytic streptococcus; GABHS) tonsillopharyngitis. Patients aged > or = 13 years with acute GABHS tonsillopharyngitis were randomised to receive telithromycin (n = 430), penicillin (n = 197) or clarithromycin (n = 231). Clinical isolates of S. pyogenes (n = 590) obtained from throat swab samples on study entry were tested for their in-vitro susceptibility to telithromycin, clarithromycin and azithromycin. Telithromycin demonstrated in-vitro activity against the clinical isolates of S. pyogenes (MIC50/90 0.03/0.06 mg/L) higher than clarithromycin or azithromycin (MIC50/90 0.06/0.06 mg/L and 0.12/0.25 mg/L, respectively), including erythromycin-resistant strains. At the post-therapy/test of cure (TOC) visit (days 16-23), satisfactory bacteriological outcome was demonstrated for 88.3% (234/265) and 88.6% (225/254) of telithromycin- and comparator-treated patients, respectively (per-protocol population). Overall, GABHS eradication rates were 88.7% (235/265) for telithromycin and 89.0% (226/254) for comparators. The clinical cure rates at the post-therapy/TOC visit were 93.6% (248/265) and 90.9% (220/242) for telithromycin and pooled comparators, respectively. Telithromycin was generally well-tolerated. Most adverse events considered to be possibly related to study medication were gastrointestinal and of mild intensity. Discontinuations as a result of adverse events were few in both treatment groups. In conclusion, telithromycin 800 mg once-daily for 5 days was as effective as penicillin V or clarithromycin for 10 days in the treatment of GABHS tonsillopharyngitis.

Relief of symptoms in patients with group A beta-hemolytic streptococcus tonsillopharyngitis: comparison between telithromycin and penicillin V.

This study compared the resolution of symptoms in patients with group A beta-hemolytic streptococcus tonsillopharyngitis treated with 5 d of telithromycin 800 mg once daily, or 10 d of penicillin V 500 mg 3 times daily. At days 3-5 of treatment, the mean improvement in total symptom score was greater with telithromycin than with penicillin V (p = 0.042). Thus, telithromycin provided faster symptom relief than penicillin V.

The Treatment of Severe Group A Streptococcal Infections.

Group A streptococci can cause a variety of diseases ranging from uncomplicated superficial infections to severe systemic infections associated with high morbidity and mortality. Since the late 1980s a drastic resurgence of highly aggressive invasive streptococcal infections, including streptococcal toxic shock syndrome and necrotizing fasciitis, have been noted worldwide. This has prompted intense research in the field and important new information has been gained regarding the pathogenesis and treatment of life-threatening invasive group A streptococcal infections. Exotoxins with superantigenic activities have been identified as central mediators of the systemic effects seen in streptococcal toxic shock syndrome. Novel therapeutic strategies include agents that can inhibit these superantigens, and one promising candidate is intravenous polyspecific immunoglobulin that contains neutralizing antibodies against a wide spectrum of streptococcal superantigens. Intravenous immunoglobulin adjunctive therapy was shown in a case-control study to reduce mortality in patients with streptococcal toxic shock syndrome.

Spherical and irregular aberrations are important for the optimal performance of the human eye.

Contrast sensitivity measured psychophysically at different levels of defocus can be used to evaluate the eye optics. Possible parameters of spherical and irregular aberrations, e.g. relative modulation transfer (RMT), myopic shift, and depth of focus, can be determined from these measurements. The present paper compares measured results of RMT, myopic shift, and depth of focus with the theoretical results found in the two eye models described by Jansonius and Kooijman (1998). The RMT data in the present study agree with those found in other studies, e.g. Campbell and Green (1965) and Jansonius and Kooijman (1997). A new theoretical eye model using a spherical aberration intermediate between those of the eye models described by Jansonius and Kooijman (1998) and an irregular aberration with a typical S.D. of 0.3-0.5 D could adequately explain the measured RMT, myopic shift, and depth of focus data. Both spherical and irregular aberrations increased the depth of focus, but decreased the modulation transfer (MT) at high spatial frequencies at optimum focus. These aberrations, therefore, play an important role in the balance between acuity and depth of focus.

Multicenter biometry study of 1 pair of eyes.

PURPOSE: To assess the accuracy of biometry for intraocular lens (IOL) power calculation. SETTING: Six ophthalmic surgery centers in Europe and 1 in the United States. METHODS: Biometry was done as if in preparation for cataract surgery in 2 eyes of the same person with 10 combinations of operator and instrument. Data analysis followed a standardized procedure to assess repeatability (within-center variability) and reproducibility (between-center variability) of the test methods. RESULTS: The reproducibility of the corneal radius measurement was 0.06 mm. The use of different keratometric indices made conversion to K-values less reliable. The repeatability of the axial length (AL) measurement of 0.30 mm and the reproducibility of 0.66 mm converted to a calculated IOL power of 0.75 diopter (D) and 1.65 D, respectively. Thus, this potential patient runs the risk of a refractive surprise of up to 1.10 D purely as a result of a measurement error within a center and up to 2.30 D if the patient goes to the worst-case center. CONCLUSIONS: The biometry results show that the measured corneal radius can be used with confidence. Reproducibility errors in AL determination require personalization of formula constants or correction at the source by proper calibration.

Injectable intraocular lens materials based upon hydrogels.

The possibilities to develop an injectable hydrogel lens were investigated. Aqueous solutions of reactive polymers in combination with a water-soluble blue light photoinitiator were transformed into hydrogels by irradiation with blue light. Poly(ethylene glycol) diacrylates (PEGDA) with low molecular weights and an acrylate modified copolymer of N-vinylpyrrolidone and vinyl alcohol with a high molecular weight were used as reactive polymers. A copolymer of (4-vinyl-2,6-dimethylbenzoyl)diphenylphosphine oxide and dimethylacrylamide was used as a water-soluble blue light photoinitiator. PEGDA showed high reactivity and the hydrogels were more transparent than the natural lens. The mass loss and the additional swelling of the hydrogel were 1.0 and 4.0%, respectively. The refractive index of these hydrogels was 1.40, lower than that of natural lens. The viscosity of the solutions before cross-linking was too low for injection into the capsular bag. Hydrogels based upon the copolymer had a transmission comparable to a 25-year-old natural lens. The materials showed no mass loss and the additional swelling after curing was less than 1%. The refractive index was comparable to that of the natural lens (1.42). The viscosity of the polymer solutions was sufficient for injection into the capsular bag without leakage.

Optimal treatment strategies for acute exacerbations of chronic bronchitis: high-risk patients.

Diagnosis of high-risk patients with acute exacerbations of chronic bronchitis (AECB) should include an evaluation of the patient's respiratory function, chest X-ray to exclude pneumonia, and sputum culture. Increasing resistance to amoxicillin, cephalosporins, macrolides, trimethoprim-sulfamethoxazole, and doxycycline means that fluoroquinolones are often the only oral empiric treatment available. Levofloxacin, a new respiratory fluoroquinolone with a wide spectrum of antibacterial activity and no cross-resistance with other classes of antibiotics, can be administered as an intravenous formulation as well as orally. Sequential therapy is easily administered due to its high oral bioavailability, and the dosing schedule can be a convenient once-daily dose. Clinical trials have established that levofloxacin is effective in AECB and is well tolerated.

Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: a prospective study.

The frequency of antibiotic-associated diarrhoea (AAD) and Clostridium difficile-associated diarrhoea (CdAD) was prospectively determined in a population of 2462 patients recruited from five Swedish hospitals, including divisions for infectious diseases, orthopaedics, surgery, geriatrics, nephrology and internal medicine. AAD developed in 4.9% of the treated patients. Faecal samples were obtained from 69% of patients with AAD and 55.4% were positive for C. difficile cytotoxin B. The frequency of AAD varied from 1.8 to 6.9% at the participating centres (P < 0.001). The frequency of AAD also varied considerably between medical disciplines and wards within different hospitals and was highest in the nephrology and geriatric units (6.7 and 7.1%, respectively). There was no difference in frequency of AAD when analysed with respect to gender or age. Medical interventions (laxative treatment, endoscopy and abdominal surgery) or presence of one concomitant disease (diabetes, malignancy, chronic renal disease and inflammatory bowel disease) did not significantly affect the frequency of AAD, whereas patients suffering from two or more of these illnesses had significantly (P = 0.001) higher frequencies of AAD. Patients treated with antibiotics for 3 days had a significantly (P = 0.009) lower frequency of AAD than those treated for longer periods. Treatment with cephalosporins, clindamycin or broad-spectrum penicillins was associated with an increased risk of AAD. With specimens from one centre, 62.5% of tested patients with AAD and 33.8% of asymptomatic patients were positive for cytotoxin B. Although C. difficile cytotoxin B in stool samples was significantly associated with AAD (P = 0.003), the causal relationship with diarrhoea is not always evident.

Hydrophilic polymeric acylphospine oxide photoinitiators/crosslinkers for in vivo blue-light photopolymerization.

Three vinyl-functionalized phosphine oxide photoinitiating monomers have been synthesized: 4-vinylbenzoyldiphenylphosphine oxide (VBPO), 2,6-dimethyl-4-vinylbenzoyldiphenylphosphine oxide (DMVBPO), and 2,4,6-trimethylbenzoylphenyl-4-vinylphenylphosphine oxide (TMBVPO). VBPO was copolymerized with vinylpyrrolidone or vinyl acetate (PPI-1a) and dimethylacrylamide (PPI-1b). DMVBPO and TMBVPO were both copolymerized with dimethylacrylamide (PPI-2 and PPI-3, respectively). The choice of vinylphosphine oxide and comonomer(s) had a significant influence on the properties of the resulting PPI. PPI-1a was not stable in solution in 2-hydroxyethyl methacrylate (HEMA), whereas the VBPO-dimethylacrylamide (DMA) copolymer (PPI-1b) was stable in HEMA but not stable in aqueous solutions. PPI-2 was both soluble and stable in water up to 22 months. PPI-1a was as effective as trimethylbenzoyldiphenylphosphine oxide (TPO, BASF Lucirin). PPI-2 was more effective in the polymerization of HEMA/water mixtures than PPI-3. PPI-2 and PPI-3 acted as self-cross-linking species, resulting in the formation of hydrogels; PPI 3 was more effective in this. PPI-2 was very effective in forming hydrogels based on poly(ethylene glycol) diacrylate.

Efficacy of short-course therapy with the ketolide telithromycin compared with 10 days of penicillin V for the treatment of pharyngitis/tonsillitis.

This randomized, double-blind study compared the efficacy and safety of a 5-d course of the new ketolide antimicrobial, telithromycin, with those of a standard 10-d course of penicillin V (phenoxymethylpenicillin) in patients with group A beta-hemolytic streptococci (GABHS) pharyngitis/tonsillitis. Patients aged 15-65 y (n = 395) with clinical signs and symptoms of pharyngitis/tonsillitis and a positive streptococcal antigen test or throat culture for GABHS were randomized to receive either telithromycin 800 mg once daily for 5 d (n = 198) or penicillin V 500 mg three times daily for 10 d (n = 197). Clinical and bacteriologic outcomes were assessed at post-therapy, test-of-cure (Days 16-20) and late post-therapy (Days 38-45) visits. Telithromycin for 5 d was equivalent to 10 d of penicillin V in terms of bacteriologic and clinical outcome (per-protocol): at post-therapy, test-of-cure visit, bacteriologic outcome was satisfactory in 84.3% and 89.1% of patients in the telithromycin and penicillin V groups, respectively, while clinical cure was achieved in 94.8% and 94.1% of patients, respectively. At late post-therapy, 82.4% of patients treated with telithromycin achieved a satisfactory bacteriologic outcome, compared with 84.7% of penicillin V recipients. The GABHS eradication rates for telithromycin and penicillin post-therapy were 85.2% and 89.1%, respectively, and 86.1% and 86.5%, respectively at late post-therapy. Both treatments were well tolerated, with a similar overall incidence of treatment-emergent adverse events. Short-course (5 d) therapy with telithromycin 800 mg once daily is comparable to a standard 10 d course of penicillin V for the treatment of GABHS pharyngitis/tonsillitis in adults and adolescents.

Age-related changes of defocus-specific contrast sensitivity in healthy subjects.

To investigate the effect of defocus on contrast sensitivity as a function of age in healthy subjects, the through focus contrast sensitivity was measured in 100 healthy subjects aged 20-69. Defocus-specific changes in contrast sensitivity reflect age-related changes in the optics of the eye. Tests were performed in cycloplegic eyes varying artificial pupil size (2, 4 and 6 mm), defocus (-1 to +2 D), and spatial frequency (1-16 cpd). Integrated contrast sensitivity was taken as a measure for the total amount of visual information transferred by the optical media. At optimal focus, integrated contrast sensitivity and log contrast sensitivity at 8 cpd showed a significant age-related decline. The log contrast sensitivity at 1 cpd appeared to be independent of age. The depth of focus for a 4-mm pupil increased significantly with age, even though contrast sensitivity at +2 D defocus decreases with age too, but not as much as the contrast sensitivity at optimal focus. Our study indicates that the effect of defocus on contrast sensitivity decreases with age; this was attributed to age-related changes in the optical media.

Carbapenems in serious infections: a risk-benefit assessment.

The tolerability of the 2 most frequently used carbapenems, imipenem/cilastatin and meropenem, is reviewed. Both of these drugs, but especially imipenem, are potentially neurotoxic and may cause seizures if overdosed relative to renal function and/or bodyweight. The therapeutic margin is considerably narrower with imipenem/cilastatin which cannot be given at doses required for treatment of bacterial meningitis. Meropenem on the other hand, is considerably less prone to cause seizures and its tolerability and efficacy are well documented in 3 relatively large, controlled studies in adults and children with meningitis. They showed that meropenem was as effective and well tolerated as cefotaxime or ceftriaxone. Another potential advantage of meropenem over imipenem/cilastatin is that it can be given intravenously at a high rate without increased risk of nausea or vomiting. An obvious reason for using a carbapenem instead of a cephalosporin for empirical treatment of life-threatening infections is that both imipenem/cilastatin and meropenem have a broader spectrum of activity. They are also more resistant to hydrolysis by the most common beta-lactamases, including the class I cephalosporinase frequently produced by Enterobacter spp. and Pseudomonas spp. and the extended spectrum enzymes, now commonly found in Escherichia coli and Klebsiella spp.