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.

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.

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.

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.

Interference of antibody production to hepatitis B surface antigen in a combination hepatitis A/hepatitis B vaccine.

A randomized trial comparing 3 manufacturing consistency lots of a combination hepatitis A/hepatitis B vaccine to each other and to hepatitis A vaccine and hepatitis B vaccine given separately and concurrently was done to evaluate safety, tolerability, and immunogenicity. Healthy volunteers >/=11 years of age were divided into 4 groups. Each of 3 groups received a separate consistency lot of the combination vaccine, and 1 group received separate but concurrent injections of hepatitis A and hepatitis B vaccines. Injections were given at weeks 0 and 24. The combination vaccine was generally well tolerated. The hepatitis A portion of the combination vaccine produced clinically acceptable high seropositivity rates 4 and 52 weeks after the first injection. The hepatitis B portion of the vaccine did not produce clinically acceptable seropositivity rates 4 weeks after the second injection. Lack of antibody production may be attributed, at least in part, to immunologic interference.

How adequate are the new guidelines on clinical evaluation of bacteriological outcome in uncomplicated UTI?

While the Infectious Diseases Society of Americas guidelines for clinical trials of antibiotics have proven valuable for defining inclusion criteria in studies of urinary tract infections, they are far from perfect when it comes to defining outcome of treatment. This was obvious in a trial comparing a beta-lactam antibiotic and a fluoroquinolone for treatment of acute uncomplicated cystitis in women. Depending on how failure was defined in terms of bacterial count and pyuria, failure rates with one and the same regimen varied between 6 and 67% of patients treated with the beta-lactam. Another finding was that pyuria measured with microscopy of urine sediment was a highly unreliable technique. Systematic studies are needed to define the optimal criteria for measuring outcome in these infections.

Safety profile of meropenem: a review of nearly 5,000 patients treated with meropenem.

Meropenem is a parenteral carbapenem that has been used clinically since 1994. Since the first review of its safety profile in 1995, the patient database has increased substantially. This new safety analysis includes data from 46 clinical trials in hospitalized patients with serious bacterial infections. The additional data comprise patients with lower respiratory tract and intra-abdominal infections, septicaemia and meningitis, and cancer patients with febrile neutropenia, and represents a group of more severely ill patients compared with the earlier review. In total, 4872 patients with 5026 meropenem treatment exposures were compared with 4642 patients treated with comparator agents (4752 exposures). Meropenem was administered most often by intravenous injection at 1g or 500 mg every 8 h. Meropenem-related adverse events most frequently reported were diarrhoea (2.3%), rash (1.4%), nausea/vomiting (1.4%) and injection site inflammation (1.1%). The most commonly reported meropenem-related laboratory adverse events were thrombocytosis (1.6%) and increased hepatic enzymes (1.5-4.3%). In meropenem-treated patients with meningitis, the incidence of seizures was low and none were drug related. In patients with infections other than meningitis, the incidence of seizures considered by the investigators to be related to meropenem was 0.08%. In general, the safety profile of meropenem was similar to that of the comparator agents. Withdrawals and deaths were similarly infrequent in the meropenem, cephalosporin and imipenem-cilastatin groups. Increased doses of meropenem were not associated with an increased incidence of adverse events. Meropenem was well tolerated in all patients, including children and patients with neutropenia. This new analysis supports the previous findings that meropenem has a favourable and acceptable safety profile.

Comparative immunogenicity and tolerance of Vaqta and Havrix.

In an open-label, randomised trial, 520 adults of both sexes aged 18-30 years were allocated to receive one of two inactivated hepatitis A vaccines; Vaqta or Havrix, at 0 and 24 weeks. Doses used were 50 or 100 antigen units (U) of Vaqta and 1440 enzyme linked immunosorbent assay U of Havrix given as 1 ml intramuscular injections. For each trial group safety data were available for all subjects and full serological data for more than 80% of randomised volunteers. Local side effects which were mild in most cases were significantly (p < 0.0001) more common with Havrix than with Vaqta, irrespective of dose given. Systemic tolerance was similar for the 3 regimens. From 4 weeks after the first dose, > or =94% of the subjects had seroconverted. The mean antibody titres 4 weeks after the second vaccine dose were 2978, 4346 and 1589 mIU/ml in subjects who were randomised to Vaqta 50 U/dose, Vaqta 100 U/dose and Havrix 1440 U/dose, respectively. The 2 vaccines had similar immunogenicity but local tolerance was better with Vaqta.

Levofloxacin.

Levofloxacin (DR-3355, Daiichi) is a new fluoroquinolone antibiotic which is the active isomer of ofloxacin (DL-8280, Daiichi). By removing the inactive isomer, the in vitro activity of levofloxacin is 8-128 times higher than that of ofloxacin. This means that bacterial species, which have borderline susceptibility to ofloxacin and other first generation fluoroquinolones (e.g., pneumococci and organisms causing atypical pneumonia), are considerably more sensitive to levofloxacin. The pharmacokinetics of levofloxacin, which is available for both oral and i.v. administration, are characterised by a very high bioavailability, low (30-40%) protein binding, high tissue concentrations and elimination via the kidneys with minimal liver metabolism. As a consequence of the low degree of metabolism, levofloxacin does not interact with other drugs to any major extent. The safety and efficacy of levofloxacin are well documented in lower respiratory tract infections, skin and soft tissue infections, and urinary tract infections. The safety profile seems advantageous and the risks of phototoxicity, CNS toxicity and cardiac reactions (prolongation of QT-time) are low. Serious liver toxicity, leading to the recent withdrawal of trovafloxacin, has not been a problem in levofloxacin studies. Levofloxacin is a valuable addition to the group of fluoroquinolone antibiotics.

A comparative study of levofloxacin and ceftriaxone in the treatment of hospitalized patients with pneumonia.

A multinational, multicentre, open, randomised study in hospitalised patients with pneumonia compared levofloxacin 500 mg twice daily with ceftriaxone 4 g i.v. once daily. Levofloxacin patients started on i.v. treatment and switched to oral on d 3-5 of therapy if signs and symptoms had improved. The minimum treatment duration was 5 d, except for treatment failure, and the median 8 d. The primary efficacy analysis was based on the per-protocol assessment of the clinical cure rate determined 2-5 d after the end of treatment in the per-protocol (PP) population (levofloxacin 127, ceftriaxone 139). Of 625 patients enrolled and randomized, 6 received no treatment, giving an intention-to-treat (ITT) population of 619 (levofloxacin 314, ceftriaxone 305). At the clinical endpoint, 2-5 d after the end of treatment, the cure rates for levofloxacin and ceftriaxone were similar in both the ITT (76% and 75%, respectively) and PP (87% and 86%, respectively) populations. Both drugs were well tolerated. Twice-daily levofloxacin 500 mg, either i.v. or as sequential i.v./oral therapy, was as effective as i.v. once-daily ceftriaxone 4 g in the treatment of hospitalized patients with pneumonia and offers the advantage of sequential therapy.

Randomized comparative trial of cefpirome versus ceftazidime in the empirical treatment of suspected bacteraemia or sepsis. Multicentre Study Group.

Cefpirome is a fourth-generation cephalosporin with good in-vitro activity against both Gram-positive and Gram-negative aerobes, including Pseudomonas spp. A multicentre, randomized trial was performed to compare cefpirome at a dose of 2 g bd iv with ceftazidime (2 g tds iv) in the empirical treatment of suspected bacteraemia in patients with severe sepsis but not septic shock. The majority of the patients had community-acquired infections. Patients were stratified into high- and low-risk groups using a Simplified Sepsis Score. Metronidazole, an aminoglycoside or a glycopeptide could be added to the treatment as required. In patients with a positive blood culture treated for > or = 48 h, the clinical success rates were 37/48 (77%) for cefpirome and 35/52 (67%) for ceftazidime with no significant difference between the two. In patients with bacteriologically proven infection, 92 (89%) of 103 patients treated with cefpirome were assessed as cured and 94 (89%) of 106 patients with treated ceftazidime. More Gram-positive pathogens, enterococci and staphylococci were resistant in vitro to ceftazidime than to cefpirome (15/90 (17%) and 5/92 (5%) respectively; chi2 = 4.8, P < 0.05) but the bacteriological response was not significantly different between the two groups (cefpirome, 54/60 (90%); ceftazidime, 54/63 (86%)). Cefpirome showed equivalent efficacy and safety to ceftazidime in the empirical treatment of suspected bacteraemia or sepsis. Regarding safety, there were no statistically significant differences between the two treatments, with adverse events thought to be possibly related to the study drug occurring in 55/187 and 40/184 patients on cefpirome and ceftazidime, respectively.

Alternating treatment with didanosine and zidovudine versus either drug alone for the treatment of advanced HIV infection. The Alter Study. Nordic HIV Therapy Group.

The efficacy and safety of an alternating regime with zidovudine and didanosine versus treatment with either drug alone were investigated in a randomized, open, controlled trial, 552 patients with advanced HIV infection, 47% of whom had received prior treatment with zidovudine, were enrolled. The patients were randomly assigned to zidovudine 600 mg/day, didanosine 400 mg/day or 4-week alternations with the 2 drugs in the same dose. The study had a median length of follow-up of 88 weeks. In the overall analyses, time to death (p = 0.48) and time to death or new AIDA event (0.80) were equally distributed between the 3 treatment groups. In the subgroup of patients with a CD4 count < 100 x 10(6)/l the survival was longer in the alternating arm (p < 0.005) primarily because of differences among zidovudine naive patients. The alternating regime was better tolerated than the 2 monotherapies, with a longer time to dose reduction or withdrawal owing to side effects (p < 0.001).

Infections due to group A streptococcus: new concepts and potential treatment strategies.

Important new information has been gained on the pathogenesis and treatment of life-threatening invasive infections caused by group A streptococci (GAS), i.e. the streptococcal toxic shock syndrome (STSS) and necrotizing fasciitis (NF). Both STSS and NF lead to superantigen reactions with activation of up to 10% of the CD4+ lymphocytes and release of large amounts of cytokines; mainly tumour necrosing factor beta, interferon gamma, interleukin 1 and interleukin 6. Streptococcal products known to trigger the superantigen reactions are the pyrogenic exotoxins, spe A, spe B and spe C and the M-proteins. Therapeutically clindamycin has been shown to reduce mortality in animal experiments in comparison to penicillin treatment. A possible mechanism is the effect of clindamycin on protein synthesis which might decrease the production of superantigens. In man, the use of intravenous immunoglobulin has been shown to significantly reduce mortality in STSS and NF. The most probable mechanism is neutralisation of superantigens by antibodies in the immunoglobulin preparations used.

Neurotoxicity of carbapenem antibacterials.

Similar to other beta-lactam antibacterials, carbapenems have a neurotoxic potential that seems to be higher than that of the penicillins and cephalosporins. Seizures have been reported in several large studies of patients treated with imipenem/cilastatin. However, it seems clear that the main factor increasing the risk of neurotoxicity with imipenem/cilastatin is administration of excessive dosages relative to bodyweight and/or renal function. If the manufacturer's dosage recommendations are followed, the risk of seizures in patients receiving this combination is minimal. With meropenem, a newly registered carbapenem, the safety margin with respect to neurotoxic reactions has been increased compared with imipenem and meropenem can be used at higher doses than imipenem/cilastatin. Since the neurotoxicity of beta-lactam antibacterials seems to be caused by an interaction with gamma-aminobutyric acid (GABA) receptors, other drugs with a similar mechanism of action, such as fluoroquinolone antibacterials, should be used with caution when combined with carbapenems.