The 50th anniversary of the discovery of 6-aminopenicillanic acid (6-APA).

This year (2007) marks the 50th anniversary of [corrected] discovery of 6-aminopenicillanic acid (6-APA), the precursor of all semi-synthetic penicillins [corrected] This review, by a scientist who played a major part in the discovery and a physician who participated in the early clinical trials of these antibiotics, tells the story of the discovery and of the early development of the beta-lactam antibiotics that revolutionised the treatment of infections.

Grepafloxacin: an overview of antibacterial activity, pharmacokinetics, clinical efficacy and safety.

The treatment of respiratory tract infection is the most common reason for antibiotic prescribing. However, therapeutic options are diminishing as antibiotic resistance to penicillins and macrolides in key respiratory pathogens is increasing. As resistance increases, there are parallel rises in the number of treatment failures and the total cost of infection management. New generation broad-spectrum fluoroquinolones, such as grepafloxacin, have recently been recommended as a first-line treatment option in guidelines for lower respiratory tract infection. Grepafloxacin is an oral fluoroquinolone, with a microbiological and clinical profile that is particularly suited to the treatment of community-acquired respiratory infections. In vitro, it is rapidly bactericidal, and compared with earlier quinolones, its broad spectrum activity encompasses all important respiratory pathogens; Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella pneumophila, including strains which are resistant to penicillin, other beta-lactam antibiotics and macrolides. In addition, grepafloxacin achieves high lung concentrations, and its long half-life (up to 15 h) enables once daily dosing. Overall, grepafloxacin combines the positive properties of the beta-lactam antibiotics against conventional Gram-positive and Gram-negative respiratory pathogens, with the activity of the macrolides against atypical pathogens. In patients with bacteriologically documented infections, clinical studies in community-acquired pneumonia have shown that treatment for 7-10 days once daily (o.d.) with approximately 600 mg is equivalent to that with either twice daily (b.i.d.) clarithromycin 250 mg, or three times daily (t.i.d.) cefaclor 500 mg, and superior to that with t.i.d. amoxycillin 500 mg. In these studies, grepafloxacin proved effective in the treatment of both typical and atypical pneumonia. In acute bacterial exacerbations of chronic bronchitis (ABECB), 7-10 days treatment with o.d. grepafloxacin 400 mg or 600 mg has been shown to be equivalent to that with either t.i.d. amoxycillin 500 mg, or b.i.d. ciprofloxacin 500 mg. In patients with a documented bacterial pathogen, microbiological success with both grepafloxacin dosage regimens was superior to amoxycillin 500 mg t.i.d. In addition, short course treatment of ABECB with 400 mg of grepafloxacin given o.d. for five days has been shown to be as effective, clinically and microbiologically as a ten-day course of the same dose. The safety profile of grepafloxacin has been well-characterised from data from over 12,000 patients treated in Phase II/III and post-marketing studies, and over 400,000 patients treated worldwide in routine clinical practice. The most commonly reported adverse events are gastrointestinal, mainly nausea and unpleasant taste. The potential for photosensitivity and central nervous system effects is low, and there have been no reports of convulsions. No unique or unexpected.

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.

Empiric therapy in lower respiratory tract infection--an ongoing challenge.

Lower respiratory tract infections are a common cause of morbidity and mortality. The pattern of pneumonia is altering, owing to changes in a number of influencing factors. These include patient characteristics, such as an aging population, increased immunosuppression and chronic disease, and changes in medical practice. There is also an increasing level of resistance to antimicrobial agents by organisms such as Streptococcus pneumoniae and Haemophilus influenzae, the pathogens most commonly associated with community-acquired pneumonia. In the management of pneumonia, it is important to be able to differentiate between atypical and typical pneumonia in the clinical setting and to grade the severity of the infection. Currently, there are no internationally agreed treatment recommendations for pneumonia. The role of antimicrobial agents in acute exacerbations of chronic bronchitis is still a controversial issue.

Tempting fate: control of communicable disease in England.

Recent changes in the NHS have left many defects in the systems for the control of communicable diseases and infection and their surveillance and the management of outbreaks. Clear, explicit legislation is needed, placing the responsibilities on health authorities. New teams led by consultants need to be set up to investigate and manage outbreaks of communicable diseases of all types.

Safety of fleroxacin in clinical trials.

This article reviews the safety of fleroxacin in clinical trials. Data from 4,450 patients treated with oral fleroxacin and 650 treated with intravenous fleroxacin were analyzed. The overall rate of adverse reactions for patients treated with oral fleroxacin was 20% for those given 200 mg daily and 20% for those given a daily dose of 400 mg. The adverse reaction rate with the intravenous formulation was 20%. The most frequent adverse reactions involved the gastrointestinal tract (11%) and the central nervous system (9%). All events were reversible. Insomnia was the most commonly reported adverse event. The safety profile of fleroxacin was similar to that reported with other fluoroquinolones.

Efficacy of cefpirome in the treatment of septicaemia.

From a total of 4180 patients entered in 15 phase II-III clinical trials involving cefpirome, an analysis was carried out on 378 patients with bacteriologically confirmed or suspected septicaemia who were treated with cefpirome (n = 282) or comparator drugs (ceftazidime, n = 80; ceftriaxone, n = 15; imipenem/cilastatin, n = 1). Gram-negative organisms were the causative pathogens in over half of the patients, with Escherichia coli being the most common species found. The most frequently isolated Gram-positive bacterium was Streptococcus pneumoniae. Causative organisms were eradicated in over 90% of patients receiving cefpirome or comparators. Only 4/230 pathogens tested were resistant to cefpirome in vitro. Among patients with bacteriologically confirmed septicaemia, a satisfactory clinical response was documented in 131/176 (74%) cefpirome vs 34/50 (68%) ceftazidime vs 5/10 (50%) ceftriaxone recipients, improvement in 39/176 (22%) vs 11/50 (22%) vs 5/10 (50%), and failure in 6/176 (4%) vs 5/50 (10%) vs 0/10 (0%), respectively. Similar results were achieved in patients with 'suspected' septicaemia. Cefpirome 1 or 2 g twice daily offers an effective treatment option for patients with septicaemia. The higher dosage regimen produced superior bacteriological clearance rates and is therefore preferable in patients with severe septicaemia.

Cefpodoxime proxetil in the treatment of lower respiratory tract infections.

Cefpodoxime proxetil is the orally absorbed ester of cefpodoxime, a new third generation cephalosporin. In the gastrointestinal tract, cefpodoxime proxetil is hydrolysed to cefpodoxime, which has potent antibacterial activity against the major bacterial pathogens involved in lower respiratory tract infections: Haemophilus influenzae, Moraxella (Branhamella) catarrhalis (including beta-lactamase-producing strains), and Streptococcus pneumoniae (including amoxicillin-resistant strains). Six randomised comparative studies in patients with lower respiratory tract infections, 5 of which were large (enrollment of more than 200 patients) and double-blind, examined the efficacy and safety of cefpodoxime proxetil. Cefpodoxime proxetil (at a dosage equivalent to 200mg of cefpodoxime) administered twice daily for 5 to 10 days was similar in clinical and bacteriological efficacy to the following: amoxicillin 500mg 3 times daily in the treatment of community-acquired pneumonia; intramuscular ceftriaxone Ig once daily in the treatment of pulmonary infections in hospitalised patients; and to amoxicillin/clavulanic acid 500/125mg 3 times daily in the treatment of acute exacerbations of chronic bronchitis (AECB). Additionally, a dosage equivalent to 100mg or 200mg of cefpodoxime twice daily was similar in clinical and bacteriological efficacy to amoxicillin 250mg 3 times daily in the treatment of bronchitis (acute or AECB). The adverse events noted with cefpodoxime proxetil administration were similar to those associated with other beta-lactam antibacterials and most commonly involved the gastrointestinal tract and skin or mucous membranes. Thus, cefpodoxime proxetil is a useful addition to the antibacterials available for the treatment of infections of the lower respiratory tract.

Open study of ciprofloxacin in enteric fever.

Thirty adult patients with typhoid or paratyphoid fever were treated with ciprofloxacin. All patients were cured with eradication of the causative organism. No major adverse reactions were seen. Ciprofloxacin is an effective agent for the treatment of enteric fever.