BACTERIAL INFECTIONS

What are bacterial infections?

Bacteria are microscopic organisms of many different types with a chemically distinctive cell wall. This gives each type a particular shape - spherical, rod-shaped or spiral. They multiply by cell division - a process that can occur every 20-30 minutes. A single bacterium entering the body and multiplying at this rate could give rise to over 30 billion new cells within 12 hours. Fortunately, most bacteria are harmless and some are even essential, such as those in the intestine which aid digestion. But a minority, called pathogens, cause disease (Figure 1 and Table 1). These may be localised near the surface of the skin, as in laryngitis, boils and abscesses, or invade internal organs and cause, for example, infections of the digestive or urinary tract, brain (meningitis), lung (pneumonia), heart (endocarditis), or the bloodstream (sepsis), which can be serious or life-threatening.

Who do bacterial infections affect?

Everyone experiences bacterial infections from time to time, but most infections heal by themselves or are readily treated with antibiotics. However, resistance to antibiotics is an ever-growing problem and infections that were easily treatable a decade ago are now staging a come-back in deadlier form.

Table 1: Bacteria are often distinguished according to whether they are stained by a method first described in 1884 by the Danish bacteriologist Hans Christian Gram.

People whose immunity is depressed by other illnesses such as cancer, or by immunosuppressive treatments, as in transplant surgery, are at greater risk of serious infection. Hospital-acquired infections are becoming increasingly frequent. If an infection (sepsis) develops, it may lead to septic shock - a cascade of inflammation, blood clotting and low blood pressure that often results in death through multiple organ failure. In 2004, people with sepsis required over 270,000 bed-days of inpatient care in hospitals in England and sepsis was recorded as the underlying cause of more than 2,000 deaths in England and Wales, 87 per cent of them in people aged 60 and over. During the same period there were more than 7,000 cases of bacteria in the blood due to methicillin-resistant Staphylococcus aureus (MRSA) in England and more than 44,000 infections due to Clostridium difficile, with over 1,200 deaths due to this organism. A study has shown that the cost of treating patients who develop sepsis after admission to an intensive care unit exceeded £10,000 per patient (in 1999).

Their average stay in the unit was 16 days, compared with 2 days for those without sepsis, and their death rate 50-60 per cent (versus 20 per cent).

Table 2: Some major types of antibiotics currently available and their mechanisms of action.

Present treatments and shortcomings

Many antibiotics have been discovered over the last fifty years, including the penicillins and cephalosporins, tetracyclines, macrolides, aminoglycosides (streptomycin group) and quinolones. (Table 2) Despite this range of medicines, the emergence of resistant organisms such as MRSA and vancomycin-resistant enterococci (VRE) is creating widespread concern.

A variety of antibiotics have been introduced in recent years, in an attempt to keep ahead of growing resistance. Synercid (quinupristin/dalfopristin, sanofi-aventis), the first of the streptogramin group, combines two components that together kill a wide range of bacteria, including MRSA strains. Linezolid (Zyvox, Pfizer) is an oxazolidinone which is used in hospital for treating pneumonia and skin and soft tissue infections due to resistant strains of Gram-positive bacteria. Another new class of antibiotic (ketolides), is represented by telithromycin (Ketek, sanofi-aventis). It is used to treat community-acquired respiratory tract infections, including those caused by resistant strains of Streptococcus pneumoniae. More recently, tigecycline (Tygacil, Wyeth) has become available for the treatment of complicated skin, soft tissue and intra-abdominal infections and Novartis has daptomycin (Cubicin) for the first two of these uses.

What's in the development pipeline?

The search continues for antibiotics that work in new ways, and so might be active against bacteria that have developed resistance to other medicines. GlaxoSmithKline has completed Phase 3 trials for retapamulin, the first in the class of pleuromutilin antibiotics, and two further members of this class (GSK 565154 and 742510) are in Phase 1 development. Retapamulin is applied to the skin (a topical medicine) in skin and soft tissue infections. Merck Sharp & Dohme's platensimycin blocks enzymes involved in fatty acid production that are used by bacteria to make their cell walls. It is still in early development, but pre-clinical experiments have shown it to be effective against MRSA and vancomycin-resistant enterococci, two key types of antibiotic-resistant bacteria.

Many new members of existing classes of antibiotics are also in development:

• A second ketolide antibiotic (cethromycin, Advanced Life Sciences) is in Phase 3 study for community-acquired pneumonia.
• Replidyne is developing the oral penem (faropenem medoxomil, Orapem) and Johnson & Johnson is conducting Phase 3 trials of doripenem in urinary tract infections, intra-abdominal infections and hospitalacquired pneumonia. Roche is also developing a new carbapenem - R1558, which has reached Phase 2 trials.
• Pfizer is investigating dalbavancin (Zeven), a lipoglycopeptide in the same class as vancomycin. Dalbavancin can be given once weekly, and is active against Gram-positive but not Gram-negative bacteria. Another lipoglycopeptide in development is telavancin (Theravance), which has reached Phase 3 trials in hospital-acquired pneumonia and complicated skin and skin structure infections.
• Other new antibiotics under development for skin infections include Arpida's Iclaprim, a dihydrofolate reductase inhibitor in the trimethoprim class, which is in Phase 3 trials as an injectable and at Phase 1 in oral form.
• Two new cephalosporins are under investigation: ceftobiprole (Basilea, Phase 3) and ceftaroline acetate (Cerexa, Phase 2).
• In addition, Enanta is investigating a new macrolide (EDP-420) in Phase 2 trials for community acquired pneumonia.
• Sanofi-aventis has a new oral streptogramin (XRP 2868) at Phase 1, as has Novexel (NXL 103).
• New quinolone antibiotics are also still being developed. Oscient Pharmaceuticals has gemifloxacin (Factive) in Phase 3 trial for bacterial sinusitis, while Schering-Plough has the broad-spectrum agent garenoxacin. Daiichi- Sankyo has the injected fluoroquinolone DU-6859a (sitafloxacin) in Phase 2 trials and is preparing Phase 3 trials for the oral form of this medicine. The company also has the quinolone DX 619 in Phase 1 trial.

Of particular interest are new treatments for the serious problem of C. difficile diarrhoea, for which metronidazole and vancomycin are the only currently available antibiotics. Two new antibiotics under development are ramoplanin, a lipoglycopeptide being studied by Oscient that acts to kill the bacteria in the intestine, and Tiacumicin B, being tested by Par Pharmaceuticals. Both have reached Phase 2 trials. Genzyme is working on a new approach that uses a non-absorbed polymer (tolevamer) to bind the toxins released by this organism and hence control the diarrhoea associated with its uncontrolled growth in the intestine. Tolevamer is now in Phase 3 trials. Another toxin-binding approach is being explored by Medarex in Phase 2 trials of MDX-066, a monoclonal antibody against C. difficile.

The remaining big problem in bacterial infection, apart from antibiotic resistance, is the lack of effective medicines for treating severe sepsis, which still causes a lot of deaths. Drotrecogin alfa activated (Xigris, Lilly), a version of the naturally occurring activated Protein C, has been introduced, but the reduction in death rate it brings is relatively modest and new alternatives are urgently needed. A major challenge to developing effective therapies is the great complexity of inflammatory and blood-clotting pathways that are activated in sepsis, making it difficult to find an agent that can shut down the cascade of events that lead to circulatory collapse and organ failure.

Eisai has a compound (E5564, eritoran) in Phase 3 trial that may offer an alternative, as it inhibits an early step in the events leading to the rapid production of inflammatory cytokines involved in sepsis. A Phase 3 study of this compound has now started to evaluate whether eritoran can significantly lower the death rate from severe sepsis. Takeda also has a TLR-4 inhibitor (TAK-242) under investigation and Novartis is investigating TFP 561 (tifacogin, Phase 3) in severe community acquired pneumonia, which may precede sepsis. Meanwhile, AstraZeneca is preparing a Phase 3 trial of the antibody CytoFab which is directed against TNF-α (one of the key inflammatory cytokines). If any of these compounds can be shown to produce a substantial decrease in sepsis-associated deaths, that will be a very welcome development for those clinicians and patients facing the most dramatic forms of bacterial infection.