Laurie Barclay, MD, July 2005

Bacterial infections are caused by growth within body tissues of harmful bacteria that normally do not reside in the body in large numbers. Release of toxins from the invading bacteria damages tissues, causing symptoms of inflammation, swelling, pain, heat, redness, and loss of function. Depending on the organ system involved, there may be pneumonia, gastrointestinal symptoms, urinary tract symptoms, or meningitis. Invasion of the blood stream by large numbers of virulent bacteria causes sepsis, with fever, chills, circulatory collapse, and ultimately death.

Worldwide, bacterial infections are the leading cause of death, and they are a significant cause of morbidity and health care expenditures. According to the England Department of Health, more than half of consultations for bacterial intestinal infections required emergency hospital admissions during 2002-2003, with a mean length of stay of 16.8 days. About two million hospitalized US patients acquire serious or fatal bacterial infections each year.

Risk factors for bacterial infections include immunocompromised state from cancer, AIDS, or other chronic diseases, burns, severe trauma, low white blood cell counts, drug or alcohol use, malnutrition, and vitamin deficiency. Spread of bacterial infection occurs by inhalation of airborne bacteria, oral ingestion from dirty hands or contaminated food or water, direct contact with an infected lesion or contaminated blood, or by insect bite.

The body's protective mechanisms against bacterial infection include antibacterial chemicals naturally present in body tissues, such as lysozymes in tears, gastric acid in the stomach, pancreatic enzymes in the bowel, and fatty acids in the skin. If bacteria penetrate these defenses, a nonspecific immune response involving inflammation occurs first, followed by a specific immune response involving the activation of T- and B-lymphocytes. T-cells activate cytotoxic cells, which engulf and destroy the invading bacteria, and B-cells generate antibodies, or immunoglobulins, directed against specific bacteria.

One of the most revolutionary and miraculous medical discoveries of all time was the advent of modern antibiotics. Penicillin, the natural product of the soil mold Penicillium, was first discovered in 1896 by Ernest Duchesne, a French medical student, and then rediscovered in 1928 by Scottish physician Alexander Fleming. During World War II, this one drug single-handedly eradicated the greatest source of wartime deaths, namely wound infections. But merely four years later, the specter of penicillin-resistance appeared, spurring the search for new antibiotics and even new classes of antibiotics. Even today, despite the plethora of approved antibiotics, bacterial resistance is a significant and increasing threat. In 1998, strains of Staphylococcus aureus, a significant cause of sometimes fatal hospital-associated infections were detected that were resistant to vancomycin, the most potent antibiotic then available.

Natural selection pressure fosters the growth of resistant organisms through genetic adaptation. Other factors encouraging microbial resistance include increased transmission of infections, higher numbers of immunocompromised patients, use of antibiotics in livestock, and widespread prescription of potent, broad spectrum antibiotics, often taken in incomplete courses and for unclear indications.

In the US, antibiotic prescriptions for sinusitis and for middle ear infections doubled between 1985 and 1992, according to a 1995 report in JAMA. The National Center for Health Statistics reported that from 1980 to 1992, there has been a tendency for doctors to prescribe more expensive, broader spectrum antibiotics.

To counteract the problem of microbial resistance to existing agents, possible solutions include development of new antibiotics, vaccines to prevent bacterial infection and immunotherapeutic agents to stimulate the body’s own defenses to bacterial attack. CenterWatch has identified a pipeline of 36 such agents in various phases of development.

Depomed has submitted a New Drug Application (NDA) for Ciprofloxacin GR, a gastric retention dosage form of ciprofloxacin used to treat urinary tract infections. In a Phase III trial involving 580 patients, a three-day course of this once-daily formulation was as effective as twice- daily CIPRO, but with fewer episodes of nausea, diarrhea, and other gastrointestinal adverse effects. Hopefully, this extended release formulation will also improve patient convenience and compliance.

Vicuron Pharmaceuticals has also submitted an NDA for dalbavancin, a second-generation glycopeptide agent. Members of this antibiotic class, such as vancomycin and teicoplanin, have proven effective against serious and difficult-to-treat hospital infections. In preclinical studies, dalbavancin was the most potent antibiotic in its class against the most resistant Staph infections, including methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE). Pivotal Phase III trials enrolling more than 1,500 patients and evaluating once-weekly dalbavancin in skin and soft tissue infections (SSTIs) caused by Gram-positive bacteria met primary and secondary endpoints. Dalbavancin is the first once-weekly injectable antibiotic, which may reduce the need for continued intravenous lines in some patients.

Cipro (ciprofloxacin) is an approved fluoroquinolone antibiotic, now in phase IIIb testing by Bayer for pediatric indications. It is rapidly absorbed after oral administration and easily penetrates extravascular tissues and other body compartments. This synthetic bactericidal antibiotic inhibits nuclear DNA synthesis by targeting the enzyme DNA gyrase (topoisomerase II).

Another orally administered fluoroquinolone is Factive (gemifloxacin mesylate). In Europe, Oscient Pharmaceuticals is in Phase III development of this broad spectrum antibiotic.

Cubist Pharmaceuticals is in phase IIIb development of the antibiotic lipopeptide Cubicin (daptomycin) for urinary tract infections. Cubicin is the first cyclic lipopeptide, with a distinct mechanism of action. It binds to the bacterial cell membrane, causing rapid depolarization of membrane potential, which inhibits protein, DNA, and RNA synthesis, resulting in bacterial cell death.

At doses up to 6 mg/kg administered once daily for seven days, Cubicin pharmacokinetics are nearly linear and time- independent, with steady-state concentrations achieved by the third daily dose. In a concentration-independent manner, Cubicin reversibly binds to human plasma proteins, primarily to serum albumin. The primary route of elimination is renal excretion, so dosage adjustment is needed in patients with severe renal insufficiency.

Iclaprim (AR-100) is a diaminopyrimidine dihydrofolate reductase inhibitor, in Phase III testing by Arpida for the treatment of severe bacterial infections requiring hospitalization. Iclaprim is a broad spectrum antibiotic highly active against MRSA and other bacterial pathogens. Arpida is developing iclaprim both as intravenous and oral formulations.

In a Phase II trial, iclaprim injected twice daily was effective and well tolerated in hospitalized patients with infected burns, ulcers, surgical abscesses and cellulitis. As part of a global Phase III program, US trials are planned for injectable iclaprim in the treatment of complicated skin infections, including infected burns, ulcers and surgical wounds. Oral iclaprim is currently being tested in Phase I clinical trials.

Another broad spectrum antibiotic for the treatment of serious bacterial infections in hospitalized patients is doripenem (S-4661), in Phase III testing by Peninsula Pharmaceuticals. This synthetic, parenteral agent belongs to the class of carbapenem antibiotics, which have potent activity, broad antibacterial spectrum, and stability against most ß-lactamases.

In preclinical testing, the overall antimicrobial potency of doripenem is comparable to that of other new and established carbapenem drugs, with enhanced activity against S. aureus and Pseudomonas aeruginosa, as well as coverage of penicillin-resistant Streptococcus pneumoniae (PRSP). Its spectrum of bactericidal activity in animal models includes aerobic and anaerobic gram-positive and gram-negative microorganisms. Like other ß-lactams, doripenem targets penicillin-binding proteins (PBPs) to inhibit biosynthesis of the bacterial cell wall. Phase III trials of doripenem for injection are underway in complicated urinary tract infections (including pyelonephritis), complicated intra-abdominal infections, and hospital acquired pneumonia (including ventilator associated pneumonia).

Another ultra-broad spectrum injectable carbapenem antibiotic is Merrem/Meronem(meropenem), in Phase IIIb development by AstraZeneca. This agent targets a wide variety of serious infections, such as meningitis and pneumonia.

Ceftobiprole (BAL5788) is the first of a new generation of cephalosporins with good activity against MRSA, now entering Phase III development by Basilea Pharmaceutica for the treatment of complicated SSTIs. Preclinical studies suggest a high degree of resistance to bacterial beta-lactamases and potent inhibition of important penicillin-binding proteins, resulting in good bactericidal activity against resistant gram-positive pathogens. In addition to MRSA, these include methicillin- resistant S. epidermidis and penicillin-resistant S. pneumoniae.

In March 2003, the U.S. Food and Drug Administration granted ceftobiprole Fast-Track designation for treatment of complicated SSTIs caused by MRSA, with an additional designation in June 2004 for treatment of ventilator- associated or other hospital-acquired pneumonia caused by MRSA.

Telavancin (TD-6424) is a multivalent lipoglycopeptide antibiotic, in Phase III testing by Theravance for serious infections due to S. aureus and other Gram-positive bacteria. This rapidly bactericidal, injectable antibiotic has multiple mechanisms of action, inhibiting formation of the bacterial cell wall and disrupting bacterial cell membrane integrity. Synergy between these mechanisms of action may improve bactericidal activity while lowering the risks of inducing resistance to telavancin or cross- resistance with other antibiotics.

InterMune is in Phase III testing of oritavancin, a semi- synthetic glycopeptide antibiotic for the treatment of a broad range of gram-positive bacterial skin infections, including those resistant to most other glycopeptides. Unlike other glycopeptides, oritavancin is bactericidal rather than bacteriostatic. Oritavancin met the primary efficacy endpoint in two Phase III trials for complicated SSTIs.

Another glycopeptide antibiotic is ramoplanin (glycolipodepsipeptide), in Phase III development by Oscient Pharmaceuticals for the treatment of Clostridium difficile-associated diarrhea. This agent binds to lipid II intermediate, thereby inhibiting further steps of cell wall biosynthesis.

A distinct approach to treatment of diarrhea associated with C. difficile is tolevamer (GT-160246), in Phase III testing by Genzyme. This non-antibiotic polymer therapy binds to C. difficile toxins A and B implicated in causing diarrhea.

Toyama Chemical/Schering Plough is in Phase III development of Garenoxacin (T-3811; des-F(6)-quinolone), a new-type quinolone synthetic antibacterial agent.

Yet another approach to bacterial infection is prevention rather than cure. Sanofi-Pasteur is in Phase III development of Pentacel, a childhood vaccine designed to protect against diphtheria, tetanus, polio, Haemophilus influenzae type B and pertussis. Unlike the old vaccine, the new Pentacel vaccine has an improved pertussis component with fewer adverse effects but with the same or better protection from whooping cough. Common adverse effects of Pentacel are fever, irritability, and local vaccination site reactions. Convulsions, shock, or allergic reaction are very rare and typically transient.

Another vaccine is StaphVAX, in Phase III testing by Nabi Biopharmaceuticals. This polysaccharide conjugate vaccine targets S. aureus types 5 and 8, which account for approximately 85% of S. aureus infections. StaphVAX is designed for patients at high risk of S. aureus infections who are able to produce their own antibodies in response to a vaccine. At approximately 200 sites across the U.S., a Phase III, double-blind, placebo-controlled, randomized trial is ongoing in approximately 3,600 patients on hemodialysis for end-stage renal disease.

Other vaccines in the pipeline in Phase II development include Holavax-typhoid, a live attenuated oral typhoid vaccine by Acambis; Antex Biologics' Activax, a multi- component vaccine to prevent diarrheal diseases caused by Shigella, Campylobacter and E. coli bacteria; CholeraGarde (Peru-15), a single dose, recombinant cholera vaccine by Avant Immunotherapeutics; rPA102, an alum-adjuvanted single-component anthrax vaccine based on recombinant protective antigen (rPA) by VaxGen; and ID Biomedical’s product StreptAvax, a multivalent recombinant vaccine developed to cover 26 serotypes of group A streptococcus (GAS). The GAS infections include strep throat, impetigo, toxic shock syndrome, flesh-eating bacteria, boils and skin abscesses (pyoderma), scarlet fever, and pneumonia.

An alternate pathway for prevention of Staph as well as Candida bacterial infections is antibody-based immunotherapy such as Veronate (INH-A21), in Phase III testing by Inhibitex. This polyclonal immune globulin product contains concentrated amounts of antibodies targeting specific MSCRAMM proteins found on the surface of staphylococci. The intended indication is for prevention of hospital-associated infections in very low birth weight (VLBW) infants.

Inhibitex is also in Phase II development of Aurexis (tefibazumab), a humanized monoclonal antibody recognizing an MSCRAMM protein found on most strains of S. aureus. Aurexis is currently being tested as first-line therapy, in combination with standard antibiotics, for the treatment of serious S. aureus bloodstream infections in hospitalized patients.

Demegen has received Orphan Drug Designation for P113D, an antibacterial peptide derived from histatins found in human saliva, for treatment of infections associated with cystic fibrosis. P113D has shown activity against resistant bacterial isolates from patients with cystic fibrosis, and the peptide appears to be stable and to maintain its activity in sputum.

As pathogenic bacteria become increasingly resistant, treatment of infections may require a multipronged approach: use of antibiotics designed to overcome resistance, vaccination of high-risk patients, and immunotherapy alone or in combination with conventional antibiotics. However, clinicians must continue to regulate prescribing patterns to avoid overuse or misuse of antibiotics that can foster selection of resistant microbes.