Infections caused by Pseudomonas aeruginosa

Several different epidemiological studies indicate that Pseudomonas aeruginosa is a nosocomial pathogen - nosocomial infections are infections resulting from treatment in a hospital or a healthcare service unit; infections are considered nosocomial if they first appear within 48 hours or more after hospital admission or within 30 days after discharge. There is also evidence suggesting that antibiotic resistance is increasing in recent years in Pseudomonas aeruginosa. According to the Center for Disease Control and Prevention (CDC), the overall incidence of Pseudomonas aeruginosa infections in US hospitals averages about 0.4 percent (4 per 1000 discharges), and the bacterium is the fourth most commonly-isolated nosocomial pathogen accounting for 10 percent of all hospital-acquired infections.

Pseudomonas aeruginosa causes urinary tract infections, respiratory system infections, dermatitis, soft tissue infections, bacteremia, bone and joint infections, gastrointestinal infections and a variety of systemic infections, particularly in patients with severe burns, in cancer and in AIDS patients who are immuno-suppressed.

Any Pseudomonas aeruginosa infection represents a serious problem in patients hospitalized with cancer, cystic fibrosis, and burns. The case fatality rate in these patients is almost 50 percent. 
Pseudomonas like other Gram-negative bacteria is per se difficult to treat with existing antibiotics, but may in addition develop resistance after unsuccessful treatment. Thus, Pseudomonas aeruginosa infections are an increasing threat to the community.

Sepsis, bacteremia

Sepsis and septic shock are inflammatory states resulting from the systemic response to bacterial infection. Common causes include Gram-negative pathogens, Staphylococci, and Meningococci. Symptoms often begin with shaking chills and include fever, low blood pressure, reduced urine production, and confusion. Acute failure of multiple organs can occur, including the lungs, kidneys, and liver. Treatment is aggressive and symptomatic to control the multiple organ failures and with antibiotics to combat the underlying bacterial infection.

Most cases of septic shock are caused by hospital-acquired Gram-negative bacteria like Pseudomonas aeruginosa or Gram-positive cocci and often occur in immuno-compromised patients and those with chronic and debilitating diseases like cancer or AIDS.

The pathogenesis of septic shock is not yet completely understood. Bacterial toxins (LPS, endotoxins) trigger the production of multiple pro-inflammatory mediators and cytokines. This “cytokine storm” has devastating effects on multiple organs with respective clinical signs and symptoms of malfunction and finally failure.

Overall mortality in patients with septic shock is high, but decreasing in recent years and now averages approximately 40% (range 10 to 90%, depending on patient characteristics and the causative pathogen). Poor outcomes are often observed when early aggressive therapy fails.

Sepsis and septic shock are life-threatening conditions that require treatment in intensive care units (ICU). The therapy is mostly symptomatic and uses standard principles of emergency medicine to maintain adequate organ function, e.g. stabilization of blood pressure, artificial ventilation, dialysis and other measures. Parenteral antibiotic therapy should be initiated after samples of blood, body fluids, and wound sites have been taken for Gram-staining and pathogen identification in culture. Very prompt empiric therapy starts immediately after suspecting sepsis, is essential and may be life-saving. Initial antibiotic selection requires an educated guess based on the suspected source, clinical setting, knowledge of or suspicion of causative pathogens and sensitivity patterns common to that specific hospital or intensive care unit. As soon as diagnosis of the causative pathogen is confirmed by culture (usually after 72h), antibiotic therapy rapidly needs to be adopted or switched to the most sensitive and effective antibiotic.

Pneumonia

Pneumonia is an acute inflammation of the lungs caused by infection. An estimated 2 to 3 million people in the USA develop pneumonia each year, about 45,000 of them die. Pneumonia is one of the most common fatal hospital-acquired infections and the most common overall cause of death in developing countries. Bacteria are the most common cause of pneumonia in adults.

Hospital-acquired pneumonia (HAP) includes ventilator-associated pneumonia (VAP), postoperative pneumonia, and pneumonia that develops in moderately or critically ill hospitalized inpatients. It also includes the new category of healthcare-associated pneumonia (HCAP), which refers to pneumonia acquired by patients in healthcare facilities such as chronic care facilities, dialysis centers, and infusion centers.

In general, the most important pathogen is Pseudomonas aeruginosa, which is especially common in pneumonia acquired in intensive care settings and in patients with cystic fibrosis, neutropenia, advanced AIDS, and bronchiectasis. Other important pathogens include enteric Gram-negative bacteria (mainly Enterobacter sp, Klebsiella pneumoniae, Escherichia coli, Serratia marcescens, Proteus sp, Acinetobacter sp) and both methicillin-sensitive and methicillin-resistant Staphylococcus aureus. The most common way of infection is aspiration of bacteria colonizing the oropharynx and upper airways in seriously ill patients.

Hospital-acquired pneumonia (HAP) occurs predominantly in patients with intubation and mechanical ventilation in the intensive care unit (ICU) and has a high risk of fatality, even with the proper use of antibiotics. If HAP is suspected, treatment with empirically chosen antibiotics is initiated which are then replaced by the most specific and effective antibiotic available for the pathogens identified in in vitro culture.

Urinary tract infections

A urinary tract infection (UTI) is a bacterial infection of the urinary bladder (cystitis) or the kidneys (pyelonephritis). The diagnosis is based on an examination of the urine. Almost all UTIs are caused by bacteria that enter the urethral opening and move upward to the urinary bladder and sometimes the kidneys. Cystitis is common in women, particularly during the reproductive years. Some women have recurring episodes of cystitis. Cystitis usually produces a frequent, urgent need to urinate and a burning or painful sensation while urinating. The urgent need to urinate may cause an uncontrollable loss of urine (urge incontinence), especially in older people.

Complicated urinary tract infections (cUTI), which occur in men and women of any age, are also caused by bacteria, but they tend to be more severe, more difficult to treat, and recurrent. They are often the result of

  • some anatomical or structural abnormality that impairs the ability of the urinary tract to clear out urine, e.g. benign prostatic hyperplasia (BPH) in men or kidney stones
  • use of catheter in the hospital setting or chronic indwelling catheter in the out-patient setting
  • bladder and kidney dysfunction and
  • conditions making an uncomplicated cystitis more severe, like diabetes mellitus, a weakened immune system (AIDS, cancer treatment), sickle cell anemia and certain neurological disorders (multiple sclerosis, stroke, spinal cord injury) that affect the nervous control of the urinary bladder.

About 40% of all nosocomial infections that develop in patients while in the hospital affect the urinary tract. The pathogens causing UTI in the hospital are different from those commonly causing UTI and include Pseudomonas aeruginosa, among others. These pathogens are also more likely to be resistant to standard antibiotic treatment. Patients in hospitals or nursing homes at highest risk for such infections are those with in-dwelling urinary catheters, patients undergoing urinary procedures, long-stay elderly men and patients with severe medical conditions. In most cases, UTIs are annoyances that cause urinary discomfort. However, if left untreated, UTIs can develop into very serious and potentially life-threatening kidney infections (pyelonephritis) that can permanently damage the kidneys. The infection may also spread into the bloodstream (sepsis) and then to many different organs in the body.

Both uncomplicated and complicated UTI are treated with antibiotics. Since the use of catheters is associated with a high degree of urinary tract infections, preventive measures are extremely important. Catheters should not be used unless absolutely necessary and they should be removed as soon as possible. Patients using catheters who develop UTI with symptoms should be treated for each episode with antibiotics and the catheter should be removed, if possible, or changed. Reducing the risk of infections during long-term catheter use, however, remains a challenge.

Cystic fibrosis

Cystic fibrosis (CF) is an inherited disease of the mucus and sweat glands. It affects mostly the lungs, pancreas, liver, intestines, sinuses and sex organs. CF causes the mucus to be thick and sticky. The thickened mucus clogs the airways, causing breathing problems and making it easy for bacteria to grow. This can lead to problems such as repeated lung infections and lung damage.

The symptoms and severity of CF vary widely. Some people have serious problems from birth. Others have a milder version of the disease which does not show up until they are teens or young adults.

Although there is no cure for CF, treatments have improved greatly in recent years. Until the 1980s, most deaths from CF occurred in children and teenagers. Today, with improved treatments, people with CF live, on average, 35 years or more.

The thick mucus and breathing problems predispose CF patients for bacterial infections. Lung infections in CF are mostly due to Pseudomonas aeruginosa. Between the ages of 6 and 10 about 40% of patients with CF have Pseudomonas aeruginosa infections, by the age of 17 this percentage has increased to almost 60% and between 25 and 34, about 80% of adults with CF have Pseudomonas aeruginosa infections.

Chronic, repeated lung infections with Pseudomonas aeruginosa are the leading cause of declining lung function and are associated with greater morbidity and mortality for people with CF. Strict infection control measures appear to reduce, but not to eliminate the risk of initial acquisition of this pathogen. There is now good evidence from randomized controlled clinical trials that early eradication regimens consisting of anti-Pseudomonas antibiotics are effective in clearing Pseudomonas aeruginosa and delaying the development of chronic infections in the majority of subjects. These regimens are safe and cost-effective. Ensuring that such regimens are widely adopted is therefore of considerable importance to improve outcomes for people with CF. The most effective antibiotic regimen, and the effects of new nebulizer technologies and methods to improve compliance remain to be determined. Novel antibiotics that effectively combat Pseudomonas aeruginosa infections like POL7080 will become part of these regimens.