Etiology

Pseudomonas aeruginosa is a gram-negative rod and is a strict aerobe. It can multiply in a great variety of environments that contain minimal amounts of organic compounds. Strains from clinical specimens do not ferment lactose, are oxidase positive, and may produce β-hemolysis on blood agar. Many produce pigments including pyocyanin, pyoverdin, and pyorubrin that diffuse into and color the surrounding medium. Strains of Pseudomonas can be differentiated for epidemiologic purposes by serologic, phage, and pyocin typing and by genome restriction fragment length polymorphisms using pulsed-field gel electrophoresis.

Epidemiology

P. aeruginosa is a classic opportunist. It rarely causes disease in people who do not have a predisposing risk factor. Compromised host defense mechanisms owing to trauma, neutropenia, mucositis, immunosuppression, or impaired mucociliary transport explain the predominant role of this organism in producing opportunistic infections. The rate of P. aeruginosa bacteremia in children is 3.8/1,000 patients over 10 yr, with a 20% mortality rate; rates vary according to the prevalent underlying diseases. P. aeruginosa and other pseudomonads frequently enter the hospital environment on the clothes, skin, or shoes of patients or hospital personnel, with plants or vegetables brought into the hospital, and in the gastrointestinal tracts of patients. Colonization of any moist or liquid substance may ensue; the organisms may be found growing in any water reservoir, including distilled water, and in hospital kitchens and laundries, some antiseptic solutions, and equipment used for respiratory therapy. Colonization of skin, throat, stool, and nasal mucosa of patients is low at admission to the hospital but increases to as high as 50-70% with prolonged hospitalization and with the use of broad-spectrum antibiotics, chemotherapy, mechanical ventilation, and urinary catheters. Patients’ intestinal microbial flora may be altered by the use of broad-spectrum antibiotics, which reduces resistance to colonization and permits P. aeruginosa in the environment to populate the gastrointestinal tract. Intestinal mucosal breakdown associated with medications, especially cytotoxic agents, and nosocomial enteritis may provide a pathway by which P. aeruginosa spreads to the lymphatics or bloodstream.

Pathology

The pathologic manifestations of Pseudomonas infections depend on the site and type of infection. Due to its elaboration of toxins and invasive factors, the organism can often be seen invading blood vessels and causing vascular necrosis. In some infections there is spread through tissues with necrosis and microabscess formation. In patients with cystic fibrosis, focal and diffuse bronchitis/bronchiolitis leading to bronchiolitis obliterans has been reported.

Pathogenesis

Invasiveness of P. aeruginosa is mediated by a host of virulence factors. Bacterial attachment is facilitated by pili that adhere to epithelium damaged by prior injury or infection. Extracellular proteins, proteases, elastases, and cytotoxin disrupt cell membranes, and in response, host-produced cytokines cause capillary vascular permeability and induce an inflammatory response. Dissemination and bloodstream invasion follow extension of local tissue damage and are facilitated by the antiphagocytic properties of endotoxin, the exopolysaccharide, and protease cleavage of immunoglobulin G. P. aeruginosa also produces numerous exotoxins, including exotoxin A, which causes local necrosis and facilitates systemic bacterial invasion. P. aeruginosa possesses a type III secretion system (TTSS) that is important for virulence in multiple animal models. This needle structure inserts into host cell membranes and allows secretion of exotoxins directly into host cells. P. aeruginosa strains with the gene encoding the TTSS dependent phospholipase ExoU have been associated with increased mortality compared with ExoU-negative strains in retrospective studies of patients with P. aeruginosa ventilator-associated pneumonia. The host responds to infection by producing antibodies to Pseudomonas exotoxin A and endotoxin.

In addition to acute infection, P. aeruginosa is also capable of chronic persistence thought to be due in part to the formation of biofilms, organized communities of bacteria encased in an extracellular matrix that protects the organisms from the host immune response and the effects of antibiotics. Biofilm formation requires pilus-mediated attachment to a surface, proliferation of the organism, and production of exopolysaccharide as the main component of the extracellular matrix. A mature biofilm is resistant to many antimicrobials and difficult to eradicate with current therapies.

Clinical Manifestations

Most clinical patterns (Table 197-1) are related to opportunistic infections (Chapter 171) or are associated with shunts and indwelling catheters (Chapter 172). P. aeruginosa may be introduced into a minor wound of a healthy person as a secondary invader, and cellulitis and a localized abscess that exudes green or blue pus may follow. The characteristic skin lesions of Pseudomonas, ecthyma gangrenosum, whether caused by direct inoculation or metastatic secondary to septicemia, begin as pink macules and progress to hemorrhagic nodules and eventually to ulcers with ecchymotic and gangrenous centers with eschar formation, surrounded by an intense red areola.

Table 197-1 PSEUDOMONAS AERUGINOSA INFECTIONS

Outbreaks of dermatitis and urinary tract infections caused by P. aeruginosa have been reported in healthy persons after use of pools or hot tubs. Skin lesions of folliculitis develop several hours to 2 days after contact with these water sources. Skin lesions may be erythematous, macular, papular, or pustular. Illness may vary from a few scattered lesions to extensive truncal involvement. In some children, malaise, fever, vomiting, sore throat, conjunctivitis, rhinitis, and swollen breasts may be associated with dermal lesions.

Pseudomonads other than P. aeruginosa rarely cause disease in healthy children, but pneumonia and abscesses due to Burkholderia cepacia, otitis media due to P. putrefaciens or P. stutzeri, abscesses due to P. fluorescens, and cellulitis and septicemia and osteomyelitis due to S. maltophilia have been reported. Septicemia and endocarditis due to S. maltophilia have also been associated with abuse of intravenous drugs.

Diagnosis

P. aeruginosa infection is rarely clinically distinctive. Diagnosis depends on recovery of the organism from the blood, cerebrospinal fluid, urine, or needle aspirate of the lung, or from purulent material obtained by aspiration of subcutaneous abscesses or areas of cellulitis. Rarely, skin lesions that resemble P. aeruginosa infection may follow septicemia due to Aeromonas hydrophila, other gram-negative bacilli, and Aspergillus. When P. aeruginosa is recovered from nonsterile sites such as skin, mucous membranes, voided urine, and the upper respiratory tract, quantitative cultures are useful to differentiate colonization from invasive infection. In general, ≥100,000 colony forming units/mL of fluid or gram of tissue is evidence suggestive of invasive infection.

Treatment

Systemic infections with Pseudomonas should be treated promptly with an antibiotic to which the organism is susceptible in vitro. Response to treatment may be limited, and prolonged treatment may be necessary for systemic infection in immunocompromised hosts.

Septicemia and other aggressive infections should be treated with either 1 or 2 bactericidal agents. While the number of agents required is controversial, little evidence shows that more than 1 agent is needed for individuals with normal immunity or when treating urinary tract infections, but dual therapy is often used for a synergistic effect in immunocompromised patients or when the susceptibility of the organism is in doubt. Whether the use of 2 agents delays the development of resistance is also controversial, with evidence both for and against. Appropriate antibiotics for single-agent therapy include ceftazidime, cefepime, ticarcillin-clavulanate, and piperacillin-tazobactam. Gentamicin or another aminoglycoside may be used concomitantly for synergistic effect.

Ceftazidime has proved to be extremely effective in patients with cystic fibrosis (150-250 mg/kg/day divided every 6-8 hr IV to a maximum of 6 g/day). Piperacillin or piperacillin-tazobactam (300-450 mg/kg/day divided every 6-8 hr IV to a maximum of 12 g/day) also has proved to be effective therapy for susceptible strains of P. aeruginosa when combined with an aminoglycoside. Additional effective antibiotics include imipenem-cilastatin, meropenem, and aztreonam. Ciprofloxacin is effective but is not approved in the USA for persons <18 yr of age except for oral treatment of urinary tract infections or when there are not other agents to which the organism is susceptible. It is important to base continued treatment on the results of susceptibility tests because antibiotic resistance of P. aeruginosa to 1 or more antibiotics is increasing.

P. aeruginosa displays intrinsic and acquired resistance to antibiotics. It has many mechanisms for resistance to multiple classes of antibiotics including but not limited to genetic mutation, production of β-lactamases, and drug efflux pumps. Critical care units throughout the USA have documented a rising rate of resistance of P. aeruginosa to all of the major classes of antibiotics.

Meningitis can occur from spread from a contiguous focus, as a secondary focus when there is bacteremia, or after invasive procedures. Pseudomonas meningitis is best treated with ceftazidime in combination with an aminoglycoside such as gentamicin, both given intravenously. Concomitant intraventricular or intrathecal treatment with gentamicin may be required when intravenous therapy fails but is not recommended for routine use.

Supportive Care

Pseudomonas infections vary in severity from superficial to intense septic presentations. With severe infections there is often multisystem involvement and systemic inflammatory response. Supportive care is similar to severe sepsis caused by other gram-negative bacilli and requires support of blood pressure, oxygenation, and appropriate fluid management.

Prognosis

The prognosis is dependent primarily on the nature of the underlying factors that predisposed the patient to Pseudomonas infection. In severely immunocompromised patients, the prognosis for patients with P. aeruginosa sepsis is poor unless susceptibility factors such as neutropenia or hypogammaglobulinemia can be reversed. Resistance of the organism to 1st line antibiotics also decreases the chance of survival. The outcome may be improved by combined antimicrobial therapy and is improved when there is a urinary tract portal of entry, absence of neutropenia or recovery from neutropenia, and drainage of local sites of infection. Pseudomonas is recovered from the lungs of most children who die of cystic fibrosis and adds to the slow deterioration of these patients. The prognosis for normal development is poor in the few infants who survive Pseudomonas meningitis.

Prevention

Prevention of infections is dependent on limiting contamination of the health care environment and preventing transmission to patients. Effective hospital infection control programs are necessary to identify and eradicate sources of the organism as quickly as possible. In hospitals, infection can be transmitted to children by the hands of personnel, from washbasin surfaces, from catheters, and from solutions used to rinse suction catheters.

Strict attention to hand hygiene, before and between contacts with patients may prevent or interdict epidemic disease. Meticulous care and sterile procedures in suctioning of endotracheal tubes, insertion and maintenance of indwelling catheters, and removal of catheters as soon as medically reasonable greatly reduce the hazard of extrinsic contamination by Pseudomonas and other gram-negative organisms.

Prevention of follicular dermatitis caused by Pseudomonas contamination of whirlpools or hot tubs is possible by maintaining pool water at a pH of 7.2-7.8.

Infections in burned patients may be minimized by protective isolation, debridement of devitalized tissue, and topical applications of bactericidal cream. Administration of intravenous immunoglobulin may be used. Approaches under investigation to prevent infection include development of a Pseudomonas vaccine and development of hyperimmune globulin against Pseudomonas. No vaccine is currently licensed in the USA.

Pseudomonas infection of dermal sinuses communicating with the cerebrospinal space can be prevented by early identification and surgical repair. Pseudomonas infection of the urinary tract is often associated with the presence of an indwelling catheter. Urinary tract infections may be minimized or prevented by prompt removal of the catheter and by early identification and corrective surgery of obstructive lesions when present.

Burkholderia Cepacia

Burkholderia cepacia is a filamentous gram-negative rod. It is ubiquitous in the environment but may be difficult to isolate from respiratory specimens in the laboratory, requiring an enriched, selective media oxidation fermentation base supplemented with polymyxin B–bacitracin-lactose agar (OFPBL) and as long as 3 days of incubation.

B. cepacia is a classic opportunist that rarely infects normal tissue but can be a pathogen for individuals with pre-existing damage to respiratory epithelium, especially persons with cystic fibrosis or those with immune dysfunction such as chronic granulomatous disease. B. cepacia has multiple virulence factors, including lipopolysaccharide and a TTSS that promotes invasion of respiratory epithelial cells. Resistance to many antibiotics and disinfectants appears to be a factor in the emergence of B. cepacia as a nosocomial pathogen. In critical care units it may colonize the tubing used to ventilate patients with respiratory failure. In some patients this colonization may lead to invasive pneumonia and septic shock. Although B. cepacia is found throughout the environment, human-to-human spread among patients with cystic fibrosis occurs either directly by inhalation of aerosols or indirectly from contaminated equipment or surfaces, accounting for the practice of cohorting patients with cystic fibrosis in some clinics, hospital wards, and social gatherings on the basis of B. cepacia colonization. B. cepacia infections in persons with cystic fibrosis may only represent colonization in many patients but in others it is associated with an acute respiratory syndrome of fever, leukocytosis, and progressive respiratory failure, as well as progressive lung deterioration and more rapid decline in pulmonary function and lower survival rate.

Treatment in hospitals should include standard precautions and avoidance of placing colonized and uncolonized patients in the same room. Persons who have cystic fibrosis and who visit or provide care and are not infected or colonized with B. cepacia may elect to wear a mask when within 3 ft of a colonized patient. The use of antibiotics is guided by susceptibility studies of a patient’s isolates, because the susceptibility pattern of this species is quite variable and multiply resistant strains are common. Ceftazidime, ciprofloxacin, and trimethoprim-sulfamethoxazole, piperacillin-tazobactam, and carbapenems such as meropenem frequently show good activity. While there is primary resistance to aminoglycosides, these agents may be useful in combination with other antibiotics. Treatment with 2 or more agents may be necessary to control the infection and avoid the development of resistance. No vaccine is currently available.

Burkholderia Mallei (Glanders)

Glanders is a severe infectious disease of horses and other domestic and farm animals due to Burkholderia mallei, a nonmotile gram-negative bacillus that is occasionally transmitted to humans. It is acquired by inoculation into the skin, usually at the site of a previous abrasion, or by inhalation of aerosols. Laboratory workers may acquire it from clinical specimens. The disease is relatively common in Asia, Africa, and the Middle East. The clinical manifestations include septicemia, acute or chronic pneumonitis, and hemorrhagic necrotic lesions of the skin, nasal mucous membranes, and lymph nodes. The diagnosis is usually made by recovery of the organism in cultures of affected tissue. Glanders is treated with sulfadiazine, tetracyclines, or chloramphenicol and streptomycin over a period of many months. The disease has been eliminated from the USA, but interest in this organism has increased due to the possibility of its use as a bioterrorism agent (Chapter 704). While standard precautions are appropriate when caring for hospitalized infected patients, biosafety level 3 precautions are required for laboratory staff working with B. mallei. No vaccine is available.

Burkholderia Pseudomallei (Melioidosis)

Melioidosis is an important disease of Southeast Asia and northern Australia and occurs in the USA mainly in persons returning from endemic areas. The causative agent is Burkholderia pseudomallei, an inhabitant of soil and water in the tropics. It is ubiquitous in endemic areas and infection follows inhalation of dust or direct contamination of abrasions or wounds. Human-to-human transmission has only rarely been reported. Serologic surveys demonstrate that asymptomatic infection occurs in endemic areas. The disease may remain latent and appear when host resistance is reduced, sometimes years after the initial exposure. Diabetes mellitus is a risk factor for severe melioidosis.

Melioidosis may present as a single primary skin lesion (vesicle, bulla, or urticaria). Pulmonary infection may be subacute and mimic tuberculosis or may present as an acute necrotizing pneumonia. Occasionally, septicemia occurs and numerous abscesses are noted in various organs of the body. Myocarditis, pericarditis, endocarditis, intestinal abscess, cholecystitis, acute gastroenteritis, urinary tract infections, septic arthritis, paraspinal abscess, osteomyelitis, mycotic aneurysm, and generalized lymphadenopathy all have been observed. Melioidosis may also present as an encephalitic illness with fever and seizures. It is also an agent of severe wound infections following contact with contaminated water following a tsunami.

Diagnosis is based on visualization of characteristic small gram-negative rods in exudates or growth on laboratory media such as eosin–methylene blue or MacConkey agar. Serologic tests are available, and diagnosis can be established by a 4-fold or greater increase in antibody titer in an individual with an appropriate syndrome. It has been recognized as a possible agent of bioterrorism (Chapter 704).

B. pseudomallei is susceptible to many antimicrobial agents, including 3rd generation cephalosporins (especially ceftazidime), aminoglycosides, tetracycline, cotrimoxazole, sulfisoxazole, chloramphenicol, and amoxicillin-clavulanate. Therapy should be guided by antimicrobial susceptibility tests; 2 or 3 agents such as ceftazidime or chloramphenicol plus either trimethoprim-sulfamethoxazole, sulfisoxazole, or an aminoglycoside are usually chosen for severe or septicemic disease. For severe disease, prolonged treatment for 2-6 mo is recommended to prevent relapses. Appropriate antibiotic therapy generally results in recovery.