Pseudomonas and Burkholderia Infections

The Pathogens

P. aeruginosa is a gram-negative, lactose nonfermenting, straight or slightly curved rod with a length ranging from 1.5 to 7 µm and a width of 0.5 to 1.0 µm. It is catalase positive, oxidase positive, and motile with one or more polar flagella. Most species oxidize glucose and reduce nitrate to nitrite or nitrogen gas. It has the ability to grow at 42° C. This pathogen contains a polysaccharide capsule along with lipopolysaccharides, pili, and flagella. The organism includes toxins such as exotoxin A, pyocyanin (blue or blue-green pigment), pyorubin (red or red-brown pigment), pyomelanin (black pigment), and pyoverdin (yellow-green pigment). P. aeruginosa is notorious for its ability to acquire resistance genes and to spread by horizontal transfer. The microorganism possesses a diversity of mechanisms that promote its survival, adaptation, and resistance to multiple classes of antibiotics that make it an emerging worldwide public health threat.

Pathogenesis and Pathophysiology

Innate immunity, primarily through inflammatory cytokine production and phagocytic clearance by neutrophils and macrophages, is the key to endogenous control of P. aeruginosa infection. P. aeruginosa binds to the cystic fibrosis transmembrane conductance regulator (CFTR), which is a channel involved in chloride movement across the cell. Release of interleukin-1 and signaling through the interleukin-1 receptor and adaptor molecule MyD88 occur. NF-κB is translocated, followed by transcription of NF-κB–dependent genes and the production of interleukin-6, interleukin-8, and intercellular adhesion molecule 1. Polymorphonuclear neutrophils are recruited to infected tissue to resolve the infection. Patients with cystic fibrosis have a defective CFTR and thus cannot mount a normal defensive response to P. aeruginosa .

Bacterial Factors

P. aeruginosa survives in aquatic as well as in soil environments. Several factors, including flagella, pili, exopolysaccharides, phospholipases, proteases, endotoxins, secreted toxins (types I, II, II, IV, and VI), exotoxins, and iron-binding proteins, are involved in pathogenesis ( E-Table 282-1 ). Pseudomonas produces high levels of an extracellular mucoid polysaccharide called alginate, which is the main constituent of the glycocalyx allowing growth in a biofilm. Furthermore, the expression of O side chains on the bacterium’s lipopolysaccharide prevents lysis by complement. Bacterial toxins and enzymes kill immune cells and invade and degrade tissues . Exotoxin A, an adenosine diphosphate–ribosylating toxin, has activity similar to that of diphtheria. The production of this cellular toxin is affected by iron levels. P. aeruginosa uses pyoverdin and pyochelin, typical siderophore systems, to acquire iron.

P. aeruginosa can induce hemolysis by PlcHR, a hemolytic phospholipase C. A nonhemolytic phospholipase C, PlcN, is also made by P. aeruginosa strains. P. aeruginosa type III secretion systems allow direct injection of bacterial toxins into eukaryotic cells and disrupt cellular trafficking by inhibiting the actin cytoskeleton and by affecting protein synthesis. Pseudomonas communicates with other members of its microbial community through quorum sensing, thereby leading to the formation of biofilms, which limit penetration of antibiotics and make it difficult to eradicate the organism. Pili and flagella, though not considered classical components of the biofilm, are important for its maturation. Furthermore, P. aeruginosa and S. aureus coinfect the lung and chronic wounds, where they form multispecies biofilms, in which P. aeruginosa can outcompete S. aureus .

Both transferable (such as β-lactamase production) and intrinsic (mutation-driven) mechanisms confer Pseudomonas resistance to antibiotics, including carbapenems. Transferable resistance to aminoglycosides entails modification of aminoglycosides through phosphoryltransferases, acetyltransferases, nucleotidyltransferases, or ribosomal methyltransferases (RmtA, RmtB, RmtC, RmtD, and ArmA). Chromosomally mediated resistance is related to mutations in the quinolone resistance-determining region of gyrase A and the topoisomerase IV gene parC , which hamper the attack of fluoroquinolones on the bacterium. Aminoglycoside-inactivating enzymes are related to the P. aeruginosa chromosome and involve 3- N -aminoglycoside acetyltransferases or nucleotidyltransferases. Impermeability resistance to aminoglycosides is also chromosomally mediated.

Pathology

The pathologic spectrum of P. aeruginosa infections depends on the site afflicted. Hemorrhage and necrosis may be present in severe Pseudomonas infections, such as in pneumonia and endocarditis. In ecthyma gangrenosum, bacteria invade the arteries and veins of the skin, with little accompanying inflammation because of the paucity of pus in these skin lesions.

Febrile Neutropenia

P. aeruginosa is a key infectious agent of concern in patients who have febrile neutropenia ( Chapters 153 and 260 ). It is the organism against which empirical coverage must always be included. The classic clinical syndromes in febrile neutropenic patients are bacteremia, pneumonia, and soft tissue infection, mainly manifested as ecthyma gangrenosum ( Fig. 260-5 ).

Bacteremia

Bacteremia is usually caused by primary infection at a specific site, such as pneumonia, urinary tract infection, complicated intra-abdominal tract infection (peritonitis, abscess), or endocarditis. Manifestations can include those of sepsis and septic shock (i.e., fever, tachycardia, tachypnea, hypotension, and mental status changes ranging from confusion to coma; Chapter 94 ). Multiorgan failure with adult respiratory distress syndrome ( Chapter 90 ) and acute renal failure ( Chapter 106 ) may occur and be accompanied by coagulation defects (e.g., disseminated intravascular coagulation; Chapter 161 ).

Eye Infections

Keratitis ( Chapter 391 ) is associated with wearing contact lenses, especially extended-wear lenses, but any form of trauma, including surgery and burns, may predispose to keratitis by direct inoculation of Pseudomonas . Pain and redness are cardinal manifestations, the entire cornea can be opacified, and perforation sometimes occurs. P. aeruginosa keratitis is a medical emergency because of the speed with which it can progress and lead to loss of vision.

Fulminant endophthalmitis ( Chapter 391 ) may result from penetrating injuries, surgery, perforation of a corneal ulcer, or seeding from bacteremia. Manifestations include severe pain, chemosis, decreased visual acuity or even loss of vision, anterior uveitis, and vitreous involvement.

Other rarer eye infections include blepharoconjunctivitis, corneal ulcer, scleritis, and canaliculitis (both primary and plug-related). P. aeruginosa bacteremia also may lead to orbital cellulitis and gangrenous necrosis of the eyelids in neutropenic patients.

Ear Infections

Acute otitis externa ( Chapter 394 ) with otalgia, which is commonly seen in children, results from infection of moist, macerated skin of the external ear canal. The source of the organism is likely to be hot tubs or swimming pools (swimmer’s ear), particularly if they are not sufficiently chlorinated.

In patients who have diabetes or chronic HIV infection, so-called malignant otitis externa can present with fever, drainage, nerve palsies, hoarseness, dysphagia, pain on traction of the pinna, facial paralysis, and altered mental status owing to infection at the junction of bone and cartilage in the meatus.

Acute Respiratory Tract Infections

P. aeruginosa is a frequent cause of ventilator-associated pneumonia and hospital-associated pneumonia ( Chapters 85 and 261 ), accounting for about perhaps 20% of cases. Clinical manifestations may include fever, productive cough, crackles, rhonchi, central cyanosis, tachypnea, use of accessory respiratory muscles, signs of septic shock, and multiorgan failure.

Community-acquired P. aeruginosa pneumonia also occurs, particularly in patients who have underlying structural lung disease such as COPD ( Chapter 76 ) or bronchiectasis ( Chapter 78 ), are immunocompromised, or who have been previously treated with antibiotics.

Chronic Respiratory Tract Infections

P. aeruginosa is responsible for chronic airway infections, mainly with cystic fibrosis ^, and COPD. P. aeruginosa also can cause a diffuse panbronchiolitis, mainly in Asian populations, manifested by persistent cough and exertional dyspnea; at least 50 to 100 mL/day of sputum; chronic paranasal sinusitis; coarse crackles; bilateral, diffuse, small nodular shadows on a plain chest radiograph or centrilobular micronodules on chest computed tomography; evidence of airway obstruction, hypoxemia, and an elevated cold hemagglutinin titer.

Bone and Joint Infections

P. aeruginosa is among the main causative pathogens of bone infections ( Chapter 251 ) in patients who have indwelling devices or prostheses and in intravenous drug users ( Chapter 365 ), in whom vertebral osteomyelitis, sacroiliac septic arthritis, and septic arthritis of the sternoclavicular joint are seen, sometimes, but not always, with pain and positive blood cultures. In vertebral P. aeruginosa osteomyelitis, clinical manifestations are more indolent than in staphylococcal osteomyelitis and often range from weeks to months. The affected region may be tender with a decreased range of motion. Low-grade fever is common.

Pseudomonas osteomyelitis ( Chapter 251 ) of the foot most frequently follows puncture wounds through sneakers. The main manifestation is pain in the foot, sometimes with superficial cellulitis around the puncture wound and tenderness on deep palpation of the wound. Patients with Charcot arthropathy (neuropathic joint) and diabetes are especially at risk for P. aeruginosa bone infection.