David Dockrell MD
Walter Wilson MD
Essentials of Diagnosis
Nosocomial colonization is much more frequent and most often occurs in patients with predisposing conditions leading to impaired immunity, especially neutropenia, the presence of instrumentation disrupting host defenses, the prolonged use of extended spectrum antibiotics, and the existence of hospital reservoirs of infection. Hospital epidemics have been investigated by a variety of epidemiologic tools including serotyping, antibiogram patterns, and phage typing, but increasingly DNA fingerprinting is used. Potential sources of infection in the hospital environment include infected respiratory equipment, endoscopes, infusion solutions, intravascular catheters, whirlpools, sinks, drains, and indoor plants.
Table 54-1. Clues to the diagnosis of P aeruginosa
Bacterial factors also contribute. Colonization often precedes infection. Colonization is aided by the bacterial pili and production of mucoid exopolysaccharide. Pili or fimbriae are of particular importance in pulmonary colonization. The alginate capsule is a feature of mucoid strains and has an important role in CF pathogenesis (see below). It protects the organism from antibodies, complement, and phagocytosis. In addition, mucoid strains are associated with decreased susceptibility to antibiotics, especially aminoglycosides. Enzymes that contribute to invasiveness are produced, including alkaline protease, hemolysins, and elastase. Alkaline protease induces necrosis in tissues, possesses strong anticoagulant activity, and inactivates a variety of cytokines including tumor necrosis factor (TNF). Elastase has a variety of pathogenic effects including the degradation of IgG and IgA, complement cleavage, inactivation of TNF, and interferon gamma, and is linked to the pathogenesis of the characteristic skin lesions of Pseudomonas septicemia referred to as ecthyma gangrenosum.
Hemolysins aid tissue invasion by degrading lipids and lecithin. One hemolysin, phospholipase c, degrades phosphatidylcholine, a component of lung surfactant, resulting in atelectasis. Cytotoxin, formerly called leukocidin, inhibits neutrophil function and is linked to the pathogenesis of Pseudomonas-induced acute lung injury in adult respiratory distress syndrome. Pyocyanin alters the function of ciliated respiratory epithelium and enhances tissue damage by means of the generation of toxic free radicals.
As with other gram-negative bacteria, lipopolysaccharide plays a key role in the manifestations of septic shock. It stimulates the production of TNF and other cytokines, prostaglandins, leukotrienes, β-endorphins, kinins, complement activation, and the activation of the coagulation and fibrinolytic cascades. Exotoxin A acts by a method similar to diphtheria toxin to inhibit protein synthesis. This toxin plays a significant role in the necrosis observed in animal models of Pseudomonas corneal or lung injury. Mutant strains of bacteria that do not produce exotoxin A produce less severe injury than strains expressing exotoxin. Exotoxin A may also be immunosuppressive to both T and B lymphocytes. Exoenzyme S ribosylates proteins of the ras gene superfamily and alters local host defense mechanisms.
Box 54-1 summarizes the principal clinical symptoms associated with P aeruginosa infection.
Pseudomonas lung infections occur in patients with chronic lung disease or impaired immunity, usually in association with nosocomial factors such as endotracheal intubation, respiratory therapy, prolonged hospitalization, antibiotic use, and neutropenia. Pneumonia takes two forms: primary and bacteremic. Primary pneumonia arises in predisposed patients following nosocomial colonization and aspiration of P aeruginosa. Pneumonia is characterized by fever, tachypnea, cough with purulent sputum, shortness of breath, cyanosis, and often signs of sepsis.
The diagnosis of pneumonia caused by P aeruginosa is established by the chest x-ray findings of bilateral bronchopneumonia often with radiolucencies resembling Staphylococcus aureus pneumonia (Figure 54-1) and recovery of P aeruginosa from pulmonary secretions or blood culture. P aeruginosa frequently colonizes hospitalized patients, especially those with chronic pulmonary disease or those with endotracheal intubation and mechanical ventilation. Colonization, especially in ventilated patients, is often difficult to differentiate from infection, and the diagnosis of infection requires the presence of signs and symptoms of infection together with recovery of P aeruginosa from expectorated sputum, blood cultures, bronchoalveolar lavage, or a protected brushing sample obtained at bronchoscopy. P aeruginosa is particularly common in patients with ventilator-associated pneumonia. One study found it caused 27% of cases of ventilator-associated pneumonia and identified risk factors such as chronic obstructive pulmonary disease, mechanical ventilation for more than 8 days, and prior antibiotic use. In the rare instances in which community acquired pneumonia is found, it occurs primarily in patients with chronic obstructive airways disease and history of prior antibiotic use.
BOX 54-1 P aeruginosa Clinical Syndromes
Bacteremic pneumonia is caused by septic embolization of the lung. Neutropenia complicating chemotherapy, underlying hematologic malignancy, or AIDS are the usual settings for this type of pneumonia. This is usually a rapidly fatal disease. Pathologically, two characteristic pulmonary lesions are encountered. One type is hemorrhagic nodules, which are primarily subpleural and surround pulmonary vessels without inflammatory infiltrates. The second type is umbilicated nodules with liquifactive necrosis and leukocyte infiltration or more frequently with coagulative necrosis. These lesions are the pulmonary form of cutaneous ecthyma gangrenosum. The radiologic appearance of bacteremic pneumonia evolves over 1 to 3 days and is initially manifested by pulmonary congestion and edema with subsequent alveolar infiltrates, pulmonary hemorrhage, and finally cavitation.
Figure 54-1. Pseudomonas aeruginosa pneumonia in an immunocompromised host. Note the bilateral pneumonia on chest x-ray with radiolucencies resembling the appearance of S aureus pneumonia.
INFECTIONS IN PATIENTS WITH CYSTIC FIBROSIS
Patients with CF demonstrate particularly complex host-parasite interactions involving P aeruginosa. CF is characterized by mutations in the CF transmembrane conductance regulator resulting in abnormal chloride ion secretion and cellular dehydration. A continuous cycle of cellular inflammation with increased numbers of neutrophils in bronchoalveolar lavage fluid, increased interleukin 8 secretion, viscous mucus, mucus plugging of airways, and infection results. Whether P aeruginosa infections play a role in the pathogenesis of the disease is still a matter of debate, but research has established a complex interaction.
Colonization rates for P aeruginosa increase with age and reach 60–80% for adult CF patients. One of the effects of the genetic mutation causing CF is an increase in levels of the receptor, α-sialo GM1, on respiratory epithelium. P aeruginosa isolates from CF patients who are colonized demonstrate the mucoid phenotype discussed above and form a biofilm that protects the bacteria from antibiotics, immunoglobulin, complement, and oxygen-free radicals. Conversely, strains lose the polysaccharide O side chains of lipopolysaccharide and become susceptible to complement, which prevents invasive infection and bacteremia. Motility is lost, and loss of flagella correlates with decreased nonopsonic phagocytosis. Immunoevasion is accomplished with the aid of a variety of bacterial products, especially elastase (which proteolyses immunoglobulin, complement, and cytokines) and cytotoxin (which induces T-lymphocyte, macrophage, and neutrophil cytotoxicity).
Colonization is facilitated by prior antimicrobial treatment of respiratory infections, which eradicates existing respiratory flora. Acute exacerbations with productive cough caused by bronchitis or pneumonia occur and are associated with further reduction of respiratory reserve. Fever is usually absent. Antimicrobial treatment of acute exacerbations is necessary, although eradication of the carrier state does not usually occur. Prophylactic or suppressive antimicrobial therapy has not been demonstrated to be efficacious; however, intermittent antipseudomonal therapy, including the use of nebulized antimicrobial agents, in particular, tobramycin, improves pulmonary function and decreases exacerbation of infection. Chest physiotherapy is essential in limiting infections. Ultimately, respiratory failure may lead to heart-lung or double lung transplantation, and P aeruginosa infection contributes to the high morbidity and mortality associated with transplantation in this population.
P aeruginosa is a common cause of nosocomial bacteremia, which may be either primary (no identifiable source) or secondary (recognizable extravascular source). Community-acquired P aeruginosa bacteremia is very rare. Host factors contributing to nosocomially acquired P aeruginosa bacteremia include neutropenia caused by hematological malignancy or chemotherapy, hypogammaglobulinemia, AIDS, organ transplantation, insulin-dependent diabetes mellitus, burns, premature births or advanced age, instrumentation or catheterization, high-dose corticosteroid use, and prolonged antibiotic therapy. P aeruginosabacteremia is associated with higher mortality than bacteremia caused by other gram-negative microorganisms, although this observation may reflect the host's underlying immunosuppression.
A poor prognosis is associated with an absolute neutrophil count of < 100 cells/mL3, septic shock, renal failure, or a serious underlying illness. Primary bacteremia or bacteremia-complicating pneumonia or skin infections are also associated with a poor prognosis.
Clinical signs of P aeruginosa bacteremia are those of gram-negative sepsis and include fever, tachycardia, respiratory distress, hypotension, obtundation, and renal failure. P aeruginosa bacteremia has a particular propensity to cause jaundice. Disseminated intravascular coagulation is less frequently encountered with P aeruginosa bacteremia than other gram-negative bacteremias.
The classic skin lesion of P aeruginosa bacteremia is ecthyma gangrenosum, which is characterized by the presence of a small vesicle with a rim of surrounding erythema that undergoes necrosis and ulcerates with localized gangrene and black discoloration (Figure 54-2). Histopathology reveals the invasion of small arteries and veins by bacteria and is characterized by the absence of a significant inflammatory infiltrate. Lesions occur most frequently on the extremities, buttocks, perineum, or axilla, although they may occur anywhere including within the oral cavity. Although occasionally reported in infections with other organisms including Escherichia coli and Candida spp., these lesions are highly suggestive of Pseudomonas infection. However, only a minority of bacteremic infections develop this lesion. Other skin lesions encountered include vesiculopustular or maculopapular lesions and cellulitis. The diagnosis is made by the characteristic appearance of gram-negative microorganisms on Gram stain and recovery of P aeruginosa from blood or tissue cultures.
Figure 54-2. Ecthyma gangrenosum in the perirectal region of a neutropenic patient receiving chemotherapy for hemolytic malignancy. Note the necrotic center of the lesions with surrounding erythema.
SKIN & SOFT TISSUE INFECTIONS
Infections caused by P aeruginosa involving the skin may be primary or secondary. Secondary infections have been described above and include ecthyma gangrenosum, subcutaneous nodules, vesicles, bullae, cellulitis, deep abscesses, and necrotizing fasciitis. Primary skin lesions are noted as complications of neutropenia, burns, decubitus ulcers, prematurity, exposure to a moist environment, and hydrotherapy. Burn wound sepsis is a serious complication that may be caused by P aeruginosa. Colonization of the burn may lead to invasive disease. The signs are black, brown, or violet discoloration of the burn eschar; destruction of granulation tissue leading to rapid eschar separation and subcutaneous hemorrhage; erythematous nodules; edema or hemorrhage of adjacent uninfected tissue; black neoeschar formation; or signs of septicemia. This complication of burns has a high associated mortality. Diagnosis is by skin biopsy of both burn tissue and adjacent viable tissue. The presence of > 105 organisms per gram of tissue cultured, the presence of P aeruginosa in adjacent healthy tissue, vasculitis, or inflammation at the burn margin are diagnostic.
Other skin and soft tissue infections caused by P aeruginosa include the following: hot tub- or hydrotherapy-associated folliculitis, which is usually self-limited (Figure 54-3); web space infection of the toe associated with humid climates or tinea pedis infection and characterized by maceration and scaling with purulent discharge, which may be green in color; green nail syndrome, which is characterized by paronychia occurring in association with a history of frequent submersion of the hands in water and nail discoloration caused by incorporation of pigment in the nail; green foot syndrome resulting from P aeruginosa colonization of rubber-soled shoes producing pigment that stains the feet, but in which P aeruginosa does not cause direct infection; diving suit dermatitis; necrotizing fasciitis after Cesarean section, and noma neonatorum, a complication of premature infants in developing countries where necrotizing hemorrhagic lesions of mucosal surfaces or the groin result in fulminant infection and often death.
Figure 54-3. Pseudomonas aeruginosa hot tub folliculitis.
URINARY TRACT INFECTION
Urinary tract infection (UTI) with P aeruginosa occurs primarily in two settings: nosocomial infection or complicated urinary tract infection. Nosocomial infections involve patients with urinary catheterization, instrumentation, or surgery. Renal transplant recipients have a high risk of P aeruginosa urinary tract infection. Complicated urinary tract infections are often nosocomially acquired and occur in association with renal stones, chronic prostatitis, or urinary tract malformations. Rarely community-acquired P aeruginosa cystitis occurs in young patients as the result of transient colonization.
The clinical presentation of P aeruginosa UTI includes dysuria, increased frequency of micturition, and hematuria. Fever and flank pain occur in cases of pyelonephritis. Diagnosis is made by the recovery of P aeruginosa from cultures of a midstream or catheterized urine sample in association with pyuria or hematuria. Urinary tract infections contribute significantly to the total number of patients with P aeruginosa bacteremia and are associated with a better outcome than bacteremia associated with other sources.
Rare complications of Pseudomonas UTI include the sloughing of bladder mucosa associated with ulceration of the urinary bladder or renal infarcts caused by invasion of small blood vessels representing a form of ecthyma gangrenosum in the kidney. Treatment of UTI infection is complicated by the tenacity with which P aeruginosa adheres to urinary epithelium predisposing to chronic infection and relapse.
EAR, NOSE & THROAT INFECTIONS
P aeruginosa infection of the external auditory canal may be acute or may be a chronic serious infection called malignant otitis externa. Acute diffuse otitis externa is often referred to as swimmer's ear. P aeruginosa may be part of the normal flora of the external auditory canal or may colonize the canal as a result of exposure to water. Swimming, a humid climate, and local trauma result in inflammation, desquamation, and bacterial proliferation. The clinical signs and symptoms are erythema, discharge, pain, and pruritus. An aggressive hemorrhagic form has been associated with hot tub use. Topical antibiotics, topical corticosteroids, and drying agents are usually effective therapy, although relapse is frequent.
Malignant otitis externa is the contiguous spread of necrotizing P aeruginosa infection from beyond the external auditory canal to the adjacent soft tissue and bone and is a serious infection usually occurring in elderly diabetics with microvascular disease but may also occur in elderly nondiabetics, or in association with systemic corticosteroid treatment, AIDS, or rarely in infants. Irrigation of the ear with water in these patients may represent a risk factor. Infection spreads from the external auditory canal through adjacent cartilage and soft tissue to the parotid space, the temporal bone, and mastoid air cells and then to the base of the skull.
Symptoms include severe pain and discharge sometimes associated with decreased hearing, but systemic symptoms are rare. On examination the external auditory canal is erythematous and edematous, and granulation tissue may be observed. The middle ear is usually spared. Ipsilateral fascial nerve palsy is a common early finding. Potential complications include parotid swelling and trismus, palsies of the 9th through 12th cranial nerves, cavernous venous thrombosis, and rarely, brain abscess or meningitis. An elevated erythrocyte sedimentation rate (ESR) in the absence of significant elevation of white blood cell count is common. For the radiologic diagnosis, magnetic resonance imaging may be more sensitive than computed tomography scans, and radionucleotide scans, such as indium-labeled white blood cell scans, are useful to detect early bone involvement.
P aeruginosa is usually recovered from cultures of the external auditory canal or from débrided tissue. Antimicrobial therapy should be combined with local débridement, and in more severe cases, extensive débridement is warranted. Cure is also dependent on successful management of underlying conditions such as diabetes mellitus or reduction of corticosteroid therapy. Early diagnosis improves the outcome, and an adequate response to therapy may be assessed by documenting decreased otalgia, a decrease in erythrocyte sedimentation rate, and improved radiologic appearance.
P aeruginosa is the most frequent pathogen identified in chronic suppurative otitis externa infections in all ages and is also a recognized pathogen in mastoiditis in diabetics, sinusitis in patients with AIDS, and perichondritis of the auricle following ear piercing or other traumatic procedures performed on the pinna.
Bone and joint infections caused by P aeruginosa may result as complications of surgery, in particular the implantation of joint prostheses, or pelvic or genitourinary surgery, in association with intravenous (IV) drug abuse, trauma resulting in open fractures such as motor vehicle or farm related accidents, complicated UTIs, diabetic foot ulcers, or puncture wounds of the foot. P aeruginosa has a predilection to infect fibrocartilaginous structures. P aeruginosa prosthetic joint infections may occur as a result of contamination during implantation, aspiration, or injection of the joint with corticosteroids.
In addition, P aeruginosa prosthetic joint infections may occur as a result of repeated surgical manipulation of the joint, joint revision, or reimplantation of the prosthesis. Polymicrobial osteomyelitis with P aeruginosa and other microorganisms is commonly associated with farm or motor vehicle accidents when open fractures become contaminated with water, soil, or vegetative materials. Vertebral osteomyelitis occurs in IV drug abusers or as a complication of UTI or genitourinary surgery. The lumbosacral spine is principally involved, although cervical involvement occurs in IV drug abusers. Sternoarticular pyarthrosis may occur in IV drug abusers or occasionally as a complication of infective endocarditis. Infection of the symphysis pubis may occur after pelvic or genitourinary surgery and must be differentiated from nonpyogenic osteitis pubis.
Puncture wound infections of the foot occur at all ages and have a particular association with punctures through rubber-soled sneakers. These infections occur as a result of the growth of P aeruginosa in the moist inner sole layer of the shoes, and puncture wounds through the shoe inoculate P aeruginosa directly into the bones of the foot and surrounding soft tissue.
Chronic osteomyelitis may occur as a result of contiguous infection following trauma, surgery, or as a complication of diabetic foot ulcers due to direct inoculation or local expansion of the organism. These infections tend to be indolent with pain and decreased range of movement in the absence of fever or leukocytosis. An elevated erythrocyte sedimentation rate, abnormalities on CT scanning or MRI or a positive radionuclide scan suggest the diagnosis, but confirmation requires demonstration of the organism on a Gram stain and recovery of P aeruginosa from cultures. Puncture wounds of the foot may be more acute in presentation, and typically the initial pain after the injury resolves and recurs a few days later with pain and swelling over the site of inoculation. Osteomyelitis of any of the bones of the foot may result (Figure 54-4).
Effective treatment requires antimicrobial therapy combined with surgical débridement. Successful treatment of P aeruginosa prosthetic joint infection requires resection of the prosthesis and other foreign material together with débridement and antimicrobial therapy.
P aeruginosa endocarditis occurs predominantly in two settings: in association with IV drug use (IVDU) or with prosthetic valve endocarditis (PVE). The majority of cases of native valve endocarditis caused by P aeruginosa occur in association with IVDU. Risk factors for endocarditis associated with IVDU include the use of substances that are not boiled after mixing before injection, the injection of drugs at shooting galleries, and the use of pentazocine and tripelennamine. Intravenous drug users often have a combination of these factors. Despite the strong association of IVDU with P aeruginosa endocarditis, S aureus and streptococci more frequently cause endocarditis in IVDU.
Figure 54-4. Puncture wound osteomyelitis of the calcaneus due to Pseudomonas aeruginosa. Note the loss of the border of the calcaneus adjacent to the tip of the nail.
The tricuspid valve is most frequently infected in intravenous drug users, occurring in over two-thirds of cases. Infection of the mitral, aortic, or pulmonic valves may also occur, and infection of multiple valves is common. Evidence of prior valvular pathology is usually absent, although foreign materials in injected substances may predispose by causing endothelial damage and fibrosis. The infection is usually subacute with fever and cardiac murmur occurring in the absence of other classic stigmata of infective endocarditis, such as Osler nodes, Janeway lesions, or Roth spots.
Presentation may be due to complications arising from septic pulmonary embolization characterized by cough, sputum production, pleuritic chest pain, or new infiltrates on chest x-ray. Left-sided valvular disease is less frequently encountered, and embolic complications and cardiogenic shock are frequent sequelae. Ecthyma gangrenosum is rarely encountered in patients with endocarditis.
PVE caused by P aeruginosa is often highly aggressive. Diagnosis is based upon clinical illness compatible with infective endocarditis and blood cultures positive for P aeruginosa. Definitive diagnosis is made by recovery of P aeruginosa from blood cultures or tissue obtained at surgery or autopsy.
In addition to antibiotic therapy, surgical intervention is often necessary especially in left-sided valvular infections. Successful treatment of P aeruginosa PVE requires surgical intervention together with antimicrobial therapy. Infection of the tricuspid valve may also require surgery if bacteremia persists after 2 weeks of effective antimicrobial therapy or recurs after a 6-week course of antibiotics. The procedure of choice is tricuspid valvulectomy. In cases without a history of IVDU, a tricuspid valve replacement can be performed ~6–8 weeks after valvulectomy. Poor prognostic factors in P aeruginosa endocarditis are an age > 30 years, fever lasting > 2 weeks on appropriate antimicrobial-agent therapy, embolization, mural vegetation, left-sided infection, PVE, and mixed infection, particularly with S aureus as the copathogen.
P aeruginosa infections involving the eye take two predominant forms: keratitis and endophthalmitis. Keratitis often results from corneal ulceration induced by trauma. Risk factors include the use of contact lenses, especially extended wear soft contact lenses; topical ophthalmic steroid use; contaminated ophthalmic solutions; burn patients; prolonged coma; tracheostomy; ocular irradiation; or AIDS. In intensive care units, tracheal colonization, corneal drying, corneal abrasion, and a decrease in the bactericidal effect of lacrimal secretions contribute to the increased risk of infection.
Symptoms include pain, erythema, photophobia, purulent discharge, and blurred vision. On exam, a necrotic pale corneal ulcer is observed with adherent mucopurulent discharge and hypopyon formation (pus in the anterior chamber). Loss of vision may be rapid, and this condition is an ophthalmologic emergency necessitating prompt diagnosis and treatment. Diagnosis is made by ophthalmologic examination, scrapings from the ulcer, demonstration of organism presence on Gram stain, and organism recovery from culture. Treatment requires the application of antibiotic-containing ophthalmic solution combined with subconjunctival injection of antibiotics.
Endophthalmitis may result from keratitis, hematogenous spread, direct trauma, or surgery. The clinical signs and symptoms include a painful red eye with chemosis, hypopyon, anterior uveitis, decreased visual acuity, and in severe cases panophthalmitis. Therapy consists of combined topical, subconjunctival, intraocular and systemic treatment often combined with vitrectomy.
CENTRAL NERVOUS SYSTEM INFECTION
Infection of the central nervous system (CNS) with P aeruginosa occurs as a result of immunosuppression and altered local defenses. Spread to the CNS may be from a local source, such as malignant otitis externa or sinusitis, direct inoculation at the time of head trauma, or surgery (including the placement of external or internal shunts or dural grafts), or by hematogenous spread from a remote focus such as endocarditis. Infection may result in either meningitis or brain abscess.
Signs and symptoms of infection depend on whether bacteremia is associated with the infection. Bacteremic cases are usually acute with fever and signs of sepsis in addition to headache, nuchal rigidity, and photophobia characteristic of meningitis. Spinal fluid analysis demonstrates elevated protein and gram-negative bacteria on Gram stain, and in nonneutropenic patients an elevation in neutrophils is usual. Cases linked to direct inoculation resulting from head trauma, surgery, or neurosurgical procedure may occur with a more indolent course of fever, headache, and nonspecific signs of CNS infection. Spinal fluid analysis may establish the diagnosis. Cases complicated by abscess formation require aspiration or biopsy to confirm the diagnosis. Successful treatment requires correction of structural defects, removal of foreign materials, and drainage of abscesses when possible, in addition to antimicrobial treatment.
The gastrointestinal tract is the principal portal of entry for Pseudomonas bacteremia in neutropenic patients receiving chemotherapy. In addition, these patients may develop localized gastrointestinal infection. Although infection may involve any part of the gastrointestinal tract, it particularly involves the cecum and rectum. Localized areas of necrosis and gangrene in the cecum are termed typhlitis. Pseudomonas infection of the cecum is characterized by hemorrhagic, necrotic ulcers with bacterial invasion of the submucosal blood vessels and an absence of inflammatory cells. Patients present with abdominal pain, and peritonitis may occur. The abdominal radiograph may reveal signs of perforation of a viscus. The rectum is also a source of bacterial abscesses in neutropenic patients, and P aeruginosa is most frequently the cause. Rectal abscesses may be the source of bacteremia or may result in localized spread causing gangrene. These lesions must be carefully searched for because the absence of inflammation in neutropenic patients may delay diagnosis. Rectal abscesses require prompt surgical drainage.
The second group of patients with ulcerative intestinal lesions due to P aeruginosa is young infants who develop necrotizing enterocolitis. Risk factors include prematurity, comorbid illness, and admission to the neonatal intensive care unit. Clinical signs are fever, irritability, vomiting, bloody diarrhea, dehydration, and abdominal distension. An abdominal radiograph may demonstrate pneumatosis intestinalis, portal air, or free peritoneal air.
INFECTION IN PATIENTS WITH AIDS
P aeruginosa infections may occur in patients with AIDS. Risk factors for infection include a CD4 count of < 100 cells/mL3, neutropenia or functional neutrophil defects, intravascular catheterization, hospitalization, and prior use of antibiotics including ciprofloxacin or trimethoprim-sulfamethoxazole. Many cases are community acquired. Bacteremia is common, and the lung or an intravenous catheter is the most frequent portal of entry. An impaired ability to mount immunotype-specific antibodies to Pseudomonas lipopolysaccharide antigen has been noted in HIV-positive individuals with bacteremia. Relapse is frequent, and mortality is high, 40%. Pneumonia is usually associated with cavitation and a high relapse rate. Bacterial sinusitis is an important and frequently undetected illness in HIV-positive individuals, and P aeruginosa is a frequent cause. Fluoroquinolone resistance may result from its use for the treatment of Mycobacterium avium complex.
Other infections caused by P aeruginosa described in patients with AIDS include malignant otitis externa, corneoscleritis, corneal ulceration and orbital cellulitis, meningitis, peritonitis, soft tissue infections, and osteomyelitis including osteitis pubis.
The diagnosis of a P aeruginosa infection requires the identification of the clinical syndrome by history, physical examination, and laboratory testing. The specific syndrome influences the duration of antimicrobial therapy and the need for surgical intervention. In patients with positive blood cultures, it is critical to determine the source of bacteremia. Microbiological diagnosis requires the recovery of P aeruginosa from culture. Gram-negative bacilli in culture should be screened for the presence of oxidase. Oxidase production excludes most gram-negative bacilli other than Pseudomonas spp. Definitive diagnosis requires the use of specific microbiological tests to distinguish P aeruginosa from other Pseudomonas spp.
Antimicrobial therapy of P aeruginosa infections is outlined in Box 54-2. Resistance of P aeruginosa in vitro to many antimicrobial agents is widespread and is increasing in frequency. Susceptibility testing should be performed on all clinically significant isolates to guide the selection of appropriate antimicrobial therapy. In addition, the following principles should be considered:
CF patients represent a particular challenge to therapy. Altered pharmokinetics frequently necessitate higher doses of antimicrobial agents than in other patients. Colonization with resistant strains is common in patients with CF. The administration of intermittent antimicrobial therapy to CF patients with chronic pseudomonal infections and the use of nebulized antimicrobial agents may reduce the frequency of Pseudomonas infection in CF patients. Despite theoretical concerns about fluoroquinolone incorporation into developing cartilage in pediatric patients, ciprofloxacin has been used successfully and safely in these patients.
Antimicrobial resistance is increasing worldwide among strains of P aeruginosa. β-Lactam resistance may be due to mutational derepression of the ampC chromosomal β-lactamase, the acquisition of plasmid- or transposon-mediated β-lactamases, reduced permeability of P aeruginosa to antimicrobial agents, multidrug efflux pump systems, and, in the case of carbapenems, loss of the D2 porin. Zinc-containing β-lactamases confer resistance to carbapenems. Many strains produce inducible cephalosporinases that account for the rapid emergence of resistance during therapy. Aminoglycoside resistance may be caused by decreased uptake owing to overproduction of the major outer membrane protein H1, aminoglycoside modifying enzymes, or modification of ribosomal targets. Mutations in the gyrA gene may cause resistance to ciprofloxacin and other fluoroquinolones.
BOX 54-2 Treatment of P aeruginosa Clinical Syndromes1
Prevention & Control
P aeruginosa is primarily a nosocomial pathogen, and control measures should be focused on hospital infection control. Appropriate sterilization of all equipment and prompt recognition of hospital outbreaks are essential. Hand washing after patient examination and additional measures such as wound and contact isolation for multiply resistant P aeruginosa should be performed. In particular, measures to decrease the spread of P aeruginosa between patients at CF clinics are necessary.
OTHER PSEUDOMONAS SPECIES OF MEDICAL IMPORTANCE
P PSEUDOMALLEI MELIOIDOSIS
This organism is endemic in Southeast Asia with the highest prevalence in Thailand. The organism is a saprophyte living in the soil. Infection may be subclinical, acute, subacute, or chronic. Pulmonary infection is most common. Histologically, the acute illness is represented by lung abscesses and the subacute form by caseation necrosis. Upper lobe cavities must be distinguished from those caused by tuberculosis. Debilitated patients may develop hematogenous spread of the organism to other organs. Skin lesions from direct inoculation cause suppurative lesions often in association with nodular lymphangitis and regional lymphadenopathy.
Diagnosis is made in a patient from an endemic area with a compatible clinical illness who has a positive P pseudomallei culture or a fourfold increase or decrease in antibody titer. Appropriate therapy requires a combination of antimicrobial agents and surgical drainage. Ceftazidime alone or in combination with either trimethoprim-sulfamethoxazole or amoxicillin clavulanate is the therapy of choice. The duration of therapy ranges from 3 to 12 months with the longest duration of treatment necessary in chronic extrapulmonary disease. Imipenem, piperacillin-tazobactam, chloramphenicol, and tetracycline are alternative agents; the microorganism is resistant to ciprofloxacin and aztreonam.
P MALLEI (GLANDERS)
Infection with P mallei (glanders) is the result of contact with an infected equine source such as horses, donkeys, or mules. The disease is confined to Africa, Asia, and South America. Human disease takes the following forms: acute suppurative infection with localized nodules and lymphangitis, mucocutaneous granuloma and ulcer, acute pulmonary infection with nodules and lymphadenopathy, acute septicemia, or a chronic suppurative form. Seroconversion or recovery of P mallei from culture confirms the diagnosis. Antimicrobial therapy is usually with the same agents effective for melioidosis administered for a period of 1–2 months often combined with surgical drainage.
This organism is a free-living microorganism that causes nosocomial infection in debilitated patients particularly in the intensive care or chronic ventilatory units. Infections encountered include pneumonia, UTI, wound infection, bacteremia, and, rarely, peritonitis, cholangitis, or endovascular infections. The emergence of this bacterium as a serious pathogen is caused by its antibiotic resistance pattern. It produces inducible β-lactamases and has low outer membrane permeability but is often susceptible to trimethoprim-sulfamethoxazole or ticarcillin-clavulanate. Alternative agents include ciprofloxacin, minocycline, doxycycline, and occasionally third-generation cephalosporins, but the microorganism is usually resistant to carbapenem or aminoglycosides.
This microorganism is a cause of nosocomial infections similar to those caused by Stenotrophomonas maltophilia. It is also an important pathogen in patients with CF, and infection is associated with progressive lung disease and high mortality. CF patients who are colonized with B cepacia preoperatively and undergo lung transplantation have higher post-transplantation mortality than those who are not colonized. In CF clinics, colonization rates are high. B cepacia is resistant to aminoglycosides and most β-lactam agents. Some strains are variably susceptible to third-generation cephalosporins, ciprofloxacin, trimethoprim-sulfamethoxazole, ampicillin-sulbactam, chloramphenicol, or meropenem.
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