P. aeruginosa is found in most moist environments. Soil, plants, vegetables, tap water, and countertops are all potential reservoirs for this microbe, as it has simple nutritional needs. Given the ubiquity of P. aeruginosa, simple contact with the organism is not sufficient for colonization or infection. Clinical and experimental observations suggest that P. aeruginosa infection often occurs concomitantly with host defense compromise, mucosal trauma, physiologic derangement, and antibiotic-mediated suppression of normal flora. Thus, it comes as no surprise that the majority of P. aeruginosa infections occur in intensive care units (ICUs), where these factors frequently converge. The organism is initially acquired from environmental sources, but patient-to-patient spread also occurs in clinics and families.
In the past, burned patients appeared to be unusually susceptible to P. aeruginosa. For example, in 1959–1963, Pseudomonas burn-wound sepsis was the principal cause of death in 60% of burned patients dying at the U.S. Army Institute of Surgical Research. For reasons that are unclear, P. aeruginosa infection in burns is no longer the major problem that it was during the 1950s and 1960s. Similarly, in the 1960s, P. aeruginosa appeared as a common pathogen in patients receiving cytotoxic chemotherapy at many institutions in the United States, but it subsequently diminished in importance. Despite this subsidence, P. aeruginosa remains one of the most feared pathogens in this population because of its high attributable mortality rate.
In some parts of Asia and Latin America, P. aeruginosa continues to be the most common cause of gram-negative bacteremia in neutropenic patients.
In contrast to the trends for burned patients and neutropenic patients in the United States, the incidence of P. aeruginosa infections among patients with CF has not changed. P. aeruginosa remains the most common contributing factor to respiratory failure in CF and is responsible for the majority of deaths among CF patients.
P. aeruginosa is a nonfastidious, motile, gram-negative rod that grows on most common laboratory media, including blood and MacConkey agars. It is easily identified in the laboratory on primary-isolation agar plates by pigment production that confers a yellow to dark green or even bluish appearance. Colonies have a shiny “gun-metal” appearance and a characteristic fruity odor. Two of the identifying biochemical characteristics of P. aeruginosa are an inability to ferment lactose on MacConkey agar and a positive reaction in the oxidase test. Most strains are identified on the basis of these readily detectable laboratory features even before extensive biochemical testing is done. Some isolates from CF patients are easily identified by their mucoid appearance, which is due to the production of large amounts of the mucoid exopolysaccharide or alginate.
Unraveling the mechanisms that underlie disease caused by P. aeruginosa has proved challenging. Of the common gram-negative bacteria, no other species produces such a large number of putative virulence factors (Table 61-1). Yet P. aeruginosa rarely initiates an infectious process in the absence of host injury or compromise, and few of its putative virulence factors have been shown definitively to be involved in disease in humans. Despite its metabolic versatility and possession of multiple colonizing factors, P. aeruginosa exhibits no competitive advantage over enteric bacteria in the human gut; neither is it a normal inhabitant of the human gastrointestinal tract, despite the host’s continuous environmental exposure to the organism.
TABLE 61-1MAIN PUTATIVE VIRULENCE FACTORS OF PSEUDOMONAS AERUGINOSA ||Download (.pdf) TABLE 61-1 MAIN PUTATIVE VIRULENCE FACTORS OF PSEUDOMONAS AERUGINOSA
|SUBSTANCE/ORGANELLE ||FUNCTION ||VIRULENCE IN ANIMAL DISEASE |
|Pili ||Adhesion to cells ||? |
|Flagella ||Adhesion, motility, inflammation ||Yes |
|Lipopolysaccharide ||Antiphagocytic activity, inflammation ||Yes |
|Type III secretion system ||Toxic activity (ExoU, ExoS) ||Yes |
|Type II secretion system ||Toxic activity ||Yes |
|Proteases ||Proteolytic activity ||? |
|Phospholipases ||Cytotoxicity ||? |
|Exotoxin A ||Cytotoxicity ||? |
Virulence attributes involved in acute P. aeruginosa infections
Motility and colonization
A general tenet of bacterial pathogenesis is that most bacteria must adhere to surfaces or colonize a host niche in order to initiate disease. Most pathogens examined thus far possess adherence factors called adhesins. P. aeruginosa is no exception. Among its many adhesins are its pili, which demonstrate adhesive properties for a variety of cells and adhere best to injured cell surfaces. In the organism’s flagellum, the flagellin molecule binds to cells, and the flagellar cap attaches to mucins through the recognition of glycan chains. Other P. aeruginosa adhesins include the outer core of the lipopolysaccharide (LPS) molecule, which binds to the cystic fibrosis transmembrane conductance regulator (CFTR) and aids in internalization of the organism, and the alginate coat of mucoid strains, which enhances adhesion to cells and mucins. In addition, membrane proteins and lectins have been proposed as colonization factors. The deletion of any given adhesin is not sufficient to abrogate the ability of P. aeruginosa to colonize surfaces. Motility is important in host invasion via mucosal surfaces in some animal models; however, nonmotile strains are not uniformly avirulent.
The transition from bacterial colonization to disease requires the evasion of host defenses followed by invasion of the microorganism. P. aeruginosa appears to be well equipped for evasion. Attached bacteria inject four known toxins (ExoS or ExoU, ExoT, and ExoY) via a type III secretion system that allows the bacteria to evade phagocytic cells either by direct cytotoxicity or by inhibition of phagocytosis. Mutants with defects in this system fail to disseminate in some animal models of infection. The type II secretion system as a whole secretes toxins that can kill animals, and some of its secreted toxins, such as exotoxin A, have the potential to kill phagocytic cells. Multiple proteases secreted by this system may degrade host effector molecules, such as cytokines and chemokines, that are released in response to infection. Thus this system may also contribute to host evasion.
Among gram-negative bacteria, P. aeruginosa probably produces the largest number of substances that are toxic to cells and thus may injure tissues. The toxins secreted by its type III secretion system are capable of tissue injury. However, their delivery requires the adherence of the organism to cells. Thus, the effects of these toxins are likely to be local or to depend on the presence of vast numbers of bacteria. On the other hand, diffusible toxins, secreted by the organism’s type II secretion system, can act freely wherever they come into contact with cells. Possible effectors include exotoxin A, four different proteases, and at least two phospholipases; in addition to these secreted toxins, rhamnolipids, pyocyanin, and hydrocyanic acid are produced by P. aeruginosa and are all capable of inducing host injury.
The inflammatory components of P. aeruginosa—e.g., the inflammatory responses to the lipid A component of LPSs and to flagellin, mediated through the Toll-like receptor (TLR) system (principally TLR4 and TLR5)—have been thought to represent important factors in disease causation. Although these inflammatory responses are required for successful defense against P. aeruginosa (i.e., in their absence, animals are defenseless against P. aeruginosa infection), florid responses are likely to result in disease. When the sepsis syndrome and septic shock develop in P. aeruginosa infection, they are probably the result of the host response to one or both of these substances, but injury to the lung by Pseudomonas toxins may also result in sepsis syndromes, possibly by causing cell death and the release of cellular components (e.g., heat-shock proteins) that may activate the TLR or another proinflammatory system.
Chronic P. aeruginosa infections
Chronic infection due to P. aeruginosa occurs mainly in the lungs in the setting of structural pulmonary diseases. The classic example is CF; others include bronchiectasis and chronic relapsing panbronchiolitis, a disease seen in Japan and some Pacific Islands. Hallmarks of these illnesses are altered mucociliary clearance leading to mucus stasis and mucus accumulation in the lungs. There is probably a common factor that selects for P. aeruginosa colonization in these lung diseases—perhaps the adhesiveness of P. aeruginosa for mucus, a phenomenon that is not noted for most other common gram-negative bacteria, and/or the ability of P. aeruginosa to evade host defenses in mucus. Furthermore, P. aeruginosa seems to evolve in ways that allow its prolonged survival in the lung without an early fatal outcome for the host. The strains found in CF patients exhibit minimal production of virulence factors. Some strains even lose the ability to produce pili and flagella, and most become complement-sensitive because of the loss of the O side chain of their LPS molecules. An example of the impact of these changes is found in the organism’s discontinuation of the production of flagellin (probably its most strongly proinflammatory molecule) when it encounters purulent mucus. This response probably dampens the host’s response, allowing the organism to survive in mucus. P. aeruginosa is also believed to lose the ability to secrete many of its injectable toxins during growth in mucus. Although the alginate coat is thought to play a role in the organism’s survival, alginate is not essential, as nonmucoid strains may also predominate for long periods. In short, virulence in chronic infections may be mediated by the chronic but attenuated host inflammatory response, which injures the lungs over decades.
P. aeruginosa causes infections at almost all sites in the body but shows a rather strong predilection for the lungs. The infections encountered most commonly in hospitalized patients are described below.
Crude mortality rates exceeding 50% have been reported among patients with P. aeruginosa bacteremia. Consequently, this clinical entity has been much feared, and its management has been attempted with the use of multiple antibiotics. Recent publications report attributable mortality rates of 28–44%, with the precise figure depending on the adequacy of treatment and the seriousness of the underlying disease. In the past, the patient with P. aeruginosa bacteremia classically was neutropenic or had a burn injury. Today, however, a minority of such patients have bacteremic P. aeruginosa infections. Rather, P. aeruginosa bacteremia is seen most often in patients in ICUs.
The clinical presentation of P. aeruginosa bacteremia rarely differs from that of sepsis in general. Patients are usually febrile, but those who are most severely ill may be in shock or even hypothermic. The only point differentiating this entity from gram-negative sepsis of other causes may be the distinctive skin lesions (ecthyma gangrenosum) of Pseudomonas infection, which occur almost exclusively in markedly neutropenic patients and patients with AIDS. These small or large, painful, reddish, maculopapular lesions have a geographic margin; they are initially pink, then darken to purple, and finally become black and necrotic (Fig. 61-1). Histopathologic studies indicate that the lesions are due to vascular invasion and are teeming with bacteria. Although similar lesions may occur in aspergillosis and mucormycosis, their presence suggests P. aeruginosa bacteremia as the most likely diagnosis.
Ecthyma gangrenosum in a neutropenic patient 3 days after onset.
TREATMENT P. aeruginosa Bacteremia
(Table 61-2) Antimicrobial treatment of P. aeruginosa bacteremia has been controversial. Before 1971, the outcome of Pseudomonas bacteremia in febrile neutropenic patients treated with the available agents—gentamicin and the polymyxins—was dismal. However, treatment with carbenicillin, with or without an aminoglycoside, significantly improved outcomes. Concurrently, several retrospective analyses suggested that the use of two agents that were synergistic against gram-negative pathogens in vitro resulted in better outcomes in neutropenic patients. Thus, combination therapy became the standard of care—first for P. aeruginosa bacteremia in febrile neutropenic patients and then for all P. aeruginosa infections in neutropenic or nonneutropenic patients.
With the introduction of newer antipseudomonal drugs, a number of studies have revisited the choice between combination treatment and monotherapy for Pseudomonas bacteremia. Although the majority of experts still favor combination therapy, most of these observational studies indicate that a single modern antipseudomonal β-lactam agent to which the isolate is sensitive is as efficacious as a combination. Even in patients at greatest risk of early death from P. aeruginosa bacteremia (i.e., those with fever and neutropenia), empirical antipseudomonal monotherapy is deemed to be as efficacious as empirical combination therapy by the practice guidelines of the Infectious Diseases Society of America. One firm conclusion is that monotherapy with an aminoglycoside is not optimal.
There are, of course, institutions and countries where rates of susceptibility of P. aeruginosa to first-line antibiotics are <80%. Thus, when a septic patient with a high probability of P. aeruginosa infection is encountered in such settings, empirical combination therapy should be administered until the pathogen is identified and susceptibility data become available. Thereafter, whether one or two agents should be continued remains a matter of individual preference. Recent studies suggest that extended infusions of β-lactams such as cefepime or piperacillin-tazobactam may result in better outcomes of Pseudomonas bacteremia and possibly Pseudomonas pneumonia.
TABLE 61-2ANTIBIOTIC TREATMENT OF INFECTIONS DUE TO PSEUDOMONAS AERUGINOSA AND RELATED SPECIES ||Download (.pdf) TABLE 61-2 ANTIBIOTIC TREATMENT OF INFECTIONS DUE TO PSEUDOMONAS AERUGINOSA AND RELATED SPECIES
|INFECTION ||ANTIBIOTICS AND DOSAGES ||OTHER CONSIDERATIONS |
|Bacteremia || || |
| Nonneutropenic host || |
Monotherapy: Ceftazidime (2 g q8h IV) or cefepime (2 g q12h IV)
Combination therapy: Piperacillin/tazobactam (3.375 g q4h IV) or imipenem (500 mg q6h IV) or meropenem (1 g q8h IV) or doripenem (500 mg q8h IV)
Amikacin (7.5 mg/kg q12h or 15 mg/kg q24h IV)
|Add an aminoglycoside for patients in shock and in regions or hospitals where rates of resistance to the primary β-lactam agents are high. Tobramycin may be used instead of amikacin (susceptibility permitting). The duration of therapy is 7 days for nonneutropenic patients. Neutropenic patients should be treated until no longer neutropenic. |
| Neutropenic host ||Cefepime (2 g q8h IV) or all other agents (except doripenem) in above dosages || |
|Endocarditis ||Antibiotic regimens as for bacteremia for 6–8 weeks ||Resistance during therapy is common. Surgery is required for relapse. |
|Pneumonia ||Drugs and dosages as for bacteremia, except that the available carbapenems should not be the sole primary drugs because of high rates of resistance during therapy ||IDSA guidelines recommend the addition of an aminoglycoside or ciprofloxacin. The duration of therapy is 10–14 days. |
|Bone infection, malignant otitis externa ||Cefepime or ceftazidime at the same dosages as for bacteremia; aminoglycosides not a necessary component of therapy; ciprofloxacin (500–750 mg q12h PO) may be used ||Duration of therapy varies with the drug used (e.g., 6 weeks for a β-lactam agent; at least 3 months for oral therapy except in puncture-wound osteomyelitis, for which the duration should be 2–4 weeks). |
|Central nervous system infection ||Ceftazidime or cefepime (2 g q8h IV) or meropenem (1 g q8h IV) ||Abscesses or other closed-space infections may require drainage. The duration of therapy is ≥2 weeks. |
|Topical therapy with tobramycin/ciprofloxacin/levofloxacin eyedrops ||Use maximal strengths available or compounded by pharmacy. Therapy should be administered for 2 weeks or until the resolution of eye lesions, whichever is shorter. |
| Endophthalmitis ||Ceftazidime or cefepime as for central nervous system infection || |
| ||plus || |
| ||Topical therapy || |
|Urinary tract infection ||Ciprofloxacin (500 mg q12h PO) or levofloxacin (750 mg q24h) or any aminoglycoside (total daily dose given once daily) ||Relapse may occur if an obstruction or a foreign body is present. The duration of therapy for complicated UTI is 7–10 days (up to 2 weeks for pyelonephritis). |
|Multidrug-resistant P. aeruginosa infection ||Colistin (100 mg q12h IV) for the shortest possible period to obtain a clinical response ||Doses used have varied. Dosage adjustment is required in renal failure. Inhaled colistin may be added for pneumonia (100 mg q12h). |
|Stenotrophomonas maltophilia infection ||TMP-SMX (1600/320 mg q12h IV) plus ticarcillin/clavulanate (3.1 g q4h IV) for 14 days ||Resistance to all agents is increasing. Levofloxacin or tigecycline may be alternatives, but there is little published clinical experience with these agents. |
|Burkholderia cepacia infection ||Meropenem (1 g q8h IV) or TMP-SMX (1600/320 mg q12h IV) for 14 days ||Resistance to both agents is increasing. Do not use them in combination because of possible antagonism. |
|Melioidosis, glanders ||Ceftazidime (2 g q6h) or meropenem (1 g q8h) or imipenem (500 mg q6h) for 2 weeks || |
| || |
TMP-SMX (1600/320 mg q12h PO) for 3 months
Respiratory infections are the most common of all infections caused by P. aeruginosa. This organism appears first or second among the causes of ventilator-associated pneumonia (VAP). However, much debate centers on the actual role of P. aeruginosa in VAP. Many of the relevant data are based on cultures of sputum or endotracheal tube aspirates and may represent nonpathogenic colonization of the tracheobronchial tree, biofilms on the endotracheal tube, or simple tracheobronchitis.
Older reports of P. aeruginosa pneumonia described patients with an acute clinical syndrome of fever, chills, cough, and necrotizing pneumonia indistinguishable from other gram-negative bacterial pneumonias. The traditional accounts described a fulminant infection. Chest radiographs demonstrated bilateral pneumonia, often with nodular densities with or without cavities. This picture is now remarkably rare. Today, the typical patient is on a ventilator, has a slowly progressive infiltrate, and has been colonized with P. aeruginosa for days. While some cases may progress rapidly over 48–72 h, they are the exceptions. Nodular densities are not commonly seen. However, infiltrates may go on to necrosis. Necrotizing pneumonia has also been seen in the community (e.g., after inhalation of hot-tub water contaminated with P. aeruginosa). The typical patient has fever, leukocytosis, and purulent sputum, and the chest radiograph shows a new infiltrate or the expansion of a preexisting infiltrate. Chest examination generally detects rales or dullness. Of course, such findings are quite common among ventilated patients in the ICU. A sputum Gram’s stain showing mainly polymorphonuclear leukocytes (PMNs) in conjunction with a culture positive for P. aeruginosa in this setting suggests a diagnosis of acute P. aeruginosa pneumonia. There is no consensus about whether an invasive procedure (e.g., bronchoalveolar lavage or protected-brush sampling of the distal airways) is superior to tracheal aspiration to obtain samples for lung cultures in order to substantiate the occurrence of P. aeruginosa pneumonia and prevent antibiotic overuse.
TREATMENT Acute Pneumonia
(Table 61-2) Therapy for P. aeruginosa pneumonia has been unsatisfactory. Reports suggest mortality rates of 40–80%, but how many of these deaths are attributable to underlying disease remains unknown. The drugs of choice for P. aeruginosa pneumonia are similar to those given for bacteremia. A potent antipseudomonal β-lactam drug is the mainstay of therapy. Failure rates were high when aminoglycosides were used as single agents, possibly because of their poor penetration into the airways and their binding to airway secretions. Thus a strong case cannot be made for the inclusion of the aminoglycoside component in regimens used against fully susceptible organisms, especially given the evidence that aminoglycosides are not optimally active in the lungs at concentrations normally reached after IV administration. Nonetheless, aminoglycosides are commonly used in clinical practice. Some experts suggest the combination of a β-lactam agent and an antipseudomonal fluoroquin-olone instead when combination therapy is desired.
Chronic respiratory tract infections
P. aeruginosa is responsible for chronic infections of the airways associated with a number of underlying or predisposing conditions—most commonly CF. A state of chronic colonization beginning early in childhood is seen in some Asian populations with chronic or diffuse panbronchiolitis, a disease of unknown etiology. P. aeruginosa is one of the organisms that colonizes damaged bronchi in bronchiectasis, a disease secondary to multiple causes in which profound structural abnormalities of the airways result in mucus stasis.
TREATMENT Chronic Respiratory Tract Infections
Optimal management of chronic P. aeruginosa lung infection has not been determined. Patients respond clinically to antipseudomonal therapy, but the organism is rarely eradicated. Because eradication is unlikely, the aim of treatment for chronic infection is to quell exacerbations of inflammation. The regimens used are similar to those used for pneumonia, but an aminoglycoside is almost always added because resistance is common in chronic disease. However, it may be appropriate to use an inhaled aminoglycoside preparation in order to maximize airway drug levels.
Infective endocarditis due to P. aeruginosa is a disease of IV drug users whose native valves are involved. This organism has also been reported to cause prosthetic valve endocarditis. Sites of prior native-valve injury due to the injection of foreign material such as talc or fibers probably serve as niduses for bacterial attachment to the heart valve. The manifestations of P. aeruginosa endocarditis resemble those of other forms of endocarditis in IV drug users except that the disease is more indolent than Staphylococcus aureus endocarditis. While most disease involves the right side of the heart, left-sided involvement is not rare and multivalvular disease is common. Fever is a common manifestation, as is pulmonary involvement (due to septic emboli to the lungs). Hence, patients may also experience chest pain and hemoptysis. Involvement of the left side of the heart may lead to signs of cardiac failure, systemic emboli, and local cardiac involvement with sinus of Valsalva abscesses and conduction defects. Skin manifestations are rare in this disease, and ecthyma gangrenosum is not seen. The diagnosis is based on positive blood cultures along with clinical signs of endocarditis.
TREATMENT Endovascular Infections
(Table 61-2) It has been customary to use synergistic antibiotic combinations in treating P. aeruginosa endocarditis because of the development of resistance during therapy with a single antipseudomonal β-lactam agent. Which combination therapy is preferable is unclear, as all combinations have failed. Cases of P. aeruginosa endocarditis that relapse during or fail to respond to therapy are often caused by resistant organisms and may require surgical therapy. Other considerations for valve replacement are similar to those in other forms of endocarditis (Chap. 24).
Bone and joint infections
P. aeruginosa is an infrequent cause of bone and joint infections. However, Pseudomonas bacteremia or infective endocarditis caused by the injection of contaminated illicit drugs has been documented to result in vertebral osteomyelitis and sternoclavicular joint arthritis. The clinical presentation of vertebral P. aeruginosa osteomyelitis is more indolent than that of staphylococcal osteomyelitis. The duration of symptoms in IV drug users with vertebral osteomyelitis due to P. aeruginosa varies from weeks to months. Fever is not uniformly present; when present, it tends to be low grade. There may be mild tenderness at the site of involvement. Blood cultures are usually negative unless there is concomitant endocarditis. The erythrocyte sedimentation rate (ESR) is generally elevated. Vertebral osteomyelitis due to P. aeruginosa has also been reported in the elderly, in whom it originates from urinary tract infections (UTIs). The infection generally involves the lumbosacral area because of a shared venous drainage (Batson’s plexus) between the lumbosacral spine and the pelvis. Sternoclavicular septic arthritis due to P. aeruginosa is seen almost exclusively in IV drug users. This disease may occur with or without endocarditis, and a primary site of infection often is not found. Plain radiographs show joint or bone involvement. Treatment of these forms of disease is generally successful.
Pseudomonas osteomyelitis of the foot most often follows puncture wounds through sneakers and mostly affects children. The main manifestation is pain in the foot, sometimes with superficial cellulitis around the puncture wound and tenderness on deep palpation of the wound. Multiple joints or bones of the foot may be involved. Systemic symptoms are generally absent, and blood cultures are usually negative. Radiographs may or may not be abnormal, but the bone scan is usually positive, as are magnetic resonance imaging (MRI) studies. Needle aspiration usually yields a diagnosis. Prompt surgery, with exploration of the nail puncture tract and debridement of the involved bones and cartilage, is generally recommended in addition to antibiotic therapy.
Central nervous system (cns) infections
CNS infections due to P. aeruginosa are relatively rare. Involvement of the CNS is almost always secondary to a surgical procedure or head trauma. The entity seen most often is postoperative or posttraumatic meningitis. Subdural or epidural infection occasionally results from contamination of these areas. Embolic disease arising from endocarditis in IV drug users and leading to brain abscesses has also been described. The cerebrospinal fluid (CSF) profile of P. aeruginosa meningitis is no different from that of pyogenic meningitis of any other etiology.
TREATMENT Central Nervous System Infections
(Table 61-2) Treatment of Pseudomonas meningitis is difficult; little information has been published, and no controlled trials in humans have been undertaken. However, the general principles involved in the treatment of meningitis apply, including the need for high doses of bactericidal antibiotics to attain high drug levels in the CSF. The agent with which there is the most published experience in P. aeruginosa meningitis is ceftazidime, but other antipseudomonal β-lactam drugs that reach high CSF concentrations, such as cefepime and meropenem, have also been used successfully. Other forms of P. aeruginosa CNS infection, such as brain abscesses and epidural and subdural empyema, generally require surgical drainage in addition to antibiotic therapy.
Eye infections due to P. aeruginosa occur mainly as a result of direct inoculation into the tissue during trauma or surface injury by contact lenses. Keratitis and corneal ulcers are the most common types of eye disease and are often associated with contact lenses (especially the extended-wear variety). Keratitis can be slowly or rapidly progressive, but the classic description is disease progressing over 48 h to involve the entire cornea, with opacification and sometimes perforation. P. aeruginosa keratitis should be considered a medical emergency because of the rapidity with which it can progress to loss of sight. P. aeruginosa endophthalmitis secondary to bacteremia is the most devastating of P. aeruginosa eye infections. The disease is fulminant, with severe pain, chemosis, decreased visual acuity, anterior uveitis, vitreous involvement, and panophthalmitis.
TREATMENT Eye Infections
(Table 61-2) The usual therapy for keratitis is the administration of topical antibiotics. Therapy for endophthalmitis includes the use of high-dose local and systemic antibiotics (to achieve higher drug concentrations in the eye) and vitrectomy.
P. aeruginosa infections of the ears vary from mild swimmer’s ear to serious life-threatening infections with neurologic sequelae. Swimmer’s ear is common among children and results from infection of moist macerated skin of the external ear canal. Most cases resolve with treatment, but some patients develop chronic drainage. Swimmer’s ear is managed with topical antibiotic agents (otic solutions). The most serious form of Pseudomonas infection involving the ear has been given various names: two of these designations, malignant otitis externa and necrotizing otitis externa, are now used for the same entity. This disease was originally described in elderly diabetic patients, in whom the majority of cases still occur. However, it has also been described in patients with AIDS and in elderly patients without underlying diabetes or immunocompromise. The usual presenting symptoms are decreased hearing and ear pain, which may be severe and lancinating. The pinna is usually painful, and the external canal may be tender. The ear canal almost always shows signs of inflammation, with granulation tissue and exudate. Tenderness anterior to the tragus may extend as far as the temporomandibular joint and mastoid process. A small minority of patients have systemic symptoms. Patients in whom the diagnosis is made late may present with cranial nerve palsies or even with cavernous venous sinus thrombosis. The ESR is invariably elevated (≥100 mm/h). The diagnosis is made on clinical grounds in severe cases; however, the “gold standard” is a positive technetium-99 bone scan in a patient with otitis externa due to P. aeruginosa. In diabetic patients, a positive bone scan constitutes presumptive evidence for this diagnosis and should prompt biopsy or empirical therapy.
TREATMENT Ear Infections
(Table 61-2) Given the infection of the ear cartilage, sometimes with mastoid or petrous ridge involvement, patients with malignant (necrotizing) otitis externa are treated as for osteomyelitis.
UTIs due to P. aeruginosa generally occur as a complication of a foreign body in the urinary tract, an obstruction in the genitourinary system, or urinary tract instrumentation or surgery. However, UTIs caused by P. aeruginosa have been described in pediatric outpatients without stones or evident obstruction.
TREATMENT Urinary Tract Infections
(Table 61-2) Most P. aeruginosa UTIs are considered complicated infections that must be treated longer than uncomplicated cystitis. In general, a 7- to 10-day course of treatment suffices, with up to 2 weeks of therapy in cases of pyelonephritis. Urinary catheters, stents, or stones should be removed to prevent relapse, which is common and may be due not to resistance but rather to factors such as a foreign body that has been left in place or an ongoing obstruction.
Skin and soft tissue infections
Besides pyoderma gangrenosum in neutropenic patients, folliculitis and other papular or vesicular lesions due to P. aeruginosa have been extensively described and are collectively referred to as dermatitis. Multiple outbreaks have been linked to whirlpools, spas, and swimming pools. To prevent such outbreaks, the growth of P. aeruginosa in the home and in recreational environments must be controlled by proper chlorination of water. Most cases of hot-tub folliculitis are self-limited, requiring only the avoidance of exposure to the contaminated source of water.
Toe-web infections occur especially often in the tropics, and the “green nail syndrome” is caused by P. aeruginosa paronychia, which results from frequent submersion of the hands in water. In the latter entity, the green discoloration results from diffusion of pyocyanin into the nail bed. P. aeruginosa remains a prominent cause of burn wound infections in some parts of the world. The management of these infections is best left to specialists in burn wound care.
Infections in febrile neutropenic patients
In febrile neutropenia, P. aeruginosa has historically been the organism against which empirical coverage is always essential. Although in Western countries these infections are now less common, their importance has not diminished because of persistently high mortality rates. In other parts of the world as well, P. aeruginosa continues to be a significant problem in febrile neutropenia, causing a larger proportion of infections in febrile neutropenic patients than any other single organism. For example, P. aeruginosa was responsible for 28% of documented infections in 499 febrile neutropenic patients in one study from the Indian subcontinent and for 31% of such infections in another. In a large study of infections in leukemia patients from Japan, P. aeruginosa was the most frequently documented cause of bacterial infection. In studies performed in North America, northern Europe, and Australia, the incidence of P. aeruginosa bacteremia in febrile neutropenia was quite variable. In a review of 97 reports published in 1987–1994, the incidence was reported to be 1–2.5% among febrile neutropenic patients given empirical therapy and 5–12% among microbiologically documented infections. The most common clinical syndromes encountered were bacteremia, pneumonia, and soft tissue infections manifesting mainly as ecthyma gangrenosum.
TREATMENT Infections in Febrile Neutropenic Patients
(Table 61-2) Compared with rates three decades ago, improved rates of response to antibiotic therapy have been reported in many studies. A study of 127 patients demonstrated a reduction in the mortality rate from 71% to 25% with the introduction of ceftazidime and imipenem. Because neutrophils—the normal host defenses against this organism—are absent in febrile neutropenic patients, maximal doses of antipseudomonal β-lactam antibiotics should be used for the management of P. aeruginosa bacteremia in this setting.
Infections in patients with AIDS
Both community- and hospital-acquired P. aeruginosa infections were documented in patients with AIDS before the advent of antiretroviral therapy. Since the introduction of protease inhibitors, P. aeruginosa infections in AIDS patients have been seen less frequently but still occur, particularly in the form of sinusitis. The clinical presentation of Pseudomonas infection (especially pneumonia and bacteremia) in AIDS patients is remarkable in that, although the illness may appear not to be severe, the infection may nonetheless be fatal. Patients with bacteremia may have only a low-grade fever and may present with ecthyma gangrenosum. Pneumonia, with or without bacteremia, is perhaps the most common type of P. aeruginosa infection in AIDS patients. Patients with AIDS and P. aeruginosa pneumonia exhibit the classic clinical signs and symptoms of pneumonia, such as fever, productive cough, and chest pain. The infection may be lobar or multilobar and shows no predisposition for any particular location. The most striking feature is the high frequency of cavitary disease.
TREATMENT Infections in Patients with AIDS
Therapy for any of these conditions in AIDS patients is no different from that in other patients. However, relapse is the rule unless the patient’s CD4+ T cell count rises to >50/μL or suppressive antibiotic therapy is given. In attempts to achieve cures and prevent relapses, therapy tends to be more prolonged than in the case of an immunocompetent patient.
(Table 61-2) P. aeruginosa has a notorious propensity to develop antibiotic resistance. During three decades, the impact of resistance was minimized by the rapid development of potent antipseudomonal agents. However, the situation has recently changed, with the worldwide selection of strains carrying determinants that mediate resistance to β-lactams, fluoroquinolones, and aminoglycosides. This situation has been compounded by the lack of development of new classes of antipseudomonal drugs for nearly two decades. Physicians now resort to drugs such as colistin and polymyxin, which were discarded decades ago. These alternative approaches to the management of multiresistant P. aeruginosa infections were first used some time ago in CF patients, who receive colistin (polymyxin E) IV and by aerosol despite its renal toxicity. Colistin is rapidly becoming the last-resort agent of choice, even in non-CF patients infected with multiresistant P. aeruginosa.
The clinical outcome of multidrug-resistant P. aeruginosa infections treated with colistin is difficult to judge from case reports, especially given the many drugs used in the complicated management of these patients. Although earlier reports described marginal efficacy and serious nephrotoxicity and neurotoxicity, recent reports have been more encouraging. Because colistin shows synergy with other antimicrobial agents in vitro, it may be possible to reduce the dosage—and thus the toxicity—of this drug when it is combined with drugs such as rifampin and β-lactams; however, no studies in humans or animals support this approach at this time.