1286 PART 5 Infectious Diseases

of the loss of the O side chain of their LPS molecules. In addition, most

strains found in CF patients overproduce a mucoid exopolysaccharide.

These changes probably dampen the host response, allowing the organism to survive in CF mucus. P. aeruginosa is also believed to lose its

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 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.

■ CLINICAL MANIFESTATIONS

P. aeruginosa causes infections at almost all sites in the body but shows

a rather marked predilection for the lungs. The infections encountered

most commonly in hospitalized patients are described below.

Bacteremia 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 and timing 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 with the lungs, the urinary tract, central venous lines,

or wounds being the most important portals for systemic invasion.

The clinical presentation of P. aeruginosa bacteremia rarely differs

from that of sepsis in general (Chap. 304). 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. 164-1). Histopathologic studies

indicate that the lesions are due to vascular invasion and are teeming

with bacteria. Although similar lesions may occur in aspergillosis,

mucormycosis, and occasionally Staphylococcus aureus bacteremia,

their presence in a neutropenic patient generally suggests P. aeruginosa

bacteremia as the most likely cause.

TREATMENT

P. aeruginosa Bacteremia

(Table 164-2) Antimicrobial treatment of P. aeruginosa bacteremia

has been controversial. Combination therapy with an antipseudomonal β-lactam and an aminoglycoside became the standard of

care because of the dismal outcome of single-drug therapy, mainly

with aminoglycosides and polymixins, prior to 1971—first for P.

aeruginosa bacteremia in febrile neutropenic patients and then

extrapolated to all P. aeruginosa bacteremic infections in both neutropenic and nonneutropenic patients.

Following the introduction of new antipseudomonal drugs, a

number of studies have revisited the choice between combination

treatment and monotherapy for Pseudomonas bacteremia. Although

some clinicians still favor combination therapy, most recent 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 (IDSA). 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 βlactams such as cefepime, piperacillin/tazobactam, or meropenem

may result in better outcomes of Pseudomonas bacteremia and possibly of Pseudomonas pneumonia. The duration of antibiotic therapy

has now become an important consideration due to the increasing

isolation of multiple drug-resistant (MDR) and extensively drugresistant (XDR) P. aeruginosa strains. Recently published studies

now strongly support the use of shorter courses of therapy (7 days)

rather than the longer duration (10−14 days) that is commonly recommended for many cases of Pseudomonas bacteremia.

Acute Pneumonia Respiratory infections are the most common

of all infections caused by P. aeruginosa. P. aeruginosa is common in

both hospital-acquired pneumonia (HAP) and ventilator-associated

pneumonia (VAP). This organism appears first or second among the

causes of 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. 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 have been increasing reports of the occurrence of communityacquired P. aeruginosa pneumonia among patients with underlying

lung diseases. While this undoubtedly occurs, it is difficult to make

this diagnosis with a great degree of certainty with the use of sputum

cultures in a population prone to airway colonization by multiple

strains of bacteria. The patient population in whom the possibility of

a community-acquired P. aeruginosa pneumonia should be considered

is the neutropenic patient, given the pivotal role that neutrophils play

in defense against this bacterium. Such a patient, whether hospitalized

or admitted from the community with a pneumonia, should be treated

FIGURE 164-1 Ecthyma gangrenosum in a neutropenic patient 3 days after onset. empirically for P. aeruginosa.

1287CHAPTER 164 Infections Due to Pseudomonas, Burkholderia, and Stenotrophomonas Species

TABLE 164-2 Antibiotic Treatment of Infections Due to Pseudomonas aeruginosa and Related Species

INFECTION ANTIBIOTICS AND DOSAGES OTHER CONSIDERATIONS

Bacteremia

Nonneutropenic host Ceftazidime (2 g q8h IV) or cefepime (2 g q8h IV) or 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)

Optional:

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 the other agents above (except doripenem) in

the 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 7 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.

Eye infection

Keratitis/ulcer 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

(UTI)

Ciprofloxacin (500 mg q12h PO) or levofloxacin (750 mg q24h) or any

aminoglycoside (total daily dose given once daily). Cefepime or ceftazidime

(1g q8h) or piperacillin/tazobactam (4.5 g q8h)

Uncomplicated cystitis may be treated for 3 days with oral

agents. 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- and extreme

drug-resistant P.

aeruginosa infection

Ceftazidime/avibactam (2.5 g q8h, infused over 2 h) or ceftolozane/

tazobactam (1.5 g q8h) or meropenem/vaborbactam (2 g q8h) or imipenem/

relebactam (500 mg q6h) or cefiderocol (2 g q8h) or colistin (100 mg q12h IV

for the shortest possible period to obtain a clinical response)

Higher doses of ceftolozane/tazobactam may be required for

pneumonias. The colistin doses used have varied. Dosage

adjustment for colistin is required in renal failure. Inhaled

colistin may be added for pneumonia (100 mg q12h).

Burkholderia cepacia

complex 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 (B.

pseudomallei), Glanders

(B. mallei)

Ceftazidime (2 g q6h) or meropenem (1 g q8h) or imipenem (500 mg q6h) for

2 weeks

followed by

TMP-SMX (1600/320 mg q12h PO) for 3 months

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.

Abbreviations: IDSA, Infectious Diseases Society of America; TMP-SMX, trimethoprim-sulfamethoxazole.

TREATMENT

Acute Pneumonia

(Table 164-2) Therapy for P. aeruginosa pneumonia remains 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.

Nonetheless, for the treatment of patients at high risk of death,

some experts suggest the combination of a β-lactam agent and an

antipseudomonal fluoroquinolone or aminoglycoside. As for the

duration of therapy, recent IDSA/American Thoracic Society (ATS)

guidelines recommend 7 days of treatment for HAP or VAP, even

when P. aeruginosa is the offending organism. However, the outcome

in neutropenic patients is poor, especially if accompanied by bacteremia; thus, therapy needs to be extended until neutropenia resolves.

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 (Chap.

291). 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.

1288 PART 5 Infectious Diseases

However, it may be appropriate to use an inhaled aminoglycoside

preparation in order to maximize airway drug levels. MDR strains

are now commonly found in such patients given their increased life

span and the repeated courses of antibiotics they receive.

Endovascular Infections 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 S. 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). Thus,

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 commonly seen in these patients. Vertebral

osteomyelitis and sternoclavicular joint septic arthritis are uncommon

but pathognomic complications of this disease. The diagnosis is based on

positive blood cultures along with clinical signs of endocarditis.

TREATMENT

Endovascular Infections

(Table 164-2) 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. Treatment is likely to

more often be successful in cases of right-sided endocarditis. 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. 128).

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 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.

Osteomyelitis due to P. aeruginosa is also seen following trauma and

with decubitus ulcers. In these settings, the cause of osteomyelitis is

often polymicrobial, and the role of P. aeruginosa can be questioned.

It is therefore critical that deep bone biopsies be requested to ascertain

its significance.

TREATMENT

Bone and Joint Infections

The treatment of bone and joint infections due to P. aeruginosa is

often governed by the primary Pseudomonas infection. Since endocarditis is often the primary infection, the agents used for endocarditis

will dictate treatment. In other situations, a 6-week course of therapy

with an antipseudomonal β-lactam is recommended, and in case of

puncture-wound osteomyelitis, oral ciprofloxacin may be used.

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, head trauma,

implanted devices, and rarely bacteremia. 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 164-2) Treatment of Pseudomonas meningitis is difficult; little information has been published. 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 reasonable CSF concentrations,

such as cefepime, piperacillin/tazobactam, 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 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. It is also a rare

complication of cataract removal with lens insertion.

TREATMENT

Eye Infections

(Table 164-2) 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.

1289CHAPTER 164 Infections Due to Pseudomonas, Burkholderia, and Stenotrophomonas Species

Ear Infections 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 use of hearing aids may also predispose to this type of infection. 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, most commonly cranial nerve

VII 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 164-2) 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.

Urinary Tract Infections UTIs due to P. aeruginosa generally

occur as a complication of a catheter in the urinary tract, an obstruction or stone in the genitourinary system, urinary tract instrumentation, or surgery. A P. aeruginosa UTI occurring in the community often

signals the presence of an abnormality in the urinary tract. It has been

reported that the urinary tract is the second most important site of

infection leading to Pseudomonas bacteremia.

TREATMENT

Urinary Tract Infections

(Table 164-2) 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 10−14 days

of therapy in cases of pyelonephritis. Urinary catheters, stents, or

stones should be removed to prevent relapse, which is common and

may not be due to antibiotic resistance but rather to factors such as

a foreign body that has been left in place or an ongoing obstruction.

Removal of a urinary catheter will allow shorter courses of antibiotic therapy if that is the only predisposing factor.

Skin and Soft Tissue Infections Besides pyoderma (ecthyma)

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, 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 between 1987 and 1994, the incidence

was reported to be 1–2.5% among febrile neutropenic patients given

empirical therapy and 5–12% among patients with 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 164-2) 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 P. aeruginosa infections were

well 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. While this entity is

now uncommon in developed nations, there are still large numbers of

patients with untreated HIV infection or poorly controlled disease in

developing nations who are likely to suffer from P. aeruginosa infections. 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 lowgrade fever and may present with ecthyma gangrenosum. Pneumonia,

with or without bacteremia, is perhaps the most common type of P.

aeruginosa infection. Patients with 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.

1290 PART 5 Infectious Diseases

Gastrointestinal Infections A poorly understood syndrome

caused by P. aeruginosa has been described in the Far East and has been

called Shanghai fever and Pseudomonas enterocolitis. This syndrome

occurs in young children; its occurrence in adults appears to be rare.

Shanghai fever manifests as severe enteric disease, sepsis with invasive disease, and complications, whereas Pseudomonas enterocolitis

is characterized by prolonged fever with bloody or mucoid diarrhea

mimicking bacterial enterocolitis. The mortality rate ranges between

23 and 89%, with ecthyma gangrenosum occurring in >50% of cases.

Early recognition and treatment have led to a reduction in the mortality rate. There is an above-average occurrence of the exoU gene among

Pseudomonas isolates from patients with this syndrome.

Multidrug-Resistant Infections (Table 164-2) P. aeruginosa has

a notorious propensity to develop antibiotic resistance. Over three

decades, the impact of resistance was minimized by the rapid development of several potent antipseudomonal β-lactams and fluoroquinolones. However, rates of resistance to these agents that revolutionized

the treatment of P. aeruginosa have risen to the point where some are

almost unusable empirically because of the worldwide emergence of

strains carrying determinants that mediate resistance. Extremely high

rates of MDR strains have been reported from Eastern and Southern

Europe, Latin America, India, and China, especially in ICUs. Physicians have had to resort to drugs such as colistin and polymyxin B,

which were discarded decades ago. This surge in resistance is mediated

by multiple mechanisms sometimes converging in individual strains.

Chief among these are chromosomal or plasmid-borne penicillinases,

extended-spectrum β-lactamases, cephalosporinases, and carbapenemases. Any of these may be combined with permeability mutations

and efflux pump overexpression. The greatest nemesis in this regard is

the worldwide presence of carbapenemases in P. aeruginosa leading to

resistance to most β-lactams except some of the newest agents recently

developed. These new agents are generally combinations of a cephalosporin or a carbapenem most often with a novel β-lactamase inhibitor.

Several have been approved for clinical use, and all are active against

MDR P. aeruginosa to varying degrees. Currently approved agents

include ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/

vaborbactam, and imipenem/relebactam. A novel cephalosporin,

cefiderocol, which uses the iron uptake pathway of P. aeruginosa, also

demonstrates activity against MDR strains. Since MDR and XDR P.

aeruginosa are unpredictable in regard to the underlying mechanisms

of resistance, laboratory testing is absolutely required before the use of

any of these agents. Most academic institutions restrict the use of these

agents as there are concerns about the development of resistance, as has

already been noted, as well the cost implications of misuse.

BURKHOLDERIA SPECIES

■ BURKHOLDERIA CEPACIA COMPLEX

The B. cepacia complex (BCC) gained notoriety as the cause of a rapidly fatal syndrome of respiratory distress and septicemia (the “cepacia

syndrome”) in CF patients. Of the more than 20 species of this complex, the three most frequently seen in CF patients are B. cenocepacia,

B. multivorans, and B. stabilis. In addition to their occurrence in CF,

members of this complex were not uncommonly encountered in ICU

patients (previously designated Pseudomonas cepacia) and patients

with chronic granulomatous disease, in whom they caused lung disease. BCC organisms are environmental organisms that inhabit moist

environments and are found in the rhizosphere. They possess multiple

virulence factors that may play roles in disease as well as colonizing

factors that are capable of binding to lung mucus—an ability that may

explain the predilection of B. cepacia for the lungs in CF. B. cenocepacia

is motile, secretes elastase, and possesses components of an injectable

toxin-secretion system like that of P. aeruginosa; its LPS is among the

most potent of all LPSs in stimulating an inflammatory response in the

lungs. Inflammation may be the major cause of the lung disease seen

in the “cepacia” syndrome. Besides infecting the lungs in CF, the BCC

organisms appear as airway colonizers during broad-spectrum antibiotic therapy and are causes of VAP, catheter-associated infections, and

wound infections.

TREATMENT

B. cepacia Complex Infections

BCC organisms are intrinsically resistant to many antibiotics, rendering empiric treatment difficult. Therefore, treatment must be

tailored according to sensitivities. Trimethoprim-sulfamethoxazole

(TMP-SMX), meropenem, and minocycline are the most active

agents in vitro and may be started as first-line agents (Table 164-2).

However, recent reports indicate that there has been increasing

resistance to these agents especially in CF patients. Some strains are

susceptible to third-generation ureidopenicillins, advanced cephalosporins, and fluoroquinolones, and these agents may be used

against isolates known to be susceptible. Newer antibiotics such

as ceftolozane/tazobactam and ceftazidime/avibactam show good

activity against MDR strains in vitro. However, there is very limited

clinical experience with these agents.

■ BURKHOLDERIA PSEUDOMALLEI

B. pseudomallei is the causative agent of melioidosis, a disease of humans

and animals that is geographically restricted to Southeast Asia and

northern Australia, with occasional cases in countries such as India

and China. This organism may be isolated from individuals returning

directly from these endemic regions and from military personnel who

have served in endemic regions. Symptoms of this illness may develop

only at a later date because of the organism’s ability to cause latent infections, which has been attributed to its ability to survive within cells. B.

pseudomallei is found in soil and water. Humans and animals are infected

by inoculation, inhalation, or ingestion; only rarely is the organism

transmitted from person to person. Humans are not colonized without

being infected. Among the pseudomonads, B. pseudomallei is perhaps

the most virulent. Host compromise is not an essential prerequisite

for disease, although many patients have common underlying medical

diseases (e.g., diabetes renal failure or alcohol abuse). B. pseudomallei is

a facultative intracellular organism whose replication in PMNs and macrophages may be aided by the possession of a polysaccharide capsule.

The organism also possesses elements of a type III secretion system that

plays a role in its intracellular survival. During infection, there is a florid

inflammatory response whose role in disease is unclear.

B. pseudomallei causes a wide spectrum of conditions, ranging from

asymptomatic infection to abscesses, pneumonia, and disseminated

disease. It is a significant cause of fatal community-acquired pneumonia and septicemia in endemic areas, with mortality rates as high

as 44% reported in Thailand. Acute pulmonary infection is the most

commonly diagnosed form of melioidosis. Pneumonia may be asymptomatic (with routine chest radiographs showing mainly upper-lobe

infiltrates) or may present as severe necrotizing disease. B. pseudomallei also causes chronic pulmonary infections with systemic manifestations that mimic those of tuberculosis, including chronic cough,

fever, hemoptysis, night sweats, and cavitary lung disease. Besides

pneumonia, the other principal form of B. pseudomallei disease is skin

ulceration with associated lymphangitis and regional lymphadenopathy. Spread from the lungs or skin, which is most often documented

in debilitated individuals, gives rise to septicemic forms of melioidosis

that carry a high mortality rate.

TREATMENT

B. pseudomallei Infections

B. pseudomallei is susceptible to advanced penicillins, cephalosporins,

and carbapenems (Table 164-2). Treatment is divided into two stages:

an intensive 2-week phase of therapy with ceftazidime or a carbapenem followed by at least 12 weeks of oral TMP-SMX to eradicate

the organism and prevent relapse. Australian guidelines for treating

this condition recommend longer periods of intensive therapy—4−8

weeks for severe infections, osteomyelitis, and CNS infections. The

recognition of this bacterium as a potential agent of biologic warfare

has stimulated interest in the development of a vaccine.