REVIEWS OF INFECTIOUS DISEASES • VOL. 5, NO.2.

MARCH-APRIL 1983
© 1983 by The University of Chicago. All rights reserved. 0162-0886/83/0502-0010$02.00

Infections Caused by Pseudomonas aeruginosa

Gerald P. Bodey, Ricardo Bolivar, From the Department of Developmental Therapeutics,

Victor Fainstein, and Leena Jadeja Section of Infectious Diseases, The University of Texas
System Cancer Center, M. D. Anderson Hospital
and Tumor Institute, Houston, Texas

Pseudomonas aeruginosa has emerged as an important pathogen during the past two
decades. It causes between 10070 and 20070 of infections in most hospitals. Pseudomonas
infection is especially prevalent among patients with burn wounds, cystic fibrosis, acute
leukemia, organ transplants, and intravenous-drug addiction. P. aeruginosa is a com-
mon nosocomial contaminant, and epidemics have been traced to many items in the
hospital environment. Patients who are hospitalized for extended periods are frequently

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colonized by this organism and are at increased risk of developing infection. The most
serious infections include malignant external otitis, endophthalmitis, endocarditis, men-
ingitis, pneumonia, and septicemia. The likelihood of recovery from pseudomonas
infection is related to the severity of the patient's underlying disease process. The intro-
duction of the antipseudomonal aminoglycosides and penicillins has improved substan-
tially the prognosis of these infections. Ticarcillin and carbenicillin have been especially
beneficial in neutropenic patients; however, prompt institution of therapy is mandatory
for optimal benefit. Many new drugs with antipseudomonal activity, including penicil-
lins, cephalosporins, and other ~-lactams, have been introduced in recent years and of-
fer the potential for new approaches to therapy for these infections.

Pseudomonas aeruginosa was first isolated by
Gessard in 1882 and first recognized as a pathogen
by Charrin in 1890. The first cases in which the or-
ganism was cultured from blood specimens of in-
fected patients during life were reported in 1896
and 1899 [1]. Pseudomonas infections occurred
infrequently until after the introduction of the sul-
fonamides and penicillin. Presently, P. aeruginosa
causes only 3%-6070 of community-acquired infec-
tions. However, in a survey of community hospi-
tals, this organism was found to have caused 343
infections per 100,000 discharged patients, or
f\.J12OJo of all reported infections. In the hospital
surveillance program of the Center for Disease
Control, 10010 of urinary tract infections, 9010 of
surgical wound infections, 17010 of lower respi-
ratory tract infections, and 11% of bacteremias
were reportedly caused by P. aeruginosa [2]. This
organism has become an important pathogen
among debilitated, burned, and immunocom-
promised individuals. It is the most common
This paper was originally presented at a symposium entitled
"Infectious Diseases Update: 1982," funded by an educational
grant from Beecham Laboratories, Bristol, Tennessee, and
held in Houston, Texas, on February 25, 1982.
Please address requests for reprints to Dr. Gerald P. Bodey,
M. D. Anderson Hospital and Tumor Institute, 6723 Bertner,
Houston, Texas 77030.
pathogen recovered from patients who have been
hospitalized for more than a week. It is also an im-
portant cause of infection following battlefield in-
juries. Other species of Pseudomonas are also
becoming increasingly important as causes of in-
fection, especially in compromised hosts, but this
review will be limited to infections due to P. aeru-
ginosa.
Epidemiologic Features of P. aeruginosa
A considerable body of literature has accumulated
on the epidemiologic characteristics of P. aerugi-
nasa. This organism lends itself to epidemiologic
studies because it is recovered only infrequently
from the endogenous microbial flora of healthy
individuals. Only 4%-12070 of the normal popu-
lation are fecal carriers of P. aeruginosa. The
organism is a readily recognizable nosocomial
pathogen, yet it is seldom cultured from home en-
vironments. It is capable of causing epidemics of
infection among susceptible hospitalized patients.
In epidemiologic studies, biotyping, antibiograms,
pyocin typing, serotyping, and bacteriophage typ-
ing have been utilized for identification of individ-
ual strains. An analysis of the merits of various
typing methods is beyond the scope of this review.
In one study, P. aeruginosa was cultured from

279
280
the feces of 24070 of 108 surgical patients when
they were first admitted to the hospital [3]. An ad-
ditional 17070 of patients acquired the organism
during hospitalization. The carrier rate was 31%
among patients who received antibiotics but only
11 % among patients who did not. Only 6% of the
hospital staff were fecal carriers of P. aeruginosa.
In another survey of surgical patients, only 25070
of patients hospitalized for less than 10 days were
colonized, whereas 43 % of patients hospitalized
for more than 15 days were carriers of the orga-
nism [4]. Sites of colonization (in descending
order of frequency) were stool, urine, groin,
throat, and nose. Burned patients appeared to ac-
quire P. aeruginosa in their stools initially and
then to experience colonization of their burn
wounds.
In a study by Schimpff et al. [5], specimens for
surveillance cultures of rectum, urine, gingiva, ax-
illa, and nose were obtained twice weekly from
190 patients with cancer. Overall, P. aeruginosa
was cultured from at least one site in 30070 of the
patients. The colonization rate was highest among
patients with acute leukemia and other marrow
diseases. The frequency of pseudomonas septi-
cemia was 21070 among patients who were colo-
nized but only 7% among patients who were not
colonized. Of the patients who were colonized, 29
had neutropenia « 1,000 neutrophils/rnm") and 28
did not; Pseudomonas septicemia occurred in
42% of the former group but in none of the latter.
Pseudomonas septicemia developed in 32% of pa-
tients who received antibiotics but in only 10% of
patients who did not.
In a survey of 87 patients hospitalized for treat-
ment of leukemia, P. aeruginosa was isolated
from throat or stool specimens of 25% of patients
on admission and from 47% after two to four
weeks of hospitalization [6]. Of the 47 colonized
patients, 26% developed pseudomonas infection;
in contrast, 13070 of the 40 patients who were not
carriers developed pseudomonas infection (table
1). Infection occurred in 50070 of patients who
were colonized for more than 50070 of their hospi-
talization but in only 12070 of patients who were
colonized for less than 25% of their hospitaliza-
tion. In another survey of 48 patients with acute
leukemia, nine patients (19070) were colonized by
P. aeruginosa when first admitted to the hospital,
and 22 (46070) became colonized in the hospital [7].
Pseudomonas infection occurred in seven (78070)
Bodeyet al.
Table 1. Relation between the Pseudomonas aeruginosa
carrier state and pseudomonas infection.
Total
no. of Percentage
Status of patients patients infected
Carriers 47 26
Noncarriers 40 13
Carriers for >500;0 of hospitalization 18 50
Carriers for <25% of hospitalization 17 12
of the former group of patients and in 15 (68%) of
the latter.
Pseudomonas aeruginosa thrives in a moist en-
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vironment. It has survived in water at ru37 C for
300 days. In one study this organism was cultured
from distilled water, with a growth of 102-10 7 or-
ganisms within 48 hr [8], and in another it was cul-
tured from mop water used to clean a burn unit
for up to eight weeks after the unit was closed [9].
Contaminated eschar from this unit contained 3
x 106 organisms/em? at eight weeks. Many disin-
fectants and bacteriostatic agents are ineffective
against P. aeruginosa, including 0.25 % acetic
acid, phenolic disinfectants, chlorhexidine, and
isopropyl alcohol. Epidemics of pseudomonas in-
fection have occurred in nurseries for newborns,
leukemia services, burn wards, orthopedic and
urologic units, and intensive-care units. The orga-
nism has been cultured from faucets, sink drains,
water pitchers, suction apparatuses, and respira-
tors. Pulmonary infections have been traced to
contaminated nebulizers and humidifiers. Oph-
thalmic solutions of fluorescein and boric acid
have introduced infection in corneal ulcers. Hydro-
therapy tanks have spread infection among burned
patients. Recognition of these potential sources of
contamination has led to more careful attention to
sterilization and has eliminated them as major
vehicles for spread of infection.
In one study P. aeruginosa was cultured from
tomatoes, radishes, celery, carrots, cabbage, cu-
cumbers, endive, onions, and lettuce delivered to
hospital kitchens [10]. About 80070 of tomatoes
were contaminated, and it was estimated that a pa-
tient eating an average portion of tomato salad
could ingest 5 x 103 P. aeruginosa organisms. The
importance of this observation is unclear. Studies
of the intentional ingestion of P. aeruginosa dem-
onstrated that organisms were not detectable in
the feces after ingestion of <10 4 organisms. P. ae-
ruginosa was regularly cultured only after inges-
P. aeruginosa Infections
tion of >10 6 organisms; the organisms gradually
decreased in number and finally disappeared after
six days. However, the selective pressure of anti-
biotic administration could facilitate continued
colonization.
The longer a patient remains in the hospital, the
greater is the likelihood of colonization by P. ae-
ruginosa. The risk of infection is substantially
greater among colonized patients, especially if
they have some defect in host defense mechanisms.
For example, the oropharynx of hospitalized pa-
tients is readily colonized by gram-negative bacilli.
If a patient requires a tracheostomy, he or she will
run a high risk of developing pneumonia. P. aeru-
ginosa is one of the organisms that frequently
cause pneumonia in patients who have tracheos-
tomies and are using respirators.
The relation between oropharyngeal coloniza-
tion and infection was illustrated by a study of 213
patients admitted to a medical intensive-care unit
[11]. Forty-five percent of those patients became
colonized with gram-negative bacilli, 22070 on the
first day in the unit. Among the patients at high
risk of colonization were those with respiratory
disease and those with leukopenia. Of the 95 pa-
tients who were colonized, 23070 developed noso-
comial respiratory infections, whereas only 3070 of
the 118 patients who were not colonized developed
infections. Although P. aeruginosa was not the
most common colonizing organism, it was cultured
from 32070 of the colonized patients. The environ-
mental sources of the organism could not be iden-
tified.
Certain populations of patients are especially
susceptible to pseudomonas infections. Some of
these populations and their most prevalent infec-
tions are listed in table 2. A common factor
among many of these patients is an interruption of
the natural barriers that protect against invasion
by bacteria. For example, in both the patient with
a corneal ulcer and the burned patient, disruption
of the epithelial surface permits the denuded area
to be colonized by P. aeruginosa. Subsequent in-
vasion of tissues can result in devastating infec-
tion. The insertion of devices into blood vessels,
the urethra, or the meninges facilitates the es-
tablishment of infection. Patients with acute leu-
kemia or cancer are frequently neutropenic as a
result of their disease or related therapy. Neutro-
penic patients are especially susceptible to pseudo-
monas infections. In one series of 67 patients with
281
Table 2. Conditions predisposing to pseudomonas
infection.
Most prevalent type(s) of
Condition infection
Diabetes Malignant otitis externa
Drug addiction Endocarditis, osteomyelitis
Leukemia Septicemia, typhlitis
Cancer Pneumonia, septicemia
Burn wound Cellulitis, septicemia
Pneumonia
Cystic fibrosis
Surgery involving central Meningitis
nervous system
Tracheostomy Pneumonia
Neonatal period Diarrhea
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Corneal ulcer Panophthalmitis
Suppurative thrombophlebitis
Vascular catheterization
Urinary catheterization Urinary tract infection
cancer who developed pseudomonas septicemia,
81070 had an absolute neutrophil count of
<l,OOO/mm\ and 36070 had a count of <lOO/mm 3
[12]. However, pseudomonas infections are be-
coming increasingly frequent among nonneutro-
penic patients with cancer, presumably because of
the selective pressures of extensive antibiotic usage
in cancer hospitals.
Host Defenses and Pseudomonas Infection
In order to understand the pathogenicity of P. ae-
ruginosa, it is important to recognize its complex
cellular structure. P. aeruginosa, like most other
gram-negative bacteria, has a cell-envelope struc-
ture consisting of an outer membrane, a peptido-
glycan layer, and an inner cytoplasmic membrane.
The outermost layer is a polysaccharide layer des-
ignated as slime. Each component of the organism
has virulent properties (with a wide range of
potency) and has different effects on host defense
mechanisms. The cell envelope, for instance, is of
paramount importance in the persistence and
growth of this organism at sites of infection. Some
components of the cell envelope control adhesion
and microcolony formation, while others control
the passage of nutrients and the exclusion of
humoral and synthetic antibacterial agents from
the bacterial cell. The most important extracellu-
lar and intracellular virulence factors are listed in
table 3 [13].
Exotoxins. Although the pathogenesis of
P. aeruginosa had been ascribed to endotoxin (the
lipopolysaccharide, or LPS, components of the cell
282
Table 3. Virulence factors of Pseudomonas aeruginosa.
Category, factor Biologic effect(s)
Extracellular
Proteases Tissue invasion, cellular damage,
decreased complement-
mediated defense mechanisms
Exotoxin A Cellular damage, toxicity for
macrophages
Phospholipase Destruction of pulmonary
surfactant
Cellular
Pili Adherence to epithelial cells
Slime polysaccharide Toxicity for neutrophils, endo-
toxin-like effects
Mucoid polysaccharide Antiphagocytic effects, de-
creased pulmonary clearance
Lipopolysaccharide Possible antiphagocytic effects
"0" antigen
Lipid A Endotoxic effects
NOTE. Data are from [13].
wall), recent evidence indicates that an exotoxin is
actually the most toxic component. In vitro
studies of a nonproteolytic strain of P. aeruginosa
identified exotoxin A, a protein with a molecular
weight of ~5 X 104 that was 20,000 times as toxic
as the endotoxin in experiments with animals [14,
15]. When exotoxin A was injected into mice, it
produced tissue necrosis and neutropenia. Dogs
that received an iv injection of the toxin died in
shock [16]. Exotoxin A also inhibits protein syn-
thesis by interfering with polypeptide transloca-
tion on messenger RNA. This effect is similar to
the action of diphtheria toxin, but the two toxins
have different cell receptors and are structurally
dissimilar.
Pro teases. Proteases are important extracellu-
lar proteolytic enzymes produced by P. aerugino-
sa; they liquefy gelatin, dissolve elastin and fibrin,
and destroy collagen. When injected into the skin
of animals, the proteases induce hemorrhagic le-
sions and necrosis similar to the ecthyma gangre-
nosum noted in human infection. In contrast, the
inoculation of exotoxin A produces bland necrosis
and reactive erythema but not hemorrhage. Thus,
the hemorrhagic component seems to be a feature
of protease activity. Hemorrhages into internal
organs, particularly the lungs, during pseudomo-
nas infection are probably triggered by proteases
[17]. Using light and electron microscopy, a recent
study characterized the pulmonary lesions induced
in rabbits by the intratracheal administration of
Bodey et al.
highly purified P. aeruginosa proteases [18]. In-
traalveolar hemorrhage, injury and necrosis of
alveolar septal cells, and infiltration of mononu-
clear cells- all of which occur during pseudomo-
nas pneumonia in humans - were elicited in this
animal model.
Pigments. P. aeruginosa produces a variety of
pigments such as chloraphin, pyomelanin,
pyorubin, and pyocyanin [19]. These pigments,
particularly the phenazines, have been implicated
in pathogenicity [20]. The active fraction of an ex-
tract, "pyocyanase," has been determined to be
alpha oxyphenazine, which has antibacterial pro-
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perties [15]. It has been postulated that pyo-
cyanins suppress the growth of other bacteria,
thus facilitating colonization by P. aeruginosa.
Phospholipase and glycolipids. Phospholipase
is a heat-labile substance that liberates phospho-
rylcholine from lecithin and may playa significant
role in the pathogenesis of pseudomonas pneu-
monia. The mechanism of pathogenesis is related
to the destruction of pulmonary surfactant (the
major component of which is lecithin), resulting in
atelectasis. Also, the phospholipase of P. aerugi-
nosa causes necrosis of pulmonary tissues. The
glycolipid of P. aeruginosa appears to enhance the
activity of the phospholipase by acting as a deter-
gent and solubilizing phospholipids [21].
Cellular factors. Pili are structures that enable
an organism to adhere to surfaces and that may
playa role in conjugation and function as recep-
tors for RNA and DNA bacteriophages [22].
Heat-labile antigens are part of the pili (as well as
of flagella), and along with the somatic antigens
form the basis of a serologic classification of
P. aeruginosa [23].
Another important component, the slime layer,
is located in the outermost part of the cell and is
composed of polysaccharide, nucleic acids (both
RNA and DNA), hyaluronic acid, lipid, and pro-
tein [24]. The slime polysaccharide from strains of
P. aeruginosa recovered from children with cystic
fibrosis has been shown to be similar to the alginic
acid usually found in brown seaweed [25]. The
polysaccharide of bacteria cultured from patients
with cystic fibrosis is a copolymer of mannuronic
acid and glucuronic acid [26]. Some components
of the slime, such as glycolipoprotein, have been
purified. The response to ip injection of the
purified glycolipoprotein of P. aeruginosa was
similar to that to lethal infection caused by viable
P. aeruginosa Infections
bacilli [27]. Type-specific protection was noted
with passive and active immunization. The toxici-
ty of slime varies greatly and probably reflects the
presence of exotoxin [28]. Also, antiphagocytic
activity in vitro can be detected in the alginic
acid-like mucoid expolysaccharide [29]. A compo-
nent that may have structural importance in main-
taining the integrity of the membrane as well as
immunologic significance is the outer-membrane
protein-LPS complex. The attribution of im-
munologic significance to LPS derives from the
observation that opsonizing antibody LPS from a
strain of a given immunotype aids in the
phagocytosis of P. aeruginosa of that im-
munotype by neutrophils [30]. The endotoxic pro-
perties of LPS are elicited by the lipid A compo-
nent. Because of differences in the composition of
its lipid A moiety, the LPS of P. aeruginosa ap-
pears to be a less potent endotoxin than the LPS
of other gram-negative bacilli [31].
Humoral immunity. Once mechanical barriers
have been breached, P. aeruginosa becomes in-
vasive and causes severe damage to tissues and
blood vessels. The organism's proteolytic enzymes
contribute to its invasiveness. Some evidence in-
dicates that the production of antibody to
bacterial cell components and toxins in infection
correlates with survival. For instance, titers of
serum antibodies to type-specific polysaccharide
and to exotoxin A were measured in 52 patients
with P. aeruginosa septicemia [32]. A high an-
titoxin titer correlated with survival; 76ltfo of 17
patients with high antitoxin titers survived,
whereas only 46% of 24 patients with low antitox-
in titers survived. A protective effect of antibody
to the polysaccharide was also noted; 85ltfo of 13
patients with high titers and 48ltfo of 29 patients
with low titers survived. The protection afforded
by the two antibodies appears to be independent
and additive. In the group of patients studied, a
significant antibody response occurred despite a
rapidly fatal underlying disease, leukopenia,
steroid administration, or immunosuppressive
drug therapy.
A later study confirmed that the production of
antibody to exotoxin A correlated with survival
after infection [33]. Mean antibody concentra-
tions were low in normal individuals (2.6 jJg/ml)
and in patients infected with strains of P. aerugi-
nosa that did not produce this toxin (0.67 jJg/ml).
Antibody concentrations were moderately ele-
283
vated in patients with nonbacteremic infections
(17.1 jJg/ml) and in patients who were only col-
onized (16.7 jJg/ml). Antibody levels were high in
septicemic patients who survived (25.8 ug/rnl),
whereas levels were low in septicemic patients who
died (4.6 IAg/m1); this observation indicates that
the antibody response to exotoxin A correlates
with the type and outcome of pseudomonas infec-
tion.
Phagocytic antibody to the polysaccharide side-
chain serotype-specific determinant is also impor-
tant in host defense against P. aeruginosa. Pa-
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tients with pseudomonas bacteremia have a good
prognosis if they develop opsonizing antibodies,
whereas the outcome is poor in the absence of
these antibodies [34].
The resistance to phagocytosis conferred by
heat-stable somatic antigens of P. aeruginosa is
neutralized by serum containing specific an-
tibodies [30]. In one study heat-stable opsonic ac-
tivity against P. aeruginosa was measured in the
sera of 33 children with acute lymphoblastic
leukemia at various times during treatment of
their disease [35]. Compared with that in adults,
opsonization was normal in children tested at the
time of diagnosis and before chemotherapy. Im-
mediately .after the achievement of remission, the
level of opsonic activity decreased significantly
compared with pretreatment levels. Activity usual-
ly returned to normal and remained so during
long-term remission maintenance therapy. The
authors of this study concluded that the decline in
levels of specific anti pseudomonas factors in se-
rum may contribute to the increased incidence of
serious and fatal infection in children with acute
lymphoblastic leukemia.
Immunization against gram-negative infection,
including that with P. aeruginosa, has been at-
tempted by the use of "core" glycolipid antigens.
These antigens, consisting of 2-keto-3-deoxyocto-
nate linked to lipid A, are shared by Enterobac-
teriaceae and non-lactose fermenters such as
P. aeruginosa [36]. Antibodies to the core glyco-
lipid have been associated with protection against
the sequelae of gram-negative bacteremia. For in-
stance, immunization with core vaccine or passive
immunization with core antiserum has consistent-
ly protected rabbits against infection by a wide
range of heterologous gram-negative bacteria, in-
cluding P. aeruginosa. The rate of survival among
experimental animals with pseudomonas bacte-
284
remia rises from 130/0 to 920/0 (P < 0.0005) after
vaccination with the core antigen [37]. The mecha-
nism of protection against P. aeruginosa by anti-
sera to core antigens is not totally clear but ap-
pears to be related largely to antitoxic properties
that prevent the hemodynamic events associated
with bacteremia. In one study, for example, the
administration of J5 human antiserum (i.e., core
glycolipid antiserum derived from the J5 mutant
of Escherichia coli 0111) to severely ill bacteremic
patients increased the recovery rate of patients in
shock from 290/0 to 820/0 [38]. The protective ef-
fect of J5 vaccine has not been observed by all in-
vestigators. In a recent study animals were immu-
nized with heptavalent P. aeruginosa vaccine or J5
vaccine prior to the induction of experimental
pseudomonas pneumonia [39]. The survival rate
was compared with that among control animals
that received only saline. Survival rates were 15070
among controls, 81% among animals receiving
pseudomonas vaccine, and 42% among animals
receiving the J5 vaccine. In this study it was also
determined that circulating opsonins against het-
erologous (P. aeruginosa) or homologous (E. cob)
bacteria were not present and that alveolar macro-
phages were not activated. Hence, only weak
cross-protection was observed in the recipients of
the J5 vaccine. This study also suggested that hu-
moral mechanisms of protection against bactere-
mia due to heterologous bacteria may be less im-
portant in pulmonary infections.
Complement. This complex system of serum
proteins is fundamental in host defense against in-
fection. Activation of complement is often in-
itiated by immunoglobulins and proceeds via the
sequential interaction of components of the classic
or alternative pathways. Both of these pathways
can be involved in the opsonization of P. aerugi-
nosa. Although some strains can be opsonized by
complement in the absence of antibodies, anti-
bodies appear to initiate the complement-medi-
ated opsonization of most strains [40]. The factors
in normal human serum that are required for pha-
gocytosis and killing of P. aeruginosa by human
polymorphonuclear leukocytes have been identi-
fied; proactivator of the third component of com-
plement, properdin, and "natural" IgG antibodies
are essential [41]. The addition of "immune" IgG
to the system eliminates the requirement for pro-
perdin. These observations suggest that two mech-
anisms of complement activation can be involved
Bodeyet al.
in the phagocytosis of P. aeruginosa. The presence
of serum factors may be critical for the mainte-
nance of natural resistance to pseudomonas infec-
tion. For instance, low properdin levels have been
reported in patients with burns and cancer [42,
43], and both of these populations are especially
susceptible to pseudomonas infection.
Phagocytosis of P. aeruginosa by pulmonary
alveolar macrophages also appears to be mediated
by the complement system. Extracellular bacterial
products may interfere with several host-defense
mechanisms by their action on the complement
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system. For example, one of the proteases of
P. aeruginosa, elastase, is highly destructive to
several complement components and inhibits
phagocytosis of bacteria opsonized with C3 [44].
The activation of the terminal components of
the complement system is critical for the
bactericidal function of serum. The importance of
serum bactericidal activity in defense of the host
against P. aeruginosa is unclear. In one study 91 %
of isolates from blood cultures were serum resis-
tant; however, the majority of saprophytic isolates
were also serum resistant [34]. In a model of
bacteremia in neutropenic rats, the difference in
the virulence of various strains of P. aeruginosa
could not be correlated with the bactericidal ac-
tivity of the animals' serum [45]. The different
methods used in determining serum sensitivity,
however, may give variable results, and this varia-
tion could account for the lack of correlation
with virulence [46].
Cell-mediated immunity. The role of cell-
mediated immunity to P. aeruginosa has been less
extensively studied than other immune functions.
Some observations suggest that cell-mediated im-
munity may be an important host-defense
mechanism [47]. For instance, in patients with
cystic fibrosis, lymphocyte proliferation in re-
sponse to P. aeruginosa but not in response to
other bacterial or T-cell mitogens was significantly
depressed [48]. Since T-cell cooperation is essen-
tial for many B-cell responses and T cells may thus
be involved in continued humoral immunity, any
T-cell dysfunction could potentially compromise
the overall immune status of the host. In animals
infected with cytomegalovirus, which causes
depression of cell-mediated immunity, the viru-
lence of P. aeruginosa is enhanced [49]. Cell-medi-
ated immunity to P. aeruginosa can be intrinsical-
ly impaired not only by a concomitant infection
P. aeruginosa Injections
but also by P. aeruginosa itself. When immunity
to Listeria and delayed-type hypersensitivity to
sheep erythrocytes were used as parameters to de-
termine the effects of P. aeruginosa on T-cell-me-
diated responses in mice [50], the results indicated
that P. aeruginosa infection changes macrophage
and T'-lymphocyte activities and results in the de-
velopment of suppressor cells, with depression of
cell-mediated immunity as a consequence. Pa-
tients with diseases characterized by impaired cell-
mediated immunity, such as Hodgkin's disease,
are not highly susceptible to P. aeruginosa infec-
tions; this fact suggests that the most important
host-defense mechanism is antibody-mediated im-
munity. The data just presented suggest, however,
that in specific disease entities such as advanced
cystic fibrosis, in which the antibody titer is
already high, one of the factors contributing to
infection could be specifically defective cell-medi-
ated immunity to P. aeruginosa. Also, P. aerugi-
nosa infections with secondary depression of cell-
mediated immunity may enhance the severity of
the process by interfering with T- and B-cell inter-
action. In general, cell-mediated immunity as a
factor in host resistance to P. aeruginosa has been
largely unexplored, and evidence for a potential
role in host defense is limited.
Phagocytic cells. Granulocytopenia is one of
the most important factors predisposing patients
with malignancy to pseudomonas infection. The
role of granulocytes was evaluated in an experi-
mental model of pseudomonas pneumonia in
granulocytopenic dogs [51]. Therapy with granu-
locyte transfusions was associated with a 27070 rate
of long-term survival; the rate was even higher if
significant levels of antibody were present. In ad-
dition to a quantitative defect, granulocytes may
exhibit functional abnormalities such as that seen
in patients with leukemia, or abnormalities may
result from interaction with bacterial products or
serum factors. For instance, slime glycolipopro-
tein is toxic to granulocytes, and this effect is re-
versible by antibodies to its substance [27]. Also of
interest is a recent in vitro observation of abnor-
mal phagocytosis and intracellular killing by pha-
gocytic cells from patients with cystic fibrosis [52].
The blocking of bactericidal activity by IgG anti-
bodies has also been demonstrated in patients with
chronic pseudomonas infections [53].
The importance of phagocytic cells has been
established by the study of P. aeruginosa isolates
285
recovered from patients with bacteremia. Ninety-
one percent of these isolates were serum resistant
and were not killed by autologous convalescent-
phase serum containing high titers of antibody.
However, when the serum was combined with nor-
mal polymorphonuclear leukocytes, a 10- to
100-fold increase in the killing of bacteria was pro-
moted [34].
The efficacy of the bactericidal activity of
granulocytes against P. aeruginosa varies with the
strain. Studies in burned animals infected with dif-
ferent strains showed that mortality was lowest in
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animals infected with strains that were most
susceptible to the bactericidal activity of granulo-
cytes [54]. Also, defects in the chemotactic func-
tion of granulocytes have been described in patients
who are prone to serious pseudomonas infections.
For instance, a decreased chemotactic index was
shown in burned patients [55]; in this study, mor-
tality was higher among patients with a low che-
motactic index than among those with a high che-
motactic index.
In addition to neutrophils, monocytes and
macrophages play an important role in host
defense against pseudomonas infection. Active
immunization with LPS protects dogs after iv
challenge with P. aeruginosa, even in the presence
of granulocytopenia; this protection has been at-
tributed to type-specific immunity mediated by the
reticuloendothelial system [56]. Pulmonary mac-
rophages are particularly important in pulmonary
host defense [47]. In vitro experiments have shown
that the rate of phagocytosis and intracellular kill-
ing of P. aeruginosa by alveolar macrophages
from normal rabbits is reduced in the presence of
serum from patients with cystic fibrosis [57]. Not
only inhibitory factors from the host but also bac-
terial products can affect macrophages. For exam-
ple, human peripheral macrophages exposed to
exotoxin A show morphologic evidence of cell
death and inhibition of PH] thymidine uptake
[58]. The CPE of exotoxin on these cells may be a
significant factor in the pathogenesis of pseudo-
monas infection.
The complex structure of P. aeruginosa and the
presence of multiple virulence factors represent a
challenge to the host's immune mechanisms. An
effective defense against P. aeruginosa depends
upon the integrated functions of the epithelial cell
barrier, antibodies, the complement system,
phagocytic cells, and lymphocytes. These host fac-
286
Figure 1. Ecthyma gangrenosum caused by Pseudo-
monas aeruginosa in the groin of a patient with acute
leukemia.
tors result in interference with bacterial growth,
promote phagocytosis and bacterial killing, and
inhibit the toxic properties of certain bacterial
components.
Important Sites of Pseudomonas Infection
Skin. Normal dry skin does not support the
growth of P. aeruginosa, but the organism
flourishes on moist skin. Hence, superficial skin
infections occur more often in tropical and sub-
tropical climates. Several dermatologic syndromes
caused by this organism have been described [59].
The "green nail" syndrome occurs in individuals
whose hands are frequently submerged in water.
This condition is actually a paronychial infection;
pseudomonal pigments diffuse into the nail plate,
causing discoloration. The color usually persists
for months after effective therapy. Toe web infec-
tion occurs primarily in hot, humid climates. The
toe web has a thick whitish or greenish exudation
due to scaling or maceration of the stratum cor-
Bodeyet 01.
neum. The use of topical antibiotics without an-
tipseudomonal activity may facilitate the
establishment of this infection. Pseudomonas
pyoderma is a purulent infection of the skin
characterized by a bluish-green exudate with a
characteristic grape odor. The border of the lesion
appears macerated and eroded. This infection
arises in patients with eczema, tinea pedis, and
bedsores. Pseudomonas cellulitis usually presents
as an erythematous area with a violaceous center.
It may be associated with fluctuant or nonfluc-
tuant subcutaneous nodules. The infection may be
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deep-seated, with large amounts of pus dissecting
into the muscle. Such extensive infection requires
surgical drainage in addition to antibiotic therapy.
Ecthyma gangrenosum is a characteristic skin
lesion that is nearly always caused by P. aerugino-
sa (figure 1). Rarely, other organisms such as
Staphylococcus aureus, Aeromonas hydrophila,
Serratia marcescens, Aspergillus species, or Mu-
cor species may cause ecthyma gangrenosum. The
lesion begins as an area of erythema and edema
and progresses to a hemorrhagic bluish bulla that
ruptures. The typical lesion consists of a bluish to
blackish central area of necrosis surrounded by an
erythematous halo. This process evolves rapidly
over 12-24 hr. The lesions are usually found in the
axilla, groin, or perianal areas but may occur any-
where, including on the lip and the tongue. Some
patients develop numerous large lesions, with ex-
tensive tissue damage (figure 2). The pathological
hallmark is a vasculitis without thrombosis; often
there is a paucity of neutrophils at the site of infec-
tion. Bacilli are found in the media and adventitia
but usually not in the intima of the vessel [60]. In
general, this lesion is indicative of pseudomonas
septicemia, but the organism is not always cul-
tured from the blood of infected patients. P. aeru-
ginosa is cultured from the ecthyma. Experimental
evidence suggests that this lesion may arise from
local invasion of the skin or from hematogenous
dissemination.
Several other skin lesions have been described in
association with pseudomonas septicemia. Painful
vesicular lesions that tend to occur in clusters have
been reported [61]. These small blebs or vesicles
have an erythematous base and contain opalescent
fluid from which the organism is cultured. Small
pink maculopapular plaques or nodules arising on
the trunk have also been described in patients with
pseudomonas septicemia. Occasional patients
P. aeruginosa Infections
develop multiple small embolic-type lesions in the
absence of endocarditis. Multiple painful sub-
cutaneous nodules may arise in patients with sep-
ticemia. The overlying skin may appear
erythematous or unremarkable, but the infected
area is extremely tender. These lesions may require
surgical drainage in addition to antibiotic therapy.
Burn wounds. P. aeruginosa emerged as a ma-
jor cause of burn wound sepsis after the introduc-
tion of effective antistaphylococal therapy. The
organism is seldom recovered from the burn dur-
ing the first 24 hr after thermal injury, but
thereafter the rate of colonization increases rapid-
ly; P. aeruginosa is cultured from the wounds of
70070 of patients by the third week [62]. Prior to
the use of effective prophylactic measures,
60%-70070 of episodes of septicemia were caused
by P. aeruginosa and the fatality rate was (\)60070
[63]. At the Brooke Army Medical Center (San
Antonio, TX), 75070 of deaths following thermal
injury were due to septicemia, and P. aeruginosa
was the infecting organism in 77070-90% of cases
[64].
Invasive burn-wound sepsis is defined as
bacterial proliferation of 105 organism/g of tissue,
with involvement of subjacent unburned tissue
[65]. Important variables affecting prognosis in-
clude the extent and severity of the burn, the
number of viable organisms in the eschar, the
amount of circulating antibody to Pseudomonas,
and the number and functional capacity of cir-
culating neutrophils. Burned patients are also at
risk of developing pseudomonas pneumonia, sup-
purative thrombophlebitis, and eye infections.
Pseudomonas burn-wound sepsis results in
hypotension, oliguria, hypothermia, ileus, and
leukopenia. The burn-wound granulation tissue
degenerates, with focal hemorrhage and produc-
tion of greenish pyocyanine pigment. The wound
margin is outlined with a violaceous to black dis-
coloration. Hemorrhage and necrosis occur below
the wound surface as a result of vasculitis, and the
lesions of ecthyma gangrenosum may appear else-
where on the body.
The prophylactic use of topical antimicrobial
agents has significantly reduced the frequency of
burn-wound sepsis. Mafenide acetate, silver sulfa-
diazine cream, and 0.5070 silver nitrate soaks are
effective in controlling bacterial proliferation. The
routine use of these topical agents has reduced
mortality from 38% to 19% among patients with
287
Figure 2. Multiple hemorrhagic lesions due to Pseu-
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domonas aeruginosa.
burns on <60070 of the body. The frequency with
which burn-wound sepsis causes death in burned
patients has decreased from 59070 to 10070 since the
introduction of these agents [64].
Eyes, ears, nose, and throat. P. aeruginosa is
capable of causing both minor and serious infec-
tions of the head and neck area. Rarely, this
organism causes primary conjunctivitis, dacryo-
cystitis, or orbital cellulitis. Orbital cellulitis is pri-
marily a disease of children and is often associated
with ethmoid sinusitis. Blepharoconjunctivitis oc-
curs occasionally in patients with cancer who are
experiencing myelosuppression due to chemother-
apy [66]. The infection may be unilateral or
bilateral, and the upper and lower eyelids and sur-
rounding structures characteristically have a
purplish hemorrhagic appearance. The patient
usually has associated septicemia, and the orbital
infection probably arises from hematogenous dis-
semination. This condition must be recognized
promptly and treated appropriately if progression
to panophthalmitis (figure 3) is to be prevented.
Pseudomonas aeruginosa is the most common
gram-negative bacillus infecting corneal ulcers. By
1965, about 100 cases of such infection had been
reported in the world literature [67]. Classically,
the infection progresses rapidly, producing
greenish pus and a hypopyon. If not treated ap-
propriately, it may progress rapidly to panop-
thalmitis. Topical antipseudomonal drugs are
usually effective if applied in the early stages [68].
Advanced infection may require the injection of
aminoglycosides beneath Tenon's capsule. In the
past, contaminated ophthalmic preparations such
as fluorescein and boric acid solutions served as
the source of these infections, but this is infre-
288
quently the case at present. Also, contamination
of storage cases for contact lens with P. aeru-
ginosa can lead to corneal infections [69].
Burned patients are susceptible to serious
pseudomonas eye infections. These patients may
suffer corneal damage from the burn injury.
Subsequent colonization of their skin lesions by
P. aeruginosa can permit the organism to spread
to the eye, causing serious infection that may be
overlooked. Failure to institute therapy promptly
can lead to panophthalmitis. The rapid develop-
ment of panophthalmitis has been attributed to
the elaboration of proteolytic enzymes by the
organism. Patients receiving radiotherapy for
malignant lesions near the eye may develop scleral
necrosis and pseudomonas infection, which also
can progress to endophthalmitis [70].
Pseudomonas aeruginosa causes rv70OJo of cases
of otitis externa [71]. Because the organism is rare-
ly cultured from dry skin but flourishes in moist
environments, swimmers are especially prone to
pseudomonas otitis externa ("swimmer's ear").
Other important predisposing factors include a
tropical climate ("hot-weather ear") and trauma.
These infections can be treated easily with topical
antipseudomonal drugs. Otitis media may be
Bodeyet at.
Figure 3. Eye of a patient with
pseudomonas panophthalmitis.
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caused by this organism, but such an infection
usually does not present as a unique entity.
However, failure to recognize the infecting
organism will result in chronic infection. P. aeru-
ginosa is the most frequent cause of chronic otitis
media [72]. The organism can spread to the mas-
toid and then through vascular channels to the lep-
tomeninges, causing an extradural or intradural
abscess or meningitis.
The most serious pseudomonas infection of the
ear is malignant otitis externa. This infection oc-
curs predominantly in the elderly and especially in
diabetics. The disease was first described by
Meltzer and Keloman in 1959 and was emphasized
by Chandler in several publications [73]. It begins
as ordinary otitis externa that fails to respond to
appropriate topical therapy. The principal com-
plaints are persistent pain, severe edema and
tenderness of the soft tissues of the ear, and
purulent drainage. The patient generally remains
afebrile. The most important sign is the per-
sistence of granulation tissue on the floor of the
external auditory canal near the junction of the
cartilaginous and bony portions. The infection
may spread anteriorly through the fissures of San-
torini to the parotid gland and temperoman-
P. aeruginosa Infections
dibular joint and progress to the stylomastoid
foramen, causing necrosis of the facial nerve. It
may spread posteriorly to involve the mastoid or
inferiorly and medially to cause osteomyelitis of
the base of the skull. In advanced cases, the
jugular foramen may be involved in the infectious
process, with paralysis of cranial nerves 10-12.
About 10070 of patients have thrombosis of the
sigmoid sinus or dome of the jugular bulb, which
is nearly always a fatal complication [73]. Usually,
the tympanic membrane remains intact. Men-
ingitis is a rare complication of this infection [74].
Prior to the availability of effective antibiotics
and the capacity to recognize malignant otitis ex-
terna early in its course, mortality exceeded 50%
[72]. Recently, with prompt administration of ap-
propriate therapy, this figure has fallen to rv25%.
However, mortality depends upon the extent of in-
fection at the onset of therapy. The death rate
among patients with facial nerve paralysis is
rv52OJo, and half of the survivors fail to regain
nerve function [73]. If other nerves are involved at
the time of presentation, mortality approaches
60%-75% [75]. The introduction of the an-
tipseudomonal penicillins and aminoglycosides
has improved the prognosis of this infection
substantially. In one study done prior to the
availability of carbenicillin, radical mastoidec-
tomy was required in all of 10 patients with facial
nerve palsy; five patients died, and only one
regained nerve function [73]. The same in-
vestigators later gave carbenicillin to 13 patients.
Six received the antibiotic only; of these, four
recovered (two with facial nerve recovery). Seven
patients required surgery as well as antibiotic
therapy; of these, five recovered, (four with facial
nerve recovery) [73]. In another recent series, the
overall cure rate among 20 patients was 85070 [75].
Pseudomonas aeruginosa is rarely cultured
from the normal mouth. Periodontal disease
which can progress to osteomyelitis, has occa-
sionally been observed in leukemic patients.
Ulceration of the pharynx, tonsils, and buccal
mucosa, with formation of an extensive necrotic
membrane simulating that of diphtheria, has been
described. Surviving patients may be left with
residual structural defects due to the extensive
necrosis. Nosocomial sinusitis has been identified
recently as an important infection in traumatized
patients who require nasopharyngeal instrumenta-
tion [76]. P. aeruginosa was identified as the most
289
common cause of this infection. Infection usually
resolves following removal of all nasal tubes and
treatment with antibiotics and decongestants.
Brain and spinal cord. The first case of
pseudomonas meningitis was reported in 1893.
Only 43 cases had accumulated in the literature by
1936 [77]. By 1955, 230 cases of pseudomonas
meningitis had been described [78]. Sixty percent
of cases were primary infections, and 40070 were
secondary to a focus elsewhere in the body. The
fatality rate was 39070 among patients with prima-
ry infection and 66% among those with secondary
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infection. In one study covering a 10-year period,
only 1.4070 of 294 cases of bacterial meningitis
were caused by P. aeruginosa [79]. This organism
causes rv5OJo of cases of meningitis in neonates and
10% of cases in patients with cancer [80]. Men-
ingitis following spinal anesthesia, chronic otitis
media, and extensive head and neck surgery [81]
has been reported. Therapy should include an an-
tipseudomonal penicillin plus an aminoglycoside.
The latter drug should be administered in-
trathecally since adequate concentrations in
cerebrospinal fluid are not achieved with
parenteral administration.
Heart. Until recently, P. aeruginosa was rare-
ly a cause of endocarditis. For example; this or-
ganism caused only one of 400 cases of endocardi-
tis seen at New York Hospital between 1944 and
1972 [82]. Of the 46 cases of P. aeruginosa endo-
carditis seen since 1897, 29 occurred in patients
with underlying heart disease. Eighteen patients
had undergone cardiac surgery; other predispos-
ing factors were skin infection, other surgical pro-
cedures, and narcotic addiction. The infection was
cured in only five patients. Among the 28 patients
without prior cardiac surgery, the mitral and aor-
tic valves were involved most often. The recent in-
crease in narcotic addiction has been associated
with an increase in the incidence of pseudomonas
endocarditis, usually involving the tricuspid valve.
This infection is discussed extensively elsewhere
[83].
Gastrointestinal tract. Several types of pseu-
domonas infection in the gastrointestinal tract
have been described. Nonspecific ulcerations of
the gastrointestinal tract may become infected
with this organism, which can invade the
bloodstream. Epidemics of pseudomonas diarrhea
in nurseries for newborns have been caused by the
use of contaminated equipment [84]. This infec-
290
tion may be either mild and self-limiting or severe,
leading to an infant's death. An awareness of the
potential hazards of pseudomonas contamination
and the institution of requirements for steriliza-
tion have reduced the risk of this problem.
"Shanghai fever" is a pseudomonas enteritis
with a presentation similar to that of typhoid
fever. Patients complain of prostration, headache,
fever, and diarrhea [1]. Physical findings include
splenomegaly and roseola spots from which the
organism can be recovered. P. aeruginosa may
make up as much as 50070-75% of the stool flora
of infected patients. The infection is prevalent
where drinking water is contaminated with the
organism.
The most important gastrointestinal infection
caused by P. aeruginosa is typhlitis. Typhlitis is a
necrotizing colitis that is frequently localized to
the cecum, although it may involve the entire col-
on [85]. It is primarily a disease of neutropenic pa-
tients and occurs most often in children with acute
leukemia. Typically, the patient presents with the
sudden onset of fever, abdominal distention, and
pain that gradually increases. A variety of gram-
negative bacilli may cause this infection, but
P. aeruginosa is one of the most common patho-
gens. If the infection is localized, the diseased seg-
ment of bowel can be surgically excised; other-
wise, the patient usually dies of this infection.
Perirectal abscesses are a common and serious
form of infection in patients with acute leukemia.
The abscesses are frequently the source of
hematogenous dissemination. In one study 55070
of cases were caused by P. aeruginosa [86]. Over
half of these infections terminate fatally. Not in-
frequently, the infecting organisms develop
resistance during antibiotic therapy.
Respiratory tract. P. aeruginosa is an uncom-
mon cause of pneumonia. In a review of 801 cases
of community- and hospital-acquired pneumonia,
only 19 cases were found to have been caused by
this organism [87]. Only two of these 19 cases were
acquired outside of the hospital. Of 292 cases of
community-acquired pneumonia treated at Grady
Memorial Hospital in Atlanta, only two were
caused by P. aeruginosa [88]. Hospital-acquired
pseudomonas pneumonia is most likely to occur in
patients with hematologic malignancies, cystic fi-
brosis, diabetes, chronic lung disease, or heart
disease, or in those who have undergone surgery
Bodeyet at.
or tracheostomy. Of 36 patients with pseudo-
monas pneumonia treated at the National In-
stitutes of Health in Bethesda, Maryland, 22 had
hematologic diseases, seven had cancer, and five
had cystic fibrosis [89]. Mortality was 81 %. In
another study P. aeruginosa caused 21070 of 217
cases of gram-negative bacillary pneumonia in pa-
tients with cancer [90].
Signs and symptoms of pseudomonas pneu-
monia include apprehension, severe toxicity, men-
tal confusion, chills, fever, cough, severe dyspnea,
and relative bradycardia [91]. Often, patients have
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associated pharyngitis, otitis, or tracheitis. The
characteristic x-ray pattern is a diffuse broncho-
pneumonia - often bilateral- involving multiple
lobes. Some patients have distinctive nodular infil-
trates with small areas of radiolucency that pre-
sumably represent normal lung tissue between
microabscesses. The posterior aspects are most in-
volved, and the apices are usually spared.
Two types of lesion have been found at autopsy
examination [92] (figure 4). Some sites of involve-
ment appear as poorly defined, hemorrhagic, nod-
ular, indurated areas, often located subpleurally.
The hemorrhagic lesions are located around small
and medium-sized pulmonary arteries. Discrete
foci of intraalveolar hemorrhage, with many
gram-negative bacilli, can be identified. An in-
flammatory reaction is usually minimal or absent.
Infected areas also appear as firm, yellow-brown,
necrotic, umbilicated nodules surrounded by
hemorrhagic parenchyma. Necrotic nodules con-
sist of an amorphous coagulum of necrotic
material, with many organisms invading vessel
walls. This situation results in marked vasculitis
but seldom in thrombosis.
The therapy for pseudomonas pneumonia is
suboptimal, and mortality varies from 50% to
80070. In one series of 45 cases in patients with
cancer, the cure rate was 64070 [90]. The poor pen-
etration of most antibiotics into bronchial secre-
tions probably accounts for the poor response
rates. Recommended therapy in the past has been
the combination of an antipseudomonal penicillin
plus an aminoglycoside, but other options now ex-
ist in the form of the third-generation cephalo-
sporins. P. aeruginosa may persist in the sputum
despite clinical improvement and may develop
low-level resistance to the antipseudomonal peni-
cillins. This emergence of resistance does not ne-
P. aeruginosa Injections
Figure 4. Section of pulmonary tissue obtained at autopsy from a patient who died of pseudomonas pneumonia.
cessarily portend the failure of antibiotic therapy
and cannot be prevented by the concomitant ad-
ministration of aminoglycosides [93].
Pseudomonas pulmonary infection is especially
prevalent among patients with cystic fibrosis. Re-
ported rates of colonization of the respiratory
tract by P. aeruginosa have varied from 18070 to
80070 [94]. In a recent study 3,052 pulmonary spe-
cimens were obtained from 134 living patients
with cystic fibrosis, and P. aeruginosa was iso-
lated from 26070 of cultures [95]. An additional
834 specimens were obtained from 26 patients
who subsequently died, and P. aeruginosa was iso-
lated from 62070 of these cultures. Colonized pa-
tients were older; had more extensive exposure to
291
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mists, aerosols, and antibiotics; and had been hos-
pitalized longer than uncolonized patients. Mu-
coid strains of P. aeruginosa predominate in pa-
tients who are chronically colonized and are found
with increasing frequency as the disease pro-
gresses. The reasons for colonization by P. aerugi-
nosa and the change to the mucoid form are not
fully understood. Ninety percent of the mortality
and most of the morbidity in cystic fibrosis are
due to pulmonary involvement. While pulmonary
infection is secondary, it is the principal cause of
irreversible damage to the lungs. Control of the in-
fection decreases the deterioration of pulmonary
function and increases the rate of survival. Many
studies have evaluated the efficacy of aminoglyco-
292
sides and penicillins against pseudomonas infec-
tions in patients with cystic fibrosis. Although
symptomatic improvement can be expected in
most patients, P. aeruginosa is seldom eradicated
from the sputum. Combination therapy with an
antipseudomonal penicillin and an aminoglyco-
side produces more favorable results than therapy
with either drug alone [96]. A recent prospective
randomized trial compared ticarcillin plus tobra-
mycin with gentamicin plus carbenicillin, primari-
ly in patients with cystic fibrosis who had pseudo-
monas respiratory-tract infections [97]. When only
pulmonary infections were considered, the
response rate was 93070 for the former regimen and
68070 for the latter regimen (P< 0.05). These inves-
tigators found that the combination of ticarcillin
plus tobramycin was more predictably synergistic
against isolates of P. aeruginosa..
Several studies have indicated that endotracheal
instillation of aminoglycoside antibiotics improves
the response rate among patients with gram-nega-
tive bacillary pneumonia. A group of 38 uncon-
scious patients with tracheostomies or endotracheal
tubes received systemic therapy with sisomicin and
carbenicillin [98]. Eighteen patients were random-
ly assigned to receive endotracheal sisomicin as
well. A favorable clinical response was observed in
77% of the 18 patients who received endotracheal
sisomicin but in only 45070 of the 20 patients who
received no endotracheal therapy (P < 0.05). The
majority of patients in both groups were infected
by P. aeruginosa. More recently, a similar group
of 20 patients received systemic therapy with mez-
locillin plus endotracheal sisomicin [99]. Ten
patients also received systemic sisomicin. A sub-
stantial number of these patients were infected
with P. aeruginosa. The similarity of the response
rates in the two groups suggested that, if given in
combination with a systemically administered an-
tipseudomonal penicillin, endotracheal therapy
with aminoglycosides may be more important
than systemic therapy with these antibiotics. Fur-
ther studies are needed to confirm these interesting
observations.
Urinary tract. P. aeruginosa seldom causes
uncomplicated urinary-tract infections. The ma-
jority of pseudomonas infections of the urinary
tract are acquired during hospitalization and oc-
cur after genitourinary manipulation, insertion of
catheters, or treatment with antibiotics. No speci-
fic characteristic distinguishes pseudomonas infec-
Bodey et 0/.
tion from other types of urinary tract infection.
Good results can be achieved with a variety of an-
tipseudomonal drugs, including orally adminis-
tered indanyl carbenicillin.
Bones and joints. Pseudomonas infections of
the bones and joints occur uncommonly, but have
increased in frequency in recent years. Only 31
cases of osteomyelitis and 17 cases of arthritis had
been reported in the world literature by 1960;
however, an additional 58 cases had been reported
by 1972. Infection may arise from hematogenous
dissemination or by extension from a contiguous
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site of infection. In one review of osteomyelitis,
none of 62 cases arising from hematogenous dis-
semination was caused by P. aeruginosa; in con-
trast, 13 of 155 cases arising from a contiguous
focus were caused by this organism [100]. In
another early study, only 2 % of 584 joint infec-
tions were caused by P. aeruginosa [101]. The ma-
jor factors predisposing to these infections are sur-
gery, compound fractures, penetrating wounds,
and drug addiction. Occasionally, patients with
extensive burns or patients undergoing genitour-
inary manipulation develop this type of infection.
A major cause of the increased frequency of
pseudomonas osteomyelitis and osteoarthritis has
been the increased use of iv narcotics. Several in-
stitutions have reported a series of these infections
in drug addicts [102-104]. The most frequent sites
of involvement in these patients are the vertebral
column, pelvis, and sternoclavicular joint, with an
apparent predilection for the last site. Why drug
addicts are predisposed to pseudomonas infec-
tions is uncertain, but the high incidence is prob-
ably related to the use of contaminated iv devices.
The observation that morphine inhibits migration
of neutrophils and decreases phagocytosis in
experimental animals may explain the increased
susceptibility to infection in persons addicted to
this drug.
At least 24 cases of pseudomonas osteoarthritis
have been reported in children who have had
puncture wounds of the foot [105-107]. The usual
course is initial improvement followed by swelling
and tenderness. The patients characteristically
complain of pain but have no systemic symptoms.
The infection begins in the cartilage and sub-
sequently causes bone destruction. Most infec-
tions arise in patients who have received antibi-
otics for their initial injury. Physicians should be
alert to the possibility of this infection so that
P. aeruginosa Infections 293

Table 4. Pseudomonas aeruginosa as a cause of gram- joint rigidity, j oint degeneration, and premature
negative bacillary septicemia: summary of 12 reports on closing of cartilaginous growth plates.
experience between 1934 and 1975.
Blood. P. aeruginosa was not an important
Percentage cause of septicemia until the last three decades.
Total no. of due to Only 1070 of cases of septicemia occurring before
episodes P. aeruginosa Reference
1950 were caused by this organism. Only 91 cases
Years (mortality) (mortality) no.
had been reported in the literature by 1947. Table
1934-1939 59 (...) 1 (...) 108 4 summarizes 12 reports on the experience with
1951-1958 173 (42) 18 (69) 109
gram-negative bacillary septicemia between 1934
1955-1959 113 (31) 17 (68) 110
1955-1967 398 (52) 14 (77) 111 and 1975. Since 1950, P. aeruginosa has caused
1958-1966 860 (51) 12 (66) 112 7070-18 % of all episodes of gram-negative bacil-
1961-1962 100 (55) 10 (40) 113 lary septicemia. The fatality rate from pseudomo-
1962-1968 218 (33) 13 (43) 114 nas septicemia has varied from 37% to 77070,

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1963-1964 100 (45) 7 (57) 115
whereas that from all episodes of gram-negative
1965-1974 612 (25) 10 (37) 116
1967-1969 149 (25) 14 (57) 117 bacillary septicemia has varied from 25% to 55070.
1968-1974 629 (38) 12 (69) 118 In all but one of these series of patients described,
1974-1975 82 (29) 15 (42) 119 the fatality rate from pseudomonas septicemia has
NOTE. Mortality is expressed as a percentage. exceeded that from all gram-negative bacillary
septicemia by 10%-37%.
The frequency and prognosis of pseudomonas
therapy can be administerd before extensive bone septicemia are determined by the patient's under-
destruction occurs. lying disease; this point is illustrated by four ma-
Therapy for bone and joint infections with an jor studies of gram-negative bacillary septicemia
antipseudomonal penicillin and an aminoglyco- (table 5). P. aeruginosa caused 9070 of the episodes
side has been successful, but the antibiotics must of gram-negative bacillary septicemia among pa-
be administerd for three to six weeks. Prosthetic tients whose underlying disease had a good prog-
devices at the site of infection must be removed. nosis, whereas it caused 14% among patients with
Usually, these infections require debridement of an intermediate prognosis and 23070 among pa-
devitalized tissue, but extensive surgery can usual- tients with a poor prognosis. The fatality rate
ly be avoided if an infection is recognized in its from septicemia correlated with the severity of the
early stages and treated appropriately. Significant underlying disease. The fatality rate from pseudo-
sequelae have been observed in children with os- monas septicemia was similar to that from other
teoarthritis of the foot, including cyst formation, types of gram-negative bacillary septicemia except

Table 5. Relation of mortality from gram-negative bacillary (GNB) septicemia to prognosis of underlying disease.
No. of patients (mortality) with indicated prognosis of underlying disease*
Years, type of infection Good Intermediate Poor Reference no.
1951-1958
Pseudomonas 8 (13) 14 (70) 10 (100) 112
Other GNB 77 (10) 51 (63) 13 (85)
1958-1966
Pseudomonas 25 (24) 44 (80) 31 (81) 109
Other GNB 298 (23) 311 (59) 118 (89)
1965-1968
Pseudomonas 14 (50) 22 (77) 7 (88) 120
Other GNB 116 (14) 45 (33) 12 (83)
1965-1974
Pseudomonas 21 (19) 33 (45) 6 (50) 116
Other GNB 241 (15) 274 (30) 37 (38)

* Mortality is expressed as a percentage.

294
among patients whose underlying disease had an
intermediate prognosis. Patients with a serious
underlying disease had a high fatality rate regard-
less of the infecting organism, and patients with-
out a serious underlying disease had a low fatality
rate regardless of the infecting organism.
One of the earliest studies of pseudomonas sep-
ticemia involved 23 patients whose illness was
treated at the National Institutes of Health from
1954 to 1957 [61]. This study does not represent
experience with a general hospital population be-
cause 21 patients had cancer and 13 of these 21 had
acute leukemia. Skin lesions, including ecthyma
gangrenosum, vesicular lesions, and hemorrhagic
cellulitis, were observed in 39% of patients.
Seventy-seven percent of the patients were already
receiving antibiotics when they developed pseudo-
monas septicemia. The median period of survival
from the time when the first positive blood
specimen was collected was only four days, and
only one patient recovered.
Since that study, several reviews of pseudo-
monas septicemia in patients with cancer have
been published. Between 1965 and 1968, 67 epi-
sodes of pseudomonas septicemia occurred in pa-
tients with cancer at M. D. Anderson Hospital in
Houston [12]. Fifteen patients had metastatic
cancer, 34 patients had acute leukemia, and the re-
mainder had other hematologic malignancies.
The organism was cultured from the blood of 49070
of the patients within 24 hr after the onset of fever
and from 75% within the first three days. The
maximal temperature exceeded 101 F in 97070 of
the patients. The majority of patients had neutro-
penia; 70070 had a neutrophil count of <500/mm 3 ,
and 37070 had a neutrophil count of <100/mm 3 •
The infection was rapidly fatal, with 16070 of pa-
tients dying within 12 hr and 33070 dying within 24
hr after P. aeruginosa was cultured from their
blood for the first time. The overall recovery rate
was only 21%. Of the 46 patients who were given a
polymyxin, 24% survived; only 14% of the 21 pa-
tients who received no antipseudomonal drug sur-
vived. Adrenal corticosteroids appeared to have
an adverse effect on outcome. Only 8070 of the 37
patients who received these drugs survived, where-
as 37070 of the 30 patients who did not receive these
drugs survived. Only 15070 of the patients who
received steroids as ancillary therapy for their in-
fection survived.
Bodeyet al.
Between 1970 and 1972, P. aeruginosa caused
28070 of all cases of septicemia at the Baltimore
Cancer Research Center [121]. This organism
caused 36070 of the cases of septicemia in patients
with acute leukemia, 28070 in patients with lym-
phoma, and only 13070 in patients with solid
tumors. Twenty-eight of 48 patients with acute
myelogenous leukemia were colonized by P. aeru-
gin osa, and 19 (68070) of these 28 patients
developed septicemia. In contrast, 42 patients
were colonized by Klebsiella species, but only six
(14%) developed septicemia. Among colonized
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patients, the major factor predisposing to pseudo-
monas septicemia was neutropenia; no patient
with a neutrophil count of>1,000/mm3 developed
septicemia, whereas 44% of patients with neutro-
penia became septicemic.
Investigators at Memorial Sloan-Kettering
Cancer Center (New York) reported on their ex-
perience with 50 episodes of pseudomonas septice-
mia in patients with malignant disease during
1967-1968 and with 52 such episodes during
1971-1972 [122, 123]. Thirty-five patients had
acute leukemia and 30 had lymphoma. Ninety-two
of the 102 infections were acquired in the hospital.
Only two of the 50 patients in the first series had
ecthyma gangrenosum. Mortality was 78070 during
1967 and 1968 and 69070 during 1971 and 1972. In
the first series, 21 patients (42070) died within 24 hr
after onset of their infection. In both series, survi-
val was dependent upon the patient's white blood
cell count. Only 15070 of the 39 patients with
<1,000 white blood cells/mm' survived; in con-
trast, 22% of the 37 patients with 1,000-10,000
white blood cells/rnm" and 50070 of the 26 patients
with>10,000 white blood cells/rnm" survived. In
the first series, 33% of the 30 patients who re-
ceived appropriate antibiotics survived, whereas
only 5070 of the 20 patients who received inappro-
priate or no antibiotics survived. In the second
series 24% of the 42 patients who received antibi-
otics, and 60% of the 10 patients who did not, sur-
vived. Six of 22 patients who received gentamicin
and seven of 20 patients who received gentamicin
plus carbenicillin survived. Only 15070 of the 26 pa-
tients who received adrenal corticosteroids sur-
vived; 45070 of the 26 patients who received no
steroids survived. In the second series, survival
was correlated with the patient's serum immuno-
globulin concentrations. None of the eight pa-
P. aeruginosa Injections
tients with IgG levels of <500 mg/dl, 38% of the
29 patients with levels of 500-1,500 mg/dl, and
50070 of the 10 patients with levels of>1,500 mg/dl
survived. Twenty-two percent of the 23 patients
with IgM levels of <50 mg/dl and 46070 of the 24
patients with levels of >50 mg/dl survived. The
serum immunoglobulin levels of five patients were
unknown.
The first large review of pseudomonas septice-
mia in a general hospital population was reported
from Johns Hopkins Hospital in Baltimore [124],
where 91 cases occurred between 1940 and 1959.
The frequency of pseudomonas septicemia doubled
during the second decade of the study. A substan-
tial proportion of the patients in this series were
children, including 18 premature infants and 27
children with severe congenital or acquired dis-
eases. Twenty-eight patients had lymphoma or
leukemia, and 18 were adults with chronic dis-
eases. P. aeruginosa was cultured from the blood
of 68 patients during life. The overall mortality in
this series was 80070. Twenty-seven of the 28 epi-
sodes in patients with acute leukemia terminated
in death. Eleven of the 18 premature infants and
eight of the 18 adults recovered. Of the 59 patients
who were already receiving antibiotics when they
developed pseudomonas septicemia, only 14
recovered. Infection was cured in only five of 14
patients given polymyxin B. Four patients had
transient bacteremia and recovered without any
antibiotic therapy.
Between 1972and 1974, 108episodes of pseudo-
monas septicemia occurred in 97 patients at the
Shands Teaching Hospital (Gainesville, FL) [125].
Eighty-four percent of the infections were ac-
quired in the hospital, and 85070 occurred in pa-
tients who had received prior antibiotic therapy.
Seventeen percent of the patients were afebrile at
the onset of their infection, 26070 were jaundiced,
10070 had disseminated intravascular coagulation,
and 3070 had ecthyma gangrenosum. More than
one organism was cultured from the blood of 32
patients. Septic shock occurred in 30 patients and
was associated with an exceptionally poor progno-
sis. The overall mortality was 70070. Pseudomonas
septicemia was the immediate cause of the deaths
of 49070 of the patients; these patients died of over-
whelming sepsis or shock shortly after the organ-
ism was cultured. Sixty-one percent of the deaths
occurred on the day septicemia was detected. Mor-
295
tality was related to the patients' underlying dis-
eases. The fatality rate was 67070 among 12 in-
fants, 92070 among 14 patients with solid tumors,
68070 among 21 patients with hematologic malig-
nancies, 71070 among 21 patients with chronic dis-
eases, and 66070 among 32 patients with acute, cur-
able underlying diseases. Mortality was 42070 and
45070 among patients whose septicemia originated
from infections of the skin and the urinary tract,
respectively; it was 91070 among patients whose
septicemia originated in the respiratory tract.
These authors concluded that appropriate antibi-
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otic therapy was not more effective than inappro-
priate therapy.
Seventy-five cases of pseudomonas septicemia
occurring between 1972 and 1975 were reported
from two hospitals in Albany, New York [126].
There were 15 cases of polymicrobial septicemia.
Seventy-three of the 75 cases were nosocomial.
The most common source of infection was the
urinary tract. Hypotension occurred in 52070 of the
patients but was not always due to their infection.
Only two patients had disseminated intravascular
coagulation, and one had ecthyma gangrenosum.
The overall fatality rate was 63070, but not all pa-
tients died of their infection. The fatality rate was
31% within the first 36 hr after the onset of infec-
tion. Several factors (on which information was
not available for all patients) were examined for
their prognostic implications. The fatality rate was
84070 among the 25 patients with cancer, and all
eight patients with leukemia died of their infec-
tion. Mortality was 57070 when septicemia
originated in the urinary tract, but it was 87070
when septicemia originated in the respiratory
tract. Nine of the 10 leukopenic patients died,
whereas only about 60070 of the remaining patients
died. The fatality rate was 80070 among the 36 pa-
tients with abnormal levels of serum creatinine
(> 1.2 mg/dl) but only 40070 among patients with
normal renal function. Of the 19 patients whose
chest x rays were normal, 26070 died; of the 46 pa-
tients whose chest x rays were abnormal 74070 died.
Of the 51 patients who received appropriate anti-
biotics, 62070 died; of the 24 patients who received
inappropriate or no antibiotics, 38070 died. The
higher fatality rate among patients who received
appropriate treatment reflects the greater severity
of their underlying illness.
It is difficult to draw many general conclusions
296
from these studies because of the diversity of the
populations of patients, different approaches to
therapy, and different methods of presenting
data. Clearly, pseudomonas septicemia is rapidly
fatal if not treated promptly with appropriate an-
tibiotics. The only finding characteristic of this in-
fection is ecthyma gangrenosum, which occurs
infrequently in most series of patients. Jaundice
and disseminated intravascular coagulation are
not regular features of this infection. Pseudo-
monas septicemia is primarily an infection of
infants and debilitated and immunocompromised
patients. It is usually acquired in the hospi-
tal, often by patients who are already receiving
antibiotic therapy. Not infrequently, other or-
ganisms are cultured from the blood concomitant-
ly. The fatality rate correlates with the seriousness
of the patients' underlying diseases. In patients
with leukopenia, immunoglobulin deficiency, and
renal impairment, pseudomonas septicemia has a
poor prognosis. The fatality rate is especially high
when this infection is associated with respiratory
tract infection or is accompanied by shock.
Adrenal corticosteroids appear to have no
beneficial effect and may actually be detrimental
to the patient. The role of antibiotic therapy will
be discussed in detail later.
Experimental Pseudomonas Infections
The results obtained from studies with animals
cannot be completely extrapolated to the human
situation; however, these studies have provided
information on the pathogenesis and treatment of
pseudomonas infections. Since P. aeruginosa is a
common cause of morbidity and death among
neutropenic patients, many experiments have been
conducted in neutropenic animals [127-129]. The
majority of these studies have focused on the
therapeutic efficacy of antibiotics and granulocyte
transfusions [130].
A realistic model of fatal bacteremia during im-
munosuppression has been developed by the instil-
lation of 108 cfu of P. aeruginosa into the intact
conjunctival sac of agranulocytic rabbits [131].
Conjunctivitis and necrotizing vasculitis are noted
within 48 hr after challenge. This result cannot be
reproduced in nonneutropenic animals or in gran-
ulocytopenic rabbits challenged with other gram-
negative bacteria or other Pseudomonas species.
Bodey et at.
Therefore, this model is specific, reliable, and
useful for the evaluation of antibiotic therapy.
Pseudomonas infection has been studied in other
animals with drug-induced neutropenia, including
dogs, monkeys, mice, and rats [127, 129, 132].
The benefit of granulocyte transfusions has
been shown in neutropenic beagles. For example,
in one study [133] increasing numbers of P. aeru-
ginosa were administered iv, and after 4 hr antibi-
otics - with or without granulocyte transfusions-
were given. The survival of animals not given
granulocytes was related to the dose of P. aerugi-
nosa injected; 108 bacteria/kg were lethal in >95070
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of animals. The survival of animals given daily
granulocyte transfusions was dependent on the
dose of cells transfused and the collection tech-
nique employed. When continuous-flow centrifu-
gation was used, none of five animals receiving 108
neutrophils/kg daily survived the infectious epi-
sode, while four of five receiving 1.5 X 108 and all
of five receiving 2.0 X 108 neutrophils/kg sur-
vived. When cells collected by filtration leukaphe-
resis were used, 2.5 to 3 times more neutrophils
were necessary for the same protection; none of
five animals survived after receiving 2.0 X 108
neutrophils/kg, one of five survived after receiv-
ing 3.0 x 108 , three of five survived after receiving
4.0 x 108 , and all of five survived after receiving
5.0 x 108 • In a model of pneumonia in leukopenic
dogs, daily granulocyte transfusions (a minimum
of 5 x 109 cells per day) and therapy with gen-
tamicin (5 mg/kg per day) were superior to treat-
ment with gentamicin alone, carbenicillin alone
(500 mg/kg per day), a combination of the two
antibiotics at the same doses, or no antibiotics or
granulocytes [134].
In rats that were given saline, carbenicillin, or
gentamicin, P. aeruginosa multiplied rapidly after
being injected ip and was associated with
bacteremia and death. Early therapy (~2 hr) with
carbenicillin plus gentamicin cured infection in
these animals [135]. Subsequently, the combina-
tion of carbenicillin with either tobramycin or gen-
tamicin was shown to be synergistic in vivo in this
animal model. Early combined therapy with car-
benicillin and either tobramycin or gentamicin in
doses equivalent (on a milligram-per-kilogram
basis) to those used in clinical practice cleared the
bloodstream of P. aeruginosa within 24-48 hr,
eliminated the infecting bacteria from the site of
P. aeruginosa Infections
challenge within 54 hr, and resulted in the survival
of animals challenged with seven times the LDso of
that pseudomonas strain. In contrast, animals
given similar doses of carbenicillin, tobramycin,
or gentamicin alone and those given no therapy
experienced rapid multiplication of the organism
at the challenge site, severe bacteremia, and death
within 72 hr. The in vivo synergy was of no benefit
when therapy was given only twice during the first
day of infection [136]. This model provides useful
information with respect to the therapeutic ef-
ficacy of antibiotics even if it does not truly
simulate the pathogenesis of pseudomonas infec-
tion in humans.
In another study, 100 or 1,000 times the LDso of
a strain of P. aeruginosa was injected into
neutropenic rats. For 24, 48, or 72 hr the animals
were given twice-daily im injections of car-
benicillin (400 mg/kg), gentamicin (10 mg/kg),
both drugs or saline. One hour after administra-
tion of carbenicillion, gentamicin, or both drugs,
the mean bactericidal titers in serum were 1:4, 1:2,
and 1:8, respectively. When two inoculum sizes
and three durations of therapy were used, com-
bination therapy was superior to treatment with
either agent alone in reducing mortality. Fourfold
or greater increases in drug MICs for P. aerugino-
sa were detected in postmortem blood cultures
from 54070 of animals that died during treatment
with carbenicillin, 15070 of those that died during
treatment with gentamicin, and none of those that
died during treatment with both drugs.
The pathogenesis of and mortality caused by
pseudomonas pneumonia in guinea pigs are close-
ly related to the number and function of circulat-
ing neutrophils [137]. When guinea pigs received
an intratracheal challenge of 108 cfu of P. aerugi-
nosa and were then given saline, they all died with-
in 3-4 hr. Therapy with a {J-Iactam antibiotic did
not affect the outcome. However, groups given
gentamicin or tobramycin had survival rates of
39% and 67%, respectively. The addition of car-
benicillin or ticarcillin to either regimen failed to
enhance the survival rates. The rate of clearance
of the organisms from lung sections from animals
sacrificed 3 hr after challenge was higher in the
aminoglycoside-treated group than in the carbeni-
cillin-treated group or in controls. Even though
this model may not accurately reflect the patho-
genesis of P. aeruginosa pneumonia because of
297
the rapid death that follows a challenge with live
cells, it is definitely useful for study of the efficacy
of different antibiotics in the treatment of this
clinical entity.
The rabbit model of endocarditis has become an
accepted method for the study of this disease pro-
cess. Archer and Fekety [138] examined various
therapeutic regimens for left-sided pseudomonas
endocarditis. Sterilization of cardiac vegetations
was accomplished more effectively when the ani-
mals were given high-dose gentamicin (7.5 mg/kg)
or the combination of gentamicin (7.5 mg/kg)
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plus carbenicillin (400 mg/kg). Low-dose gentami-
cin (5 mg/kg) or carbenicillin (400 mg/kg) alone
was less effective. These investigators also showed
that combination therapy for two weeks prevented
relapse in all animals studied and that therapeutic
success was associated with the use of a synergistic
combination, with peak serum bactericidal titers
of ~ 1:6, and with high serum concentrations of
gentamicin.
Van Wingerden et al. [139] have developed a
rabbit model of pseudomonas osteomyelitis in
which normal, healthy animals are used. The
infection is not as severe as pseudomonas infec-
tions induced in neutropenic animals. Combina-
tion therapy with carbenicillin and sisomicin for
four weeks is significantly more effective than
treatment with either drug alone in eradicating
viable bacteria from diseased bone and in preven-
ting sequestrum formation.
Pseudomonas aeruginosa is a common cause of
bacterial keratitis, and several animal models have
been used for the study of this problem [140, 141].
In the guinea pig, tobramycin or gentamicin ap-
plied locally was superior to polymyxin B, and the
combination of carbenicillin and tobramycin
reduced the number of bacteria to a greater extent
than did either drug alone. However, the dif-
ference between the effect of an aminoglycoside
alone and that of an aminoglycoside-carbenicillin
combination was not statistically significant.
Another study showed that early therapy is essen-
tial and that the administration of systemic or sub-
conjunctival antibiotics is ineffective if the infec-
tion is already established [141].
In summary, the following gl neral principles
can be derived from the experience obtained with
experimental pseudomonas infections. In neutro-
penic animals, the early institution of antibiotic
298
therapy is critical for optimal survival rates.
Granulocyte transfusion are helpful in the treat-
ment of pseudomonas infections if they are ad-
ministered with appropriate antibiotic therapy and
if adequate numbers of granulocytes are trans-
fused. Survival rates are higher when combination
therapy with a ~-lactam antibiotic and an amino-
glycoside is utilized rather than either drug alone.
Antibiotic synergy may be important for optimal
therapy, but this benefit is lost if therapy is
delayed. Therapy with a single drug may lead to
the development of drug resistance. In endocar-
ditis, high-dose therapy with an aminoglycoside
plus a ~-lactam drug for at least two weeks is best
for sterilization of cardiac vegetations and preven-
tion of relapse. Combination therapy for pro-
longed periods is best for osteomyelitis. Local and
systemic adminstration of aminoglycosides is opti-
mal for keratitis and endophthalmitis. Whether all
of these principles are totally applicable to the
treatment of pseudomonas infections in humans
remains to be determined.
Treatment of Pseudomonas Infections
Antibiotic therapy. For many years, there was
no effective therapy for pseudomonas infections..
Occasional strains were susceptible to oxytetracy-
cline and kanamycin in vitro, but these drugs had
minimal impact on serious infections. Sporadic
cases of serious pseudomonas infection, includ-
ing bacteremia and meningitis, resolved without
specific therapy, but in most instances death was
the inevitable outcome. In 1947 Stanley reported a
45070 rate of recovery from pseudomonas meningi-
tis treated only with sulfonamides [77].
Polymyxin B and colistin were the first antibiot-
ics introduced into clinical practice that had sub-
stantial antipseudomonal activity. Most isolates of
P. aeruginosa were inhibited in vitro by very low
concentrations (median, 0.78 IAg/ml) of these an-
tibiotics [12]. Unfortunately, their therapeutic ef-
ficacy did not match their in vitro activity. In a
review of 91 cases of pseudomonas bacteremia,
Curtin et al. reported that infection was cured in
only five of 12 patients given polymyxins [124].
The polymyxins were of little benefit in the treat-
ment of pseudomonas bacteremia in patients with
cancer. Only 24070 of 46 such patients who re-
ceived a polymyxin recovered from their infection,
whereas 14070 of 21 patients who received no anti-
Bodeyet al.
pseudomonal therapy recovered [12]. One-third of
the patients in this series were already receiving a
polymyxin when P. aeruginosa was cultured from
their blood for the first time. Among severely
burned patients, mortality from pseudomonas
wound sepsis ranged from 62 % to 93070 during the
time when polymyxins were the only available
therapy [142].
Gentamicin was the first antibiotic with impor-
tant activity against P. aeruginosa, When it was
first introduced, the majority of clinical isolates
were inhibited by ~5 ug/rnl [143]. Many articles
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attested to the efficacy of gentamicin against sim-
ple and complex pseudomonas infections. How-
ever, certain limitations were recognized as greater
experience was gained. Jackson and Riff reported
a cure rate of only 29070 among 21 patients with
pseudomonas bacteremia [144]. Eradication of
P. aeruginosa from the blood and cure of infec-
tion depended upon the peak serum concentration
of gentamicin. However, even with adequate peak
serum concentrations, septicemia could not be
cured in patients with "rapidly fatal" underlying
diseases. Bodey et al. demonstrated in patients
with cancer that the rate of cure of infection with
gentamicin was inversely correlated with the neu-
trophil count at the onset of infection [145]; the
cure rate for gram-negative bacillary infections
was 79% among patients with an adequate neutro-
phil count (> 1,OOO/mm3 ) but only 23% among pa-
tients with severe neutropenia « 1DO/mm 3 •
Response was also related to changes in the neu-
trophil count during the course of infection; the
cure rate was 74070 among patients whose neutro-
phil count increased during infection but only
31070 among those patients whose neutrophil count
decreased.
Several properties of gentamicin have limited its
usefulness as a single agent for the treatment of
pseudomonas infections. Some isolates of P. aeru-
ginosa are only marginally sensitive to this antibi-
otic, and resistance has emerged as a problem in
several institutions. The results of in vitro suscep-
tibility testing can vary considerably depending
upon the concentration of calcium and magne-
sium in the medium. These cations interfere with
the activity of gentamicin, but the clinical rele-
vance of this observation is uncertain. Gentamicin
penetrates poorly into some tissues. The fact that
minimal concentrations are detected in sputum
probably explains the marginal efficacy of this
P. aeruginosa Infections
drug in the treatment of pseudomonas pneumo-
nia. Pus inactivates gentamicin in vitro; therefore,
drainage remains important in the management of
abscesses. In recent years, the recommended
dosage of gentamicin for serious infections has
been increased to 5 mg/kg per day. Even higher
doses have improved the rate of cure of pseudo-
monas endocarditis [146]. However, the potential
for irreversible auditory toxicity and nephrotoxici-
ty prevents the administration of gentamicin at
doses that would provide optimal bactericidal ac-
tivity against some isolates of P. aeruginosa.
Many new aminoglycosides with substantial an-
tipseudomonal activity have been discovered during
the past decade. The results of published in vitro
studies are summarized in table 6. Of the drugs
listed, only tobramycin, amikacin, and gentamicin
are currently available for clinical use in the
United States. In most in vitro studies, tobramycin
was more active against P. aeruginosa than was
gentamicin. However, most isolates that are resis-
tant to gentamicin are also resistant to tobramycin.
In one general hospital, only 19070 of gentamicin-
resistant strains of P. aeruginosa were sensitive to
tobramycin [153]. Most strains are less susceptible
to amikacin in vitro than to tobramycin or genta-
micin, but the use of higher doses of amikacin
eliminates this disadvantage.
Several prospective randomized clinical trials
have failed to demonstate the superiority of one
aminoglycoside over the others for the treatment
of pseudomonas infections. Most large studies of
serious infections have involved neutropenic pa-
tients with cancer, and the number of pseudomon-
as infections in each group has been too small to
permit detection of even major differences [154].
The greater antipseudomonal activity of tobramy-
cin would be of importance in the treatment of
infections caused by isolates that were only mar-
ginally sensitive or marginally resistant to genta-
micin. Amikacin is active against many isolates of
P. aeruginosa that are resistant to other aminogly-
cosides. In one general hospital population, 79070
of gentamicin-resistant isolates were susceptible to
amikacin [153]. Hence, amikacin should be used
routinely in those institutions where gentamicin
resistance is common.
During the early years after the introduction of
gentamicin, many investigators believed that
resistance to this antibiotic would not be a prob-
lem. The first large-scale experience with gentami-
299
Table 6. In vitro activity of aminoglycoside antibiotics
against Pseudomonas aeruginosa.
No. of
Drug strains MIC 9 0 t
Gentamicin 899 2 32
Tobramycin 934 1 6
Amikacin 1,542 2 32
Sisomicin 231 6 128
Netilmicin 124 4 64
Fortimicin 983 16 128
Kanamycin 325 50 100
Dibekacin 247 2 4
Fosfomycin 71 12.5 100
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NOTE. Data are from [147-152].
* The MIC so is the lowest concentration (in /-lg/ml) inhibit-
ing the growth of 50010 of all strains tested.
t The MIC 9 0 is the lowest concentration (in ug/ml) inhibit-
ing the growth of 90% of all strains tested.
cin-resistant strains of P. aeruginosa was gained
on the burn service at Grady Memoral Hospital in
1968 and 1969 [155]. Topical gentamicin prepara-
tions had been utilized effectively from 1964 to
1968 for prophylaxis of pseudomonas burn-
wound sepsis, and 80070-90% of pseudomonas
isolates recovered from patients had been suscepti-
ble to gentamicin in vitro. The incorporation of
hydrotherapy into the management of patients on
this service was associated with an increase in the
frequency of isolation of strains of gentamicin-
resistant P. aeruginosa. Only 20070 of all strains of
P. aeruginosa cultured from burned patients in
1968 and only 9070 of those cultured in 1969 were
susceptible to gentamicin. Resistant strains were
cultured from the whirlpool tanks, sinks, soap,
towel racks, and hands of personnel, but only on
the burn service. When the use of topical gentami-
cin was discontinued, the incidence of gentamicin-
resistant isolates fell promptly to 5070.
Gentamicin resistance among isolates of P. aer-
uginosa varies considerably from hospital to hos-
pital. Despite the extensive use of this drug at the
M.D. Anderson Hospital, only 6070 of isolates are
resistant. At the Baltimore Cancer Research Cen-
ter, none of 197 isolates of P. aeruginosa cultured
between October 1969 and March 1971 was resis-
tant to gentamicin [156]. Oral prophylaxis with
antibiotics, including gentamicin, was initiated at
this institution in July 1970. Between April 1971
and December 1971, 8070 of 145 isolates of P. aeru-
ginosa were resistant to gentamicin; during the six
months beginning in January 1972, 14070 of 142
300
isolates were resistant. Colonization by resistant
strains occurred primarily while patients were
receiving the antibiotic. In a community hospital
surveyed between 1974 and 1975, 19070 of isolates
of P. aeruginosa were resistant to ~161Ag of genta-
micin/ml [153]. Topical or oral preparations of
this antibiotic were not being used at the time of
this survey. Most aminoglycoside-resistant strains
of P. aeruginosa have been cultured from patients
with urinary tract or burn wound infections. Gen-
tamicin resistance has become so common at some
institutions that amikacin is used routinely [157].
Most resistance to aminoglycosides is due to en-
zymatic modification of the drugs by acetylation,
adenylation, or phosphorylation. These enzymes
can be transmitted to other organisms via plas-
mids. Most enzymes that inactivate gentamicin
also inactivate tobramycin; thus, cross-resistance
usually is demonstrated between these two amino-
glycosides. Because amikacin is effectively modi-
fied by only one enzyme found in P. aeruginosa,
many isolates resistant to other aminoglycosides
are sensitive to amikacin. Resistance to aminogly-
cosides also can be caused by decreased membrane
permeability, which would affect all of these anti-
biotics.
The discovery of the antipseudomonal activity
of carbenicillin represented a major advance in the
treatment of pseudomonas infections. Initial re-
ports provided somewhat conflicting data regard-
ing the efficacy of this antibiotic because some in-
vestigators utilized marginal doses. Also, because
of the relatively short half-life of carbenicillin, op-
timal therapy requires frequent dosing, especially
in neutropenic patients. In a study of 59 pseudo-
monas infections in patients with cancer, the rate
of response to carbenicillin was 750/0 overall and
71% among patients with septicemia [158]. The
rate of cure was independent of the patient's neu-
trophil counts-Le., 750/0 among patients with se-
vere neutropenia and 560/0 among patients with
adequate neutrophil counts. Also, the cure rate in
this study was similar whether the patients' neutro-
phil counts increased or decreased during infec-
tion (82070 vs. 76%). Subsequently, pseudomonas
infections in an additional 53 patients with cancer
were treated with combination antibiotic regimens
in which carbenicillin was the only antipseudomo-
nal agent; infection was cured in 800/0 of these
patients [159]. In a collated series of 114 pseudo-
monas infections, 94 (820/0) responded to carbeni-
Bodeyet al.
cillin [160-163]. Twenty-eight (85%) of 33 epi-
sodes of septicemia were cured. Some of these
patients also received gentamicin, but usually their
infection had failed to respond to this antibiotic
before carbenicillin was used. It is difficult to
assess fully the impact of carbenicillin from the lit-
erature because of the diversity of the populations
studied, types of infections, dosage schedules, and
methods of evaluation and the use by some inves-
tigators of antibiotic combinations rather than
carbenicillin alone. Most reports include data on
only a small number of serious infections.
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Shortly after the introduction of carbenicillin,
reports began to appear of rapidly emerging resis-
tance among isolates of P. aeruginosa from pa-
tients receiving this drug. Lowbury et al. reported
isolates of P. aeruginosa that were highly resistant
to carbenicillin on a burn unit where this drug had
been used extensively [164]. Resistance was due to
a penicillinase that was transferable in vitro to
other strains of P. aeruginosa and Enterobac-
teriaceae. This problem was localized to the burn
service and disappeared when carbenicillin usage
was curtailed. Several other investigators reported
a stepwise increase in resistance to carbenicillin
among organisms that persisted during therapy
[165]. In most instances, the MIC increased by
about fourfold but the increase did not result in
failure of therapy. Often, the resistant isolate dis-
appeared when therapy was discontinued. The
rapid emergence of highly resistant organisms dur-
ing treatment was an infrequent cause of thera-
peutic failure. Another factor contributing to con-
cern about the rapid emergence of resistance
resulted from errors in disk sensitivity testing.
Some laboratories did not use standardized proce-
dures and erroneously reported increased resis-
tance to carbenicillin. In one study of 234 "resis-
tant" isolates of P. aeruginosa, 690/0 were found to
be sensitive on retesting [166]. In 1967 and 1968,
89070 of 643 strains of P. aeruginosa were sensitive
to carbenicillin; in 1974, 88070 of 152 strains were
sensitive [166].
Ticarcillin is a relatively new antipseudomonal
penicillin that is twice as active as carbenicillin
against P. aeruginosa in vitro (table 7). However,
most isolates that are resistant to carbenicillin are
also resistant to ticarcillin. Although ticarcillin has
been used extensively for the treatment of pseudo-
monas infections, it has usually been administered
in combination with an aminoglycoside. Hence,
P. aeruginosa Infections 301

large-scale studies evaluating ticarcillin alone have Table 7. In vitro activity of (J-Iactam antibiotics
not been published. According to the material against Pseudomonas aeruginosa.
submitted to the manufacturer, 10 of 12 cases of No. of
septicemia, 24 of 35 evaluable skin and soft-tissue Drug strains MIC so*
infections, and 26 of 52 evaluable respiratory tract Carbenicillin 1,956 85 180
infections caused by P. aeruginosa were cured Ticarcillin 1,834 32 100
with ticarcillin (R. Vann, personal communica- Azlocillin 1,070 16 64
tion). Of a series of 43 pseudomonas infections in Piperacillin 1,008 6 54
Mezlocillin 1,180 34 128
patients with cancer, ticarcillin cured 84070, in-
Furazlocillin 164 4 24
cluding seven of 11 episodes of septicemia [159]. Cefotaxime 1,392 16 64
The overall rate of response to ticarcillin was 74070 Cefoperazone 1,267 6 25
in a study of 94 pseudomonas infections, in- Moxalactam 596 25 100
Ceftazidime 374 1 4

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cluding 12 cases of septicemia, 66 of respiratory
tract infection, 10 of urinary tract infection, and
six of soft-tissue infection [167]. Eleven of the 12
cases of septicemia responded. Although some pa-
tients also received an aminoglycoside, the authors
concluded that ticarcillin alone was equally effec-
tive. Hypokalemia occurred in only 3070 of these
patients. Ticarcillin plus tobramycin was com-
pared with carbenicillin plus gentamicin in a ran-
domized trial involving mostly patients with cystic
fibrosis [97]. The former regimen was found to be
more effective than the latter. Although few com-
parative studies of ticarcillin and carbenicillin
have been conducted, ticarcillin has replaced car-
benicillin at many institutions because it can be
administered at a lower dosage that probably
causes less frequent and severe hypokalemia and
hyponatremia.
The discovery of a penicillin with antipseudo-
monal activity provided an impetus for the synthe-
sis of many new penicillins and, subsequently,
cephalosporins and other {3-lactam antibiotics.
Several early penicillins such as BL-P1654 and pir-
benicillin were abandoned after early clinical trials
[168, 169]. Penicillins recently introduced into the
United States, Europe, or Japan include mezlocil-
lin, azlocillin, piperacillin, and apalcillin. All of
these agents are as active as or more active than
carbenicillin or ticarcillin in vitro (table 7). The
third-generation cephalosporins also have sub-
stantial in vitro activity against P. aeruginosa.
Among these newer cephalosporins, ceftazidime
has the greatest antipseudomonal activity in vitro.
Cefsulodin is an interesting analog because its ac-
tivity against gram-negative bacilli is limited to
P. aeruginosa. In addition, new {3-lactam struc-
tures such as azthreonam and thienamycin have
been found to have impressive antipseudomonal
activity in vitro.
Ceftizoxime 370 50 100
Ceftriaxone 182 50 100
Cefsulodin 865 2 16
Cefmenoxime 158 16 64
Azthreonam 161 3.12 12.5
N-formimidoyl thienamycin 192 2 8
NOTE. Data are from [163-174].
* The MIC so is the lowest concentration (in IAg/ml) inhibit-
ing the growth of 50010 of all strains tested.
t The MIC 9 0 is the lowest concentration (in ug/rnl) inhibit-
ing the growth of 90% of all strains tested.
The in vitro activity of several important anti-
pseudomonal drugs is illustrated in table 8. All
isolates of P. aeruginosa cultured from the blood
of patients with cancer at our institution during
the past five years were tested simultaneously.
However, some isolates from earlier years were no
longer available. Despite extensive use of carbeni-
cillin, ticarcillin, and tobramycin, no substantial
changes in susceptibility have occurred. Cef-
tazidime was the {3-lactam antibiotic most active
against P. aeruginosa in this study.
Several of the new {3-lactam antibiotics have
been introduced into clinical practice, but experi-
ence with their use as antipseudomonal agents is
somewhat limited. It has become rare for large
numbers of cases of pseudomonas infection to ac-
cumulate at a single institution in recent years. For
example, a total of 1,026 febrile episodes were
studied in three large prospective trials of different
antibiotic regimens, and only 50 infections were
caused by P. aeruginosa [170-172]. Hence, a max-
imum of 10 cases of pseudomonas infection were
treated with any of the antibiotic regimens. This
small number of cases makes it impossible to draw
definite conclusions regarding the relative efficacy
of different regimens. The decreased frequency of
pseudomonas infections reflects changes in thera-
302 Bodeyet al.

Table 8. In vitro activity of severalantibiotics against Pseudomonas aeruginosa at M. D. Anderson Hospital (Hous-
ton, TX) during a five-year period.
MIC so/MIC9 0 for isolates in indicated year*
Drug 1977 (48) 1978 (43) 1979 (64) 1980 (122) 1981 (146)

Carbenicillin 50/200 50/100 50/200 50/200 100/>200

Ticarcillin 25/100 25/50 25/100 25/100 25/200
Piperacillin 3.12/12.5 3.12/12.5 3.12125 3.12/12.5 6.25/50
Azlocillin 6.25/25 6.25/25 6.25/25 6.25/25 12.5/100
Moxalactam 25/50 25/25 25/50 25/50 25/100
Cefoperazone 3.12/12.5 6.25/12.5 6.25/25 6.25/12.5 6.25/50
Ceftazidime 1.56/6.25 1.56/3.12 1.56/6.25 1.56/6.25 3.12/6.25
Tobramycin 0.20/0.39 0.39/0.78 0.39/0.78 0.39/0.78 0.39/0.78

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* Numbers in parentheses after years represent numbers of isolates tested. The MIC so and MIC 9 0 are the lowest concentrations
(in jJg/ml) inhibiting the growth of 50% and 90% of all strains tested, respectively.

peutic practices and improvement in antipseu- of these new agents. All of the drugs have sub-
domonal therapy. At our institution, P. aerugino- stantial antipseudomonal activity, but the data on
sa caused 490/0 of all episodes of gram-negative most of these antibiotics have been obtained
bacillary septicemia during 1966-1968 (before primarily from cases of urinary tract infection.
carbenicillin became available) but only 18070 of Most of the lower respiratory-tract infections were
the episodes during 1969-1972 (after carbenicillin cases of pneumonia. Even with this very large data
was used routinely) [173]. base, only a few cases of pseudomonas septicemia
Table 9 summarizes the results obtained with could be evaluated, the largest number of which
several of the new fJ-Iactam antibiotics in the treat- were treated with moxalactam. With this limited
ment of pseudomonas infections. These data were experience, it is not possible to ascribe superior ef-
obtained from the files of the relevant pharma- ficacy to any of these antibiotics.
ceutical companies and represent the collated ex- The potential for emergence of resistant orga-
perience of all clinical investigators involved in the nisms during therapy with the newer fJ-Iactam
initial clinical trials. This information has certain antibiotics has been of some concern. For ex-
limitations, such as differences in the populations ample, in one study of moxalactam, six of 30 in-
studied and the dosage schedules used, but it pro- fections caused by P. aeruginosa failed to respond
vides some indication of the therapeutic efficacy to therapy and 11 isolates developed resistance
during therapy [174]. In another study of this anti-
Table 9. Therapeutic results with new antipseudo- biotic, most organisms that persisted during ther-
monal penicillins. apy became resistant [175]. However, the manu-
No. of episodes of infection at indicated facturer's data indicate that only 43 of 4,400
site (070 responding to therapy*) strains cultured from patients receiving moxalac-
Lower
tam developed resistance during therapy [154].
Antibiotic All sites respiratory tract Bloodstream Thirty of the 43 strains were P. aeruginosa, and
these 30 strains represented only 5.3070 of the total
Mezlocillin 80 (85) 13 (85) 4 (100)
Azlocillin 231 (90) 78 (90) 11 (73)
number of strains of P. aeruginosa cultured. Re-
PiperaciIIin 155 (70) 61 (75) 6 (67) sistance occurred primarily in strains from patients
Moxalactam 395 (71) 57 (67) 30 (80) with urinary tract infections (which were usually
Cefoperazone 76 (79) 23 (87) 8 (100) treated with <1 g of moxalactam per day) and in
Note. Data were obtained from the files of pharmaceutical those from patients with lower respiratory-tract
companies by means of personal communications from the fol- infections, usually complicating cystic fibrosis.
lowing: E. Griffith, Miles Pharmaceuticals; West Haven, CT; It is a generally accepted practice to treat serious
M. Gannt, Lederle Laboratories, Pearl River, NY; D. Fay, pseudomonas infections with the combination of
Pfizer Pharmaceuticals, New York, NY; and R. Kammer, Eli
Lilly and Co., Indianapolis, IN.
an antipseudomonal penicillin and an aminoglyco-
* Response is defined as bacteriologic and clinical cure plus side. This practice is based upon the results of
clinical improvement. studies in vitro and in animals, which indicate that
P. aeruginosa Infections
these agents act synergistically. An antipseudo-
monal penicillin plus an aminoglycoside act syner-
gistically against 30070-50070 of isolates of P. aeru-
ginosa. The mortality from experimental pseu-
domonas infection approaches 90070 when such
infection is treated with carbenicillin or gen-
tamicin but is only 5070 when these drugs are used
in combination [135]. Klastersky et al. [176] and
Anderson et al. [178] reported that synergistic an-
tibiotic combinations are more effective than non-
synergistic combinations. However, in the study
of Anderson et al., synergism benefited only those
patients who had "rapidly fatal" underlying dis-
eases, neutropenia, shock, and pseudomonas in-
fection. Our experience has not indicated a signifi-
cantly higher rate of response to a combination
regimen than to an antipseudomonal penicillin
alone. Table 10 shows the results of treatment of a
large number of pseudomonas (and a few proteus)
infections collated from the literature [154]. Car-
benicillin plus gentamicin was not superior to car-
benicillin alone. The only important difference
was the superiority of carbenicillin alone over gen-
tamicin alone. Only one prospective randomized
trial has evaluated single-agent vs. combination
therapy for pseudomonas infections [177]. The
cure rates were 57070 for gentamicin alone, 50070
for carbenicillin alone, and 83070 for the combina-
tion. A major problem with this study was the
dosage schedule of carbenicillin (10 g every 8 hr).
Because of the short half-life of carbenicillin, this
regimen was probably inappropriate and may
have accounted for the poorer results with this
drug.
Why does a synergistic combination appear to
be superior to a nonsynergistic combination? The
difference in results probably reflects the dif-
ference in efficacy of the antipseudomonal peni-
cillins and aminoglycosides in neutropenic pa-
tients. The only type of synergistic combination
included in the studies reviewed was an amino-
glycoside plus a penicillin. Nonsynergistic com-
binations generally included an aminoglycoside
plus an antibiotic without antipseudomonal activi-
ty, such as a cephalosporin. Hence, what was real-
ly being compared in the treatment of pseudomo-
nas infections was an aminoglycoside alone vs. a
combination containing an antipseudomonal peni-
cillin. The only valid comparison would involve
testing of a combination with strains of P. aerugi-
303
Table 10. Summary of results of treatment of pseudo-
monas and proteus infections with carbenicillin, an
aminoglycoside, or carbenicillin plus aminoglycoside.
Regimen No. of cases (010 cured)
Carbenicillin 73 (71)
Aminoglycoside 64 (48)
Carbenicillin plus aminoglycoside 171 (74)
nasa against which it did and did not have syner-
gistic activity.
Another reason for using the combination of a
Downloaded from http://cid.oxfordjournals.org/ at University of Sussex on December 14, 2012
penicillin plus an aminoglycoside is that it may re-
duce the likelihood of emergence of resistant
P. aeruginosa. In several studies where this possi-
bility was examined, the use of an aminoglycoside
with an antipseudomonal penicillin did not pre-
vent colonization with penicillin-resistant orga-
nisms [180, 181]. The availability of third-genera-
tion cephalosporins requires a critical reappraisal
of this question. The combination of an antipseu-
domonal penicillin plus an antipseudomonal
cephalosporin may be as effective as the combina-
tion of either of these drugs plus an aminoglyco-
side. One study already suggests that this hypothe-
sis holds true for general therapy, although too
few pseudomonas infections were included for the
comparison to be meaningful [182]. If the penicil-
lin-cephalosporin combination should turn out to
be effective, patients with pseudomonas infections
could avoid the risk of nephrotoxicity from
aminoglycosides-an important consideration for
patients with cancer who are receiving other neph-
rotoxic drugs and for patients with impaired renal
function.
The introduction of the antipseudomonal
penicillins and aminoglycosides has had a pro-
found impact on the treatment of pseudomonas
infections. Figure 5 illustrates the different rates
of survival after onset of pseudomonas septicemia
in patients with cancer before and after the intro-
duction of carbenicillin [7]. Despite this impres-
sive difference, several recent papers have ques-
tioned the efficacy of current antipseudomonal
therapy [125, 183]. What accounts for this differ-
ence in perspective? First, different studies use dif-
ferent criteria for failure. Since serious pseudomo-
nas infection occurs primarily in patients with
serious underlying diseases, some patients die of
causes other than their infection. Often this fact is
304
__e_
e - e_ _e
~ Vodey, 19l1+
eo ~ ~hlmPff;1971'
.
~ 60
vi
~
"E::l
40 ~~. ~.~~mPff'1971
...............
(J)
20
+ Rx incl Carbenicillin
Whitecor,1970
---.
,--.---::1
Forkner.195~
o
Survival, days
Figure 5. Effect of therapy on survival after onset of
pseudomonas septicemia: comparison in patients with
cancer before and after the introduction of carbenicillin
(for details, see [7].)
not taken into account in assessing the efficacy of
antibiotic therapy. Second, the population of pa-
tients developing pseudomonas infections is
changing. More intensive antitumor chemother-
apy is being given to patients with cancer, bone
marrow transplants are being performed more fre-
quently, and prosthetic devices are being used
more extensively than in the past. These and other
factors influence the outcome of pseudomonas in-
fection. Third, and most important, clinicians
may fail to administer appropriate antibiotic
therapy at the onset of pseudomonas infection.
Antipseudomonal agents are often administered
only after the diagnosis has been established. Mor-
tality in the first 24 hr approaches 35070 if ap-
propriate therapy is not instituted immediately.
Those studies showing major improvement in the
results of treatment were conducted in closely con-
trolled units where antipseudomonal therapy was
administered at the onset of fever, not after the
establishment of the diagnosis.
Pseudomonas vaccines. The development of
antipseudomonal vaccines for use in humans was
triggered by observations of the protective role of
antibody to P. aeruginosa in animals. For in-
stance, 800/0 of rabbits immunized with whole-cell
vaccine and then challenged with P. aeruginosa
survived; in contrast, <200/0 of the control group
survived [184]. In another study, burned mice
were immunized with extracellular fractions of
P. aeruginosa. The survival rate among the 60 vac-
cinated animals was 930/0, whereas that among the
15 controls was only 33% [185]. Since these early
Bodey et at.
observations, additional studies have been con-
ducted with purified products and multiple an-
tigens in different experimental models.
The protective role of serotype-specific and non-
type-specific active immunity against P. aerugino-
sa infection was evaluated in neutropenic dogs
[56]. Dogs were immunized with either specific
serotype 6 vaccine or nonspecific serotype 3 vac-
cine and then challenged iv with viable serotype 6
P. aeruginosa. A control group was challenged
but not immunized. Animals that received the
serotype-specific vaccine had less fever, markedly
less severe bacteremia, and a significantly higher
Downloaded from http://cid.oxfordjournals.org/ at University of Sussex on December 14, 2012
survival rate than did the other two groups. This
study demonstrated that type-specific immunity
induced by active immunization offers effective
protection against pseudomonas infection during
granulocytopenia.
Recently, a new polyvalent vaccine (PEV-Ol)
has been developed [186]. This vaccine is made
from single components of 16 selected strains of
P. aeruginosa. The method of preparation of the
vaccine suggests that LPS is the serologically ac-
tive component; however, the vaccine has not
been chemically characterized, and the active im-
munogenic entity has yet to be identified. Studies
in animals and in human volunteers have shown
that this new polyvalent vaccine can increase titers
of protective antibody and enhance the bacterici-
dal function of leukocytes within a week after in-
jection [187, 188].
Animal models of respiratory tract infection
have been used for evaluation of the PEV -01 vac-
cine. The effects of intratracheal instillation of
P. aeruginosa were determined in a guinea pig
model [188]. Guinea pigs routinely developed
fourfold rises in HA antibodies to P. aeruginosa
after the administration of vaccine in four injec-
tions over two weeks. The survival rate among
vaccinated animals was significantly higher (13 of
14, or 930/0) than that among control animals (five
of 14, or 360/0). Also, the rate of clearance of
viable P. aeruginosa from the lung was higher and
the amount of tissue damage was smaller in the
vaccinated animals. This type of vaccine is capable
of eliciting a specific protective response in the res-
piratory tract. A recent study found a high level of
pseudomonas opsonins in the bronchial fluid of
vaccinated animals after establishment of experi-
mental pseudomonas pneumonia; this develop-
ment was presumably secondary to diffusion of
P. aeruginosa Infections 305

serum proteins into local inflammatory fluids
[189]. This opsonic antibody appears to be
necessary for the augmentation of phagocytosis by
alveolar macrophages.
In humans, numerous immunization trials have
been conducted; some of these studies are sum-
marized in table 11. Initially, whole-cell vaccines
were used. In one study, both vaccines and hyper-
immune plasma were given to 100 burned patients,
and the results were compared with those for 41
historical controls. In the control groups, 51070 of
patients had pseudomonas septicemia and 32070
deaths of 3.1070 ofvaccinees and 14.1% of controls.
Again, concurrent study of a control group would
have been advantageous.
Since pseudomonas infections are a serious
problem in immunocompromised patients, deter-
mination of the effect of the vaccine in this popu-
lation was of great importance. In a large study,
176 patients with leukemia and solid tumors were
vaccinated, and the outcome of their infections
was compared with that in 185 control patients
[193]. Fatal pseudomonas septicemia occurred in
19 controls and in 10 vaccinees. Thus, the vaccine

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died; in the immunized group, 5070 of patients had
pseudomonas septicemia and 4070 died [190].
Although this difference is impressive, it may be
accounted for by improvements in patient care
during the intervening period. A whole-cell prep-
aration also was used in burned patients. The
percentage of survivors was higher in the group
that received more than three doses than in the
group that received three doses [191].
In later studies, the vaccine most widely used
was the heptavalent preparation described by
Hanessian et al. [197]. This vaccine contains seven
LPS antigens found in more than 90% of the
pseudomonas infections encountered in many in-
stitutions. The early clinical trials with this vaccine
were carried out in burned patients [192]. The out-
come of infection in 96 patients who had burns
over >20070 of their bodies and who were vac-
cinated was compared with that in 75 historical
controls. Pseudomonas septicemia resulted in the
did not provide significant protection against fatal
septicemia. However, mortality associated with
pseudomonas infection was 7070 for the vaccinated
group and 17% for the control groups, and this
difference was statistically significant. A major
problem with the vaccine was the occurrence of
adverse reactions. Ninety-two percent of the vac-
cinated patients developed local tenderness at the
injection site or had fever. More severe reactions,
such as hypotension, bronchospasm, and exten-
sive skin rash, occurred in a few patients.
Although the majority of patients (even those with
acute leukemia and Hodgkin's disease) developed
augmented titers of circulating antibody to one or
more of the antigens used for immunization, these
elevated titers were short-lived.
Two other studies have been conducted in pa-
tients with leukemia. In one study, 28 patients
were immunized, and the outcome of their infec-
tions was compared with that in appropriate con-

Table 11. Summary of results of immunization trials with pseudomonas vaccines.

No. of patients Mortality/sepsis (070)*
Ref-
Risk factor in Vac- Con- Vac- Con- ence
Vaccine population immunized cinees trols cinees trols no.

Whole-cell plus hyperimmune sera Burn wounds 100 41 4/5 32/51 190
Whole-cell Burn wounds 39 0 .. .t ...t 191
Heptavalent (Parke-Davis) Burn wounds 96 75 3.118 14.1118 192
Heptavalent Neoplasia (intensive-care unit) 176 185 7.3/7.8 16.7/10.2 193
Heptavalent Acute leukemia 28 30 10.7/... 16.6/... 194
Heptavalent Acute leukemia 22 20 0/4.5 5/10 195
Polyvalent (16 antigens) Burn wounds 18 20 0/ ... 15/ ... 187
(Burroughs Wellcome)
Polyvalent Burn wounds SIt 56§ 0/0 18.7/12.5 196

* Percentages reflect all instances of mortality and sepsis that were related to pseudomonas infection.
t The proportion of patients that survived was higher among those given more than three doses of vaccine than among those
given three doses.
:\: This group included 30 adults and 21 children.
§ This group included 32 adults and 24 children.
306 Bodeyetal.

troIs [194]. Mortality was 10.7070 in the vaccinated
group and 16.6070 in the control group. In another
study, heptavalent vaccine was evaluated in 22 pa-
tients with acute leukemia, and the results were
compared with those in 20 controls [195]. Twelve
patients with cystic fibrosis were also immunized.
Serum titers of HA antibodies to P. aeruginosa
were determined at regular intervals in vaccines
and controls. Compared with the patients with
cystic fibrosis, the patients with acute leukemia
had a lower and shorter-lived antibody response
and experienced greater toxicity from the vaccine.
from the clinical trials that have been reported so
far, and no comparative studies with heptavalent
vaccine have been carried out.
Efforts to improve outcome among patients at
high risk of pseudomonas infection have involved
the administration of hyperimmune globulin alone
and in combination with vaccine. Table 12 sum-
marizes the results of two studies of immunother-
apy in burned patients. In one study of 96 patients
who received the vaccine, 3.1070 died. In contrast,
none of the 186 patients who received the vaccine
plus hyperimmune globulin died [198]. In the

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Adverse reactions occurred in 100% of patients other study, the PEV-Ol vaccine and/or hyper-
with leukemia and 92 % of patients with cystic immune globulin derived from volunteers immun-
fibrosis. The mixing of steroids with the vaccine ized with the vaccine were administered to burned
greatly decreased the incidence of adverse reac- patients [199]. Ninety-one patients received the
tions without significantly inhibiting antibody vaccine, 48 the hyperimmune globulin, and 37
production. Pseudomonas septicemia occurred in both; 103 patients served as controls. Gram-
4.5070 of patients with leukemia and in 10% of negative septicemia occurred in 27 (45070) of 60
controls. No vaccinees with leukemia died of pseu- control patients from whom blood specimens were
domonas infection, but 5% of controls did. obtained and in 18 (21 %) of 84 immunologically
Although this vaccine has been shown to have a treated patients. Only 2070 of immunologically
protective effect in patients with burns and treated patients had pseudomonas septicemia;
neoplasia, no significant clinical benefit has been 20070 of controls developed this condition. The
demonstrated in patients with cystic fibrosis overall mortality was 5 % among patients who re-
despite adequate antibody levels [195]. For in- ceived the vaccine, 10% among patients who re-
stance, 77% of patients with cystic fibrosis har- ceived both vaccine and hyperimmune globulin,
bored P. aeruginosa, and an antibody response and 29% among controls. In this study, the rate of
occurred in 71% of this group. However, despite colonization of burns with P. aeruginosa was
high antibody titers, the organism was not lower three weeks after immunization in the
eradicted from the respiratory tract. Since such groups that received hyperimmune globulin than
patients are frequently colonized with mucoid in those that did not.
strains, the mucoid polysaccharide may mask cell-
wall LPS and limit enhanced opsonization by anti-
Table 12. Results of immunotherapy for pseudomon-
bodies to LPS. as infections in burned patients.
Jones et aI. conducted several trials with the
Study [reference], group, No. of Mortal-
PEV-01 vaccine in burned patients and found that
type of treatment* vaccinees ity (070)
it prevented pseudomonas septicemia and reduced
the frequency of septicemia caused by other gram- Alexander and Fisher [198], all patients
negative bacteria [187, 196]. The protection Heptavalent vaccine 96 3.1
Heptavalent vaccine and HIS 186
associated with nonpseudomonal infections and Jones et al. [199]
the early occurrence of death secondary to burn Adult
wound sepsis suggest that some of the protection Polyvalent vaccine 60 8.3
was nonspecific. In patients with burns, studies of Polyvalent vaccine and HIS 22 13.6
both heptavalent and PEV-Ol vaccine suggest that Hffi m 10
None (control) 61 36
protection is conferred by active immunization. Children
However, definitive, randomized, controlled Polyvalent vaccine 31 6.4
studies to support this conclusion are lacking. The Polyvalent vaccine and HIS 15 6.6
PEV-OI vaccine is believed to be less toxic than the HIS 18
None (control) 42 21
heptavalent preparations; however, no quan-
titative data on human reactivity are available * HIS = hyperimmune sera.
P. aeruginosa Infections
Although the major impact of immunotherapy
has been in burned patients, such treatment has
also been beneficial in patients with cancer. In the
latter group, it is possible that the new PEV-01
vaccine and hyperimmune serum will be effective
both as prophylaxis and as therapy. These current
vaccines provide variable degrees of protection,
and the ideal vaccine has yet to be developed. Be-
cause most of the preparations now available are
LPS vaccines that frequently cause adverse reac-
tions, the search for less toxic immunizing sub-
stances continues. Interest has also been directed
towards identification of "common antigens" that
might be useful in producing a monovalent vac-
cine. New preparations, such as pseudomonas ri-
bosomal vaccine and antisera, are being tested in
animals, and the results are encouraging [200]. Re-
cently, a high-molecular-weight polysaccharide
vaccine has been tested for safety and immunoge-
nicity in adult volunteers [201]. The results indi-
cate that the vaccine has minimal toxicity and that
a significant rise in binding and opsonic antibody
titers occurs two weeks after immunization. The
antibody titers remain unchanged for up to six
months. These new preparations appear promis-
ing in terms of tolerability and efficacy.
Conclusions
Pseudomonasaeruginosa has become an impor-
tant cause of infection, especially in patients with
compromised host-defense mechanisms. Many
studies have contributed to our knowledge of the
pathogenesis, immunology, and treatment of
these infections. Although the aminoglycosides
represented a significant step forward in the treat-
ment of pseudomonas infections, the most impor-
tant advance was the discovery of the antipseu-
domonal penicillins. These antibiotics are more
effective than aminoglycosides in neutropenic pa-
tients, who are especially susceptible to pseudo-
monas infections. Although the accepted practice
has been the use of a penicillin plus an aminogly-
coside, the introduction of new {3-lactam agents
with antipseudomonal activity offers the possibil-
ity of other approaches to combination therapy.
However, since pseudomonas infection usually
progresses rapidly, optimal results will always de-
pend upon prompt initiation of appropriate ther-
apy in febrile patients who are at high risk. It is
hoped that continuing investigation of pseudomo-
307
nas vaccines will lead to the discovery of effective
prophylaxis for highly susceptible patients.
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