Pseudomonas aeruginosa

By Thomas P. Lodise, Jr., Pharm.D., Ph.D.; and Monique R. Bidell, Pharm.D., BCPS

Reviewed by James S. Lewis II, Pharm.D.; Jamie L. Wagner, Pharm.D., BCPS; and Stephen B. Vickery, Pharm.D., BCPS

LEARNING OBJECTIVES

1. Evaluate the microbiology, epidemiology, pathogenesis, mechanisms of resistance, and clinical presentation in patients
with a possible Pseudomonas aeruginosa infection.
2. Evaluate patient populations at greatest risk of having an infection caused by P. aeruginosa, including multidrug-resis-
tant strains.
3. Design a therapeutic regimen for a patient with a suspected or documented P. aeruginosa infection.
4. Justify the role of antimicrobial stewardship and the pharmacist in treating patients with P. aeruginosa infections.

INTRODUCTION
ABBREVIATIONS IN THIS CHAPTER
Pseudomonas aeruginosa is among the more common causes of infec-
AME Aminoglycoside-modifying
enzyme tions in the hospital setting. These infections are associated with
CDI Clostridioides difficile infection significant morbidity and health care expenditures, especially when
ESBL Extended-spectrum β-lactamase receipt of appropriate antibiotic therapy is delayed. Antibiotic selec-
HABP Hospital-acquired bacterial tion for patients with P. aeruginosa infections is challenging because
pneumonia of the pathogen’s intrinsic resistance to many commercially avail-
HAP Hospital-acquired pneumonia able antibiotics. Multidrug-resistant strains are prevalent, and often
MBL Metallo-β-lactamase require treatment with novel or “last resort” agents. Infectious dis-
MDR Multidrug-resistant eases pharmacists can help provide optimal care for patients with P.
PBP Penicillin binding protein aeruginosa infections by being familiar with key aspects of its microbi-
PDR Pandrug-resistant ology, epidemiology, pathogenesis, innate and acquired mechanisms
VABP Ventilator-associated bacterial of resistance, and clinical presentation. In addition, pharmacists pro-
pneumonia viding care to patients with P. aeruginosa infections should be able
VAP Ventilator-associated pneumonia to proactively identify patient populations at greatest risk of having
XDR Extensively drug-resistant an infection caused by multidrug-resistant (MDR) strains, detail the
available treatment options for its varying clinical presentations, and
Table of other common abbreviations. provide timely evidence-based treatment recommendations, espe-
cially for patients with suspected or documented MDR P. aeruginosa
infections.

MICROBIAL CHARACTERISTICS
Microbiology
P. aeruginosa is a ubiquitous gram-negative aerobe belonging to the
family Pseudomonadaceae. P. aeruginosa is rod shaped and occurs
singly, in pairs, or in short chains. The term aeruginosa stems from the
green-blue hue within colonies of many clinical isolates. P. aeruginosa
does not ferment carbohydrates but produces acid from sugars such
as glucose, fructose, and xylose but not lactose or sucrose. P. aerugi-
nosa can also grow anaerobically if nitrates are available. Almost all

IDSAP 2019 BOOK 2 • MDR Gram-Negative Infections 7 Pseudomonas aeruginosa

 P. aeruginosa strains carry the biosynthetic genes to produce
an extracellular polysaccharide known as alginate. Alginate
BASELINE KNOWLEDGE STATEMENTS
is often called “mucoid exopolysaccharide” or “glycocalyx,”
Readers of this chapter are presumed to be familiar and overproduction is responsible for the mucoid colony phe-
with the following: notype. On the molecular level, P. aeruginosa has an impres-
• Common antibiotics with (and without) in vitro sively large genome. Genetic sequencing shows the presence
activity against P. aeruginosa of 6.26 megabase pairs (Mbp), encoding 5567 genes. Around
• Common dosing strategies of antibiotics with in 1500 genes are used in cell growth, division, metabolism, and
vitro activity against P. aeruginosa protein structural integrity. Comparatively, Escherichia coli and
• General understanding of susceptibility data and Haemophilus influenzae have 2.81 (2594 genes) and 1.83 Mbp
MIC distributions (i.e., knowledge of low vs high (1714 genes), respectively. This enhanced coding ability of the
MICs for antibiotics with in vitro activity against P.
P. aeruginosa genome allows greater metabolic versatility and
aeruginosa)
high adaptability to environmental changes (Pang 2019).
Table of common laboratory reference values
Reservoirs

ADDITIONAL READINGS P. aeruginosa is naturally found in soil, in water, and on plants

and animals. Although P. aeruginosa is tolerant of a variety
The following free resources have additional back- of physical conditions, it has a predilection for moist envi-
ground information on this topic: ronments. Hospital reservoirs include humid environmental
• Mensa J, Berberan J, Soriano A, et al. Antibiotic sources such as respiratory equipment, cleaning solutions,
selection in the treatment of acute invasive infec- sinks, and mops. P. aeruginosa is also introduced into the hos-
tions by Pseudomonas aeruginosa: guidelines by the
pital environment by visitors (e.g., bringing plants, fruits, and
Spanish Society of Chemotherapy. Rev Esp Quimi-
oter 2018;31:78-100. vegetables) and patients transferred from other facilities.
Water-related reservoirs outside hospitals for P. aeruginosa
• Moradali MF, Ghods S, Rehm BH. Pseudomonas include swimming pools, whirlpools, hot tubs, and contact
aeruginosa lifestyle: a paradigm for adaptation, sur-
vival, and persistence. Front Cell Infect Microbiol lens solutions.
2017;7:39. P. aeruginosa is not a typical member of the human micro-
• Livermore DM. Multiple mechanisms of antimicro- biome, and the prevalence of colonization in healthy individ-
bial resistance in Pseudomonas aeruginosa: our uals is relatively low. Up to 5%–10% of healthy humans carry
worst nightmare? Clin Infect Dis 2002;34:634-40. P. aeruginosa in the throat, in the nasal mucosa, or on the skin,
• Pang Z, Raudonis R, Glick BR, et al. Antibiotic resis- and stool carriage rates have been reported to be as high as
tance in Pseudomonas aeruginosa: mechanisms 24% (Berthelot 2001). Human colonization can also occur at
and alternative therapeutic strategies. Biotechnol
moist sites, such as the perineum, axilla, and ear. Hospitaliza-
Adv 2019;37:177-92.
tion and other health care facility exposures greatly increase
• Shortridge D, Gales AC, Streit JM, et al. Geographic the risk of carriage with P. aeruginosa. Carriage is particu-
and temporal patterns of antimicrobial resistance
in Pseudomonas aeruginosa over 20 years from the larly common on the skin of patients with compromised skin
SENTRY Antimicrobial Surveillance Program, integrity, in the lower respiratory tract of patients undergoing
1997-2016. Open Forum Infect Dis 2019;6(suppl 1): mechanical ventilation, and in the GI tract of patients receiv-
S63-S68. ing chemotherapy for neoplastic diseases or those with prior
• Hawkey PM, Warren RE, Livermore DM, et al. Treat- antibiotic exposure.
ment of infections caused by multidrug-resistant
gram-negative bacteria: report of the British Soci- Pathogenesis
ety for Antimicrobial Chemotherapy/Healthcare P. aeruginosa is an opportunistic pathogen, and most P. aerugi-
Infection Society/British Infection Association
nosa infections occur in individuals with altered host defense
Joint Working Party. J Antimicrob Chemother
2018;73(suppl_3):iii2-iii78. mechanisms. Individuals with compromised immune func-
tion are particularly vulnerable to P. aeruginosa infections. The
• Kalil AC, Metersky ML, Klompas M, et al. Manage- original source of the organism and the precise mode of trans-
ment of adults with hospital-acquired and ventila-
tor-associated pneumonia: 2016 clinical practice mission are often unclear in most patients. Health care–asso-
guidelines by the Infectious Diseases Society of ciated transmission typically occurs from patient to patient
America and the American Thoracic Society. on the hands of hospital personnel, by direct patient contact
Clin Infect Dis 2016;63:e61-e111. with contaminated reservoirs, and by the ingestion of contam-
• Bassetti M, Vena A, Croxatto A, et al. How to man- inated foods and water. In most cases, entry of P. aeruginosa
age Pseudomonas aeruginosa infections. Drugs into humans occurs by the oral or respiratory route, and col-
Context 2018;7:212527.
onization often precedes overt infection. Once host entry is

IDSAP 2019 BOOK 2 • MDR Gram-Negative Infections 8 Pseudomonas aeruginosa

gained, the pathogenesis of P. aeruginosa infections is best determine the degree of resistance (i.e., low or high) to specific
viewed as occurring in three stages: (1) bacterial attachment agents or classes (e.g., aminoglycoside-modifying enzymes
and colonization, (2) local invasion, and (3) dissemination and [AMEs]) or an array of agents in unrelated classes (e.g., efflux
systemic disease. This process often occurs in the setting of pumps that can confer resistance to β-lactams, fluoroquino-
disruption of the integrity of natural anatomic barriers to bac- lones, and aminoglycosides) (Table 1).
terial invasion (e.g., skin, mucous membranes) or by circum- Resistance mechanisms present in P. aeruginosa can be
vention of them, as with medical devices (e.g., central venous classified as intrinsic, acquired, or adaptive (Figure 1). Intrin-
catheters, urinary catheters, endotracheal tubes). P. aerugi- sic resistance mechanisms stem from genes that encode the
nosa has an array of innate and acquired immune factors that inherent properties of cell structures and composition that
enable it to surmount host defenses and establish infection. provide protection against toxic molecules and antimicrobi-
als. Acquired resistance mechanisms result through muta-
Quorum Sensing and Biofilms tion of intrinsic genes or horizontal acquisition from other
P. aeruginosa expresses several virulence factors that promote bacteria through transferring plasmids carrying genetic
the establishment and persistence of infection. Many of these materials encoding for antibiotic resistance. Acquired resis-
factors are believed to be regulated by cell density–dependent tance typically occurs in response to selective antibiotic pres-
quorum sensing. This process involves single bacteria releas- sures. These mechanisms are stable and can be transferred
ing small molecules called “acylated homoserine lactones” vertically (e.g., upon bacterial replication) or horizontally
that diffuse to other cells, signaling activation of intracellu- (e.g., resistance genes by plasmids). Adaptive resistance is
lar transcriptional regulators. This signaling ability is believed induced in the presence of specific antibiotics and other envi-
to create a substantial advantage for the bacteria against ronmental stresses and is transient, given that susceptibility
the host, given that coordinated gene regulation can occur is restored upon removal of the stimuli. This type of resis-
within the cellular community. Quorum sensing is believed tance mainly relies on induced alterations in gene expression,
to contribute to pathogen dissemination within the host and resulting in increased protein production or alterations in anti-
contribute to its virulence (Smith 2003). Quorum sensing con- biotic targets.
tributes to biofilm formation and maturation, which can result
in persistent or chronic infection. Biofilms promote microbial Outer Membrane Porins and Permeability
persistence given that cells are shielded from antibiotic pen- Alterations
etration by an extracellular matrix. Subpopulations within the Intrinsic resistance in P. aeruginosa is partly because of the
biofilm can exist as “persister variants,” which are essentially relative impermeability of its outer membrane to many anti-
dormant cells with low metabolic function. Persister variants biotics. Membrane porins are a means of cellular entry for
in biofilms may have decreased susceptibility to antibiotics, certain antibiotics such as β-lactams. Mutations including
presumably because of slowed metabolic function and lack modification of the size or conductance of the porin channel,
of active replication (Grassi 2017). The simultaneous interplay decrease in the number of porins, and complete porin loss
of biofilms, persisters, and quorum sensing among the bacte- can occur as an important mechanism of resistance. The
rial population promotes persistent colonization or recurrent best-characterized porin mutation for P. aeruginosa is loss of
infections. OprD, which confers resistance to carbapenems. Imipenem
(i.e. imipenem/cilastatin) appears to be most affected, fol-
ANTIMICROBIAL RESISTANCE lowed by meropenem. Reduced expression of OprF appears
MECHANISMS to impair the permeability of fluoroquinolones and β-lactams.
The best-characterized mechanisms of antimicrobial resis- In isolation, porin changes or loss tends to confer low-level
tance in P. aeruginosa include outer membrane porins and resistance and results in isolates with MIC values slightly
permeability alterations, efflux pumps, antibiotic-inactivating above the susceptibility breakpoint.
enzymes, and target binding site mutations. Many resistance In addition to porin mutations, other alterations in mem-
mechanisms are often present and expressed simultaneously brane characteristics can affect antibiotic activity. Unlike
in a given patient with a P. aeruginosa infection. The terms the carbapenems, aminoglycosides do not depend on porin
MDR, extensively drug resistant (XDR), and pandrug-resistant channels for cellular entry, given that they can traverse the
(PDR) are often used to characterize the different patterns of membranes of porin-deficient P. aeruginosa isolates. Instead,
multidrug resistance exhibited by P. aeruginosa. An MDR iso- aminoglycosides appear to undergo a type of self-promoted
late is nonsusceptible to at least one agent in three or more uptake across the bacterial membrane secondary to mem-
antibiotic classes with intrinsic activity. An XDR isolate is brane disruption. This may involve interaction with negatively
nonsusceptible to at least one agent in all but two or fewer charged lipopolysaccharides, given that aminoglycosides
antibiotic classes with intrinsic activity, and a PDR isolate is are positively charged molecules. Changes in the polarity or
nonsusceptible to all agents with intrinsic activity. The mecha- charge of the outer cellular membrane are believed to contrib-
nisms of resistance present and the extent of their expression ute to aminoglycoside nonsusceptibility. Lipid modifications

IDSAP 2019 BOOK 2 • MDR Gram-Negative Infections 9 Pseudomonas aeruginosa

 Table 1. Mutational Resistance in P. aeruginosa

Effect on strain, according to antipseudomonal drug

Mutation
Mechanism site Fq Carb-Tic Pip-Azl Czid-Atm Cpm-Cpr Imi Mero Agl Pm

Reduced affinity

  Of topoisomerase II gyrA r/R — — — — — — — —

  Of topoisomerase IV parC r/R — — — — — — — —

Derepression of AmpC

 Partial ampD — R R R r — — — —

 Total ampD + other — R R R R — — — —

Up-regulation
  Of MexAB-OprM nalB at mexR; R/R R r/R r/R r/R — r — —
nalC at other
  Of MexCD-OprJ nfxB r/R r/R r/R r/R R — r — —
  Of MexEF-OprN nfxC at mexT r/R r/R r/R r/R r/R r r — —
  Of MexXY-OprM r/R r/R r/R r/R r/R — r r/R —
Reduced — — — — — — — r/R —
aminoglycoside
transport
Loss of OprD oprD; nfxC at — — — — — R r — —
mexT
Membrane changes — — — — — — — — R

Agl = aminoglycosides; Atm = aztreonam; Azl = azlocillin; Carb = carbenicillin; Czid = ceftazidime; Cpm = cefepime; Cpr = cefpirome;
FQ = fluoroquinolone; Imi = imipenem; Mero = meropenem; Pip = piperacillin; Pm = polymyxin; r = reduced susceptibility; R = frank
resistance, which may vary in its distinction from r according to the breakpoints adopted; Tic = ticarcillin.
Reprinted with permission from Livermore DM. Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our
worst nightmare? Clin Infect Dis 2002;34:634-40.

in the bacterial membrane by incorporating positively charged antibiotics such as β-lactams, fluoroquinolones, amino-
sugars may decrease the affinity for, or even repel, aminogly- glycosides, macrolides, tetracyclines, sulfonamides, and
cosides. This is expected to result in moderate resistance, chloramphenicol, among other compounds. Multidrug-re-
likely resulting in a susceptibility interpretation of “interme- sistant isolates are very likely to have efflux pump system
diate.” A similar mechanism of resistance is described for up-regulation.
polymyxins. Mutations in the regulatory systems PhoPQ, P. aeruginosa has several multidrug efflux pump systems.
PmrAB, and ParRS reduce the negative charge of the cell sur- Of the five protein efflux system families described to date,
face, thereby reducing favorable interactions with positively most of those expressed in P. aeruginosa are members of the
charged polymyxins. Although still largely uncommon, this is same (i.e., resistance-nodulation-cell division) superfamily.
the most well-characterized mechanism for polymyxin resis- These efflux systems usually have three components: a cyto-
tance among P. aeruginosa. plasmic membrane pump, a cytoplasmic membrane “exit”
porin, and a linker protein. The best-described pump system
Efflux Pump Systems in P. aeruginosa is MexAB-OprM, which is expressed in all iso-
P. aeruginosa has a robust efflux pump system. The primary lates to varying degrees. Wild-type strains tend to have rel-
purpose of these pumps is to expel toxic environmental com- atively low expression, but mutations in the mexR repressor
pounds or metabolites from the cytoplasm that might oth- gene can result in pump overexpression. Overexpression of
erwise disorganize the cytoplasmic membrane. Substrates MexAB-OprM results in high-level resistance (e.g., increases
of these pump systems include many clinically relevant in MIC by 8-fold) to a range of antibiotics. Genetic deletion

IDSAP 2019 BOOK 2 • MDR Gram-Negative Infections 10 Pseudomonas aeruginosa

 Figure 1. Intrinsic, acquired, and adaptive mechanisms confer antibiotic resistance in P. aeruginosa.
Car = carbapenems; Ceph = cephalosporins; Pen = penicillins; Ami = aminoglycosides; Flu = fluoroquinolones; Mac = macrolides
and Pol = polymyxins
CM = cytoplasmic membrane; LPS = lipopolysaccharide; OM = outer membrane
Reprinted with permission from Moradali MF, Ghods S, Rehm BH. Pseudomonas aeruginosa lifestyle: a paradigm for adaptation,
survival, and persistence. Front Cell Infect Microbiol 2017;7:39.

of this pump restores susceptibility to many agents that are OprM system, pump expression for these other systems
not considered clinically active against P. aeruginosa such can vary. Several of these systems can be up-regulated in
as amoxicillin, cefuroxime, and tetracycline. The antipseu- the presence of low concentrations of certain antibiotics,
domonal agents perhaps most affected by efflux pumps are as shown with MexCD-OprJ in the presence of fluoroquino-
β-lactams and aminoglycosides, with fluoroquinolones possi- lones and MexXY-OprM in the presence of aminoglycosides.
bly less affected. In some cases, pump up-regulation can be associated with
Other pump systems that have been described in Pseudo- increased pump efficiency by enhancing the affinity for spe-
monas include MexCD (or MexXY)-OprJ, MexEF-OprN, MexXY cific antibiotic substrates. For example, genetic alterations
(AmrAB), MexJK-OprM, and MexVW-OprM. These pumps associated with up-regulation of the MexXY pump system
tend to have fewer substrates than MexAB-OprM, and sub- confer increased resistance to aminoglycosides, fluoroquino-
strate affinity can vary within antibiotic classes. For exam- lones, and cefepime. Antibiotic exposure activates mutant
ple, ceftazidime appears to be a poor substrate of MexXY regulatory genes that simultaneously induce up-regulation of
compared with other cephalosporins, whereas meropenem is efflux pumps (e.g., MexEF-OprN) while down-regulating mem-
more prone to efflux than imipenem. Similar to the MexAB- brane porins (e.g., OprD). Genetic alterations that encode for

IDSAP 2019 BOOK 2 • MDR Gram-Negative Infections 11 Pseudomonas aeruginosa

increased pump expression appear to be tightly regulated, mechanisms of resistance. Ultimately, decreased intracellular
and strains having up-regulation of MexAB and MexCD are antibiotic concentrations by either porin mutations or efflux
less virulent than wild-type strains. can tip the drug-enzyme balance in favor of enzymatic hydro-
lysis. For example, imipenem is a strong inducer of AmpC
enzyme expression but, like other carbapenems, is largely
Enzyme Mediated
considered stable against these enzymes. However, in the
ß-Lactamases setting of concurrent porin loss (e.g., OprD), lower intracellu-
Chromosomally Mediated lar concentrations of imipenem can result in decreased sta-
P. aeruginosa has chromosomally encoded inducible molec- bility against hydrolysis because of higher concentrations of
ular class C AmpC β-lactamases (Table 2). This contributes AmpC enzyme relative to the drug.
to the inherent nonsusceptibility of P. aeruginosa to aminope- Another notable chromosomally mediated β-lactamase
nicillins and early (i.e., first and second) generation cepha- expressed in P. aeruginosa is the molecular class D enzyme,
losporins. However, expression tends to be more variable in OXA-50. This is a relatively narrow-spectrum oxacillinase
P. aeruginosa than in “classic” AmpC-producing Enterobacte- that confers nonsusceptibility to ampicillin and first- and sec-
riaceae. In wild-type strains, production levels are low enough ond-generation cephalosporins. However, MIC elevations
to allow for retained activity of antipseudomonal β-lactams. in aztreonam, ceftazidime, and imipenem, as well as other
However, AmpC β-lactamases can be hyperproduced, with or agents, can be conferred.
without stable de-repression, often in response to the pres-
ence of an antibiotic. Examples of agents that are considered Acquired ß-Lactamases
strong and weak inducers of AmpC in Pseudomonas include The most common acquired β-lactamases are the PSE (Pseu-
imipenem and cefepime, respectively. AmpC hyperproduc- domonas-specific enzyme) penicillinases, which belong to
tion can confer resistance to β-lactams that would other- molecular class A (see Table 2). The PSE penicillinases appear
wise be stable against these enzymes, including prototypical to affect the activity of narrow-spectrum β-lactams but not
antipseudomonal cephalosporins (ceftazidime, cefepime), extended-spectrum cephalosporins, monobactams, or car-
penicillins (piperacillin), and monobactams (aztreonam). bapenems. Other class A β-lactamases, such as TEM, SHV,
Stable de-repression of AmpC is usually believed to occur and CTX-M, occur infrequently in P. aeruginosa. PER-1, another
through mutations in the regulatory ampD or ampR genes. class A β-lactamase, confers high-level resistance to ceftazi-
In some cases, the effectiveness of AmpC β-lactamase dime but does not hydrolyze piperacillin or carbapenems.
activity can be enhanced in the setting of other concurrent

Table 2. β-Lactamase Activity

Wild Cephalosporinase
Type Penicillinase Extended-Spectrum ß-Lactamase AmpC Carbapenemase
WT TEM PSE OXA PER VEB TEM SHV OXA AmpC IMP VIM NDM
CARB CTX-M KPC

Carboxypenicillins S R R R R R R
Carboxypenicillins S S/I I/R S/I I/R R R
+BLI
Ureidopenicillins S I/R R I/R R I/R R
Ureidopenicillins S S/I I/R S/I I/R I/R R
+BLI
Ceftazidime S S S R I/R I/R R
Cefepime S S I/R R I/R I/R R
Aztreonam S S S R I/R I/R S
Imipenem S S S S S S R

BLI = β-lactamase inhibitor; CARBA = carbapenemase; CEPH = cephalosporinase AmpC; ESBL = extended-spectrum β-lactamase;
I = intermediate resistance; PENI = penicillinase; R = resistance; S = susceptible; WT = wild type.
Reprinted with permission from: Bassetti M, Vena A, Croxatto A, et al. How to manage Pseudomonas aeruginosa infections. Drugs
Context 2018;7:212527.

IDSAP 2019 BOOK 2 • MDR Gram-Negative Infections 12 Pseudomonas aeruginosa

 The acquired β-lactamases with the broadest spectrum of Target Site Mutations
resistance are the molecular class A and B KPC and metal- Aminoglycosides
lo-β-lactamases (MBLs), respectively. These enzymes con-
Although up-regulated efflux pumps and AME expression
fer significant resistance to carbapenems, antipseudomonal
are generally considered the best-described mechanisms
cephalosporins, and antipseudomonal penicillins. These
of resistance against aminoglycosides, target binding site
enzymes are not inhibited by clavulanate or tazobactam.
mutations can also occur. The 16S ribosomal RNA methyl-
However, aztreonam activity is maintained in the setting of
transferases, also called RMTases or 16S RNA methylases,
MBLs. Unfortunately, these enzymes rarely occur in isolation;
can modify the A-site on the 16S RNA, part of the 30S ribo-
therefore, aztreonam would likely be hydrolyzed by another
somal subunit, interfering with effective aminoglycoside
β-lactamase (e.g., AmpC) in the absence of an effective inhib-
binding. Although many RMTases exist, the most predomi-
itor. Six types of MBLs have been described for Pseudomonas:
nant are RmtB and ArmA. Clinically, the only aminoglycoside
IMP, VIM, NDM, SPM [Sao Paulo MBL], GIM [Germany imipen-
that appears to retain activity against RMTases is streptomy-
emase], and FIM [Florence imipenemase]. These resistance
cin. RMTases are most commonly acquired by plasmid gene
genes are commonly transported on plasmids and integrons.
transfer. Of note, these enzymes commonly coexist with other
To further complicate clinical treatment, these β-lactamase
genetic elements of resistance, such as β-lactamase–encod-
genes are often transported with AME determinants, confer-
ing bla genes.
ring concomitant resistance to these agents. There are now
widespread reports of MBL-producing, in particular VIM-2– Fluoroquinolones
producing, P. aeruginosa isolates worldwide. Fluoroquinolone resistance, in addition to being efflux and
Acquired molecular class D OXA β-lactamases have been porin mediated, is conferred by mutational changes in DNA
described, though these may be more common outside the gyrase (gyrA and gyrB) and/or topoisomerase IV. The pri-
United States. Many of these are broad spectrum and confer mary binding target for fluoroquinolones in P. aeruginosa is
resistance against antipseudomonal cephalosporins, mono- DNA gyrase. Resistance is conferred by point mutations in
bactams, and penicillins, but not carbapenems. Substrate the gyrA (DNA gyrase) and parC (topoisomerase IV) genes.
affinity can differ depending on the specific enzyme; for exam- A single-point mutation in gyrA can confer elevated MICs to
ple, OXA-31 is a mutant that confers greater resistance to ciprofloxacin and levofloxacin. Two or more point mutations
cefepime than to ceftazidime. Uncommon extended-spectrum in the same gene (e.g., gyrA), or mutations involving multi-
β-lactamases (ESBLs) reported to occur in P. aeruginosa ple genes (e.g., gyrA and parC), are associated with high-level
include VEB, GES, and IBC. These uncommon ESBLs appear resistance. Mutational resistance occurs more readily in
to originate from Enterobacteriaceae and are transmitted by P. aeruginosa than in Enterobacteriaceae because of its
genetic mobile elements such as integrons. poorer inherent susceptibility to these agents by many of the
mechanisms discussed previously (i.e., efflux, permeability).
Aminoglycoside-Modifying Enzymes
Like with β-lactams, resistance to aminoglycosides in Pseudo- ß-Lactams
monas can be enzyme mediated. These AMEs catalyze modifi- Although less well described in P. aeruginosa than in other
cation of specific amino or hydroxyl functional groups, which pathogens, mutations in penicillin binding proteins (PBPs)
results in suboptimal drug binding to ribosomes. The most may occur and contribute to decreased β-lactam susceptibil-
well-described AMEs are the N-acetyltransferases (AACs), ity. Alterations in PBP5 are believed to contribute to the intrin-
O-nucleotidyltransferases, and O-phosphotransferases. sic resistance of P. aeruginosa. Alterations in PBP4, resulting
These enzymes vary in their target sites on the various ami- in lower affinity, may also contribute to imipenem resistance.
noglycosides, which confers differences in aminoglycoside Penicillin binding protein mutations may also occur related
vulnerability to modification. Although aminoglycoside resis- to other resistance mechanisms, such as with the dacB muta-
tance is usually plasmid mediated, it can also be conferred tion, which encodes PBP4 and induces overexpression of
by transposons, integrons, and other transposable genetic AmpC β-lactamase. Alterations in PBP3 have also been
elements. In addition, bifunctional enzymes have been iso- described in P. aeruginosa.
lated in P. aeruginosa (e.g., AAC(6’)-30/AAC(6’)-Ib) that have
more than one mechanism of aminoglycoside modification. CLINICAL PRESENTATION AND RISK
If these enzymes are expressed in some form in wild-type FACTORS
strains, their activity against aminoglycosides is believed to P. aeruginosa infections can involve any part of the body,
be too poor to confer resistance. Increased enzyme expres- including the lungs, urinary tract, skin/skin structure, GI tract,
sion, to the extent of detectable aminoglycoside resistance, bloodstream, heart valves, and CNS, and are most common
is believed to be stimulated by drug exposure. in patients with compromised host defenses. P. aeruginosa
predominantly causes infections in the health care setting
(e.g., hospital-acquired bacterial pneumonia [HABP] and

IDSAP 2019 BOOK 2 • MDR Gram-Negative Infections 13 Pseudomonas aeruginosa

ventilator-associated bacterial pneumonia [VABP]) and infre- temporal bone can result in osteomyelitis, and further exten-
quently causes community-acquired infections. Patients col- sion can create cranial nerve palsies and possibly CNS infec-
onized with P. aeruginosa in the lungs and GI tract, especially tion. P. aeruginosa is a common cause of bacterial keratitis,
those with positive pressure ventilation and endotracheal scleral abscess, and endophthalmitis in adults and ophthal-
tubes, are at greatest risk of P. aeruginosa–associated pneu- mia neonatorum in children. Predisposing conditions for cor-
monia. Pneumonia secondary to P. aeruginosa can also result neal involvement are trauma, prolonged contact lens use,
from hematogenous spread to the lungs. Chronic infection predisposing ocular conditions, exposure to an ICU environ-
of the lower respiratory tract with P. aeruginosa is prevalent ment, and AIDS.
among patients with cystic fibrosis. Although infrequent, P.
aeruginosa can infect the GI tract, and the disease spectrum Incidence and Prevalence of P. aeruginosa
can range from very mild symptoms to severe necrotizing P. aeruginosa is a common nosocomial pathogen and one
enterocolitis. of the top three causes of opportunistic human infections.
P. aeruginosa is a common cause of UTI in hospitalized About 8% of all health care–associated infections reported to
patients. These infections are often associated with cath- the CDC’s National Healthcare Safety Network are caused by
eterization, instrumentation, and surgery. P. aeruginosa is P. aeruginosa, resulting in around 51,000 infections in hospi-
also a major cause of bloodstream infections in hospitalized talized patients each year in the United States. P. aeruginosa
patients. Bloodstream infections may be acquired through ranks sixth among all pathogens and third among gram-nega-
medical devices, whereas colonization of the GI tract may be a tive pathogens reported to the national nosocomial infections
source of bacteremia in patients who are immunosuppressed. surveillance system. In hospitalized patients, P. aeruginosa
P. aeruginosa may infect native/prosthetic heart valves in indi- is implicated in more than 16% of all ventilator-associated
viduals who recreation-ally use intravenous drugs; it also can pneumonia (VAP) (second most common pathogen), more
cause meningitis and brain abscesses. Most infections fol- than 10% of all catheter-associated UTIs (third most common
low an extension from a contiguous parameningeal structure, pathogen) and bloodstream infections (10th) and surgical
such as an ear or a mastoid; from para-nasal sinus surgery; site infections (fifth). Among patients with surgical site infec-
or from diagnostic procedures. In some patients, CNS involve- tions, the most common types of surgery associated with
ment is the result of hematogenous spread of the organism P. aeruginosa infections are breast (10.9%), cardiac (8.1%), vas-
from infective endocarditis, pneumonia, or UTI. cular (7.3%), and neck (6.1%) (Weiner 2016; CDC 2013). Knowl-
P. aeruginosa can also cause skin and bone and joint infec- edge of the incidence and prevalence of P. aeruginosa in the
tions. The most common sites of involvement are the ver- community setting is incomplete. Because P. aeruginosa
tebral column, the pelvis, and the sternoclavicular joint. is not a reportable disease, its prevalence remains largely
Infection may be spread hematogenously or contiguously unknown in most communities.
because of penetrating trauma, surgery, or overlying soft tis-
sue infections. Patients at risk of pseudomonal bone and Prevalence of Resistance in P. aeruginosa
joint infections include those with puncture wounds to the The CDC estimates that 13% of P. aeruginosa infections (over
foot, peripheral vascular disease, intravenous drug abuse, 6700) are MDR (CDC 2013). In the National Healthcare Safety
and diabetes mellitus. Network in the most recent year of reporting, MDR rates for
Skin infections related to the use of hot tubs, whirlpools, patients with VAP, central line–associated bloodstream infec-
swimming pools, and other types of baths are common tions, catheter-associated UTIs, and surgical site infections
sources of community-acquired P. aeruginosa dermatologic were 19.9%, 17.9%, 17.7%, and 4.3%, respectively (2012–2014)
infections. “Hot tub rash” is almost exclusively associated (Weiner 2016). Among patients with VAP, central line–asso-
with dermatitis or folliculitis caused by P. aeruginosa. Patients ciated bloodstream infections, and catheter-associated UTIs,
can present with pruritic follicular, maculopapular, vesicular, resistance for each antibiotic class varied at 15%–33%. Resis-
or pustular lesions on any part of the body that was immersed tance rates were highest for the fluoroquinolones and carbap-
in water. Another type of P. aeruginosa skin infection is green enems and lowest for the aminoglycosides and piperacillin/
nail syndrome. This paronychial infection can develop in indi- tazobactam (Weiner 2016).
viduals whose hands are often submerged in water. Second- Data analyses on P. aeruginosa resistance rates are also
ary wound infections occur in patients with decubiti, eczema, available from the SENTRY Antimicrobial Surveillance Pro-
and tinea pedis. Pseudomonal bacteremia can produce dis- gram (Shortridge 2019). During 1997–2016, 52,022 clinically
tinctive skin lesions known as ecthyma gangrenosum. significant, consecutive P. aeruginosa isolates were collected
P. aeruginosa infections can also involve the eyes and from over 200 medical centers representing the Asia-Pacific
ears. Otitis externa (swimmer’s ear) is often caused by region, Europe, Latin America, and North America. Isolates
P. aeruginosa. Malignant otitis externa can occur and is a with the MDR phenotype were most often isolated in Latin
manifestation of invasive infection predominantly in patients America (41.1%), followed by Europe (28.4%), North America
with uncontrolled diabetes. Extension of the infection to the (18.9%), and Asia-Pacific (18.8%) (Table 3).

IDSAP 2019 BOOK 2 • MDR Gram-Negative Infections 14 Pseudomonas aeruginosa

 Table 3. P. aeruginosa Isolates from SENTRY Program (1997–2016) Stratified by Infection Type and Percentage of Isolates
with Resistance Phenotypes

Skin and
Pneumonia in Skin Intra- Urinary
Bloodstream Hospitalized Structure abdominal Tract
Resistant Infection Patients Infection Infection Infection Other Infection Total
Phenotypea (n = 14 539) (n = 23 227) (n = 9952) (n = 648) (n = 2838) (n = 818) (n = 52 022)

Multidrug resistant 23.7% 27.7% 21.7% 19.3% 23.0% 19.1% 24.9%

Extensively drug 17.4% 19.0% 15.8% 12.7% 16.5% 12.3% 17.6%
resistant
Pan drug resistant 0.1% 0.1% 0.0% 0.5% 0.1% 0.0% 0.1%
Ceftazidime 22.0% 24.7% 20.1% 19.1% 18.4% 17.2% 22.5%
nonsusceptible
Meropenem 22.3% 27.1% 20.6% 21.9% 19.2% 18.1% 23.9%
nonsusceptible

a
Criteria as published by European Committee on Antimicrobial Susceptibility Testing (EUCAST) 2018.
Reprinted with permission from: Shortridge D, Gales AC, Streit JM, et al. Geographic and temporal patterns of antimicrobial
resistance in Pseudomonas aeruginosa over 20 years from the SENTRY Antimicrobial Surveillance Program, 1997-2016. Open Forum
Infect Dis 2019;6(suppl 1):S63-S68.

Risk Factors for Antibiotic-Resistant prior hospitalization, including in the ICU. Compared with non-
P. aeruginosa Infections MDR strains, significant risk factors for MDR P. aeruginosa
Risk factors for acquiring an antibiotic-resistant P. aeruginosa infection were prior ICU stay or prior use of fluoroquinolones.
infection are consistent with other those for antibiotic-resis-
tant gram-negative pathogens. Compromised host defenses
ANTIBIOTIC TREATMENT OF
are a hallmark characteristic of patients with antibiotic-resis-
PATIENTS WITH P. AERUGINOSA
tant P. aeruginosa. In most cases, a combination of risk fac-
INFECTIONS
tors is present, simultaneously augmenting a patient’s risk of
having an antibiotic-resistant versus a susceptible P. aerugi- Antibiotics are the cornerstone of therapy for patients with
nosa infection. Prior antibiotic exposure is an important and serious infections caused by P. aeruginosa. Treatment goals
well-characterized risk factor. Prior receipt of carbapenems for patients with P. aeruginosa infections are to cure the
and fluoroquinolones is also a commonly reported risk factor patient, minimize the occurrence of the unintended conse-
for antibiotic-resistant P. aeruginosa. Data analyses also sug- quences associated with antibiotic use, and prevent trans-
gest that the cumulative number of prior antibiotics received mission. Cure implies both the eradication of P. aeruginosa
augments a patient’s risk of acquiring an infection caused by from the infection site(s) and the complete resolution of the
an antibiotic-resistant P. aeruginosa. Constant and cumulative signs and symptoms associated with the infection. Unin-
exposure to antibiotics disturbs the natural bacterial flora, tended consequences associated with antibiotic use include
especially in the GI tract, and predisposes patients to coloni- the development of recurrent P. aeruginosa infections, sub-
zation by resistant strains. Extensive time in health care facil- sequent resistant P. aeruginosa infections, superinfections,
ities (e.g., long-term care stay, prolonged hospitalizations) development of Clostridioides difficile infection (CDI), and
also predisposes patients to colonization and infection, par- occurrence of adverse events.
ticularly in areas with endemic rates of antibiotic-resistant P. aeruginosa should be considered a potential pathogen
P. aeruginosa. Residence in the ICU and prolonged courses in all “at-risk” patient populations presenting with a clinical
of mechanical ventilation further contribute to risk. Several syndrome consistent with P. aeruginosa. Initial treatment of
studies have tried to characterize the most clinically relevant patients with suspected or documented P. aeruginosa infec-
risk factors for infections caused by resistant P. aeruginosa. tions is largely empiric, given that definitive culture and
A systematic review on studies that examined risk factors for antibiotic susceptibility results are typically not available
infections caused by MDR P. aeruginosa has been published until several days after infection onset. Gram stain results
(Raman 2018). Overall, the most significant predictors of and rapid diagnostics can facilitate early identification of
resistant P. aeruginosa infection were prior antibiotic use and patients with P. aeruginosa infections. Prompt initiation of

IDSAP 2019 BOOK 2 • MDR Gram-Negative Infections 15 Pseudomonas aeruginosa

antimicrobial therapy with in vitro activity at infection onset critical pharmacokinetic/pharmacodynamic (PK/PD) dos-
is critically important. Failure to administer early, appropri- ing targets associated with maximal response and to prevent
ate therapy substantially increases the morbidity and mor- the emergence of resistance during therapy. Intensive dos-
tality associated with P. aeruginosa infections by 2- to 3-fold. ing is particularly important for infection sites where antibi-
To minimize delays in appropriate therapy among patients otic concentrations are less than what is in the bloodstream,
with P. aeruginosa infections, clinicians need to assess the such as patients with lower respiratory tract infections and
patient’s risk of an MDR, XDR, or PDR P. aeruginosa infec- CNS infections.
tion when selecting empiric therapy. One of the most predic-
tive risk factors for a highly resistant P. aeruginosa infection Empiric Therapy for Patients with Suspected
is prior isolation of a highly resistant P. aeruginosa. Prior or Documented P. aeruginosa Infections
receipt of several antibiotics, extensive time in health care Type 2 carbapenems (meropenem, imipenem, or doripe-
facilitates, presence of invasive devices, and altered immune nem), piperacillin/tazobactam, or antipseudomonal cepha-
function also increase the likelihood of a highly resistant losporins are recommended as first-line empiric treatment
P. aeruginosa infection, especially when several risk fac- for patients with suspected or documented P. aeruginosa
tors are present in the same patient. Source control is also infections (Figure 2). Selection of specific antipseudomonal
critically important for achieving a cure. All infected cathe- β-lactams for empiric use depends on factors such as the
ters and prosthetic devices should be removed, abscesses infection site, local resistance rates of P. aeruginosa, prior
should be drained, and obstructions should be relieved, culture data, patient’s history of allergies, patient’s anti-
whenever possible. biotic history, and local hospital formulary. The preferred
Selection of agent(s), dose, infusion duration, dosing fre- β-lactam for serious P. aeruginosa has not been established.
quency, and therapy duration for a patient with a suspected Currently, no significant differences have been reported in
or documented P. aeruginosa infection greatly depends on clinical response or mortality rates between carbapenems,
the infection site(s), severity of infection, patient-related piperacillin/tazobactam, and antipseudomonal cephalospo-
factors, and likelihood of a resistant P. aeruginosa infection. rins except for doripenem, which was associated with worse
Higher/maximum daily doses are typically required for pre- outcomes than imipenem among patients with VAP (Kollef
sumptive or known P. aeruginosa infections to achieve the 2012). One of the meta-analyses conducted as part of the

Patient risk factors Assessment

Critically ill or septic shock 1 or more risk factors No risk factors

Risk factors for P. aeruginosa: Empiric therapy Local P. aeruginosa resistance rates to
• Broad-spectrum antibiotic (consider local epidemiology Yes cephalosporins, piperacillin/tazobactam,
therapy in last 90 days and patient-specific factors): or carbapenems >25%
• Prolonged hospitalization or
long term care residence Cefepime, piperacillin/tazobactam, No
• Current or prior ICU admission carbapenem, ceftazidime
• Invasive devices +/-
• Immunosuppression Aminoglycoside, polymyxin, Empiric therapy:
or fluoroquinolone Cefepime, piperacillin/tazobactam,
OR carbapenem, ceftazidime
Associated comorbidities: Ceftolozane/tazobactam, OR
• Diabetes ceftazidime/avibactam (often Aminoglycoside (monotherapy for UTI)
• COPD reserved for history of MDR strains)
• Liver/renal disease, including
hemodialysis
• Structural lung disease
• Elderly De-escalate to single agent when antimicrobial susceptibility results become available
• Immunosuppression/neutropenia
• Solid tumor
• Organ transplantation
• Trauma

Figure 2. Clinical approach to the patient with P. aeruginosa infection.

Information from: Mensa J, Barberan J, Soriano A, et al. Antibiotic selection in the treatment of acute invasive infections by
Pseudomonas aeruginosa: guidelines by the Spanish Society of Chemotherapy. Rev Esp Quimioter 2018;31:78-100.

IDSAP 2019 BOOK 2 • MDR Gram-Negative Infections 16 Pseudomonas aeruginosa

2016 hospital-acquired pneumonia (HAP)/VAP clinical prac- activity of plazomicin against P. aeruginosa is similar that of
tice guidelines showed that patients with HAP/VAP caused by the other aminoglycosides, limiting its potential for use in
P. aeruginosa and treated with carbapenems alone or in com- P. aeruginosa infections that are resistant to other aminogly-
bination with an aminoglycoside had less treatment success, cosides. Despite their in vitro activity, aminoglycosides are
lower eradication rates, and a higher incidence of antibiot- not recommended as monotherapy for patients with P. aerugi-
ic-resistant rates than patients who received an alternative nosa infections, except for UTIs and UTI-related bloodstream
antibiotic (fluoroquinolone or a β-lactam) (Kalil 2016). These infections. Use of aminoglycosides should be discouraged in
findings were mainly a function of studies that included patients with renal insufficiency, patients at risk of aminogly-
imipenem as the carbapenem comparator, given that no coside-associated vestibular and auditory ototoxicity, and in
appreciable differences in outcomes occurred in analyses those hospitalized in institutions with a high percentage of
that were restricted to meropenem. A meta-analysis that P. aeruginosa isolates resistant to aminoglycosides.
included five randomized nosocomial pneumonia trials simi- Levofloxacin or ciprofloxacin, are also alternatives to
larly found that patients with P. aeruginosa infections treated antipseudomonal β-lactams for the empiric treatment of sus-
with imipenem were more likely to have clinical failure and pected or documented P. aeruginosa infections, especially
to develop resistance than those treated with piperacillin/ when oral therapy is needed. However, increasing resistance
tazobactam or cefepime (O’Donnell 2018). Carbapenems, rates and growing safety concerns limit their use as empiric
compared with other antipseudomonal β-lactams, have agents. Delafloxacin also exhibits anti-Pseudomonal activity,
a greater propensity to select for CDI and antibiotic- though clinical data with this agent are lacking compared to
resistant organisms at both the individual patient level and other fluoroquinolones.
the hospital level. Conversely, piperacillin/tazobactam is
associated with a lower risk of acquiring CDI and a higher Combination Therapy
loss of CDI colonization than the antipseudomonal cepha- One of the most controversial issues in treating patients with
losporins (Dubberke 2015). Distinctions in the ability of pip- serious infections caused by P. aeruginosa involves the use of
eracillin/tazobactam and antipseudomonal cephalosporins combination therapy. The rationale for combination therapy
to select for other antibiotic-resistant bacteria have not been is to broaden empiric coverage and increase the likelihood of
established. timely appropriate therapy, achieve synergistic bacterial kill-
Other agents with activity against P. aeruginosa can be ing, prevent emergence of resistance, ensure activity against
considered empiric treatment in select situations. Aztre- planktonic and sessile organisms, and inhibit toxin produc-
onam is a suitable empiric option if a patient has a severe tion. Combination therapy is typically reserved for empiric
penicillin allergy. However, aztreonam should be avoided treatment of suspected or documented P. aeruginosa infec-
in patients with a severe allergy to ceftazidime because of tions in patients at an increased risk of death or when there
similar side chains. When possible, aztreonam should be is a high risk of resistance to commonly used antipseudomo-
reserved because it has lower susceptibility rates than other nal agents. Combination therapy should especially be con-
β-lactams against P. aeruginosa. It may be still possible to use sidered in patients for whom inappropriate antibiotic therapy
a cephalosporin or carbapenem in a penicillin-allergic patient. would likely be associated with substantially increased mor-
Cross-reactivity between piperacillin/tazobactam, third/ tality, such as patients with severe sepsis or septic shock,
fourth-generation cephalosporins, and type 2 carbapenems bacteremia, infective endocarditis, and immunosuppres-
is negligible, likely because of their dissimilar side chains. sion. In vitro PK/PD infection models and animal studies of
Empiric use of the recently approved β-lactam/β-lactamase P. aeruginosa clearly show that combination therapy improves
inhibitors with activity against P. aeruginosa should be consid- bacterial killing compared with monotherapy and is often
ered in patients with suspected or documented XDR or PDR P. required for bacterial sterilization and resistance suppres-
aeruginosa infections, or in those with a history of a P. aerugi- sion (Drusano 2018).
nosa infection that was resistant to type 2 carbapenems, pip- No randomized clinical trial has conclusively shown that
eracillin/tazobactam, and antipseudomonal cephalosporins using two active agents compared with one improves out-
(see section that follows titled “Strategies for Empiric Treat- comes (e.g., survival or treatment success rates) or lessens
ment of Patients with Suspected or Documented Highly Resis- the emergence of resistance in patients with serious infec-
tant P. aeruginosa Infections”). tions caused by P. aeruginosa. No significant differences in
Aminoglycosides with activity against P. aeruginosa include the development of antibiotic-resistant strains and superin-
gentamicin, tobramycin, amikacin, and the recently approved fections were noted between combination and monotherapy
plazomicin. Tobramycin is the aminoglycoside with the high- across meta-analyses, though few studies assessed these
est intrinsic activity against P. aeruginosa. Tobramycin is end points. A significantly higher incidence of adverse events,
twice as active as gentamicin and 3–4 times more active than mainly nephrotoxicity with aminoglycosides, was consistently
amikacin. However, susceptibility rates are highest with ami- associated with combination therapy. These study findings
kacin because it is hydrolyzed by fewer enzymes. The in vitro should be interpreted with caution. Most of the randomized

IDSAP 2019 BOOK 2 • MDR Gram-Negative Infections 17 Pseudomonas aeruginosa

clinical trials predate 2000 (and therefore are not necessar- aztreonam can also be used as an adjunctive agent with
ily reflective of pathogens encountered in clinical practice another β-lactam–based agent because it has different tar-
today), and few evaluated combinations consisting of newer gets within the bacterial cell wall.
agents. Disease severity was also generally low. Most stud-
ies included diverse groups of patients and infection types Strategies for Empiric Treatment of Patients
(febrile neutropenia was the most common). Caution also with Suspected or Documented Highly
needs to be used when examining the results of observational Resistant P. aeruginosa Infections
studies that included more critically ill patients, given that Strategies for treating patients with highly resistant P. aeru-
such patients are highly vulnerable to prescribing and other ginosa infections include using alternative dosing strategies,
selection biases. combination drug therapy, and, for HAP/VAP, inhaled anti-
The best rationale for using combination therapy is to biotics. However, clinical data analyses supporting these
provide empiric broad-spectrum activity when multidrug strategies are limited. For infections caused by P. aeruginosa
resistance is a risk. Combination therapy provides a higher resistant to other first-line β-lactams, ceftazidime/avibactam
probability that one of the agents will be active against the and ceftolozane/tazobactam should be considered. Ceftazi-
pathogen infecting the patient. Although the benefits of early dime/avibactam and ceftolozane/tazobactam are two new
administration of microbiologically active agents are clear, cephalosporin/β-lactamase inhibitor combinations. Ceftazi-
outcomes do not appear to be improved with receipt of two dime is a third-generation antipseudomonal cephalosporin
active agents compared with one (Pena 2013). with a well-established efficacy and safety profile, and avibac-
If combination empiric therapy is used, two agents from tam is a diazabicyclooctane β-lactamase inhibitor. Avibac-
different classes with in vitro activity against P. aeruginosa tam has no intrinsic activity alone but expands the spectrum
are recommended. In general, a β-lactam is used in combi- of activity of ceftazidime against E. coli, Klebsiella spp.,
nation with an aminoglycoside or a fluoroquinolone. The Enterobacter spp., and certain P. aeruginosa strains by inhib-
2016 American Thoracic Society/Infectious Diseases Soci- iting a broad range of serine β-lactamases, including Ambler
ety of America (ATS/IDSA) HAP/VAP guidelines recommend class A (ESBL and KPC), class C (AmpC), and some class D
two antipseudomonal antibiotics for empiric treatment of (such as OXA-48) enzymes. However, avibactam alone does
HAP (non-VAP) in patients with a risk factor for antimicrobial not appreciably inhibit MBLs such as NDM-1 and VIM-1. Cef-
resistance (e.g., intravenous antibiotic use during the prior 90 tazidime/avibactam is approved for adults with complicated
days) or need for ventilator support because of pneumonia UTIs (including pyelonephritis), complicated intra-abdom-
and septic shock. For patients with VAP, the guidelines rec- inal infections (cIAIs) (used in combination with metronida-
ommend two antipseudomonal antibiotics for empiric treat- zole), HABP/VABP, and other infections caused by aerobic
ment in patients with any of the following: a risk factor for gram-negative organisms in patients with limited treatment
antimicrobial resistance (prior intravenous antibiotic use options. Ceftolozane is a novel oxyimino-aminothiazolyl
within 90 days, septic shock at time of VAP, acute respiratory cephalosporin and a potent PBP3 inhibitor with a higher affin-
distress syndrome preceding VAP, 5 or more days of hospital- ity for PBP1b than other β-lactam agents. Ceftolozane has
ization before VAP occurs, or acute renal replacement ther- less affinity for hydrolysis by AmpC cephalosporinases, is a
apy before VAP onset), patients in units where more than weak substrate for drug efflux systems, and is not affected
10% of gram-negative isolates are resistant to an agent being by OprD loss. Ceftolozane/tazobactam is approved for adults
considered for monotherapy, and patients in an ICU where with complicated UTIs (including pyelonephritis), cIAIs (used
local antimicrobial susceptibility rates are not available. For in combination with metronidazole), and HABP/VABP.
patients without any of these additional risk factors for mor- Many P. aeruginosa isolates resistant by in vitro testing
tality or resistant organisms, empiric treatment with a sin- to first-line β-lactams retain susceptibility to ceftazidime/
gle antipseudomonal agent is preferred (Kalil 2016). These avibactam and/or ceftolozane/tazobactam. Large surveil-
guidelines also suggest avoiding aminoglycosides when lance studies suggest that ceftazidime/avibactam and
alternative agents with adequate gram-negative activity are ceftolozane/tazobactam retain activity against over 85%
available because of aminoglycosides’ poor lung penetration, of MDR P. aeruginosa isolates (Nichols 2016; Torrens 2016).
aminoglycosides’ increased risk of nephrotoxicity and ototox- Limited in vitro data analyses suggest that ceftolozane/
icity, and meta-analysis data suggesting they are associated tazobactam has more microbiologic activity against XDR
with poorer clinical response rates than other classes. Intra- P. aeruginosa isolates than ceftazidime/avibactam. Suscep-
venous polymyxins (colistin or polymyxin B) and intravenous tibility profiles vary between ceftazidime/avibactam and
fosfomycin can also be used in combination for empiric treat- ceftolozane/tazobactam against XDR P. aeruginosa isolates,
ment of suspected or documented P. aeruginosa infections; and some MDR isolates that are resistant to ceftazidime/
however, these agents should be reserved for XDR strains avibactam may be susceptible to ceftolozane/tazobactam
and avoided if alternative agents with adequate gram-neg- and vice versa (Grupper 2017; Humphries 2017). The vary-
ative activity are available. In the absence of other options, ing susceptibilities are a function of the particular resistance

IDSAP 2019 BOOK 2 • MDR Gram-Negative Infections 18 Pseudomonas aeruginosa

mechanisms present in the tested P. aeruginosa isolates. some strains of MDR P. aeruginosa. Clinical data with these
These findings highlight the importance of using local sus- agents against MDR, XDR, and PDR P. aeruginosa are lim-
ceptibility data to guide decision-making, given that suscep- ited, and no comparator studies have been published to date.
tibility rates can vary greatly. Clinicians should treat each Combination therapy for patients with XDR or PDR P. aerugi-
patient on an individual basis and conduct susceptibility test- nosa often includes a polymyxin with at least two agents that,
ing with both ceftazidime/avibactam and ceftolozane/tazo- individually, have little or no activity against the isolate. Poly-
bactam when determining optimal treatment for a patient myxins are well known to cause nephrotoxicity and neurotox-
with a suspected or documented P. aeruginosa infection that icity and should be avoided if alternative agents with in vitro
is resistant to other first-line β-lactams. Clinical experience activity are available. Polymyxins should also not be used as
with these agents against MDR, PDR, and XDR P. aeruginosa monotherapy, given the frequent development of resistance
is limited, and no comparator studies have been published and regrowth of bacteria observed by 24 hours in several in
to date. Most real-world, non-comparator data against XDR vitro studies. Clinically, monotherapy has been associated
P. aeruginosa are with ceftolozane/tazobactam, and results with increased mortality; however, these data are largely
have been mixed; emergence of resistance during therapy to observational and were not limited to patients with P. aerugi-
these agents has been reported (Santevecchi 2018; Caston nosa infections. Polymyxins also may be problematic for the
2017; Haidar 2017; Munita 2017; Xipell 2017). treatment of pneumonia. In preclinical models, bactericidal
Meropenem/vaborbactam and imipenem/relebactam are activity (and, in some cases, even bacteriostatic activity) was
two additional novel β-lactamase inhibitor combinations. not achievable even at maximal tolerated doses. Although
Meropenem/vaborbactam was recently approved, but add- the exact mechanism for this is unknown, it may be related
ing vaborbactam does not appreciably increase the activity to poor penetration of these agents into the epithelial lining
of meropenem against P. aeruginosa. In addition, there is cur- fluid, as well as the binding of polymyxin molecules by mucin
rently no breakpoint for meropenem/vaborbactam against that has been observed ex vivo (Boisson 2014). For colistin,
P. aeruginosa. Imipenem/relebactam is another treatment conversion from colistin methanesulfonate to the active drug
option for infections caused by MDR P. aeruginosa. Unlike may be even further limited in the epithelial lining fluid. This
vaborbactam’s limited effect of meropenem susceptibility has prompted the addition of inhaled colistin, in combination
for P. aeruginosa, relebactam appears to substantially poten- with intravenous colistin, for patients with VAP caused by
tiate imipenem activity against imipenem-resistant isolates. MDR pathogens.
Neither imipenem nor relebactam appear to be substrates for Amikacin and tobramycin often retain activity against MDR
the efflux pumps present in P. aeruginosa, and relebactam pre- P. aeruginosa strains and are treatment options, though these
serves imipenem activity in the setting of AmpC. drugs should be used in combination with other agents. For
Treatment of infections caused by MBL-producing P. aerugi- patients with VABP caused by P. aeruginosa that is suscep-
nosa is an emerging problem. The aforementioned β-lactam/ tible to only aminoglycosides or polymyxins, the guidelines
β-lactamase inhibitor combinations do not have in vitro suggest that both inhaled and systemic antibiotics, rather
activity against these strains, given that no clinically avail- than systemic antibiotics alone, be used. Intravenous fosfo-
able β-lactamase inhibitors effectively inhibit these enzymes. mycin may also play a role in the treatment of highly resistant
Adding aztreonam to avibactam has activity in MBL-produc- P. aeruginosa. Fosfomycin monotherapy, however, should be
ing isolates, given that aztreonam is not hydrolyzed by MBLs avoided, given the frequency of heteroresistance in P. aeru-
and avibactam provides protection against Ambler class A, C, ginosa and the propensity for developing resistance on ther-
and some D enzymes. Although this combination has been apy (Mensa 2018). Combination therapy may be appropriate
established as an option for treating NDM-producing Entero- for some strains, and synergy has been shown for combina-
bacteriaceae, few data are available for P. aeruginosa. Dual tions of fosfomycin and antipseudomonal β-lactams (e.g.,
β-lactam therapy may also provide synergy for some MDR or meropenem, ceftolozane/tazobactam, and ceftazidime/
XDR P. aeruginosa isolates. Most recently, the combination of avibactam). Lastly, cefiderocol, a first-in-class siderophore
ceftolozane/tazobactam and meropenem has shown signifi- cephalosporin, may be an additional option against MDR P.
cant synergy against MDR P. aeruginosa (Monogue 2018; Mon- aeruginosa if approved by the FDA. As a siderophore cepha-
tero 2018). In vitro synergy against P. aeruginosa isolates has losporin, cefiderocol binds to ferric iron and is actively trans-
also been described for other combinations of β-lactams, such ported across the outer membrane and into the periplasmic
as ceftazidime or cefepime plus aztreonam (Rahme 2014). space of P. aeruginosa. This results in high concentrations of
Polymyxins, aminoglycosides, intravenous fosfomycin cefiderocol in the periplasmic space, where it can then bind
(currently under FDA review), and cefiderocol (currently under to PBPs and inhibit cell wall synthesis. It is also stable to
FDA review) are additional options for patients with XDR P. both serine- and MBL-carbapenemases, making it a potential
aeruginosa infections and are the only therapeutic options for option for XDR P. aeruginosa possessing those β-lactamases.

IDSAP 2019 BOOK 2 • MDR Gram-Negative Infections 19 Pseudomonas aeruginosa

Directed Therapy Concentration-Dependent Antibiotics
Once the results of susceptibility tests are available, defini- Many agents with clinically relevant activity against P. aerugi-
tive therapy can be tailored accordingly. For most infections, nosa fall into this category, including fluoroquinolones, poly-
definitive therapy with a single active agent is appropriate, myxins, and fosfomycin. Recent changes in the Clinical &
given that no convincing clinical data analyses show a mor- Laboratory Standards Institute (CLSI)-recommended break-
tality benefit to combination therapy. The rare exceptions points for fluoroquinolones reflect the limitations of expo-
when continuing the combination regimen may be warranted sures achieved with maximal recommended dosing regimens
include neutropenia, bacteremia, and infective endocarditis. for ciprofloxacin (e.g., 400 mg intravenously every 8 hours)
Initiating a second antipseudomonal agent may be reason- and levofloxacin (750 mg intravenously every 24 hours). Prob-
ability of target attainment remains low for pathogens with
able in infections that are slow, or that fail, to respond to a sin-
MICs at the new P. aeruginosa breakpoints for ciprofloxacin
gle active agent, though few data support this practice. For
and levofloxacin (0.5 and 1 mg/L, respectively), though these
patients with HAP/VAP who remain in septic shock or at a
doses are likely adequate for lower MICs (Cojutti 2017; Bur-
high risk of death when the results of antibiotic susceptibility
gess 2007).
testing are known, the ATS/IDSA HAP/VAP guidelines recom-
Polymyxins also follow AUC/MIC pharmacodynamics;
mend combination therapy using two antibiotics to which the
however, dose escalation is significantly limited by the high
isolate is susceptible, rather than monotherapy (Kalil 2016).
nephrotoxicity rates associated with these agents. At maximal
Continuation of combination therapy in a patient with an MDR recommended exposures (AUC0-24hr = around 50 mg*hour/L),
P. aeruginosa infection is also reasonable, especially if the the probability of target attainment is acceptable for organ-
patient had delays in receiving appropriate therapy. isms with MICs of up to 2 mg/L, the current CLSI and EUCAST
(European Committee on Antimicrobial Susceptibility Test-
Dosing Considerations ing) breakpoints. Of note, optimal exposure targets for pneu-
ß-Lactams monia have not been defined, with preclinical models unable
The conventional intermittent β-lactam dosing schemes to achieve bacterial killing at maximal tolerable doses. Given
often used in practice have suboptimal PD profiles against the propensity for development of resistance when used as
P. aeruginosa. Extending the duration of infusion (i.e., increas- monotherapy, combination therapy is recommended when
ing the infusion duration to several hours instead of 30–60 using polymyxins. It is unknown how adding other agents
minutes) is one way to maximize the PK/PD profiles of β-lact- affects the pharmacodynamic target for these drugs, though
ams against P. aeruginosa, especially against strains with ele- the current guidelines recommend static doses regardless of
vated MIC values. Administering a dose of a β-lactam agent organism MIC or use of other agents.
as an infusion longer than the conventional 30- to 60-min- Intravenous fosfomycin is currently under FDA review for
ute infusion duration has two main effects. First, it produces use in adult patients with complicated UTIs in the United
a lower peak concentration of the drug. Because the bacte- States, though it has been clinically available in Europe and
rial kill rate for these agents is not concentration-dependent, Australia for some time. Fosfomycin has some in vitro activ-
this does not present a major disadvantage. Second, the ity against P. aeruginosa; however, formal breakpoints have
drug concentrations remain in excess of the MIC for a longer not been established. Bactericidal activity appears to be
period. Because this is what drives the antibacterial effect for most closely linked to the fAUC/MIC ratio, though develop-
β-lactams, this consequence will yield a more favorable prob- ment of resistance may be linked to a time over threshold
ability of achieving an adequate f T>MIC. index. According to preclinical data using fosfomycin against
Extended infusions may either be prolonged (e.g., over P. aeruginosa, combination therapy may be necessary to pre-
3–4 hours) or administered as a continuous infusion. Recent vent the emergence of resistance, despite the use of high sim-
meta-analyses show significant improvements in all-cause ulated doses in these models.
mortality with extended infusion or continuous infusion com- Although the prevailing wisdom has historically been that
pared with intermittent infusion (Rhodes 2018; Vardakas the fCmax /MIC ratio is the critical exposure target for amino-
2018; Falagas 2013). Although the continuous infusion of glycosides, an equivalent body of evidence suggests that
β-lactams is often perceived to be better than extended infu- the fAUC/MIC ratio is the PK/PD driver for bacterial killing
sion, the two infusion methodologies yield almost identical and efficacy. Preclinical dose-fractionation studies of ani-
PK/PD profiles. Of note, continuous infusion confers an “all- mals and in vitro PK/PD infection models have shown no dif-
or-nothing” probability of target result (0% or 100%) at a given ferences in efficacy between once-daily, multiple-daily, and
MIC value. Because it is only required to be above the MIC for continuous infusion aminoglycoside dosing regimens, indi-
a fraction of the dosing interval to maximize the PK/PD profile cating that the PK/PD driver for efficacy is better linked to the
of β-lactams, the higher initial concentrations associated with fAUC/MIC than to the fCmax /MIC. The available literature sug-
extended infusion compared with continuous infusion (with- gests that an fAUC/MIC ratio of 30–50 for aminoglycoside
out a loading dose) early in treatment have a better probabil- therapy provides optimal outcomes when targeting noncriti-
ity of achieving an adequate f T>MIC for infections with higher cally ill, immunocompetent patients with low bacterial burden
MICs (Natesan 2017). gram-negative infections (e.g., UTIs) or in patients receiving

IDSAP 2019 BOOK 2 • MDR Gram-Negative Infections 20 Pseudomonas aeruginosa

additional gram-negative therapy with good source control. reinfection in patients with VAP infected with P. aeruginosa
However, an fAUC/MIC ratio target of 80–100 or greater may associated with short (8 days) therapy compared with longer
be more prudent when treating patients with aminoglycoside therapy (15 days) (Chastre 2003). However, a meta-analysis
monotherapy or in critically ill patients with high bacterial bur- conducted as part of the new HAP/VAP guidelines identified
den infections, such as nosocomial pneumonia. Higher doses
no increased risk of all-cause mortality or pneumonia recur-
or combination therapy is needed for infections caused by
rence in patients with P. aeruginosa between short (7–8 days)
organisms with reduced susceptibility, which is common in
and longer (more than 14 days) treatment courses (Kalil
P. aeruginosa. Minimizing toxicity is another critical compo-
2016). Recent data analyses also have suggested that 7-day
nent of optimizing aminoglycoside therapy. Typically, recom-
treatment courses have clinical outcomes similar to longer
mendations for minimizing the risk of nephrotoxicity rely on
(e.g., at least 14 days) treatment courses for uncomplicated
extended interval dosing and attaining low trough concentra-
bacteremia (Sousa 2019; Yahav 2019; Chotiprasitsakul 2018).
tions (i.e., 1 mg/L or less for gentamicin and tobramycin; 4–5
These data are primarily from patients with Enterobacteria-
mg/L or less for amikacin) before re-dosing.
ceae bacteremia; however, no signal for an increased risk of
Inhaled Antibiotics failure with shorter courses in patients infected with P. aeru-
The ATS/IDSA guidelines for treating VAP recommend inhaled ginosa has been identified. Suggested treatment for compli-
antibiotics, in combination with systemic agents, for infections cated UTIs caused by MDR P. aeruginosa is 7–14 days.
caused by organisms only susceptible to aminoglycosides or
polymyxins. Because both inhaled antibiotics and systemic ROLE OF ANTIMICROBIAL
agents achieve relatively low (and potentially subtherapeutic) STEWARDSHIP AND THE
exposures in the epithelial lining fluid, direct administration PHARMACIST
of antibiotic to the infection site improves target attainment.
Antimicrobial Stewardship Programs
A meta-analysis identified a significantly improved clinical
cure rate when inhaled antibiotics were added for treating Antimicrobial stewardship programs promote appropriate anti-
MDR pathogens, though no differences in mortality or adverse biotic use using a range of methods, including prescriptive
effects were identified (Kalil 2016). A recent randomized trial audit and feedback, prior authorization, and implementation
comparing inhaled amikacin/fosfomycin with placebo identi- of institutional clinical pathways. Many efforts are aimed at
fied an improvement in microbiologic eradication, though no optimizing antimicrobial therapy by ensuring early, appropriate
difference in clinical outcomes (Kollef 2017). broad-spectrum empiric therapy in patients at risk of P. aerugi-
nosa infections and minimizing use of broad-spectrum agents
Patients with Cystic Fibrosis (often with antipseudomonal activity) in patients without asso-
Cystic fibrosis is associated with pulmonary exacerbations ciated risk factors for resistant gram-negative infections.
that are often managed with antibiotics targeting pathogens Antimicrobial stewardship programs minimize overall anti-
such as Pseudomonas. For intermittent infections, the pri- biotic use to reduce the spread of resistant pathogens, includ-
mary goal of antibiotic treatment during an exacerbation is to ing P. aeruginosa, secondary to antibiotic selective pressures.
eradicate the infection to prevent colonization/chronic infec- Initiatives aimed at reducing antibiotic use have been shown to
tion. This is often accomplished with inhaled (e.g., tobramy- reduce resistance, especially in institutions with endemic rates
cin, colistin) and systemic antibiotic therapy. Progression to of resistance. One non-U.S. program assessed the incidence
chronic infection is associated with increased patient mor- rates of XDR and MDR Pseudomonas among 2241 isolates in
bidity and mortality. For chronic infections, prior microbio- 2012–2017 after structured efforts to decrease antibiotic use
logic data can help drive agent selection early in exacerbation and increase use of alcohol-based hand sanitizer. The number
treatment. For many patients, pulmonary exacerbations are of defined daily doses of antimicrobials significantly decreased
believed to be more likely because of redistribution of existing over the study period, and the use of hand sanitizer increased
P. aeruginosa or other bacterial colonies, rather than because significantly. The incidence of MDR and XDR P. aeruginosa iso-
of infection with new isolates. Therefore, given that these bac- lates showed a sustained decrease from 2013 to 2017 (from
teria are most often present at baseline, the treatment goal is 22% to 15% and from 4% to 1%, respectively) (Liu 2018).
not necessarily to sterilize the lungs, but to restore the balance Antimicrobial stewardship programs also may examine how
in favor of the immune response. In these patients, assessing manipulating the use of specific agents affects P. aeruginosa
historic clinical response to therapy, rather than microbiologic susceptibility rates. Several studies have looked specifically at
response, appears most helpful when selecting treatment for carbapenem and fluoroquinolone use, given that these classes
subsequent exacerbations. confer a greater risk of resistant P. aeruginosa. For exam-
ple, studies have examined whether ertapenem use affects
Therapy Duration antipseudomonal carbapenem susceptibilities. Although find-
The optimal therapy duration for serious infections caused ings vary, one review of 10 clinical studies suggested that ertap-
by P. aeruginosa is highly debated. A randomized controlled enem use did not improve P. aeruginosa susceptibility rates to
trial of patients with VAP identified an increased risk of antipseudomonal carbapenems (Nicolau 2012). Therefore,

IDSAP 2019 BOOK 2 • MDR Gram-Negative Infections 21 Pseudomonas aeruginosa

stewardship-based efforts to promote the use of ertapenem knowledge of PK/PD principles and both in vitro and clin-
over meropenem for non-pseudomonal infections may not pre- ical data can support efforts to optimize therapy, such as
serve class susceptibility. Other studies have focused on fluo- recommending prolonged infusions of β-lactam therapy. Fur-
roquinolone use and whether use of specific fluoroquinolones thermore, a general understanding of common resistance
may affect susceptibility trends. One retrospective study at a patterns can help in recommending for or against additional
medical center in Taiwan found, unsurprisingly, that increased susceptibility testing. For example, if MICs to meropenem
fluoroquinolone (i.e., ciprofloxacin, levofloxacin) use was asso- and other β-lactams are elevated, susceptibility testing for
ciated with decreased fluoroquinolone susceptibility at the ceftolozane/tazobactam and ceftazidime/avibactam should
institutional level. However, when evaluating each drug inde- be considered. Limiting therapy to the shortest effective
pendently, levofloxacin (both parenterally and orally) was asso- duration also provides significant benefits. Excessive anti-
ciated with increased fluoroquinolone resistance rates among biotic use can lead to the development of resistance, and
P. aeruginosa, whereas ciprofloxacin was not (Lee 2010). decreasing therapy durations by one-half (e.g., from 14 to 7
days) can substantially decrease unnecessary exposure with-
Role of the Pharmacist out compromising positive patient outcomes.
Pharmacists can play a substantial role in treating patients
with P. aeruginosa infections. Having knowledge of patient risk
CONCLUSION
factors for Pseudomonas infection and understanding PK/PD P. aeruginosa is an opportunistic pathogen that most com-
principles, resistance mechanisms, dosing strategies, and monly colonizes and infects patients in health care settings
clinical outcomes data place pharmacists in a unique role to with compromised host defense mechanisms. In health care
help select optimal therapy. To minimize the receipt of inap- settings, P. aeruginosa is a common cause of pneumonia,
propriate therapy, pharmacists need to assess a patient’s risk UTIs, bloodstream infections, and surgical site infections.
of having an MDR, XDR, or PDR P. aeruginosa infection when P. aeruginosa is intrinsically resistant to many commercially
making empiric treatment recommendations. Pharmacists available antibiotics and has a remarkable ability to develop
also need to consider whether combination empiric therapy resistance to commonly used antibiotics like carbapenems,
is needed, especially among patients at an increased risk of aminoglycosides, and fluoroquinolones through various
death or when patients have a high risk of resistance to com- acquired and adaptive resistance mechanisms that are often
monly used antipseudomonal agents. Combination therapy expressed simultaneously. Prevalence of resistance to com-
should especially be considered in patients for whom inap- monly used first-line antibiotics among patients with P. aeru-
propriate antibiotic therapy would likely be associated with
ginosa infections now exceeds 20% in most hospitals, and
substantially increased mortality. This includes patients with
MDR, XDR, and PDR strains are increasing.
severe sepsis or septic shock, bacteremia, infective endocar-
Pharmacists play a critical role in treating patients with
ditis, and immunosuppression.
P. aeruginosa infections. To minimize the receipt of inap-
For empiric treatment of suspected or documented P. aerugi-
propriate therapy, pharmacists need to assess a patient’s
nosa infections, pharmacists can also ensure that patients are
risk of having an MDR, XDR, or PDR P. aeruginosa infection
receiving appropriate doses of antipseudomonal agents. Many
patients with P. aeruginosa present with renal impairment. when recommending empiric therapy. Selection of empiric
A patient’s renal impairment should be characterized as chronic agent(s), dose, infusion duration, and dosing frequency for
or acute by assessing observed SCr concentrations in relation a patient with a suspected P. aeruginosa infection should be
to prior baseline values. Large changes in SCr from baseline in based on the infection site(s), infection severity, patient-re-
shorter time intervals are most associated with severe dysfunc- lated factors, likelihood of a resistant P. aeruginosa infec-
tion and sepsis. For these patients, the risk-benefit of using a tion, and local resistance patterns. Combination therapy with
“loading” dose and selecting dosing regimens on the basis of antibiotics from two different classes should be advocated
baseline renal function relative to their acutely estimated renal in patients at an increased mortality risk (e.g., septic shock)
function should be considered, especially if patients are criti- or when there is a high risk of resistance to commonly used
cally ill. Consideration for this aggressive approach is based on antipseudomonal agents. Higher or maximum daily doses
the need to optimize the PK/PD profile in the first 24 hours of are typically required for presumptive or known P. aeruginosa
infection onset to ensure the highest probability of a success- infections to optimize PK/PD target attainment and chances
ful outcome. This consideration is also based on the finding of clinical success. Pharmacists should reevaluate therapy
that most nonimmunologic exposure–dependent drug adverse as culture and susceptibility data become available and offer
events occur after several days of therapy, and the risk of tox- therapeutic and dosing recommendations to prescribers to
icity, even in the presence of high exposures, is typically low further optimize and potentially streamline therapy. As part
during the first 1–2 days of therapy (Bidell 2018). of definitive therapy recommendations, pharmacists should
For definitive treatment, pharmacists can provide addi- look to limiting therapy to the shortest effective duration
tional therapeutic recommendations related to MIC data
because excessive antibiotic use perpetuates the develop-
and susceptibility patterns. With elevated MICs, a working
ment of resistance.

IDSAP 2019 BOOK 2 • MDR Gram-Negative Infections 22 Pseudomonas aeruginosa

 Practice Points
Clinical pharmacists face many challenges when optimiz- • P. aeruginosa should be considered a potential pathogen in
ing pharmacotherapy for patients with suspected or docu- all “at-risk” patient populations presenting with a clinical
mented P. aeruginosa infections. Pharmacists can benefit syndrome consistent with P. aeruginosa. Prompt initiation of
from the ability to recognize patient-specific risk factors antimicrobial therapy with in vitro activity at infection onset
associated with these infections, including those asso- is critically important because data analyses show that fail-
ciated with MDR strains. Knowledge of common mech- ure to administer early, appropriate therapy substantially
anisms of resistance, including among MDR strains, increases morbidity and mortality.
together with knowledge of clinical data, guideline recom- • Combination therapy with antibiotics from two different
mendations, and newer therapies empower pharmacists classes should be advocated in patients at an increased
to effectively provide optimal care for their patients. mortality risk (e.g., septic shock) or when there is a high
• P. aeruginosa is a highly adaptive opportunistic pathogen that risk of resistance to commonly used antipseudomonal
commonly affects those with compromised immune systems agents.
or anatomic barriers (e.g., large surface area burns, mechani- • Higher doses are generally most appropriate for treating
cal ventilation), as well as those with health care or antibiotic serious infections caused by P. aeruginosa in order to optimize
exposure. the PK/PD indices associated with clinical treatment success
• Common sites of P. aeruginosa infections include the urinary and resistance prevention.
tract, respiratory tract, bloodstream, and skin/soft tissue. • Newer therapies that may play a role in treating MDR
• P. aeruginosa has several mechanisms of intrinsic, adaptive, and P. aeruginosa include ceftolozane/tazobactam, ceftazidime/
acquired antibiotic resistance. Multidrug resistance on a cul- avibactam, and imipenem/relebactam, and several agents
ture susceptibility report often suggests involvement of efflux in late clinical stage development may be future options for
pumps, β-lactamases, and/or other mechanisms of resistance. treating infections caused by MDR pathogens.

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IDSAP 2019 BOOK 2 • MDR Gram-Negative Infections 24 Pseudomonas aeruginosa

Self-Assessment Questions
Questions 1–4 pertain to the following case. A. 5 days
N.S., a 19-year-old man with a medical history of allergic rhini- B. 7 days
tis, presents to the ED febrile and in septic shock believed to C. 10 days
be caused by a viral illness. He is initiated on high-dose vaso- D. 14 days
pressor therapy and quickly progresses to respiratory failure
requiring intubation. A flu swab is positive for influenza A. Questions 5 and 6 pertain to the following case.
N.S. receives treatment for influenza and has some response
J.S. is a 54-year-old woman with a medical history of multi-
with improving fever curve but remains intubated. On day 6
ple sclerosis (complicated by neurogenic bladder and supra-
of intubation, he requires increasing ventilatory settings and
pubic catheter/nephrostomy tube) and recurrent UTIs with
has a temperature of 101.3°F. A sputum sample grows the fol-
extended-spectrum β-lactamase (ESBL)-producing organ-
lowing P. aeruginosa:
isms, admitted 3 days ago with fevers, suprapubic pain, leu-
kocytosis, and nausea/vomiting. Her urine culture is positive
Antibiotic MIC Value Interpretation for the following P. aeruginosa:
Piperacillin/ 32 Intermediate Isolate 1
tazobactam
Antibiotic MIC Value Interpretation
Ceftazidime 8 Susceptible
Piperacillin/ ≤4 Susceptible
Cefepime 16 Intermediate tazobactam
Imipenem ≥16 Resistant Ceftazidime ≤1 Susceptible
Meropenem ≥16 Resistant Cefepime ≤1 Susceptible
Tobramycin ≤1 Susceptible Imipenem 2 Susceptible
Ciprofloxacin 1 Susceptible Meropenem ≤0.25 Susceptible
Levofloxacin 4 Intermediate Amikacin    ≤2 Susceptible

1. Which one of the following places N.S. at greatest risk of Tobramycin ≤1 Susceptible
a P. aeruginosa infection? Ciprofloxacin ≤0.25 Susceptible

A. Age Levofloxacin 0.5 Susceptible

B. Influenza
5. Which one of the following most likely caused the ele-
C. Allergic rhinitis
vated imipenem MIC in this isolate (isolate 1) from J.S.?
D. Mechanical ventilation
A. Porin mutation
2. Which one of the following treatments is best to recom-
B. Efflux pump
mend for N.S.?
C. Carbapenemase
A. Tobramycin, high-dose extended interval D. AmpC production
B. Cefepime, prolonged infusion
6. J.S. is treated for her UTI. She is admitted 6 months later
C. Ceftazidime, prolonged infusion
with another UTI, again caused by P. aeruginosa:
D. Piperacillin/tazobactam, prolonged infusion
3. Given the susceptibility patterns of N.S.’s isolate, which Isolate 2
one of the following agents would be best to recommend Antibiotic MIC Value Interpretation
for susceptibility testing?
Ceftazidime 8 Susceptible
A. Ceftolozane/tazobactam Cefepime ≥64 Resistant
B. Amikacin
Imipenem 2 Susceptible
C. Meropenem/vaborbactam
D. Aztreonam Meropenem 1 Susceptible

4. According to the most recent (2016) ATS/IDSA hos- Amikacin ≥64 Resistant
pital-acquired pneumonia (HAP)/ventilator-associ- Tobramycin 4 Susceptible
ated pneumonia (VAP) guidelines, which would be the Ciprofloxacin ≥4 Resistant
best treatment duration (assuming appropriate clinical
Levofloxacin ≥8 Resistant
response) to recommend for N.S.?

IDSAP 2019 BOOK 2 • MDR Gram-Negative Infections 25 Pseudomonas aeruginosa

Which one of the following mechanisms of resistance best an MIC of 4 for both isolates, which is susceptible. If clin-
explains the multidrug-resistant (MDR) profile in this isolate ical decompensation occurs while on his current regi-
(isolate 2) from J.S.? men, which one of the following regimens is best to
A. Efflux pump up-regulation recommend for this patient?
B. ESBL
A. Change piperacillin/tazobactam to extended
C. AmpC hyperproduction
infusion.
D. Carbapenemase
B. Change to ceftolozane/tazobactam intermittent
7. Which one of the following patients would most likely infusion.
benefit from dual antipseudomonal empiric therapy? C. Change to ceftolozane/tazobactam extended
infusion.
A. 67-year-old woman presenting from a nursing home
D. Change to cefepime extended infusion.
with suspicion of pneumonia; history of chronic
obstructive pulmonary disease (COPD) 9. Each of the following patients is thought to have a
B. 74-year-old man presenting from skilled nursing P. aeruginosa infection, as well as acute moderate renal
facility with complicated diabetic foot infection; impairment. Assuming you are assessing these patients
history of dry gangrene on admission, which one of the following would be most
C. 80-year-old man presenting from home with likely to benefit from high-dose (i.e., 2 g intravenously
confusion and septic shock; history of Pseudomonas every 8 hours) meropenem?
UTI
A. 25-year-old man with a ventriculoperitoneal shunt
D. 78-year-old woman presenting from assisted living
infection
facility with suspicion of osteomyelitis; history of
B. 88-year-old man with a COPD exacerbation
ESBL-producing organisms
C. 73-year-old woman with a diabetic foot infection
8. A 28-year-old man with a history of cystic fibrosis after D. 32-year-old woman with a UTI
a bilateral lung transplant 3 years ago presents with a
10. In a patient with biofilm-implanted device infection
splenic infarct in the setting of a new diagnosis of anti-
caused by P. aeruginosa, which one of the following
phospholipid syndrome. He is known to be colonized
microbiologic abilities most contributes to the persister
with Pseudomonas and has a history of exacerbations;
variants in biofilms?
these were successfully treated with cefepime and pip-
eracillin/tazobactam in the past year. The patient is cur- A. Quorum sensing and biofilm production
rently stable from a respiratory process, and is receiving B. Endotoxin production
inhaled tobramycin and piperacillin/tazobactam. Spu- C. Coagulase production
tum cultures were obtained, despite relative clinical D. Catalase production
stability, and grow the following mucoid Pseudomonas 11. The antimicrobial stewardship program wants to pre-
strains: serve antibiotic susceptibilities against P. aeruginosa
at your institution. According to the available literature,
Antibiotic Strain 1 Strain 2
which one of the following initiatives would be best for
Interpretation Interpretation
the program to prioritize?
Piperacillin/ Susceptible Resistant
A. Minimize broad-spectrum antibiotic use overall.
tazobactam
B. Change from meropenem to ertapenem depending
Ceftazidime Resistant Resistant on definitive culture and susceptibility data (e.g., for
Cefepime Resistant Resistant ESBL Enterobacteriaceae)
C. Promote fluoroquinolone use.
Imipenem Resistant Resistant
D. Use extended infusions of β-lactams in all ICUs.
Meropenem Susceptible Resistant
12. Which one of the following patients is at highest risk of
Amikacin Intermediate Resistant
infection caused by an MDR strain of P. aeruginosa?
Tobramycin Susceptible Resistant
A. 65-year-old man with respiratory failure who has
Ciprofloxacin Intermediate Resistant been mechanically ventilated for 48 hours
Levofloxacin Susceptible Resistant B. 65-year-old man with indwelling central intravenous
Aztreonam Susceptible Resistant catheter for total parenteral nutrition
C. 65-year-old with prior receipt of two courses of
Additional testing is done on both mucoid strains fluoroquinolones for UTIs
obtained from D.S. Ceftolozane/tazobactam results at D. 65-year-old with inflammatory bowel disease on
chronic prednisone

IDSAP 2019 BOOK 2 • MDR Gram-Negative Infections 26 Pseudomonas aeruginosa

13. A patient has ventilator-associated bacterial pneumonia 15. From the perspective of the clinical pharmacist and anti-
(VABP) caused by an extensively drug-resistant (XDR) biotic stewardship program, which one of the following
P. aeruginosa strain that was only susceptible to amikacin patients would be best to prioritize to increase the likeli-
and colistin on the initial susceptibility report. Suscepti- hood of a positive clinical outcome?
bility data to ceftolozane/tazobactam and ceftazidime/
A. Clinically stable 70-year-old woman who is on day
avibactam are pending. Together with inhaled amikacin,
14 of hospital-acquired bacterial pneumonia (HABP)
which one of the following therapy regimens is best to
treatment for P. aeruginosa
recommend for this patient while awaiting the suscepti-
B. Clinically unstable 65-year-old woman presenting
bility data?
with sepsis and a history of MDR P. aeruginosa
A. Ceftolozane/tazobactam with intravenous amikacin infection
B. Ceftolozane/tazobactam and intravenous colistin C. Clinically unstable 70-year-old man receiving
C. Ceftazidime/avibactam and intravenous colistin meropenem with a pan-susceptible P. aeruginosa
D. Ceftazidime/avibactam and intravenous amikacin infection
D. Clinically stable 65-year-old man with suspected
14. Assuming similar medical histories, which one of the fol-
VABP receiving intravenous polymyxin B plus an
lowing patients is most at risk of becoming colonized
antipseudomonal β-lactam for P. aeruginosa that is
with P. aeruginosa?
only susceptible to polymyxins
A. 45-year-old man who frequents whirlpools and hot
tubs
B. 45-year-old woman who eats vegetables and fruits
from the hospital cafeteria she works in
C. 45-year-old man who cleans sinks in the common
bathroom at hospitals
D. 45-year-old woman who is hospitalized for more
than 72 hours

IDSAP 2019 BOOK 2 • MDR Gram-Negative Infections 27 Pseudomonas aeruginosa