1272 PART 5 Infectious Diseases

P. mirabilis causes 90% of Proteus infections, which occur in the

community, LTCFs, and hospitals. By contrast, Proteus vulgaris and

Proteus penneri are associated primarily with infections acquired in

LTCFs or hospitals. Correspondingly, P. mirabilis colonizes healthy

humans (prevalence, 50%), whereas P. vulgaris and P. penneri are isolated primarily from individuals with underlying disease. By far the

most common site of Proteus infection is the urinary tract, where the

principal known urovirulence factors of Proteus include adhesins, flagella, IgA-IgG protease, iron acquisition systems, and urease. Proteus less

commonly causes infection at a variety of other extraintestinal sites.

■ INFECTIOUS SYNDROMES

UTI P. mirabilis causes only 1–2% of UTIs in healthy women, and

Proteus species collectively cause only 5% of hospital-acquired UTIs.

However, Proteus is responsible for 10–15% of cases of complicated

UTI, primarily those associated with catheterization; indeed, Proteus

accounts for 20–45% of urine isolates from chronically catheterized

patients. This high prevalence is due in part to bacterial production of

urease, which hydrolyzes urea to ammonia and results in alkalization of

the urine. In alkaline urine, organic and inorganic compounds precipitate, contributing to the formation of struvite and carbonate–apatite

crystals, biofilms on catheters, and/or frank calculi. Proteus becomes

associated with the stones and biofilms; thereafter, it usually cannot

be eradicated without removal of the stones or catheter. Over time,

staghorn calculi may form within the renal pelvis and lead to obstruction and renal failure. Although biologically plausible, clinical support

is lacking for the concept that urine samples exhibiting unexplained

alkalinity should be cultured, and that isolation of a Proteus species

(or other urea-splitting organism) should prompt consideration of an

evaluation for urolithiasis.

Other Infections Proteus occasionally causes pneumonia (primarily in LTCF residents or hospitalized patients), nosocomial sinusitis,

intraabdominal abscesses, biliary tract infection, surgical site infection, soft tissue infection (especially decubitus and diabetic ulcers),

and osteomyelitis (primarily contiguous); in rare cases, it causes nontropical myositis. In addition, Proteus uncommonly causes neonatal

meningitis, with the umbilicus frequently implicated as the source;

this disease is often complicated by development of a cerebral abscess.

Otogenic brain abscess also occurs.

Bacteremia Most episodes of Proteus bacteremia originate from

the urinary tract, although intravascular devices and any of the less

common sites of Proteus infection are also potential sources. Endovascular infection is rare. Proteus species are occasional agents of sepsis in

neonates and of bacteremia in neutropenic patients.

■ DIAGNOSIS

Proteus is readily isolated and identified in the laboratory. Most

strains are lactose-negative, produce H2

S, and demonstrate characteristic swarming motility on agar plates. P. mirabilis and P. penneri are

indole-negative, whereas P. vulgaris is indole-positive. The inability

to produce ornithine decarboxylase differentiates P. penneri from P.

mirabilis.

TREATMENT

Proteus Infections

Intrinsic resistance occurs in all Proteus spp. to nitrofurantoin,

polymyxins, imipenem, and the tetracycline derivatives (e.g.,

tigecycline, eravacycline, omadacycline) and, in P. vulgaris and

P. penneri, also to ampicillin and the first- and second-generation

cephalosporins. Acquired resistance (% of isolates) occurs in

P. mirabilis to ampicillin (15–65%), and in Proteus spp. to fluoroquinolones (10–55%), fosfomycin (7–22%), and TMP-SMX

(20–50%). In P. mirabilis, ampicillin-sulbactam is more active than

ampicillin, with resistance prevalences of 6–18%, but the prevalence of ESBL production (which confers ampicillin-sulbactam

resistance) is increasing in the United States (5–10%) and Asia (up

to 60%). Isolates of P. mirabilis that produce CTX-M ESBLs have

been recovered from ambulatory patients with no recent health

care contact (see the section on the treatment of extraintestinal

E. coli infections for treatment considerations). The use of thirdgeneration cephalosporins can induce or select for stable de-repression

of AmpC β-lactamase in P. vulgaris. Acquired carbapenem resistance remains relatively infrequent (<10%). However, production

of a class B metallo-β-lactamase (e.g., NDM) limits treatment

options due to the inherent resistance of Proteus spp. to polymyxins and tetracycline derivatives (see “Carbapenemase” above). For

critically ill patients, agents with excellent activity overall against

Proteus spp. (90–100% of isolates susceptible) include carbapenems

(excepting imipenem), amikacin, piperacillin-tazobactam, aztreonam, cefepime, ceftazidime-avibactam, ceftolozane-tazobactam,

and meropenem-vaborbactam.

ENTEROBACTER AND CRONOBACTER

INFECTIONS

The E. cloacae complex is responsible for most Enterobacter infections,

whereas Cronobacter sakazakii (formerly Enterobacter sakazakii),

Cronobacter malonaticus, Enterobacter cancergenus, and Enterobacter

gergoviae are less commonly isolated (<1% for each). Enterobacter

bugandensis has been recently described as an agent of sepsis in neonates and was isolated from the International Space Station. Enterobacter spp. cause primarily health care–related infections. The organisms

are widely prevalent in foods, environmental sources (including equipment at health care facilities), and a variety of animals.

Colonization with these organisms is uncommon among healthy

humans, but increases significantly with LTCF residence or hospitalization. Although colonization is an important prelude to infection, direct

introduction via IV lines (e.g., contaminated IV fluids or pressure

monitors) or contaminated non-FDA-approved stem cell products also

occurs. Extensive antibiotic resistance has developed in Enterobacter

spp. and probably has contributed to these organisms’ emergence as

prominent nosocomial pathogens. Risk factors for Enterobacter infection include prior antibiotic treatment, comorbid disease, and ICU residency. Enterobacter spp. causes a spectrum of extraintestinal infections

similar to those described for other GNB.

■ INFECTIOUS SYNDROMES

The most commonly encountered syndromes include pneumonia,

UTI (particularly catheter-associated), intravascular device–related

infection, surgical site infection, and abdominal infection (primarily

postoperative or related to devices such as biliary stents). Nosocomial

sinusitis, meningitis related to neurosurgical procedures (including

use of intracranial pressure monitors), osteomyelitis, and endophthalmitis after eye surgery are less frequent. Neonates (particularly

if low-birth-weight) are at risk for C. sakazakii infection, including

neonatal bacteremia, necrotizing enterocolitis, and meningitis (which

is often complicated by brain abscess or ventriculitis). Contaminated

powdered infant formula has been implicated as a source for such

neonatal infections. The WHO recommends that, to reduce the initial

number of bacteria, powdered infant formula should be reconstituted

with hot water (>70°C) and, to limit replication of residual bacteria,

the reconstituted formula should be stored at <5°C or its storage time

minimized.

Enterobacter bacteremia can result from primary infection at any

anatomic site. In bacteremia of unclear origin, particularly in an outbreak setting, sources for consideration should include contaminated

IV fluids or medications, blood components or plasma derivatives,

catheter-flushing fluids, pressure monitors, and dialysis equipment.

Enterobacter can also cause bacteremia in neutropenic patients.

Enterobacter endocarditis is rare, occurring primarily in association

with illicit IV drug use or prosthetic valves.

■ DIAGNOSIS

Enterobacter is readily isolated and identified in the laboratory. Most

strains are lactose-positive and indole-negative.

1273CHAPTER 161 Diseases Caused by Gram-Negative Enteric Bacilli

TREATMENT

Enterobacter Infections

E. cloacae is intrinsically resistant to ampicillin, ampicillin-sulbactam,

ampicillin-clavulanate, the first-generation cephalosporins, and the

cephamycins. The prevalence of acquired resistance has ranged

from 15 to 40% for piperacillin-tazobactam, 5 to 23% for polymyxin

E, 15 to 17% for fosfomycin, 15 to 30% for TMP-SMX, and 5 to

20% for fluoroquinolones and is ~10% for omadacycline (53% if

tetracycline resistant). USNHSN data from 2015−2017 identified

8.9% of E. cloacae isolates as presumptively ESBL-producing, based

on cefepime resistance. The prevalence of ESBLs in E. cloacae outside of the United States is 20−50%. The use of third-generation

cephalosporins can induce or select for stable de-repression of

AmpC β-lactamase. Because resistance may emerge during therapy

(in one study, this phenomenon was documented in 20% of clinical

isolates), these agents should be avoided in the treatment of serious

Enterobacter infection.

Cefepime is stable in the presence of AmpC β-lactamases; thus,

it is a suitable option for treatment of Enterobacter infections so

long as no coexistent ESBL is present. Overall, resistance prevalence

generally ranges from 10 to 25% for cefepime and 25 to 50% for

aztreonam and the third-generation cephalosporins. Carbapenem

resistance remains relatively uncommon (USNHSN data from

2015−2017 identified a 5% prevalence) and is more commonly

associated with increased AmpC expression and decreased permeability due to porin mutations rather than carbapenemase production, although acquisition of carbapenemase genes is increasing

(see “Carbapenemase” above). Uncertainty exists on the optimal

treatment for non-CP-CR-Enterobacter spp. Fortunately, overall, the

percentage of susceptibility is high (90–99%) for carbapenems, amikacin, plazomicin, ceftazidime-avibactam, meropenem-vaborbactam,

imipenem/cilastatin-relebactam, cefiderocol, tigecycline, eravacycline, and omadacycline (the latter three for tetracycline-susceptible

isolates). Once susceptibility data for a patient’s isolate become

available, de-escalation of the antimicrobial regimen is advisable

whenever possible.

SERRATIA INFECTIONS

S. marcescens causes >90%, and Serratia liquefaciens complex <10%, of

Serratia infections. Serratiae are found primarily in the environment

(including in health care institutions), particularly in moist settings.

Serratiae have been isolated from a variety of animals, insects, and

plants, but only infrequently from healthy humans. In LTCFs and

hospitals, reservoirs for the organisms include the hands and fingernails of health care personnel, food, milk (on neonatal units), sinks,

medical equipment or devices, IV solutions or parenteral medications

(particularly those generated by compounding pharmacies), prefilled

syringes and multiple-access medication vials (e.g., for heparin, propofol, saline), blood products (e.g., platelets), hand soaps and lotions,

irrigation solutions, and even disinfectants such as chlorhexidine.

Infection results from either direct inoculation (e.g., via contaminated injected substances [IV fluids, medications, or recreational

drugs] or snake bite) or colonization (primarily of the respiratory

tract). Sporadic infection is most common, but outbreaks (often

involving MDR strains in adult and neonatal ICUs) also occur.

Hygiene, medication-compounding standards, sterile technique, and

infection control programs are critical measures to prevent infection.

The spectrum of extraintestinal infections caused by Serratia is

similar to that for other GNB. Serratia species are usually considered to

cause mainly health care–associated infections; they account for 1–3%

of hospital-acquired infections. However, population-based laboratory

surveillance studies in Canada and Australia have demonstrated that

community-acquired Serratia infections occur more commonly than

was previously appreciated, and case reports have documented serious

infection in otherwise healthy hosts. Serratia also is one of the pathogens associated with chronic granulomatous disease.

■ INFECTIOUS SYNDROMES

The most common primary sites of Serratia infection are the respiratory and genitourinary tracts, intravascular devices, the eye (contact

lens–associated keratitis and other ocular infections), surgical wounds,

and the bloodstream (from contaminated infusions), although most

episodes of Serratia bacteremia arise from one of the listed focal infections rather than contaminated infusate. Less common syndromes are

soft tissue infections (including myositis, fasciitis, mastitis), osteomyelitis, abdominal and biliary tract infections (usually postprocedural),

and septic arthritis (primarily from intraarticular injections). Serratiae

are uncommon causes of neonatal meningitis; postsurgical meningitis,

endophthalmitis, or breast implant infection; and bacteremia in neutropenic patients. Endocarditis is rare, occurring most commonly in

IV drug users.

■ DIAGNOSIS

Serratiae are readily cultured and identified by the laboratory and are

usually lactose- and indole-negative. The red pigmentation of some S.

marcescens strains and Serratia rubidaea can produce distinctive clinical findings (e.g., pink breast milk or hypopyon; pseudohemoptysis).

TREATMENT

Serratia Infections

Most Serratia strains (>80%) are intrinsically resistant to ampicillin, amoxicillin-clavulanate, ampicillin-sulbactam, first- and secondgeneration cephalosporins, cephamycins, nitrofurantoin, and

polymyxins; likewise, tetracycline derivatives are poorly active.

By contrast, fluoroquinolones, TMP-SMX, piperacillin-tazobactam,

fosfomycin, and omadacycline are active against 85−95% of

U.S. and European isolates, including those resistant to tetracycline. Both in the United States and globally, the prevalence of

ESBL-producing isolates is generally low (<10%), but rates of

20–30% have been reported in Asia and Latin America. The use

of third-generation cephalosporins may result in the induction

or selection of variants with stable de-repression of chromosomal

AmpC β-lactamases during therapy but is uncommon. Resistance

prevalence generally ranges from 10 to 20% for aztreonam and

the third-generation cephalosporins. Acquisition of carbapenemaseencoding genes is uncommon but increasing. Production of a

class B metallo-β-lactamase (e.g., NDM) limits treatment options

due to Serratia’s predictable resistance to polymyxins and tetracycline derivatives (see “Carbapenemase” above). For critically

ill patients, the most active agents overall (>90% susceptible)

are carbapenems, piperacillin-tazobactam, cefepime, amikacin,

plazomicin, ceftazidime-avibactam, ceftolozane-tazobactam, and

meropenem-vaborbactam.

CITROBACTER INFECTIONS

C. freundii and Citrobacter koseri cause most human Citrobacter infections, which are epidemiologically and clinically similar to Enterobacter

infections. Citrobacter species are commonly present in water, food,

soil, and certain animals. Colonization with these organisms is uncommon among healthy humans, but increases significantly with LTCF

residence or hospitalization. Citrobacter species account for 1–2% of

nosocomial infections. The affected hosts are usually immunocompromised and/or have comorbid disease or disruption of skin or mucosal

barriers. Infection from treatment with contaminated, non-FDAapproved stem cell products has been described. Citrobacter causes

extraintestinal infections similar to those described for other GNB.

■ INFECTIOUS SYNDROMES

The urinary tract accounts for 40–50% of Citrobacter infections. Less

commonly involved sites include the biliary tree (particularly with

stones or obstruction), the respiratory tract, surgical sites, soft tissue

(e.g., decubitus ulcers), the peritoneum, and intravascular devices.

Osteomyelitis (usually from a contiguous focus), central nervous system infection in adults (from neurosurgical or other types of meningeal

1274 PART 5 Infectious Diseases

disruption), and myositis occur rarely. Citrobacter (primarily C. koseri)

also causes 1–2% of neonatal meningitis cases, of which 50–80% are

complicated by brain abscess. Further, case reports in adults suggest

that C. koseri infection has a predilection for abscess formation. Citrobacter bacteremia is most often due to UTI, biliary/abdominal infection, or intravascular device infection, and occurs in some neutropenic

patients. Endocarditis and other endovascular infections are rare.

■ DIAGNOSIS

Citrobacter species are readily isolated and identified; 35–50% of isolates are lactose-positive, and 100% are oxidase-negative. C. freundii is

indole-negative, whereas C. koseri is indole-positive.

TREATMENT

Citrobacter Infections

C. freundii is more extensively antibiotic-resistant than is C. koseri.

Most C. freundii isolates are intrinsically resistant to ampicillin, ampicillin-sulbactam, amoxicillin-clavulanate, first-generation

cephalosporins, and cephamycins. C. koseri exhibits intrinsic resistance to ampicillin and ampicillin-sulbactam. Overall, the prevalence of acquired resistance generally ranges from 15 to 35% for

third-generation cephalosporins, piperacillin-tazobactam, fluoroquinolones, and TMP-SMX and is ~10% for nitrofurantoin and

omadacycline (but 39% for omadacycline if tetracycline-resistant).

The prevalence of ESBL production ranges from 5 to 30%. The use

of third-generation cephalosporins may result in the induction

or selection of variants with stable de-repression of chromosomal

AmpC β-lactamases during therapy. Presently, <10% of isolates have

acquired carbapenemases (see “Carbapenemase” above). Carbapenems, amikacin, plazomicin, fosfomycin, polymyxins, cefepime,

ceftazidime-avibactam, cefiderocol, tigecycline, eravacycline, and

omadacycline (the latter three if tetracycline-susceptible) are the

most active agents against Citrobacter isolates (>90% susceptible).

MORGANELLA AND PROVIDENCIA

INFECTIONS

M. morganii, Providencia stuartii, and (less frequently) Providencia

rettgeri are the members of their respective genera that cause systemic

human infections. P. alcalifaciens has been implicated as a cause of

food-borne gastroenteritis. These organisms’ epidemiologic associations, pathogenic properties, and clinical manifestations resemble

those of Proteus species. Morganella and Providencia occur more

commonly among LTCF residents than among hospitalized patients,

largely resulting from chronic urinary catheter use. Because of these

organisms’ intrinsic resistance to polymyxins and tigecycline, they may

become increasingly common in settings with extensive use of these

agents.

■ INFECTIOUS SYNDROMES

These species are primarily urinary tract pathogens, causing UTIs that

are most often associated with long-term (>30-day) catheterization.

Such infections commonly lead to biofilm formation and catheter

encrustation (sometimes causing catheter obstruction) or the development of struvite bladder or renal stones (sometimes causing renal

obstruction, abscess, and extrarenal extension, and serving as foci for

relapse). They can cause purple urine (“purple bag syndrome”), as can

P. mirabilis, K. pneumoniae, E. coli, and P. aeruginosa. Morganella is also

commonly isolated from snakebite infection.

Other, less common infectious syndromes due to Morganella and

Providencia include surgical site infection, soft tissue infection (primarily involving decubitus and diabetic ulcers), burn site infection,

pneumonia (particularly ventilator-associated), intravascular device

infection, and intraabdominal infection. Rarely, the other extraintestinal infections described for GNB also occur. Bacteremia is uncommon;

when it does occur, any infected site can serve as the source, but the

urinary tract accounts for most cases, followed by surgical site, soft

tissue, and hepatobiliary infections.

■ DIAGNOSIS

M. morganii and Providencia are readily isolated and identified. Nearly

all isolates are lactose-negative and indole-positive.

TREATMENT

Morganella and Providencia Infections

Morganella and Providencia are intrinsically resistant to ampicillin, ampicillin-clavulanate, ampicillin-sulbactam, first-generation

cephalosporins, nitrofurantoin, tetracyclines and derivatives (e.g.,

tigecycline), imipenem (but not the other carbapenems), and the

polymyxins. P. stuartii additionally exhibits intrinsic resistance to

gentamicin and tobramycin, as does M. morganii to second-generation

cephalosporins. Fosfomycin is poorly active (>50% resistance). The

prevalence of resistance generally ranges from 10 to 30% for the

third-generation cephalosporins, from 10 to 40% for fluoroquinolones, and from 20 to 40% for TMP-SMX; the prevalence is more

widely variable for piperacillin-tazobactam. The prevalence of ESBL

production is generally <10%. The use of third-generation cephalosporins can induce or select for stable de-repression of AmpC

β-lactamase for both Morganella and Providencia. The prevalence

of acquired carbapenemase production is <10%. Production of a

class B metallo-β-lactamase (e.g., NDM) limits treatment options

due to the inherent resistance of the Proteeae to polymyxins and

tetracycline derivatives (see “Carbapenemase” above). Overall, the

most active agents (>90% of isolates susceptible) are carbapenems

(excepting imipenem), amikacin, cefepime, ceftazidime-avibactam,

ceftolozane-tazobactam, meropenem-vaborbactam, and cefiderocol. Removal of a colonized urinary catheter or stone is critical for

eradication of UTI.

EDWARDSIELLA INFECTIONS

E. tarda is the only member of the genus Edwardsiella that is associated

with human disease. This organism is found predominantly in freshwater and marine environments and in the associated aquatic animal species. Human acquisition occurs primarily from interaction with these

reservoirs or ingestion of raw or inadequately cooked aquatic animals.

E. tarda infection is rare in the United States, where acquisition occurs

mainly along the Gulf of Mexico; recently reported cases are mostly

from Asia. This pathogen shares clinical features with Salmonella

species (as an intestinal pathogen; Chap. 165), Vibrio vulnificus (as an

extraintestinal pathogen; Chap. 168), and Aeromonas hydrophila (as

both an intestinal and an extraintestinal pathogen; Chap. 158).

■ INFECTIOUS SYNDROMES

Gastroenteritis is the predominant Edwardsiella-associated infectious

syndrome (50–80% of reported cases). Self-limiting watery diarrhea

is most common, but severe colitis also occurs. The most common

extraintestinal infection is wound infection due to direct inoculation, which is often associated with brackish or freshwater injuries,

snakebites, or fish-related trauma. A case of pneumonia occurred

after a near-drowning incident. Cholecystitis, cholangitis, and hepatic

abscess may be due to ascending infection via the biliary tree. Other

infectious syndromes result from invasion of the gastrointestinal

tract and subsequent bacteremia. A primary bacteremic syndrome,

sometimes complicated by meningitis, has a 40% case–fatality rate;

hematogenous seeding may result in hepatic and intra- and extraperitoneal abscesses, endocarditis, mycotic aneurysm, septic arthritis,

osteomyelitis, necrotizing fasciitis, and empyema. Most hosts who

develop systemic Edwardsiella infection have significant comorbidities

(e.g., hepatobiliary disease, iron overload, cancer, or diabetes mellitus).

■ DIAGNOSIS

Although E. tarda can readily be isolated and identified, most laboratories do not routinely screen for or identify it in stool samples. Production of hydrogen sulfide is a characteristic biochemical property.

1275CHAPTER 162 Acinetobacter Infections

TREATMENT

Edwardsiella Infections

E. tarda is susceptible to most antimicrobial agents appropriate for use

against GNB. Gastroenteritis is generally self-limiting, but treatment with a fluoroquinolone may hasten resolution. In the setting

of severe sepsis, fluoroquinolones, third- and fourth-generation

cephalosporins, carbapenems, and amikacin—either alone or in

combination—are the safest choices pending susceptibility data.

INFECTIONS CAUSED BY MISCELLANEOUS

GENERA

Other gram-negative organisms such as Hafnia, Kluyvera, Cedecea,

Pantoea, Ewingella, Leclercia, Raoultella, and Photorhabdus spp. are

occasionally isolated from diverse clinical specimens, including blood,

sputum, urine, cerebrospinal fluid, joint fluid, bile, and wounds. Such

organisms cause infection predominantly in compromised hosts or

in association with an invasive procedure or foreign body. Cephalosporinases from Kluyvera have been implicated as the progenitors of

CTX-M ESBLs. Kluyvera and Raoultella may produce carbapenemases.

■ FURTHER READING

Anesi JA et al: Poor clinical outcomes associated with communityonset urinary tract infections due to extended-spectrum cephalosporin-resistant Enterobacteriaceae. Infect Control Hosp Epidemiol

39:1431, 2018.

Baker TM et al: Epidemiology of bloodstream infections caused by

Escherichia coli and Klebsiella pneumoniae that are piperacillintazobactam-nonsusceptible but ceftriaxone-susceptible. Open Forum

Infect Dis 5:ofy300, 2018.

Boisen N et al: Shiga toxin 2a and enteroaggregative Escherichia

coli—A deadly combination. Gut Microbes 6:272, 2015.

Bonten M et al: Epidemiology of Escherichia coli bacteremia: A systematic literature review. Clin Infect Dis 72:1211, 2021.

Cheng MP et al: Beta-lactam/beta-lactamase inhibitor therapy for

potential AmpC-producing organisms: A systematic review and

meta-analysis. Open Forum Infect Dis 6:ofz248, 2019.

David S et al: Epidemic of carbapenem-resistant Klebsiella pneumoniae

in Europe is driven by nosocomial spread. Nat Microbiol 4:1919,

2019.

Gurieva T et al: The transmissibility of antibiotic-resistant Enterobacteriaceae in intensive care units. Clin Infect Dis 66:489, 2018.

Harris PNA et al: Effect of piperacillin-tazobactam vs meropenem

on 30-day mortality for patients with E coli or Klebsiella pneumoniae

bloodstream infection and ceftriaxone resistance: A randomized

clinical trial [published correction appears in JAMA 321:2370, 2019].

JAMA 320:984, 2018.

Holy O, Forsythe S: Cronobacter spp. as emerging causes of healthcareassociated infection. J Hosp Infect 86:169, 2014.

Kamiyama S et al: Edwardsiella tarda bacteremia, Okayama, Japan,

2005-2016. Emerg Infect Dis 25:1817, 2019.

Lim C et al: Epidemiology and burden of multidrug-resistant bacterial

infection in a developing country. Elife 5:E18082, 2016.

Nordmann P et al: Carbapenem resistance in Enterobacteriaceae:

Here is the storm! Trends Mol Med 18:263, 2012.

Peirano G, Pitout JDD: Extended-spectrum β-lactamase-producing

Enterobacteriaceae: Update on molecular epidemiology and treatment options. Drugs 79:1529, 2019.

Russo TA, Marr CM: Hypervirulent Klebsiella pneumoniae. Clin

Microbiol Rev 32:e00001, 2019.

van Duin D et al: Molecular and clinical epidemiology of carbapenemresistant Enterobacterales in the USA (CRACKLE-2): A prospective

cohort study Lancet Infect Dis 20:731, 2020. [Erratum in Lancet

Infect Dis 19:30755, 2020].

Weiner-Lastinger LM et al: Antimicrobial-resistant pathogens associated with adult healthcare-associated infections: Summary of data

reported to the National Healthcare Safety Network, 2015-2017.

Infect Control Hosp Epidemiol 41:1, 2020.

■ DEFINITION

Acinetobacter species were first described in 1911 and named Micrococcus calcoaceticus. Thereafter, the genus was renamed multiple

times; since 1950, it has been known as Acinetobacter. Acinetobacter

species are gram-negative, oxidase-negative, nonmotile, nonfermenting coccobacilli that are easily recovered on standard culture media.

Differentiation among Acinetobacter species on the basis of phenotypic

characteristics alone is very difficult. Molecular-based methods such as

matrix-assisted laser desorption–ionization–time-of-flight mass spectrometry (MALDI-TOF-MS) and quantitative real-time polymerase

chain reaction (PCR) are usually necessary to identify Acinetobacter

baumannii, the most clinically relevant species of the genus.

■ ETIOLOGY AND EPIDEMIOLOGY

Acinetobacter species are naturally encountered in water and soil

and have also been recovered from fruits and vegetables. In humans,

Acinetobacter can be found on the skin and in the respiratory and

gastrointestinal tracts. A. baumannii is capable of surviving environmental desiccation for weeks; this characteristic is important from an

infection-control perspective as it allows this organism to persist in the

hospital environment and on equipment.

Acinetobacter was historically considered a pathogen of hot and

humid climates. In recent years, however, hospital outbreaks caused

by A. baumannii have been reported worldwide, even in temperate

climates. In the United States, the Centers for Disease Control and

Prevention (CDC) estimates that 12,000 Acinetobacter infections occur

every year, 7300 of which are caused by multidrug-resistant strains,

with 500 attributable deaths. The increase in the number of infections

with A. baumannii is suspected to be due to the rapid spread of certain

genetically distinct lineages; of the three international clonal lineages

(ICLs), ICL I and ICL II are multidrug resistant. The predominance of

these lineages remains unexplained, although it has been proposed that

this population structure is the result of two waves of expansion. The

first wave followed a bottleneck (possibly linked to a restricted ecologic

niche) that occurred in the distant past. The second wave is ongoing

and is being driven by the rapid expansion of a limited number of

multidrug-resistant clones.

Analysis of the A. baumannii pangenome (the sum of the core and

dispensable genomes) has shown that its organization is characterized by a small core genome and a large accessory or disposable

genome. This organization reflects A. baumannii’s high plasticity,

which enables it to acquire exogenous genetic material. With few

exceptions, gene functions associated with virulence are found in the

core genome; this observation suggests a limited role for the acquisition of new virulence traits in the recent nosocomial expansion of A.

baumannii clones. Genes associated with resistance to antimicrobial

agents are found in both the species core genome and the accessory

genome. In the accessory genome, these genes have been found in alien

islands, often flanked by integrases, transposases, or insertion

sequences. This pattern suggests possible acquisition by horizontal

gene transfer from other Acinetobacter strains or even from different

bacterial species present in the immediate environment. Acquisition of

these antimicrobial resistance genes is hypothesized to have led to the

recent rapid expansion of highly homogeneous clonal lineages, whose

main difference from nonclonal A. baumannii appears to be their antimicrobial resistance.

Health Care–Associated Infections Infections caused by A.

baumannii occur frequently among patients admitted to intensive

care units (ICUs). Risk factors for colonization and infection with

this pathogen include nursing home residence, prolonged ICU stay,

central venous catheterization, tracheostomy, mechanical ventilation,

enteral feedings, and treatment with third-generation cephalosporins,

162 Acinetobacter Infections

Rossana Rosa, L. Silvia Munoz-Price

1276 PART 5 Infectious Diseases

fluoroquinolones, and carbapenems. Acquisition of carbapenemresistant A. baumannii is most common among patients exposed to

carbapenems. Spread of A. baumannii across different regions is facilitated by the movement of patients between health care systems and

throughout the continuum of health care. Within the hospital, environmental spread of A. baumannii occurs as a result of inappropriate

hand hygiene among workers providing health care for infected or

colonized patients and the contamination of hospital equipment, such

as respiratory therapy and ventilation equipment. The air surrounding

the patient may also play a role in environmental colonization with

A. baumannii, especially in inpatient areas without physical barriers

between patients and with an inadequate number of air exchanges.

A. baumannii strains identified during hospital outbreaks are typically resistant to more antibiotic classes than strains from the community. The prevalence of colonization with A. baumannii at the time of

admission or during a stay in a long-term acute-care hospital (LTACH)

or nursing home is variable and depends on regional flora. Outbreaks

of A. baumannii in acute-care hospitals and LTACHs that “share”

patients have been described in Ohio, Michigan, Illinois, and Indiana.

Community-Acquired Infections Community-acquired infections caused by Acinetobacter have been described in Australia and

Asia. Few cases have been reported in regions with a temperate climate,

and even those few cases have taken place during warm and humid

months. Risk factors for community-acquired pneumonia due to this

organism include a history of alcohol abuse, diabetes mellitus, smoking, and chronic lung disease.

War Zone–Associated Infections Infections caused by Acinetobacter in war zones include skin and soft tissue infections associated

with traumatic injuries and bloodstream infections. Outbreak investigations of A. baumannii infections among military personnel returning

from Iraq and Afghanistan suggested the acquisition of A. baumannii

in field hospitals rather than colonization of the skin before an injury.

This view is supported by the recovery of A. baumannii isolates with

similar genetic characteristics from inanimate surfaces in field hospitals and from patients.

Disaster Medicine A. baumannii is linked to infections among

victims of trauma during tsunamis, earthquakes, and terrorist attacks.

The types of infections most frequently observed in these settings are

soft tissue injuries, but bloodstream infections and pneumonia have

also been reported. In addition, outbreaks of A. baumannii infection in

ICUs caring for disaster victims have been described.

■ PATHOGENESIS

Mechanisms of pathogenesis and virulence in Acinetobacter species have

not been fully elucidated. However, A. baumannii seems to have greater

virulence potential than other Acinetobacter species, as evidenced by its

ability to grow at 37°C and to resist uptake by macrophages.

Initial A. baumannii colonization of the host and the environment

is facilitated by the organism’s ability to adhere to surfaces and human

cells and to create biofilms. The ability to form a biofilm is phenotypically associated with exopolysaccharide production and pilus formation. A quorum-sensing molecule encoded by the abaI autoinducer

synthase gene has been implicated in A. baumannii biofilm formation

on abiotic surfaces. Outer-membrane porins appear to mediate cell

apoptosis. A. baumannii can survive in harsh environments within

the host and on inanimate surfaces by modifying the structure of its

lipid A, with a consequent decrease in susceptibility to antibiotics and

antimicrobial peptides and an increase in survival upon desiccation.

Acinetobacter species produce an extracellular capsule that protects

the bacteria from external threats, including complement-mediated

killing. Studies of mouse models showed that Acinetobacter species can

increase capsule production in the presence of subinhibitory levels of

antibiotic—an ability that leads to increased resistance to complementmediated killing and a hypervirulent phenotype.

Phospholipase C and phospholipase D have been identified as virulence factors in A. baumannii. These enzymes exert cytotoxic effects on

epithelial cells and facilitate their invasion.

Iron-acquisition systems are also important virulence mechanisms in

A. baumannii. Through secretion of siderophores (low-molecular-mass

ferric-binding compounds), A. baumannii is able to grow despite iron

deficiencies in the surrounding environment (e.g., in the human host).

Several protein-secretion systems have been identified in A. baumannii. The most recently described is a type II secretion system. The

substrate for this system, the LipA lipase, is required for growth on

medium containing lipids as a sole carbon source. Mutants lacking the

genes for the type II secretion system or its substrate exhibit defective

in vivo growth in a neutropenic murine model of bacteremia. A. baumannii also has a type VI secretion system whose primary function

seems to be to secrete antibacterial toxins that kill competing bacteria,

including other strains in the same species.

The type V autotransporter system has been characterized in A.

baumannii. In a murine systemic model of Acinetobacter infection, the

Acinetobacter trimeric autotransporter mediates biofilm formation and

maintenance; adherence to extracellular matrix components such as

collagen I, II, and IV; and virulence.

Outer-membrane vesicles (OMVs) play a special role in protein

secretion. Many A. baumannii strains secrete OMVs containing various virulence factors, including outer-membrane protein A (OmpA),

proteases, and phospholipases. The membrane proteins in OMVs are

responsible for eliciting a potent innate immune response. Several

studies have shown that A. baumannii OMVs could be used as an acellular vaccine to effectively control A. baumannii infections.

Nosocomial strains of Acinetobacter can deploy multiple mechanisms of resistance, including alterations in porins and efflux pumps

and expression of β-lactamases. More specifically, Acinetobacter species can reduce the expression of porins, thus hindering the passage

of β-lactam antibiotics into the periplasmic space. These species can

overexpress bacterial efflux pumps and decrease the concentration of

β-lactam antibiotics in the periplasmic space. Efflux pumps can also

actively remove quinolones, tetracyclines, chloramphenicol, disinfectants, and tigecycline. Acinetobacter species possess chromosomally

encoded cephalosporinases and are capable of acquiring β-lactamases,

including serine and metallo-β-lactamases. AmpC β-lactamases are

class C β-lactamases intrinsic to all A. baumannii strains. Although

these enzymes are expressed at low levels and are not inducible,

the addition of the insertion sequence ISAba1 next to the AmpC

gene increases β-lactamase production, with resulting resistance to

cephalosporins.

Carbapenem resistance in Acinetobacter species is mostly tied to

the emergence of Ambler class D oxacillinases of group 2d, some of

which are intrinsic and chromosomal (e.g., OXA-51-like) while others

are acquired and are found in plasmids or are chromosomally encoded

(e.g., OXA-23-like, 24 [33-like, 40-like], 58-like, 143-like, and 235-like).

■ CLINICAL MANIFESTATIONS

Pneumonia A. baumannii is a notorious cause of nosocomial pneumonia, most frequently among patients requiring prolonged mechanical ventilation. The onset of disease tends to be later than that caused

by other gram-negative bacilli; however, clinical symptoms of hospitalacquired or ventilator-associated pneumonia due to A. baumannii are

similar to those of nosocomial or ventilator-associated pneumonia due

to other nosocomial pathogens. Thus, the most common indicators of

infection include fever and increased sputum production. The positivity of respiratory cultures in most cases may present a challenge for the

clinician, since airway colonization with A. baumannii is a risk factor

for infection itself. Radiologic findings are nonspecific and can include

lobar consolidations and pleural effusions, but cavitations are rarely

seen. The crude mortality rates associated with nosocomial pneumonia

due to A. baumannii are reported to be as high as 65%. However, since

these infections occur in debilitated patients, their attributable mortality has been difficult to establish.

Community-acquired pneumonia due to A. baumannii is a relatively rare entity. Its clinical presentation is characterized by fever,

severe respiratory symptoms, and multiple-organ dysfunction. Patients

frequently have a cough productive of purulent sputum, shortness of

1277CHAPTER 162 Acinetobacter Infections

breath, and chest pain. Imaging studies usually show lobar consolidation. Mortality rates associated with this process are >50%.

Bloodstream Infections Bloodstream infections due to A. baumannii are most frequent among ICU patients and usually occur in the

presence of a central venous catheter or as a secondary complication of

hospital-acquired or ventilator-associated pneumonia. Polymicrobial

growth has been reported in 20–36% of bacteremia episodes. Fever

is the most common sign of infection (developing in >95% of cases),

and presentation with septic shock and disseminated intravascular

coagulopathy has been described in as many as 25 to 30% of patients,

respectively. A. baumannii bloodstream infections often result in

higher hospitalization costs and longer ICU stays. Crude mortality

rates from this infection are as high as 40%; however, rates can be as

high as 70% from infections caused by carbapenem-resistant isolates.

In patients with infections caused by extremely drug-resistant strains,

poor outcomes are thought to be driven by delays in the initiation of

adequate antimicrobial therapy.

Skin and Soft Tissue Infections Acinetobacter species have been

described as part of the skin flora, yet the majority of the organisms

from this genus that colonize the skin are not those associated with

nosocomial infections. Discerning infection from wound colonization is challenging. Gunshot wounds and the presence of orthopedic

external-fixation devices are common among patients with combat

trauma–associated A. baumannii skin and soft tissue infections. The

report on a case series of eight U.S. military patients described the

clinical presentation of their infections as evolving from an edematous

peau d’orange appearance to a sandpaper appearance with overlying

vesicles and then to a necrotizing process with hemorrhagic bullae.

Other case series have also included necrotizing fasciitis. A. baumannii

is an important pathogen in burn units worldwide. Large burns provide ideal conditions for A. baumannii and facilitate patient-to-patient

transmission. The presence of A. baumannii in wounds contributes to

healing delays and graft loss. In addition, wound colonization is a risk

factor for bloodstream infections among patients with extensive burn

injuries.

A. baumannii infections resulting from trauma to soft tissues in the

setting of natural disasters, such as tsunamis and earthquakes, have

been reported. The implication is that A. baumannii should be considered in the differential diagnosis of soft tissue infections following

exposure to tropical and subtropical environments.

Urinary Tract Infections A. baumannii is an infrequent cause of

urinary tract infections. The majority of cases reported are catheterassociated infections, reflecting the ability of A. baumannii to form

biofilms on these devices. A few reports have described communityacquired infections occurring in the setting of nephrolithiasis and after

renal transplantation.

Meningitis Central nervous system infections with A. baumannii

have been reported in the context of outbreaks, traumatic injuries,

neurosurgical procedures, and external ventricular drains. One case

series described a petechial rash in up to 30% of patients. Acinetobacter

species may look similar to Neisseria meningitidis on a Gram’s stain of

cerebrospinal fluid; both appear as gram-negative paired cocci.

Other Miscellaneous Infections A few cases of A. baumannii

keratitis associated with the use of contact lenses have been reported.

Cases of native- and prosthetic-valve endocarditis have also been

described.

TREATMENT

Acinetobacter Infections

Treatment of Acinetobacter infections is challenging because Acinetobacter can develop resistance to most available antibiotics. Therefore, the choice of empirical therapy should be based on local

epidemiology and the patient’s colonization status. Definitive therapy should be determined by antimicrobial susceptibility testing.

Antimicrobial options for the management of infections caused by

A. baumannii are displayed in Table 162-1.

Acinetobacter species possess intrinsic β-lactamases that inactivate first- and second-generation cephalosporins. Through acquisition of extended-spectrum β-lactamases, the organisms can also

become resistant to third- and fourth-generation cephalosporins.

Nevertheless, when the isolate is susceptible, β-lactam agents are

the drugs of choice for the treatment of A. baumannii. Among βlactamase inhibitors, sulbactam is active against A. baumannii

and is as effective as carbapenems and polymyxins. Cefiderocol

is a novel cephalosporine and is stable against many β-lactamase

classes, including extended-spectrum β-lactamases, AmpC, and

carbapenemases. Cefiderocol has shown in vitro activity against A.

baumannii isolates producing OXA-23, OXA-40, OXA-58, NDM,

and IMP. However, published clinical trials have not included

patients with infections caused by carbapenem-resistant strains.

Carbapenems have been the preferred drugs for treatment of

invasive or hospital-acquired infections. Unfortunately, surveillance

data from U.S. hospitals show that up to 50% of A. baumannii isolates recovered from ICUs are carbapenem resistant, and rates of

carbapenem resistance are even higher around the world.

Aminoglycosides are of limited utility against A. baumannii

because of toxicity and lack of lung penetration. Inhaled formulations of tobramycin have been used with variable success.

Polymyxins are cationic detergents that fell out of use as a result

of nephrotoxicity and neurotoxicity. In vitro, they are the most

active agents against carbapenem-resistant A. baumannii. Colistin has been used in both intravenous and inhaled formulations,

although the optimal dosage has not yet been determined. Combination therapy using colistin as a base has long been preferred but

randomized controlled trials have failed to show improved survival

compared to colistin monotherapy.

Tigecycline is a glycylcycline with clinical activity against A.

baumannii. It reaches only low serum concentrations and therefore

cannot be used for bloodstream infections. The susceptibility of

TABLE 162-1 Therapeutic Options for the Management of

Multidrug-Resistant Acinetobacter baumannii Infections

ANTIBIOTIC DOSINGa COMMENTS

Sulbactam 3–9 g/d (9–27 g/d if given

in combination with

ampicillin)

Unavailable as single drug in many

countries (including the United

States)

Meropenem 2 g q8h Prolonged infusion (3–4 h) has been

used; limited data

Imipenem 500 mg q6h Prolonged infusion (3–4 h) has been

used; limited data

Cefiderocol 2g q8h Prolonged infusion (3 h) used in

pharmacokinetic models

Colistin Loading dose of 5 mg/

kg followed by 2.5–5.0

mg/kg per day of colistin

base given in 2–4 divided

doses

Optimal dosing regimen unknown

Inhaled formulation has been used as

adjunct treatment in lung infections.

Polymyxin B 1.5–3 mg/kg q12h

Tigecycline 100-mg loading dose

followed by 50 mg q12h

Low serum concentrations and

bacteriostatic activity limit use in

bacteremia.

Minocycline 100 mg q12h Loading dose of 200 mg IV has been

used.

Eravacycline 1 mg/kg q12h

Amikacin 15 mg/kg qd Inhaled formulation of tobramycin

has been used as adjunct treatment

in lung infections.

Rifampin 600 mg qd or 600 mg q12h Use in combination therapy

Fosfomycin 4 g q12h PO Use in combination therapy

IV formulation not available in the

United States

a

All drugs are given by the IV route unless otherwise stated.

1278 PART 5 Infectious Diseases

isolates is variable, especially in outbreak settings, and the emergence of resistance during treatment has been reported.

Minocycline is a tetracycline that has a bacteriostatic effect

on A. baumannii. Synergistic and bactericidal activity has been

noted when minocycline is used in combination with colistin or a

carbapenem.

Eravacycline is a novel tetracycline with in vitro activity against

multidrug-resistant and extensively drug-resistant strains of

A. baumannii. However, only a small number of carbapenemresistant isolates have been included in clinical studies. Furthermore, eravacycline has been approved for the treatment of complicated intraabdominal infections but was shown to be inferior to

levofloxacin and ertapenem for the management of complicated

urinary tract infections.

Fosfomycin is an inhibitor of peptidoglycan synthesis that has

no direct activity against A. baumannii but has been observed to

be synergistic in vitro in combination with colistin or sulbactam.

Clinical data have shown higher rates of microbiologic cure, but no

differences in clinical response, with combinations of fosfomycin

and colistin.

In vitro data favor combination therapy with colistin in many

different regimens containing a carbapenem (imipenem, meropenem), rifampin, minocycline, ceftazidime, azithromycin, doxycycline, trimethoprim-sulfamethoxazole, or ampicillin-sulbactam.

However, clinical data have not shown such combination therapy

to be superior to colistin alone.

Bacteriophage therapy against multidrug-resistant A. baumannii

has been reported with varied success rates. Furthermore, dosing

and duration of therapy vary by syndrome and resistance can also

arise during treatment.

■ COMPLICATIONS AND PROGNOSIS

Infections caused by A. baumannii can be associated with high mortality rates. Factors contributing to higher mortality are thought to

include severity of the patient’s underlying illness and drug resistance

in the infecting strain.

■ INFECTION CONTROL AND PREVENTION

Acinetobacter species are capable of surviving on hospital surfaces for

prolonged periods. In the hospital environment, A. baumannii has

been associated with establishment of a fecal patina; this term refers

to a coating of enteric organisms that can cover the skin of colonized

patients and extend to their surrounding environment. Concentrations

of enteric organisms are highest in the colonized patient’s rectum,

with spread in a target-like concentric pattern covering the patient’s

body and the surrounding environment. High-frequency touch areas

in rooms occupied by patients colonized with A. baumannii are more

likely to be contaminated. The hands, gloves, and gowns of health care

workers can be contaminated after entry into the room of a patient

colonized with A. baumannii (Fig. 162-1).

Outbreaks caused by A. baumannii are frequently mono- or oligoclonal. A common source of infection has been identified in ~50% of

outbreaks. These sources include respiratory therapy equipment, the

hands of health care workers, bedside humidifiers, warm bathwater,

hospital-prepared distilled water, bedpans, urine jugs, heparinized

saline solution, mattresses, reusable pressure transducers in arterial

lines, and fluids used for pressure lavage of wounds.

Control of multidrug-resistant Acinetobacter outbreaks starts with

early recognition, with subsequent halting of the spread of infection throughout a facility and prevention of the establishment of an

endemic strain. It is important to identify the outbreak strain and

differentiate it from nonoutbreak strains so that infection control

activities can be better targeted. Traditionally, the strain was identified

with phenotypic typing systems (biotyping) or by determination of

antimicrobial susceptibility patterns. Molecular typing systems have

ushered in an era of molecular epidemiology that allows more precise

identification of outbreak strains through use of techniques such as

ribotyping, pulse-field gel electrophoresis, repetitive sequence-based

PCR, and multilocus sequence testing.

During outbreaks, the simultaneous introduction of multiple

(“bundled”) measures makes it difficult to assess the impact of each

individual measure. These interventions include aggressive cleaning of

the general environment, active surveillance, contact isolation of colonized or infected patients, cohorting of medical staff, reinforcement

of compliance with hand hygiene by health care workers, and use of

aseptic care devices.

Colonization with A. baumannii is a strong predictor of subsequent

clinical infection by this organism. Exposure to carbapenems is a risk

factor for initial acquisition of this pathogen; therefore, efforts to curtail unnecessary use of antibiotics are fundamental to the prevention of

A. baumannii–

positive patient

A. baumannii–

negative patient

Health care worker’s

hands

Health care

-Physical separation from environment

A. baumannii–negative

patients

-Rectal surveillance

-Cohorting nursing

personnel

-Chlorhexidine baths

-Antibiotic stewardship

-Hand hygiene

-Contact precautions

-Daily and terminal

disinfection

-Limits on shared equipment

-Disinfection of equipment

between patients

-Physical separation from

A. baumannii–positive

patients

-Cohorting nursing

personnel

-Chlorhexidine baths

-Antibiotic stewardship

Shared equipment

FIGURE 162-1 Strategies for the prevention of dissemination of Acinetobacter baumannii in health care facilities.