Klebsiella Infections 

Updated: Jun 10, 2019
Author: Shahab Qureshi, MD, FACP; Chief Editor: Michael Stuart Bronze, MD 

Overview

Background

The genus Klebsiella belongs to the tribe Klebsiellae, a member of the family Enterobacteriaceae. The organisms are named after Edwin Klebs, a 19th century German microbiologist. Klebsiellae are nonmotile, rod-shaped, gram-negative bacteria with a prominent polysaccharide capsule. This capsule encases the entire cell surface, accounts for the large appearance of the organism on gram stain, and provides resistance against many host defense mechanisms.

Members of the Klebsiella genus typically express 2 types of antigens on their cell surface. The first is a lipopolysaccharide (O antigen); the other is a capsular polysaccharide (K antigen). Both of these antigens contribute to pathogenicity. About 77 K antigens and 9 O antigens exist. The structural variability of these antigens forms the basis for classification into various serotypes. The virulence of all serotypes appears to be similar.

Three species in the genus Klebsiella are associated with illness in humans: Klebsiella pneumoniae, Klebsiella oxytoca, and Klebsiella granulomatis. Organisms previously known as Klebsiella ozaenae and Klebsiella rhinoscleromatis are considered nonfermenting subspecies of K pneumoniae that have characteristic clinical manifestations. With those exceptions, strains within this genus ferment lactose, most produce highly mucoid colonies on plates because of the production of a luxuriant polysaccharide capsule, and all are nonmotile.[1] In recent years, klebsiellae have become important pathogens in nosocomial infections.[2] See the image below.

This scanning electron micrograph (SEM) reveals so This scanning electron micrograph (SEM) reveals some of the ultrastructural morphologic features of Klebsiella pneumoniae. Courtesy of CDC/Janice Carr.

Pathophysiology

Host defense against bacterial invasion depends on phagocytosis by polymorphonuclear granulocytes and the bactericidal effect of serum, mediated in large part by complement proteins. Both classic-pathway and alternate-pathway complement activation have been described, but the latter, which does not require the presence of immunoglobulins directed against bacterial antigens, appears to be the more active pathway in K pneumoniae infections.

Recent data from preclinical studies suggest a role for neutrophil myeloperoxidase and lipopolysaccharide-binding protein in host defense against K pneumoniae infection. Neutrophil myeloperoxidase is thought to mediate oxidative inactivation of elastase, an enzyme implicated in the pathogenesis of various tissue-destroying diseases. Lipopolysaccharide-binding protein facilitates transfer of bacterial cell wall components to inflammatory cells. Investigators showed higher rates of infection in experimental mice deficient in the genes that control expression of these 2 agents.

The bacteria overcome innate host immunity through several means. They possess a polysaccharide capsule, which is the main determinant of their pathogenicity. The capsule is composed of complex acidic polysaccharides. Its massive layer protects the bacterium from phagocytosis by polymorphonuclear granulocytes. In addition, the capsule prevents bacterial death caused by bactericidal serum factors. This is accomplished mainly by inhibiting the activation or uptake of complement components, especially C3b. The bacteria also produce multiple adhesins. These may be fimbrial or nonfimbrial, each with distinct receptor specificity. These help the microorganism to adhere to host cells, which is critical to the infectious process.

Lipopolysaccharides (LPS) are another bacterial pathogenicity factor. They are able to activate complement, which causes selective deposition of C3b onto LPS molecules at sites distant from the bacterial cell membrane. This inhibits the formation of the membrane attack complex (C5b-C9), which prevents membrane damage and bacterial cell death.

Availability of iron increases host susceptibility to K pneumoniae infection. Bacteria are able to compete effectively for iron bound to host proteins because of the secretion of high-affinity, low molecular weight iron chelators known as siderophores. This is necessary because most host iron is bound to intracellular and extracellular proteins. In order to deprive bacteria of iron, the host also secretes iron-binding proteins.

Epidemiology of Klebsiellae

Klebsiellae are ubiquitous in nature. In humans, they may colonize the skin, pharynx, or gastrointestinal tract. They may also colonize sterile wounds and urine. Carriage rates vary with different studies. Klebsiellae may be regarded as normal flora in many parts of the colon and intestinal tract and in the biliary tract. Oropharyngeal carriage has been associated with endotracheal intubation, impaired host defenses, and antimicrobial use.

K pneumoniae and K oxytoca are the 2 members of this genus responsible for most human infections. They are opportunistic pathogens found in the environment and in mammalian mucosal surfaces. The principal pathogenic reservoirs of infection are the gastrointestinal tract of patients and the hands of hospital personnel. Organisms can spread rapidly, often leading to nosocomial outbreaks.

Infection with Klebsiella organisms occurs in the lungs, where they cause destructive changes. Necrosis, inflammation, and hemorrhage occur within lung tissue, sometimes producing a thick, bloody, mucoid sputum described as currant jelly sputum. The illness typically affects middle-aged and older men with debilitating diseases such as alcoholism, diabetes, or chronic bronchopulmonary disease. This patient population is believed to have impaired respiratory host defenses. The organisms gain access after the host aspirates colonizing oropharyngeal microbes into the lower respiratory tract.

Klebsiellae have also been incriminated in nosocomial infections. Common sites include the urinary tract, lower respiratory tract, biliary tract, and surgical wound sites. The spectrum of clinical syndromes includes pneumonia, bacteremia, thrombophlebitis, urinary tract infection (UTI), cholecystitis, diarrhea, upper respiratory tract infection, wound infection, osteomyelitis, and meningitis. The presence of invasive devices, contamination of respiratory support equipment, use of urinary catheters, and use of antibiotics are factors that increase the likelihood of nosocomial infection with Klebsiella species. Sepsis and septic shock may follow entry of organisms into the blood from a focal source.

Klebsiella granulomatis (formerly Calymmatobacterium granulomatis) is a fastidious member of the genus that causes chronic genital ulcerative disease also known as granuloma inguinale or donovanosis. It is a relatively rare disease in the United States, with fewer than 100 cases reported annually. It has long been a recognized cause of genital ulceration in parts of India, Papua New Guinea, the Caribbean, and South America (particularly Brazil). Fortunately, the incidence of the disease has decreased in recent years.

Rhinoscleroma and ozena are 2 other infections caused by Klebsiella species. These diseases are rare. Rhinoscleroma is a chronic inflammatory process involving the nasopharynx, whereas ozena is a chronic atrophic rhinitis characterized by necrosis of nasal mucosa and mucopurulent nasal discharge.

K oxytoca has been implicated in neonatal bacteremia, especially among premature infants and in neonatal intensive care units. Increasingly, the organism is being isolated from patients with neonatal septicemia.

Extensive use of broad-spectrum antibiotics in hospitalized patients has led to both increased carriage of klebsiellae and, subsequently, the development of multidrug-resistant strains that produce extended-spectrum beta-lactamase (ESBL). These strains are highly virulent, show capsular type K55, and have an extraordinary ability to spread. Most outbreaks are due to a single clone or single gene; the bowel is the major site of colonization with infection of the urinary tract, respiratory tract, and wounds. Bacteremia and significant increased mortality have resulted from infection with these species.

In addition to prior antibiotic use, risk factors for infection include the presence of an indwelling catheter, feeding tube, or central venous catheter; poor health status; and treatment in an intensive care unit or nursing home. Acquisition of these species has become a major problem in most hospitals because of resistance to multiple antibiotics and potential transfer of plasmids to other organisms.

Carbapenem-resistant Enterobacteriaceae (CRE), which are sometimes known as K pneumoniae carbapenemase (KPC) and New Delhi metallo-beta-lactamase (NDM), are a family of bacteria that are difficult to treat because of their high levels of resistance to antibiotics. Some CRE bacteria have become resistant to most available antibiotics and cause mortality rates of up to 50%.

Hypervirulent K pneumoniae (hvKp), also termed as hypermucoviscous strains, have been reported globally with invasive infections and varying degrees of resistance and virulence patterns.[3, 4, 5, 6]

Epidemiology

Frequency

United States

In some parts of the world, K pneumoniae is an important cause of community-acquired pneumonia in elderly persons. Studies conducted in Malaysia and Japan estimate the incidence rate in elderly persons to be 15-40%, which is equal to, if not greater than, that of Haemophilus influenzae. However, in the United States, these figures are different. Persons with alcoholism are the main population at risk, and they constitute 66% of people affected by this disease. Mortality rates are as high as 50% and approach 100% in persons with alcoholism and bacteremia.

Klebsiellae are also important in nosocomial infections among adult and pediatric populations. Klebsiellae account for approximately 8% of all hospital-acquired infections. In the United States, depending on the study reviewed, they comprise 3-7% of all nosocomial bacterial infections, placing them among the top 8 pathogens in hospitals. Klebsiellae cause as many as 14% of cases of primary bacteremia, second only to Escherichia coli as a cause of gram-negative sepsis. They may affect any body site, but respiratory infections and UTIs predominate.

Of 145 reported epidemic outbreaks of nosocomial bacteremias during 1983-1991, 13 were attributed to Klebsiella organisms. The US Centers for Disease Control and Prevention report that Klebsiella strains were responsible for 3% of all pathogenic epidemic outbreaks.

An investigation of Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae among patients of acute and long-term acute care hospitals was conducted in 2011. The investigation found extensive spread of KPC-producing Enterobacteriaceae throughout 4 adjacent counties in Indiana and Illinois over a 1-yr period. Long-term acute care hospitals played a central role in the outbreak, suggesting that guidelines for controlling KPC should be expanded to include long-term care facilities. Education of personnel and coordinated regional efforts among health care facilities are crucial for KPC control.[7]

Another multihospital study on transmission risk found that patients admitted to acute care hospitals from high-acuity long-term–care facilities were more likely to be colonized with KPC-producing Enterobacteriaceae than were patients admitted from the community.[8]

K oxytoca is among the top 4 pathogens that cause infection in patients in neonatal intensive care units. It is the second most frequent cause of gram-negative neonatal bacteremia.

International

Outbreaks of neonatal septicemia occur worldwide. Infection with K pneumoniae also has a worldwide distribution. Infection with K rhinoscleromatis is not common in the United States, although it has a worldwide distribution and is usually observed in areas of eastern Europe, southern Asia, central Africa, and Latin America. K granulomatis is more common outside the United States in countries such as India, Papa New Guinea, Caribbean, South America, Zambia, Zimbabwe, South Africa, Southeast Asia, and some parts of Australia.

Mortality/Morbidity

Klebsiella pneumonia is a necrotizing process with a predilection for debilitated people. It has a high mortality rate of approximately 50% even with antimicrobial therapy. The mortality rate approaches 100% for persons with alcoholism and bacteremia.

Klebsiella bacteremia and sepsis produce clinical manifestations similar to those caused by other gram-negative enteric organisms. Morbidity and mortality rates are comparable to those for other gram-negative organisms that cause sepsis and septic shock. In neonatal units, outbreaks caused by ESBL-producing strains present a more serious problem and may be associated with increased mortality.

Age

Community-acquired Klebsiella (Friedländer) pneumonia is a disease of debilitated middle-aged and older men with alcoholism.

Nosocomial infections may affect adults or children, and they occur more frequently in premature infants, patients in neonatal intensive care units, and hospitalized individuals who are immunocompromised.

 

Presentation

History

Klebsiellae cause various clinical syndromes. Common klebsiellae infections in humans include (1) community-acquired pneumonia, (2) UTI, (3) nosocomial infection, (4) rhinoscleroma and ozena, (5) chronic genital ulcerative disease, and (6) colonization.

Community-acquired pneumonia

Lobar pneumonia differs from other pneumonias in that it is associated with destructive changes in the lungs. It is a very severe illness with a rapid onset and often-fatal outcome despite early and appropriate antimicrobial treatment.

Patients typically present with an acute onset of high fever and chills; flulike symptoms; and productive cough with an abundant, thick, tenacious, and blood-tinged sputum sometimes called currant jelly sputum.

An increased tendency exists toward abscess formation, cavitation, empyema, and pleural adhesions.

Most pulmonary diseases caused by K pneumoniae are in the form of bronchopneumonia or bronchitis. These infections are usually hospital-acquired and have a more subtle presentation.

Urinary tract infection

Klebsiellae UTIs[9] are clinically indistinguishable from UTIs caused by other common organisms.

Clinical features include frequency, urgency, dysuria, hesitancy, low back pain, and suprapubic discomfort. Systemic symptoms such as fever and chills are usually indicative of a concomitant pyelonephritis or prostatitis.

Nosocomial infection

Important manifestations of klebsiellae infection in the hospital setting include UTI, pneumonia, bacteremia, wound infection, cholecystitis, and catheter-associated bacteriuria. The presence of invasive devices in hospitalized patients greatly increases the likelihood of infection. Patients with these infections have similar presentations to those with infections caused by other organisms.

Other nosocomial infections in which klebsiellae may also be implicated include cholangitis, meningitis, endocarditis, and bacterial endophthalmitis. The latter occurs especially in patients with liver abscesses[10] and diabetes. These infectious presentations are relatively uncommon.

Rhinoscleroma and ozena

K rhinoscleromatis and K ozaenae cause rhinoscleroma and ozena, respectively. Both are rare in the United States and are associated with upper respiratory infection.

Rhinoscleroma is a chronic granulomatous infection. Patients present with a purulent nasal discharge with crusting and nodule formation that leads to respiratory obstruction. Diagnosis is aided by histology findings and positive results from blood culture.

Ozena is a primary atrophic rhinitis that often occurs in elderly persons. Common symptoms include nasal congestion and a constant nasal bad smell. Patients also may complain of headache and symptoms attributable to chronic sinusitis. Unlike rhinoscleroma, nasal congestion is not a prominent feature.

Chronic genital ulcerative disease

K granulomatis infection can result in granuloma inguinale or donovanosis, although these are uncommon in developed temperate countries. The mode of transmission is uncertain but is believed to be sexually transmitted. The incubation period is 1-3 weeks.

Ulcerative infection is likely transmitted by contact with microabraded skin. Nonulcerative infection is probably transmitted transepithelially.

Coinfection with other sexually transmitted diseases (STDs) is common.

Klebsiella chronic genital ulcerative disease presents as a firm papule or subcutaneous nodule that later ulcerates. An ulcerogranulomatous presentation is most common and is characterized as a beefy red ulcer. A hypertrophic or verrucous presentation may mimic condylomata acuminate. A necrotic presentation is characterized by a deep ulcer. Sclerotic and cicatricial presentations are rare.

Diagnosis is based on clinical suspicion. Direct microscopy shows intracytoplasmic bipolar staining inclusion bodies (Donovan bodies).

Colonization

Differentiating nosocomial colonization from infection presents a formidable challenge in clinical practice. It is a common problem in patients with indwelling catheters.

Duration of catheterization is the most important risk factor for the development of bacteriuria. Keeping catheter systems closed and removing catheters as soon as possible are ways to prevent development of bacteriuria.

Most catheter-related UTIs are asymptomatic; the usual complaints of frequency, urgency, dysuria, hesitancy, low back pain, and suprapubic discomfort typically are absent. Therefore, demonstration of bacteriuria is necessary to make a diagnosis. A density of 100,000 colony-forming units per milliliter is usually required to make a diagnosis. Concomitant presence of pyuria is usually present in patients with catheter-associated infection as opposed to those with colonization.

In general, the presence of symptoms in conjunction with bacteriological evidence of infection helps distinguish infection, in which organisms cause disease, from colonization, in which organisms coexist without causing harm.

Physical

Klebsiella pneumonia characteristically affects one of the upper lobes of the lung, although infection of the lower lobes is not uncommon.

Examination of patients with community-acquired pneumonia usually reveals unilateral chest signs, predominantly in the upper lobes. When these signs are observed in a patient such as described in History, the diagnosis of Klebsiella pneumonia is strongly suggested.

Clinical signs observed in patients with extrapulmonary disease depend on the organ system involved. In cases of nosocomial infections, physical examination should include a search for factors that predispose the individual to the development of such infections. These should include inspection for the presence and duration of invasive devices, wounds, and burn sites.

Causes

Host factors that lead to colonization and infection include the following:

  • Hospitalization (especially admission to an intensive care unit)

  • Immunocompromised states (eg, diabetes, alcoholism)

  • Antimicrobial therapy

  • Prolonged use of invasive medical devices

  • Inadequate infection control practices

  • Severe illness, including major surgery

The organism gains access to the body either by direct inoculation through breached epithelial surfaces or following aspiration of oropharyngeal organisms.

 

DDx

Diagnostic Considerations

Community-acquired pneumonia

  • Staphylococcal pneumonia (see Staphylococcal Infections)

  • Pneumococcal pneumonia (see Pneumococcal Infections)

  • Legionellosis

  • Pleuropulmonary empyema (see Empyema, Pleuropulmonary)

  • Lung Abscess

Urinary tract infection

  • Urinary Tract Infection, Females

  • Urinary Tract Infection, Males

  • Pseudomonas infection (see Pseudomonas Aeruginosa Infections)

  • Cholecystitis

Nosocomial infection

  • Pseudomonas infection (seePseudomonas Aeruginosa Infections)

  • Acinetobacter infection (see Acinetobacter)

  • Serratia infection (see Serratia)

Rhinoscleroma and ozena

  • Pseudomonas mallei infection (rare in humans) (seePseudomonas Infection)

  • Viral rhinitis (eg, rhinovirus infection) (see Rhinoviruses)

 

Workup

Laboratory Studies

A complete blood cell count usually reveals leukocytosis with a left shift, but this is not invariably present. Persistence of leukocytosis may signify empyema formation.

Obtain a sputum sample for Gram stain. Klebsiellae appear as short, plump, gram-negative bacilli. They are usually surrounded by a capsule that appears as a clear space.

Serology results are not useful for detection of infection with Klebsiella organisms.

Cultures should be obtained from possible sites (eg, wounds, peripheral or central intravenous access sites, urinary catheters, respiratory support equipment).

  • Klebsiellae may be isolated from blood, urine, pleural fluid, and wounds.

  • Klebsiellae are microaerophilic and, thus, can grow in the presence of oxygen or in its absence. They have no special culture requirements. Most species can use citrate and glucose as sole carbon sources; thus, they grow well on most ordinary media.

  • Klebsiellae are lactose-fermenting, urease-positive, and indole-negative organisms, although K oxytoca and some strains of K pneumoniae are exceptions. Klebsiellae do not produce hydrogen sulfide, and they yield positive results on both Voges-Proskauer and methyl red tests.

  • Wounds may be infected with Klebsiella organisms as the sole pathogens or as a component of a multipathogenic infection. Swabs for Gram stain and culture taken from possible sites may aid in establishing the diagnosis.

Imaging Studies

Chest radiography

The organism usually involves one of the upper lobes; however, involvement of lower lobes is not uncommon.

The affected lobe typically appears swollen, producing the bulging fissure sign. This presentation is not necessarily exclusive to Klebsiella infection. Other organisms, such as H influenzae, may produce a similar radiographic appearance.

Cavitation, especially in the presence of a unilateral necrotizing pneumonia, strongly supports the possibility of a Klebsiella organism as the etiologic agent.

Pleural effusion, empyema, abscess formation, and pleural adhesions occur with increased frequency in patients with Klebsiella pneumonia.

Chest tomography

Chest tomography may be required for patients with nonresolving or slowly responding cases of pneumonia.

The findings from this imaging test help exclude entities that are treatable with drainage or debridement such as empyema and respiratory tract obstruction caused by K rhinoscleromatis infection.

Other Tests

Susceptibility testing for ESBL-producing organisms

The rising importance of ESBL-producing organisms has mandated effective screening methods for their detection. Use of aztreonam or ceftazidime resistance as a marker misses approximately 15-20% of ESBL-producing organisms. Resistance to cefpodoxime as a screening method, with sensitivity breakpoints of ≥2 mcg/mL by minimal inhibitory concentration or < 22 mm by disk diffusion (for a 30-mcg cefpodoxime disk), has a sensitivity of at least 98% for ESBL detection.

Different tests that help confirm ESBL susceptibility are available. One test involves using disks that contain cefotaxime and ceftazidime alone and disks containing a combination of clavulanic acid with these antibiotics. These are placed on Mueller-Hinton agar. A positive test result is defined as a 5-mm or greater increase in the size of the zone diameter for either cefotaxime or ceftazidime tested in combination with clavulanic acid versus the zone for either antibiotic tested alone. Another method is the E-test screen, which evaluates third-generation cephalosporins with and without a beta-lactamase inhibitor. Finally, the Vitek ESBL test, which is an automated broth microdilution test, uses cefotaxime and ceftazidime alone and in combination with clavulanic acid.

A good screening strategy might include a cefpodoxime screen followed by confirmatory disk diffusion for screen-positive isolates. The Vitek test has sensitivity of at least 99.5% and specificity of 100%. It is a reliable single-test alternative.

The Clinical and Laboratory Standards Institute recently updated their susceptibility criteria.

European Committee clinical breakpoints for susceptibility are available online from European Committee on Antimicrobial Susceptibility Testing (EUCAST).[11] Reduced breakpoints eliminate the need for phenotypic modified Hodge test.

DNA microarray technology may allow rapid identification of TEM, SHV, and CTX-M ESBLs and KPC in clinical isolates.[12]

Infection-control practices include early detection by providing screening swabs, cultures, contact precautions, patient cohorting, dedicated staffing, antimicrobial stewardship, and limited use of invasive devices (eg, urinary catheters).[13]

Procedures

Diagnostic thoracocentesis may be performed if a pleural fluid pocket is large enough for aspiration.

Bronchoalveolar lavage with fiberoptic bronchoscopy may be helpful in occasional cases in which the diagnosis cannot be made by other means and can be used to ascertain the microbial organisms involved.

 

Treatment

Medical Care

Initial antibiotic selection

Klebsiella organisms are resistant to multiple antibiotics. This is thought to be a plasmid-mediated property. Length of hospital stay and performance of invasive procedures are risk factors for acquisition of these strains.

Treatment depends on the organ system involved. In general, initial therapy of patients with possible bacteremia is empirical. The choice of a specific antimicrobial agent depends on local susceptibility patterns. Once bacteremia is confirmed, treatment may be modified.

Agents with high intrinsic activity against K pneumoniae should be selected for severely ill patients. Examples of such agents include third-generation cephalosporins (eg, cefotaxime, ceftriaxone), carbapenems (eg, imipenem/cilastatin), aminoglycosides (eg, gentamicin, amikacin), and quinolones. These agents may be used as monotherapy or combination therapy. Some experts recommend using a combination of an aminoglycoside and a third-generation cephalosporin as treatment for non–ESBL-producing isolates. Others disagree and recommend monotherapy.

Ceftazidime/avibactam is indicated to treat adults with complicated intra-abdominal infections (in combination with metronidazole) and complicated UTIs, including kidney infections (pyelonephritis), who have limited or no alternative treatment options. Ceftolozane/tazobactam and ceftazidime/avibactam are two novel beta-lactam/beta-lactamase combination antibiotics available. Ceftazidime/avibactam is also active against carbapenem-resistant Enterobacteriaceae that produce K pneumoniae carbapenemases.[14]

The novel carbapenem/beta-lactamase inhibitor meropenem/vaborbactam (Vabomere) specifically addresses carbapenem-resistant Enterobacteriaceae (CRE) (eg, E coli, K pneumoniae) by inhibiting the production of enzymes that block carbapenem antibiotics, one of the more powerful classes of drugs in the antibiotic arsenal. In August 2017, meropenem/vaborbactam was FDA approved for complicated urinary tract infections (cUTI) caused by CRE.

The approval was based on data from a phase 3 multicenter, randomized, double-blind, double-dummy study, TANGO-I (n=550) in adults with cUTI, including those with pyelonephritis. The primary endpoint was overall cure or improvement and microbiologic outcome of eradication (defined as baseline bacterial pathogen reduced to < 104 CFU/mL). Data showed about 98.4% of patients treated with intravenous meropenem/vaborbactam exhibited cure/improvement in symptoms and a negative urine culture result, compared with 94.3% of patients treated with piperacillin/tazobactam. About one week posttreatment, approximately 77% of patients treated with meropenem/vaborbactam had symptom resolution and a negative urine culture result, compared with 73% of patients treated with piperacillin/tazobactam.[15]

Aztreonam may be used in patients who are allergic to beta-lactam antibiotics. Quinolones are also effective treatment options for susceptible isolates in patients with either carbapenem allergy or major beta-lactam allergy.

Other antibiotics used to treat susceptible isolates include ampicillin/sulbactam, piperacillin/tazobactam, ticarcillin/clavulanate, ceftazidime, cefepime, levofloxacin, norfloxacin, moxifloxacin, meropenem, and ertapenem.

Treatment of Klebsiella pneumonia has discrepant results. For patients with severe infections, a clinically prudent approach is the use of an initial short course (48-72 h) of combination therapy with an aminoglycoside, followed by a switch to an extended-spectrum cephalosporin when susceptibility is confirmed.

Antibiotic considerations for resistant infections

Beta-lactamases are constitutive, are usually produced at low levels, and provide resistance against ampicillin, amoxicillin, and ticarcillin.

ESBLs are plasmid mediated, confer multidrug resistance (TEM or SHV types), and are detected by in vitro resistance to ceftazidime and aztreonam. CTX-M type ESBLs, which hydrolyze ceftazidime much less than other third- and fourth-generation cephalosporins, are more prevalent and have proliferated in the Escherichia coli ST131 lineage.[16]

K pneumoniae carbapenemases (KPC; Ambler class A beta lactamases) confer broad resistance and are associated with a higher mortality rate (>50%). Many isolates are a single sequence type, ST258. Susceptibility is limited to gentamicin, tigecycline, and colistin.

Metallo-beta-lactamases (Amber class B) include imipenemase (IMP), Verona integron-encoded MBL (VIM), and NDM-1 and are generally resistant to all antibiotics except tigecycline and colistin.

OXA-type carbapenemases (Amber class D) include OXA-48 and weakly hydrolyze carbapenems, broad-spectrum cephalosporins, and aztreonam but express resistance or decreased susceptibility to carbapenems.

ESBL-producing isolates are treated with carbapenems.

Isolates that produce carbapenemase are resistant to carbapenems, penicillins, cephalosporins, fluoroquinolones, and aminoglycosides. Treatment options are limited to colistin (preferred for UTIs), tigecycline, and, occasionally, intravenous fosfomycin.

Combination treatment with colistin, tigecycline, and carbapenem may improve survival in bacteremic patients.[1]

Consider tissue drug penetration such as lung penetration for pneumonia and urine concentration for UTIs.

For liver abscess, percutaneous drainage may be considered.

Community-acquired pneumonia

The mortality rate may be 50%, regardless of treatment.

Effective treatment for this rare condition consists of empirical coverage for gram-negative organisms, aggressive ventilation, and supportive care.

Other measures include clinical and radiologic surveillance for surgically treatable entities such as pulmonary gangrene, lung abscess, and empyema.

Third-generation cephalosporins or quinolones provide coverage for community-acquired K pneumoniae infection. In one study, combination therapy with aminoglycosides was shown to be superior; this benefit was not observed in other studies. Macrolides have no useful activity against K pneumoniae.

Antibiotic therapy should be implemented for at least 14 days.

Nosocomial K pneumoniae pneumonia

Choose antibiotics with high intrinsic activity. A regimen that includes imipenem, third-generation cephalosporins, quinolones, or aminoglycosides may be used alone or in combination. Always confirm susceptibility. Treatment should last at least 14 days.

If response is slow, chest tomography scans may be useful in helping exclude entities that are treatable with debridement or drainage.

In patients who rapidly respond to intravenous therapy, switching to an oral quinolone is regarded as safe so long as the isolate is susceptible.

K pneumoniae UTI

Uncomplicated cases caused by susceptible strains may be treated with most oral agents except ampicillin. Monotherapy is effective, and therapy for 3 days is sufficient.

Complicated cases may be treated with oral quinolones or with intravenous aminoglycosides, imipenem, aztreonam, third-generation cephalosporins, or piperacillin/tazobactam. Duration of treatment is usually 14-21 days. Intravenous agents are used until the fever resolves.

Other measures may include correction of an anatomical abnormality or removal of a urinary catheter.

Other K pneumoniae infections

Combination therapy with a beta-lactam antibiotic and an aminoglycoside is considered the standard for empiric treatment of cholangitis. Few comparative data exist to establish this as the optimal therapy.

Ciprofloxacin monotherapy is as effective as combination therapy for acute suppurative cholangitis. Antimicrobials are administered for at least 10 days. Biliary decompression may be required.

Klebsiella meningitis in adults is rare. Nosocomial disease complicates shunts in children. Third-generation cephalosporins are the drugs of choice because of superior central nervous system penetration. Reports indicate success with cefotaxime, and meropenem is a useful alternative. Adjunctive measures include removal of infected shunts. The suggested duration of treatment is 3 weeks because higher relapse rates have been noted in patients treated with shorter courses of therapy.

Klebsiella endophthalmitis and endocarditis are rare. Therapy for endophthalmitis may be intravitreal, intravenous, or both. Clinical experience is greatest with intravenous ceftazidime and aminoglycosides; however, intravenous therapy alone results in very poor drug levels at the site of infection. Endocarditis has been treated with a combination of an intravenous aminoglycoside and a beta-lactam antibiotic. Few data exist to guide treatment duration; however, 6 weeks of antibiotic therapy is considered reasonable.

Infection with other Klebsiella species

Antibiotic susceptibility and treatment guidelines for K oxytoca infection are virtually identical to those for K pneumoniae. In one study of very ill patients, K oxytoca bacteremia had a 21% mortality rate at 14 days.

Rhinoscleroma is treated with combination antimicrobial therapy for 6-8 weeks. Therapeutic choices include aminoglycosides, tetracycline, sulfonamides, rifampin, and quinolones.

Ozena may be treated with a 3-month course of ciprofloxacin. Intravenous aminoglycosides and trimethoprim/sulfamethoxazole are also useful in the treatment of these conditions. Susceptibility testing is usually required.

K granulomatis genital and mucocutaneous infections are preferably treated with doxycycline for 3 weeks and until the lesions are healed. Consider adding gentamicin if no improvement is noted within the first 36-72 hours. Alternative antibiotics include azithromycin, ciprofloxacin, erythromycin, and trimethoprim/sulfamethoxazole.

Surgical Care

Surgery is required if drainage or debridement is necessary (eg, empyema, lung abscess, pulmonary gangrene, respiratory tract obstruction following persistent K rhinoscleromatis infection).

Surgery may also be needed to correct underlying anatomical abnormalities that predispose patients to infection. An example is correction of posterior urethral valves in patients with recurrent UTIs. Cosmesis is another reason patients require surgical care. This is observed in deforming K rhinoscleroma infection.

Thoracotomy with tube placement is required for empyema.

Pleural decortication is a therapeutic option for persistent pleural adhesions, and extensive lung necrosis may require surgical resection.

Consultations

Surgical consultation is required for the conditions discussed in Surgical Care.

 

Medication

Medication Summary

The following is a discussion on the specific agents used in the antimicrobial therapy of Klebsiella infections. In vitro data show that a wide range of beta-lactams, aminoglycosides, quinolones, and other antibiotics are useful for treatment of klebsiellae infections.[17, 18, 19]

Cephalosporins have been widely used as monotherapy and in combination with aminoglycosides. Cephalosporins should be avoided if ESBL strains are present. In such instances, the carbapenems, especially imipenem, are effective.

Aztreonam and quinolones are useful in patients allergic to penicillin, and rifampin has been used for treatment of rhinoscleroma. TMP/SMZ is not used in primary treatment of pneumonia. They may be used as initial treatment in uncomplicated UTI and as second-line agents for ozena.

For isolates that produce ESBLs and carbapenemases, see Treatment.

Antibiotics

Class Summary

Therapy must cover all likely pathogens in the context of this clinical setting. Antibiotic selection should be guided by culture and sensitivity results whenever feasible.

Cefotaxime (Claforan)

Useful for most Klebsiella infections. Third-generation cephalosporin with gram-negative activity. Arrests bacterial cell wall synthesis, which, in turn, inhibits bacterial growth.

Ceftriaxone

Effective for K pneumoniae meningitis and other Klebsiella infections. Third-generation cephalosporin with broad-spectrum, gram-negative activity and higher efficacy against resistant organisms. Arrests bacterial growth by binding to one or more penicillin-binding proteins.

Gentamicin

Aminoglycoside antibiotic for gram-negative coverage. Bactericidal drug that may be used synergistically with third-generation cephalosporins. Works by binding the bacterial 30S ribosomal subunit, thereby inhibiting protein synthesis. Dosing regimens are numerous; adjust dose based on CrCl and changes in volume of distribution. May be given IV/IM. Monitoring may be required because of the potential to cause cochlear, vestibular, and tubular damage.

Amikacin

For gram-negative bacterial coverage of infections resistant to gentamicin and tobramycin. Irreversibly binds to 30S subunit of bacterial ribosomes, blocks recognition step in protein synthesis, and causes growth inhibition. The same principles of drug monitoring for gentamicin apply to amikacin.

Piperacillin/tazobactam (Zosyn)

Antipseudomonal penicillin plus beta-lactamase inhibitor. Inhibits biosynthesis of cell wall mucopeptide and is effective during stage of active multiplication.

Imipenem/cilastatin (Primaxin)

When given alone, this beta-lactam carbapenem antibiotic is metabolized by renal dehydropeptidase I, resulting in metabolites toxic to the proximal tubule. Cilastatin is an inhibitor of this enzyme, ensuring adequate levels of imipenem.

Ciprofloxacin (Cipro)

Indicated for a variety of Klebsiella infections. May be used PO or IV. Inhibits bacterial DNA synthesis and, consequently, growth.

Aztreonam (Azactam)

Monobactam inhibits cell wall synthesis during bacterial growth. Active against gram-negative bacilli. Bactericidal.

Rifampin (Rifadin)

Inhibits DNA-dependent bacterial RNA polymerase. Indicated as second-line agent in select klebsiellae infections.

Trimethoprim/sulfamethoxazole (Bactrim, Bactrim DS, Sulfatrim Pediatric)

Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Antibacterial activity of TMP-SMZ includes common urinary tract pathogens except Pseudomonas aeruginosa. Indicated as second-line agent for select infections. Not used for routine treatment of pneumonia.

Ampicillin/sulbactam (Unasyn)

This agent features ampicillin combined with a beta-lactamase inhibitor. It interferes with bacterial cell wall synthesis during active replication, causing bactericidal activity against susceptible organisms. 

Ceftazidime (Fortaz, Tazicef)

Ceftazidime is a third-generation cephalosporin with broad-spectrum activity against gram-negative organisms, lower efficacy against gram-positive organisms, and higher efficacy against resistant organisms. By binding to 1 or more of the penicillin-binding proteins, it arrests bacterial cell wall synthesis and inhibits bacterial replication.

Cefepime (Maxipime)

Cefepime is a fourth-generation cephalosporin. Its gram-negative coverage is comparable to ceftazidime, but it has better gram-positive coverage (comparable to ceftriaxone). Cefepime is a zwitterion; it rapidly penetrates gram-negative cells. Cefepime is the best beta-lactam for intramuscular administration. Its poor capacity to the cross blood-brain barrier precludes its use for meningitis.

Meropenem (Merrem)

Meropenem is a bactericidal broad-spectrum carbapenem antibiotic. Inhibits bacterial cell wall synthesis by binding to several of the penicillin-binding proteins, which in turn inhibits cell wall biosynthesis. It is effective against most gram-positive and gram-negative bacteria.

Ertapenem (Invanz)

Bactericidal activity results from inhibition of cell wall synthesis and is mediated through ertapenem binding to penicillin-binding proteins. Stable against hydrolysis by a variety of beta-lactamases, including penicillinases, cephalosporinases, and extended-spectrum beta-lactamases. Hydrolyzed by metallo-beta-lactamases.

Ceftazidime/avibactam (Avycaz)

Indicated for the treatment of complicated intra-abdominal infections, in combination with metronidazole, and complicated UTI caused by designated susceptible microorganisms.

Meropenem/vaborbactam (Vabomere)

Indicated for complicated urinary tract infections (cUTI) caused by carbapenem-resistant Enterobacteriaceae (CRE). Vaborbactam is a nonsuicidal beta-lactamase inhibitor that protects meropenem from degradation by certain serine beta-lactamases such as K pneumoniae carbapenemase (KPC). Vaborbactam does not have any antibacterial activity and does not decrease the activity of meropenem against meropenem-susceptible organisms.

Levofloxacin (Levaquin, Levofloxacin)

Levofloxacin is a second-generation quinolone that acts by interfering with DNA gyrase in bacterial cells. It is bactericidal and is highly active against gram-negative and gram-positive organisms, including Pseudomonas aeruginosa.

Moxifloxacin (Avelox)

Inhibits the A subunits of DNA gyrase, resulting in inhibition of bacterial DNA replication and transcription. Its activity is similar to that of ciprofloxacin and levofloxacin.

Colistin (Coly Mycin M)

Prodrug hydrolyzed to colistin, which acts as cationic detergent and damages bacterial cytoplasmic membrane, causing leaking of intracellular substances and cell death.

Tigecycline (Tygacil)

A glycylcycline antibiotic that is structurally similar to tetracycline antibiotics. Inhibits bacterial protein translation by binding to 30S ribosomal subunit and blocks entry of amino-acyl tRNA molecules in ribosome A site. Indicated for complicated skin and skin structure infections.

Metronidazole (Flagyl, Flagyl ER, Metro)

An imidazole ring-based antibiotic that is active against anaerobes. It is usually given in combination with other antimicrobial agents, except in the setting of Clostridium difficile enterocolitis, in which monotherapy is appropriate.

 

Follow-up

Transfer

Transfer patients with serious infections to a tertiary care facility.

Deterrence/Prevention

Follow hospital protocols for infection control to limit the spread of infection and resistant organisms. Restricting certain antibiotic use for specific indications and duration may help prevent the spread of resistant organisms.

Proper hand washing is crucial to prevent transmission from patient to patient via medical personnel. Contact isolation should be used for patients colonized or infected with highly antibiotic–resistant Klebsiella strains, such as ESBL-producing organisms.

Single-use devices may minimize transmission from contaminated equipment.

Contaminated nebulizers are a major source of hospital-acquired infection; this source has been eliminated through the use of disposable devices.

Use of protective isolation is generally not recommended. Outbreaks of diarrhea associated with Klebsiella infection in neonatal nurseries should necessitate isolation of affected infants.

Other suggested measures to prevent nosocomial infections include the following:

  • Remove medical devices (eg, catheters, tubes) when no longer needed.

  • Use nonalkalinizing gastric cytoprotective agents.

  • Place intubated patients in a semirecumbent position.

  • When possible, consider decreasing the duration and intensity of immunosuppression in patients who are immunocompromised.

Complications

Lung abscesses can occur days to weeks after Klebsiella infection. A lung abscess in a patient with a non–community-acquired pneumonia strongly suggests K pneumoniae infection.

Pulmonary gangrene leading to necrosis involves rapid destruction of part of the lung. This is believed to follow vascular compromise. Fortunately, this is rare.

Other pulmonary complications include cavitation, empyema, bronchopulmonary fistula, and pleural adhesions.

Superinfections can occur while patients are treated for K pneumoniae infection; likewise, K pneumoniae infection can be a superinfection that develops during inpatient treatment for another type of pneumonia.

Sepsis can complicate bacteremia and can result in shock and disseminated intravascular coagulopathy.

Prognosis

K pneumoniae pneumonia has a 50% mortality rate, even with adequate therapy. The prognosis is worse in patients with alcoholism and bacteremia. Preventive strategies and early diagnosis/treatment help to reduce morbidity.

 

Questions & Answers

Overview

What are Klebsiellae?

Which antigens do members of the Klebsiella genus typically express?

Which species of Klebsiellae are pathogenic in humans?

What are the host defenses against Klebsiella infections?

Which two agents are needed for defense against Klebsiella pneumoniae (K pneumoniae) infection?

How do Klebsiella bacteria overcome innate host immunity?

What is the role of lipopolysaccharides (LPS) in the pathogenesis of Klebsiella infections?

What is the role of iron in the pathogenesis of Klebsiella infections?

What is the prevalence of Klebsiellae bacteria in humans?

Which Klebsiellae species are most often responsible for human infections?

What is the typical disease course of Klebsiella infections?

What are the risk factors for nosocomial Klebsiella infections?

What causes granuloma inguinale (donovanosis) and what is the incidence in the US?

What are rhinoscleroma and ozena?

Which Klebsiella pathogen may cause neonatal bacteremia?

What has led to multidrug-resistant strains and increased mortality from Klebsiellae pathogens?

What are risk factors for Klebsiella infection?

What is K pneumoniae carbapenemase (KPC)?

What is the global incidence of Klebsiella pneumoniae (K pneumoniae) infection?

What is prevalence of Klebsiellae in nosocomial infections in the US?

In which settings are patients at highest risk of Klebsiella pneumoniae carbapenemase (KPC) transmission?

What is the prevalence of Klebsiella oxytoca (K oxytoca) in NICUs?

What is the global distribution of Klebsiella infections?

What is the mortality and morbidity of Klebsiella infections?

How does the incidence of Klebsiella infections vary among age groups?

Presentation

What are the common Klebsiella infections in humans?

What are the signs and symptoms of community-acquired Klebsiella pneumoniae (K pneumoniae)?

What are the signs and symptoms of Klebsiella urinary tract infection (UTI)?

What are the signs and symptoms of nosocomial Klebsiella infection?

What are the signs and symptoms of rhinoscleroma and ozena Klebsiella infections?

What are the signs and symptoms of Klebsiella chronic genital ulcerative disease?

What is the role of catheterization in nosocomial Klebsiella infections?

Which physical findings suggest Klebsiella pneumonia?

What should physical exams include for suspected nosocomial Klebsiella infections?

Which factors increase the risk of Klebsiella colonization and infection?

DDX

Which conditions should be included in the differential diagnosis of community-acquired Klebsiella pneumonia?

Which conditions should be included in the differential diagnosis of Klebsiella urinary tract infection (UTI)?

Which diagnoses should be included in the differential diagnosis of nosocomial Klebsiella infections?

Which conditions should be included in the differential diagnoses of rhinoscleroma and ozena?

Workup

Which CBC findings suggest Klebsiella infections?

What is the appearance of Klebsiellae on sputum Gram strain?

What is the role of serology testing in the workup of Klebsiella infections?

Which sites should be cultured in the workup of Klebsiella infections?

What is the role of chest tomography in the workup of Klebsiella infections?

Which chest radiography findings suggest Klebsiella infection?

Which radiographic findings support a Klebsiella etiology in patients with pneumonia?

Which radiographic findings occur with increased frequency in patients with Klebsiella pneumonia?

Which methods are used to screen for extended-spectrum beta-lactamase (ESBL) organisms?

Which organizations have defined criteria for susceptibility testing for extended-spectrum beta-lactamase (ESBL) organisms?

What is the role of DNA microarray technology in the workup of Klebsiella infections?

Which infection-control practices should be performed in suspected Klebsiella infections?

What is the role of thoracocentesis in the workup of Klebsiella infections?

What is the role of bronchoscopy in the workup of Klebsiella infections?

Treatment

What are the treatment options for Klebsiella infections?

Which antibiotic agents are indicated in severely ill patients with Klebsiella infections?

What is the role of beta-lactam/beta-lactamase combination antibiotics in the treatment of Klebsiella infections?

What is the role of meropenem/vaborbactam (Vabomere) in the treatment of Klebsiella infections?

What is the role of aztreonam or quinolones in the treatment of Klebsiella infections?

Which antibiotics are used to treat susceptible isolates of Klebsiella infections?

What is the treatment for severe Klebsiella pneumonia?

Which antibiotics are effective for treatment of resistant extended-spectrum beta-lactamase (ESBL) infections?

Which antibiotics are effective for treatment of resistant Klebsiella pneumoniae carbapenemase (KPC) infections?

Which antibiotics are effective for treatment of resistant metallo-beta-lactamases infections?

Which antibiotics are effective for treatment of resistant for OXA-type carbapenemases infections?

Which antibiotic is effective for treating resistant extended-spectrum beta-lactamase (ESBL) producing isolates?

Which antibiotic is effective for treating isolates that produce carbapenemase in Klebsiella infections?

Which combination therapy may improve survival in patients with Klebsiella-related bacteremia?

What antibiotic tissue penetration should be considered in the treatment of Klebsiella infection?

When is percutaneous drainage indicated in the treatment of Klebsiella infections?

What is the mortality rate of community-acquired Klebsiella pneumonia?

What is the treatment for community-acquired Klebsiella pneumonia?

What is the antibiotic treatment regimen for nosocomial Klebsiella pneumonia?

What is the role of tomography scans in the management of nosocomial Klebsiella pneumonia?

What is the treatment for Klebsiella-related urinary tract infections (UTIs)?

What is the treatment for Klebsiella-related cholangitis?

What is treatment for Klebsiella meningitis?

What are the treatments for Klebsiella endophthalmitis and endocarditis?

What is the treatment for Klebsiella oxytoca (K oxytoca) infection and what is the mortality rate?

How is rhinoscleroma treated?

How is ozena treated?

What is the treatment for Klebsiella granulomatis (K granulomatis) genital and mucocutaneous infections?

What is the role of surgery in the treatment of Klebsiella infections?

Medications

Which agents are used for the treatment of Klebsiella infections?

What is the role of cephalosporins in the treatment of Klebsiella infections?

Which mediations are used in the treatment of Klebsiella infections?

Which medications in the drug class Antibiotics are used in the treatment of Klebsiella Infections?

Follow-up

What is the indication for transfer of patients with Klebsiella infections?

Which infection control measures prevent the spread of Klebsiella infection?

What is a major source of hospital-acquired Klebsiella infections?

When is protective isolation indicated to prevent the spread of Klebsiella infections?

What measures should be taken to prevent nosocomial Klebsiella infections?

What are the possible complications of Klebsiella infections?

What is the prognosis of Klebsiella pneumonia?