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The emergence of Klebsiella pneumoniae carbapenemases (KPCs) producing bacteria has become a significant global public health challenge while the optimal treatment remains undefined. IntroductionThe increasing incidence of Klebsiella pneumoniae carbapenemases (KPCs) is a significant public health challenge[1]. Treatment of KPC infectionsCases received regimens containing the following antimicrobials or antimicrobial classes: 45 cases received a polymyxin, 39 cases received a carbapenem, 30 cases received an aminoglycoside, 26 cases received a glycylcycline, 7 cases received a fluoroquinolone, 5 cases received a beta-lactam plus beta-lactamase inhibitor, 2 cases received cephalosporins, 2 cases received a tetracycline, 2 cases received a monobactam, 1 case received fosfomycin, and 1 case received trimethoprim-sulfamethoxazole.
ConclusionInfections caused by KPC-producing bacteria have been associated with high mortality rates and frequent treatment failure. Competing interestsThe authors declare that they have no competing interests.Authorsa€™ contributionsGL carried out the systematic review, performed the analysis, and drafted the manuscript. Klebsiella pneumoniae is a Gram-negative, non-motile, encapsulated, lactose-fermenting, facultative anaerobic, rod-shaped bacterium. In the clinical setting, it is the most significant member of the Klebsiella genus of Enterobacteriaceae. Seven species of the Klebsiella genus, with demonstrated similarities in DNA homology are known. Members of the Klebsiella genus typically express 2 types of antigens on their cell surface. The Danish scientist Hans Christian Gram (1853–1938), developed the technique now known as Gram staining in 1884 to discriminate between K. Multiple-resistant Klebsiella pneumoniae have been killed in vivo via intraperitoneal, intravenous, or intranasal administration of phages in laboratory tests.[4] While this treatment has been available for some time, a greater danger of bacterial resistance exists to phages than to antibiotics. As a general rule, Klebsiella infections are seen mostly in people with a weakened immune system. The most common infection caused by Klebsiella bacteria outside the hospital is pneumonia, typically in the form of bronchopneumonia and also bronchitis. In addition to pneumonia, Klebsiella can also cause infections in the urinary tract, lower biliary tract, and surgical wound sites. Infection with carbapenem-resistant Enterobacteriaceae (CRE) or carbapenemase-producing Enterobacteriaceae is emerging as an important challenge in health-care settings.[8] One of many carbapenem-resistant Enterobacteriaceae (CRE) is Carbapenem-Resistant Klebsiella pneumoniae (CRKP). Put another way, the most important mechanism of resistance by CRKP is the production of a carbapenemase enzyme, blakpc.
The Centers for Disease Control and Prevention (CDC) released guidance for aggressive infection control to combat CRKP.
Place all patients colonized or infected with CRE or carbapenemase-producing Enterobacteriaceae on contact precautions.
One specific example of this containment policy could be seen in Israel in 2007.[14] This policy had an intervention period from April, 2007 to May, 2008.
In the United States, the reasons that the CDC is recommending the detection of carbapenem resistance or carbapenemase production only for Klebsiella spp.
Effective sterilization and decontamination procedures are important to keep the infection rate of this antibiotic resistant strain, CRKP as low as possible.
As with many bacteria, the recommended treatment has changed as the organism has developed resistances.
The choice of a specific antimicrobial agent or agents depends on local susceptibility patterns and on the part of the body that is infected. After touching hospital surfaces such as bed rails, bedside tables, doorknobs, remote controls, or the phone. Time-kill synergy tests of tigecycline combined with imipenem, amikacin, and ciprofloxacin against clinical isolates of multidrug-resistant Klebsiella pneumoniae and Escherichia coli. Yim H, Woo H, Song W, Park MJ, Kim HS, Lee KM, Hur J, Park MS.SourceDepartment of Burn Surgery, Hallym University Medical Center and College of Medicine, Seoul, Korea. This study evaluated the activity of tigecycline combined with imipenem, amikacin, and ciprofloxacin against clinical isolates of multidrug-resistant Klebsiella pneumoniae and Escherichia coli co-producing extended-spectrum ?-lactamases and acquired AmpC ?-lactamases. An atomic force microscopy study of Galleria mellonella apolipophorin III effect on bacteria. Zdybicka-Barabas A, Januszanis B, Mak P, Cytry?ska M.AbstractApolipophorin III (apoLp-III) is an abundant hemolymph protein involved in lipid transport and immune response in insects. Bacterial decolorization and detoxification of black liquor from rayon grade pulp manufacturing paper industry and detection of their metabolic products.
This study deals with the decolorization of black liquor (BL) by isolated potential bacterial consortium comprising Serratia marcescens (GU193982), Citrobacter sp.
Multiple-resistant Klebsiella pneumoniae have been killed in vivo via intraperitoneal, intravenous or intranasal administration of phages in laboratory tests.
A study of 22 consecutive patients by Yang et al.5 showed that 89 % of patients achieved a visual acuity of light perception at best, with 41 % requiring enucleation or evisceration. Therefore clinicians should consider this diagnosis in patients presenting with the suggestive ocular symptoms and having the risk factors for endogenous endophthalmitis. We performed a systematic review of published studies and reports of treatment outcomes of KPC infections using MEDLINE (2001a€“2011). Previously confined to sporadic outbreaks in the northeastern United States, KPCs have now spread throughout the world and have reached endemic proportions in countries such as Israel and Greece[2, 3]. Overall, 49 (47%) cases received monotherapy and 56 (53%) cases received combination therapy directed at KPC-infections.Summary of treatment outcomesA summary of the treatment outcomes is provided in Tablea€‰3. A recent retrospective cohort study of 21 patients with UTIs described similar positive clinical responses in 16 (76%) patients[70].
Clinical data on treatment are limited and appropriate therapy for KPC infections is not well defined.
Although found in the normal flora of the mouth, skin, and intestines,[1] it can cause destructive changes to human lungs if aspirated. These are (1) Klebsiella pneumoniae, (2) Klebsiella ozaenae, (3) Klebsiella terrigena, (4) Klebsiella rhinoscleromatis, (5) Klebsiella oxytoca, (6) Klebsiella planticola, and (7) Klebsiella ornithinolytica.
The first, O antigen is a component of the lipopolysaccharide (LPS), of which 9 varieties exist. Resistance to phages may cause a bloom in the number of the microbe in environment as well as among humans (if not obligate pathogenic).
These patients have an increased tendency to develop lung abscess, cavitation, empyema, and ural adhesions.
The range of clinical diseases includes pneumonia, thrombophlebitis, urinary tract infection (UTI), cholecystitis, diarrhea, upper respiratory tract infection, wound infection, osteomyelitis, meningitis, and bacteremia and septicemia. The concern is that carbapenem is often used as a drug of last resort when battling resistant bacterial strains.
These include (1) Hyperproduction of ampC beta-lactamase with an outer membrane porin mutation (2) CTX-M extended-spectrum beta-lactamase with a porin mutation or drug efflux, and (3) Carbapenemase production. The gene that encodes the blakpc enzyme is carried on a mobile piece of genetic material (a transposon; the specific transposon involved is called Tn4401), which increases the risk for dissemination. Acute-care facilities are to establish a protocol, in conjunction with the guidelines of the Clinical and Laboratory Standards Institute (CLSI) to detect nonsusceptibility and carbapenemase production in Enterobacteriaceae, in particular Klebsiella spp. A nationwide outbreak of CRE (which peaked in March, 2007 at 55.5 cases per 100,000 patient days) necessitated a nationwide treatment plan.
For patients with severe infections, a prudent approach is the use of an initial short course (48-72 h) of combination therapy, followed by a switch to a specific mono-therapy once the susceptibility pattern is known for the specific patient. Surgical clearing (frequently done as interventional radiology drainage) is often needed after the patient is started on antimicrobial agents. Prompt investigation and meticulous treatment should be instituted as soon as the suspicion arises.
Articles or cases were excluded if one of the following was fulfilled: no individual patient data provided, no treatment regimen specified, no treatment outcome specified, report of colonization, or greater than three antibiotics were used to treat the KPC infection. Furthermore, KPC-producing organisms can confer resistance to multiple different antimicrobial classes, including all available I?-lactams, fluoroquinolones, and aminoglycosides[4, 5]. Antimicrobial dosing, procedures, residual colonization, antimicrobial timing were not always reported and therefore not considered in the outcome analysis.Characteristics of casesCharacteristics of cases evaluated in this review are presented in Tablea€‰1.


Of the nine patients treated for bloodstream infections (BSIs), six patients were treatment failures. This review demonstrated that monotherapy is associated with higher treatment failure rates compared to combination therapy when managing infections due to KPC-producing bacteria, particularly when treating respiratory infections. Of these, K oxytoca and K rhinoscleromatis have also been demonstrated in human clinical specimens.
It naturally occurs in the soil, and about 30% of strains can fix nitrogen in anaerobic conditions.[2] As a free-living diazotroph, its nitrogen fixation system has been much-studied.
The second is K antigen, a capsular polysaccharide with more than 80 varieties.[3] Both contribute to pathogenicity and form the basis for serogrouping.
They cause destructive changes to human lungs via inflammation and hemorrhage with cell death (necrosis) that sometimes produces a thick, bloody, mucoid sputum (currant jelly sputum).
This patient population is believed to have impaired respiratory host defenses, including persons with diabetes, alcoholism, malignancy, liver disease, Chronic obstructive pulmonary diseases (COPD), glucocorticoid therapy, renal failure, and certain occupational exposures (such as paper mill workers). For patients with an invasive device in their body, contamination of the device becomes a risk; for example, respiratory support equipment and urinary catheters put patients at increased risk. Ozena is a chronic atrophic rhinitis that produces necrosis of nasal mucosa and mucopurulent nasal discharge. It is also an opportunistic pathogen for patients with chronic pulmonary disease, enteric pathogenicity, nasal mucosa atrophy, and rhinoscleroma.
The worry is that new slight mutations could result in infections for which there is very little, if anything, healthcare professionals can do to treat patients with resistant organisms. CRE can be difficult to detect because some strains that harbor blakpc have minimal inhibitory concentrations (MICs) that are elevated but still within the susceptible range for carbapenems.
The intervention entailed physical separation of all CRE carriers and appointment of a task force to oversee efficacy of isolation by closely monitoring hospitals and intervening when necessary.
An atomic force microscopy (AFM) study of bacterial cells after apoLp-III treatment showed considerable alterations in the cell surface of Bacillus circulans, Klebsiella pneumoniae and Salmonella typhimurium. Our case clearly is a good clinical example showing the importance of how the proper approach can affect the visual outcome positively in eyes with KPEE. Data extracted included patient demographics, site of infection, organism, KPC subtype, antimicrobial therapy directed at KPC-infection, and treatment outcome. As such, infections due to KPCs are associated with high therapeutic failure and mortality rates of at least 50%[6, 7].
Pulmonary infections were associated with the highest rate of treatment failure (47%) followed by blood infections (39%). The eight cases treated successfully with monotherapy received either a carbapenem (3), tigecycline (2), an aminoglycoside (1), ciprofloxacin (1) or cefepime (1)[8, 16].
Polymyxins and carbapenems when used alone were associated with higher treatment failure than when used in combination. These bacteria gain access typically after a person aspirates colonizing oropharyngeal microbes into the lower respiratory tract. Many of these infections are obtained when a person is in the hospital for some other reason (a nosocomial infection). Also, the use of antibiotics can be a factor that increases the risk of nosocomial infection with Klebsiella bacteria.
Feces are the most significant source of patient infection, followed by contact with contaminated instruments. Because these strains are susceptible to carbapenems, they are not identified as potential clinical or infection control risks using standard susceptibility testing guidelines. All acute-care facilities are to review microbiology records for the preceding 6--12 months to ensure that there have not been previously unrecognized CRE cases. After the treatment plan (measured in May, 2008), the number of cases per 100,000 patient days decreased to 11.7.
Klebsiella with the ability to produce extended-spectrum beta-lactamases ESBL are resistant to many classes of antibiotics. Healthcare facilities also must follow strict cleaning procedures to prevent the spread of Klebsiella. Our results clearly demonstrate that apoLp-III disturbed the proper structure of the bacterial cell surface.
Palpation revealed left costovertebral angle tenderness and mild tenderness of the suprapubic region. The limited number of agents available for the treatment of KPCs presents a tremendous challenge to clinicians. Patients with unrecognized CRKP colonization have been reservoirs for transmission during nosocomial outbreaks.
The plan was effective because of strict hospital compliance, wherein each was required to keep detailed documentation of all CRE carriers.
The alterations were dissimilar to those caused by cationic antimicrobial peptide, cecropin B, suggesting a different mode of action against bacteria.
Given the lean pipeline of new antimicrobials, further investigations into optimal treatment modalities are urgently needed. Of these 24 patients, the most common treatment regimen was tigecycline plus colistin (50%), followed by carbapenem plus polymyxin (33%) and aminoglycosides plus polymyxin (13%). The pulmonary site of infection was associated with higher rates of treatment failure with monotherapy compared to combination therapy (67% vs. In fact, for each increase in compliance by 10%, incidence of cases per 100,000 patient days decreased by 0.6. The present results indicate that AFM provides a powerful tool for studying the interactions of apoLp-III with microbial cells. Urinalysis revealed the following: positive nitrites, a small amount of leukocyte esterase, 30 to 35 WBCs, 5 to10 red blood cells, and 3+ bacteria. The authors concluded that patients presenting with hypopyon and unilateral involvement had a poorer visual prognosis. However, studies on the treatment of KPC infections are scarce and mainly limited to case series and case reports.
After the procedure, the patient’s WBC count decreased and she no longer had fevers and her condition continued to improve.
Therefore, we sought to perform a systematic review of individual cases in an effort to summarize therapeutic outcomes of various treatment regimens for KPC infections.Case selectionA systematic review of English language articles using MEDLINE (2001a€“2011) was conducted. Five patients were treated for BSIs with the following regimens: carbapenem plus colistin (3), tigecycline plus colistin (1), and amikacin plus colistin (1)[8, 9, 12]. Among the 17 patients with pulmonary infections treated successfully, more than 75% of cases received combination therapy. A retrograde nephrostogram was performed to evaluate the relationship between the left renal cyst and the left renal communicating system; it revealed that there was a connection.
The most common site of infection was blood (52%), followed by respiratory (30%), and urine (10%). Additional studies were identified by searching bibliographies of primary articles and annual conference abstracts from 2008a€“2011. The most common regimen for the successful treatment of pulmonary infections consisted of tigecycline plus colistin (8), followed by an aminoglycoside plus colistin (3). At this point, there was a small amount of clear yellow fluid draining from the nephrostomy tube; the fluid was no longer purulent.
Forty-nine (47%) cases received monotherapy and 56 (53%) cases received combination therapy directed at the KPC-infection. Likewise, there was a lower failure rate treating blood-stream infections with combination therapy compared to monotherapy, (28% vs. After aggressive therapy including pars plana vitrectomy 70 % of eyes had counting fingers vision or worse.
Various in-vitro studies have demonstrated bactericidal activity and synergy when polymyxins are tested in combination with carbapenems, rifampin or tigecycline, while monotherapy often led to significant re-growth by 24 hours[27a€“29].


Acute pyelonephritis and renal abscesses in adults—correlating clinical parameters with radiological (computer tomography) severity. Respiratory infections were associated with higher rates of treatment failure with monotherapy compared to combination therapy (67% vs 29% p= 0.03). Articles were eligible if they included patients with infections due to KPC-producing bacteria.
Furthermore, a report by Lee and colleagues[30] evaluated 12 patients with persistent blood cultures positive for KPC-K. Ascending UTI with obstructive pyelonephritis causes renal lobar necrosis, which leads to abscess formation. Articles were excluded from further review if they fulfilled at least one of the following criteria: no individual patient data reported, no treatment regimen specified, no treatment outcome specified, or greater than three antibiotics or multiple antibiotic regimens directed at the KPC infection.
Renal abscess cannot be distinguished from severe acute pyelonephritis by the clinical presentation alone. The most common successful combination employed in this cohort was a polymyxin in combination with either tigecycline or a carbapenem. In conclusion, combination therapy is recommended for the treatment of KPC infections; however, which combination of antimicrobial agents needs to be established in future prospective clinical trials. Analysis of the proportion of clinical failures was calculated as the number of failures divided by the number of treated patients. The authors hypothesized that combination therapy may have prevented resistance in patients who received both polymyxin B and tigecycline.
Tumbarello et al.[72] conducted a study in three Italian hospitals and demonstrated that combination therapy, particularly a triple-drug regimen including tigecycline, colistin, plus a carbapenem, was independently associated with improved survival.
Also, ultrasonography has limited diagnostic use because it cannot distinguish pus, blood, and cystic fluid. Several characteristics from the cases were extracted including the patienta€™s age, sex, medical history, site(s) of infection, type of infection, organism, KPC subtype, APACHE II score, admission to the intensive care unit (ICU), length of stay before infection, total length of stay, minimum inhibitory concentration (MIC) of selected antimicrobials (carbapenem, polymyxin, and tigecycline), antimicrobial therapy before isolation, antimicrobial therapy directed at KPC-infection, and treatment outcome. Similar reports of gram negative organisms developing resistance to colistin have been described[31a€“33]. Likewise, in a previous pool of 55 individual cases, combination therapy was associated with successful outcomes compared to monotherapy, particularly if polymyxins were part of the regimen[73]. In contrast to renal cortical abscesses that are caused by hematogenous spread of bacteria, renal abscesses that arise from complicated UTI can occur in the medulla, the cortex, or both sites.Treatment of patients with renal abscess includes antibiotics and drainage. Antimicrobial agents were categorized into the following classes: polymyxins, carbapenems, glycylcycline, aminoglycosides, cephalosporins, beta-lactam plus beta-lactamase inhibitors, fluoroquinolones, trimethoprim-sulfamethoxazole, monobactams, fosfomycin, and tetracyclines.
Polymyxins are one of the few antimicrobial classes that remain susceptible to KPC-producing organisms. Combination therapy was defined as at least two but no more than three, antibiotics with gram-negative activity reported to be directed at KPC infections.
Increasing reports of polymyxin resistance described in case reports and recent outbreaks of polymyxin-resistant strains are troubling[33a€“39].
A more recent study found that antibiotics alone are effective treatment for abscesses that are 5 cm or smaller.5 In addition to the size of the abscess, a nonresponding clinical course may indicate the need for drainage. Combination therapy may be an important strategy for the management of KPC infections when utilizing polymyxins. Renal abscesses measuring 5 cm or less: outcome of medical treatment without therapeutic drainage. The initial choice of an antibiotic should cover common urinary tract pathogens, especially Escherichia coli and K pneumoniae.6Once the culture and sensitivity results are available, the antibiotic therapy should be modified to the most appropriate agent.
Carbapenem monotherapy had higher rates of treatment failure compared to carbapenem-based combination therapy (60% versus 26% p=0.03). The total course of treatment is usually 2 to 3 weeks.K pneumoniae, the pathogen in our patient, is a primary cause of UTI, liver abscess, and pneumonia in otherwise healthy persons.
The majority of those who failed treatment had pneumonia or tracheobronchitis (7), followed by BSI (3), and urinary tract infection (UTI) (1)[40, 43, 48, 49]. Characteristics and factors influencing treatment outcome of renal and perinephric abscess—a 5-year experience at a tertiary teaching hospital in Taiwan. A total of 38 reports comprising 105 cases met the inclusion criteria, and consisted of case series (47%), retrospective cohort studies (35%), and case reports (17%). In these 14 patients, the most common treatment regimen was polymyxin plus carbapenem (8), followed by aminoglycoside plus carbapenem (4), and beta-lactam plus beta-lactamase inhibitor plus carbapenem (2). A total of 5 patients receiving carbapenem-based combination therapy experienced treatment failure. All but one of these 5 patients were treated with a carbapenem plus polymyxin.Several issues regarding the use of carbapenems for the treatment of KPC-infections should be considered. Nine of the cases who received carbapenem monotherapy were reported from one retrospective case series[40]. Five-year prospective study of bacteraemic urinary tract infection in a single institution. There has been only one case report describing the successful use of high-dose continuous infusion meropenem monotherapy for a carbapenem non-susceptible KPC K. In contrast, an in vitro model, simulating human exposure to a high-dose prolonged-infusion meropenem (2 g every 8 h over 3-hr infusion), demonstrated that the killing activity at 24 hours, against KPC-producing K. The authors attributed this to the rapid in-vitro hydrolysis of meropenem, resulting in lower exposure of meropenem to the KPC K.
The Clinical and Laboratory Standards Institute (CLSI) recently lowered clinical breakpoints of carbapenems to exclude KPC-producing organisms in the previous susceptible range[54]. The utility of carbapenem monotherapy against strains containing KPCs remains controversial.
Until further data are available, the use of combination or alternative therapy may be warranted.TigecyclineOf the 26 cases who received tigecycline, 7 cases received tigecycline monotherapy and 19 received tigecycline-based combination therapy[8, 9, 11, 12, 17, 26, 40, 41, 47, 55, 56].
There was no significant difference in treatment failure rates between cases receiving tigecycline monotherapy compared to those receiving combination therapy (29% vs. One patient was treated for urosepsis and the other was treated for nosocomial pneumonia and empyema[40, 56]. Of the 19 patients who received tigecycline combination therapy, 14 (74%) received polymyxin plus tigecycline, 3 (16%) received tigecycline plus aminoglycoside, and 2 (11%) received tigecycline plus carbapenem. Both patients who received tigecycline plus a carbapenem experienced treatment failures[40, 41]. In a collection of 106 carbapenemase-producing strains from various countries, tigecycline was the only antimicrobial with 100% activity[5].
However, tigecycline has been used successfully in treating these infections; both patients included in this review who were treated with tigecycline monotherapy for their UTIs, were treated successfully[40, 59]. There was no significant difference in treatment failure rates between those who received aminoglycoside monotherapy compared to combination therapy (0% vs.
Interestingly, all six cases who received aminoglycoside monotherapy reported success: three cases were treated for BSIs, two cases were treated for UTIs, and one case was treated for a respiratory infection[11, 13, 40, 64]. A recent study demonstrated that aminoglycosides, when active in vitro, were associated with a significantly higher rate of microbiologic clearance of carbapenem-resistant K.
Of the patients who received aminoglycoside-based combination therapy, the most common treatment was amikacin plus colistin (11), followed by aminoglycoside plus a carbapenem (4), aminoglycoside plus a fluoroquinolone (5), aminoglycoside plus tigecycline (2), gentamicin plus aztreonam (1), and amikacin plus tetracycline (1). Despite in-vitro evidence of antagonism when using polymyxins and aminoglycosides in combination, 6 clinical cases of polymyxin plus an aminoglycoside reported treatment success[11, 19, 22, 65]. Significantly more treatment failures were seen in cases treated with monotherapy than those treated with combination therapy (49% vs.
In three cases, triple antimicrobial therapy directed at the KPC infection was used: one case received doripenem plus polymyxin B plus rifampin and 2 cases received tigecycline plus colistin plus garamycin[11, 17].



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