Bloodstream infections caused by carbapenemase

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Bloodstream infections caused by carbapenemase-producing Klebsiella pneumoniae: a clinical perspective Expert Rev. Anti Infect. Ther. 10(12), 1393–1404 (2012)

George L Daikos*1, Antonis Markogiannakis2, Maria Souli3 and Leonidas S Tzouvelekis4 First Department of Propaedeutic Medicine, University of Athens, Athens, Greece 2 Department of Pharmacy, Laiko General Hospital, Athens, Greece 3 Fourth Department of Medicine, University of Athens, Athens, Greece 4 Department of Microbiology School of Medicine, University of Athens *Author for correspondence: Tel.: +30 210 7462636, Fax: +30 210 7462635, [email protected] 1

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Dissemination of carbapenemase-producing Klebsiella pneumoniae (CP-Kp) has caused a public health crisis that can be paralleled with that caused by the spread of MRSA. CP-Kps, being multidrug-resistant, mainly affect patients with severe underlying conditions in the acute-healthcare setting. CP-Kps are responsible for a variety of life-threatening infections including bacteremia and pneumonia. The shortage of therapeutic options has forced clinicians to use colistin as well as tigecycline, a novel bacteriostatic agent. Although both drugs are generally active in vitro against CP-Kps, therapeutic failures, especially in bacteremias, are quite common. The authors suggest here, after reviewing the literature, that use of the latter drugs should be re-assessed and optimized. The authors have also summarized experimental and clinical data indicating that exploitation of the pharmacokinetic/pharmacodynamic features of carbapenems may provide solutions in bloodstream infections caused by CP-Kps with low-level resistance to the latter drugs. Most importantly, there is evidence that monotherapy must be avoided. Keywords: antibiotic resistance • antibiotic therapy • bacteremia • carbapenemases • Klebsiella pneumoniae

Klebsiella pneumoniae, a member of the Enterobacteriaceae family, was best known as the causative agent of a severe form of community-acquired pneumonia with high mortality rates [1] . In the last few decades, the microorganism, along with other Gram-negative species, is consistently recognized as one of the leading causes of hospital-acquired infections [2] . Multidrug-resistant strains of K. pneumoniae frequently infect severely ill, immunocompromised patients hospitalized for prolonged time p eriods especially in the intensive care units (ICUs). The spectrum of the relevant infections is wide, including urinary tract infections, pneumonia, bloodstream infections, intra-abdominal and surgical site infections [3] . Wild-type K. pneumoniae strains exhibit a narrow phenotype of resistance to antimicrobial agents active against Gram-negatives. The species is inherently resistant to penicillins due to constitutive production of moderate amounts of chromosomal penicillinases (SHV-1-like enzymes). Occasionally, increased production of SHV-1, primarily due to alterations in the promoter 10.1586/ERI.12.138

sequence, may lead to decreased susceptibility to penicillin-inhibitor combinations and affect slightly the MICs of expanded-spectrum cephalosporins such as ceftazidime. Nevertheless, wildtype antibiotic resistance phenotypes are encountered quite infrequently among hospital isolates of K. pneumoniae. For yet not adequately clarified reasons, K. pneumoniae is prone to acquire and maintain plasmids including those carrying multiple antibiotic resistance determinants. Indeed, during the 1970s, soon after their establishment in the hospital flora, K. pneumoniae strains with plasmid-mediated resistance to aminoglycosides were implicated in extensive outbreaks [4] . Since the 1980s, K. pneumoniae has become the index species for a variety of plasmid-borne class A extended-spectrum β-lactamases (ESBLs) as well as class C cephalosporinases that inactivate expanded-spectrum cephalosporins [5,6] . The respective plasmids commonly confer resistance also to non-β-lactam antimicrobials such as aminoglycosides, trimethoprim, sulfonamides and tetracyclines. The dubious clinical efficacy of penicillin-inhibitor combinations and the fact

© 2012 Expert Reviews Ltd

ISSN 1478-7210

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that a meaningful proportion of such isolates have developed resistance to fluorinated quinolones have left carbapenems as the most reliable therapeutic option [7] . Nowadays, we face a global crisis due to spread of multidrug-resistant K. pneumoniae strains that produce β-lactamases with wide hydrolysis spectra that include the carbapenems (carbapenemases) [8] . It would be plausible to hypothesize that increased use of carbapenems has facilitated, at least partly, the propagation of such strains, although such a direct association is difficult to be documented. The potential magnitude of the problem had been predicted [9] ; nevertheless, it caught the public health systems unprepared. Infection spectrum of carbapenemase-producing K. pneumoniae (henceforth CP-Kp) is the typical one of the species in the hospital setting. Based on in vitro susceptibility data, the long-forgotten colistin (polymyxin E), as well as tigecycline, a novel drug for which clinical experience is still insufficient, are currently the first-line antibiotics in the treatment of CP-Kp infections. However, clinical data accumulated over time clearly indicate the need to improve our therapeutic approaches. Herein, after a presentation of some important biological and epidemiological traits of CP-Kp isolates, the authors attempt a critical appraisal of the relevant literature with regard to the most common antimicrobial regimens used in CP-Kp bacteremias and discuss potential ways that could enhance our ability to treat these life-threatening infections. Characteristics of CP-Kps

Acquired carbapenemases encountered in CP-Kps comprise a group of heterogeneous β-lactamases belonging to molecular classes A, B and D (Table 1) and exhibit significant structural and functional differences. Apart from this heterogeneity, carbapenems are not the most preferable substrates for many of these enzymes. Hence, the term ‘carbapenemase’ rather reflects the clinical impact of inactivation of carbapenems that were (and in many instances still are) the last-line antibiotics for the treatment of severe Gram-negative infections. KPC producers

The most widespread carbapenemase among CP-Kps is K. pneumoniae carbapenemase (KPC)-2 and its point mutants (KPC-3 to KPC-13). KPCs belong to molecular class A, sharing Table 1. Main carbapenemases encountered in Klebsiella pneumoniae clinical isolates. Molecular Functional Type of Common class† group‡ carbapenemase representative variants A

2f

KPC

KPC-2, -3, -4

B

3a

VIM

VIM-1, -2, -4, -5, -6

IMP

IMP-1, -3, -4, -6, -8

NDM

NDM-1, -4, -5, -6

OXA

OXA-48, -163, -181

D

2df

Molecular classification [102]. ‡ Functional classification [103]. †

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many common structural–functional features with other clinically important β-lactamases such as the TEM, SHV and CTX-M types. In contrast with the latter enzymes, however, it seems that the arrangement of the KPC active site allows the efficient acylation–deacylation of carbapenems [10] . KPCs are also capable of hydrolyzing penicillins, cephamycins, early generation and newer oxyimino-cephalosporins and aztreonam. Although KPCs are moderately susceptible to mechanism-based inhibitors, the vast majority of KPC-positive K. pneumoniae are nonsusceptible to penicillin–inhibitor combinations, including piperacillin–tazobactam [11] . Consequently, KPC producers exhibit either decreased susceptibility or resistance to virtually all clinically available β-lactams. Carbapenem MICs may vary significantly. However, according to the current breakpoints adopted by the Clinical and Laboratory Standards Institute [12] , the majority of the KPC K. pneumoniae isolates are classified as resistant to these agents. The blaKPC genes in K. pneumoniae are invariably carried by plasmids belonging to several incompatibility groups such as FII, L/M and N, suggesting the operation of mobilization mechanisms. Irrespective of the plasmid carriers, blaKPCs are always associated with similar segments of a single transposon, the Tn3-related Tn4401, a fact that may explain their acquisition by distinct genetic units [13] . Carriage of blaKPC by various plasmids apparently facilitated the dissemination of the gene to various K. pneumomiae strains. However, the majority of KPC K. pneumoniae belong to sequence type (ST) 258 that was first detected in New York hospitals in the 2000s [14] and disseminated rapidly in other neighboring states. KPC K. pneumoniae afterwards occurred in Israel, Latin America, Greece and China [15] . According to a widely held scenario, a central event in the international spread of the KPC producers was their transfer via colonized patients from USA to Israel, causing a nationwide epidemic [16] . There have also been claims for a subsequent transfer in Greece via the island of Crete but index cases were not identified [17] . Whichever the transmission routes, KPC-producing K. pneumoniae is currently among the predominant multiresistant Gram-negatives in the latter country [18] . Also, recent reports from Italy and Poland indicate a rapid spread of KPC K. pneumoniae isolates [19,20] while isolation frequencies in most western and northern European countries remain so far low. Hospital outbreaks have also been documented in China [21] but systematic data from this country are not available. Metallo-β-lactamase producers

Metallo-β-lactamases (MβLs) belong to molecular class B. They are phylogenetically distinct from the enzymes of the A, C and D classes (all serine β-lactamases), being likely descendants of metalloproteases. They characteristically possess divalent cations (usually Zn2+) in the active site that are essential for hydrolysis of the β-lactam ring [22] . Three MβL types, the acquired VIM, IMP and NDM enzymes, all of unknown origin, have been found in a wide variety of K. pneumoniae strains. Variants of these MβL types exhibit a broad hydrolysis spectrum including all β-lactams except monobactams. Thus, the MβL-producing K. pneumoniae isolates Expert Rev. Anti Infect. Ther. 10(12), (2012)

Bloodstream infections caused by carbapenemase-producing Klebsiella pneumoniae

exhibit extensive resistance phenotypes to β-lactams including penicillins, penicillin-inhibitor combinations, cephamycins, older and newer cephalosporins and carbapenems, although MICs, especially of the latter drugs, may vary considerably. blaVIM and bla IMP genes occur as cassettes of multiresistant integrons carried by transmissible plasmids while blaNDM variants, also of plasmid origin, are found in structures containing several IS elements [8] . The first MβL-positive K. pneumoniae clinical isolates to be detected were IMP producers identified in the Far East, mainly in Japan. VIM-positive K. pneumoniae were frequently isolated during the previous decade in various Mediterranean countries [23] . Greek hospitals were the most heavily affected [24] , although recent data indicate a rapid decline in their isolation frequency since 2009 [Daikos GL, Unpublished Data] . Despite some cases of colonization and/or infection by VIM producers in Western Europe and the USA, including limited outbreaks, these strains were not established in the hospital flora of these countries. NDM is the latest MβL type encountered in K. pneumoniae and, according to some investigators, a global spread analogous to that of the KPC producers is likely. It has been clearly documented that the epicenter of the NDM-positive K. pneumoniae epidemic is the Indian subcontinent [25] . The relatively rapid spread of such isolates observed recently in Europe, North America, the Far East and Australia has, in many instances, associated with patients transferred from India, Pakistan and Bangladesh [26] . OXA-48 producers

OX A-48 and its derivatives, OX A-163 and OX A-181 (molecular class D) carbapenemases are recently encountered in K. pneumoniae. Sequence and structure–function studies have shown that they are significantly different from their closest relatives such as OXA-23, -40 and -58 from Acinetobacter spp., exhibiting more potent activity against carbapenems [27] . OXA-48 also efficiently hydrolyzes penicillins and early generation cephalosporins but is virtually inactive against the newer oxyimino-cephalosporins [28] . The blaOXA-48 gene is mainly borne by transmissible IncL/M plasmids. Moreover, it is associated with IS1999, a mobile element that, apparently, has contributed to its plasmid acquisition from a yet unknown source [29] . OXA-48-producing K. pneumoniae were first noticed in Turkish hospitals in 2001, causing extensive outbreaks in a relatively small time period [30] . They have also been expanded to other Middle Eastern as well as North African countries, which still remain the main epidemic foci [29] . However, OXA-48 producers have also emerged, albeit sporadically, in various distant geographic locations, suggesting an evolving global spread [8] .

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Other anatomic sites including the nasopharynx as well as the respiratory and urinary tract may also become colonized [3] . Personto-person transmission through the hands of the nursing and medical staff is most likely the main way of CP-Kp dissemination within a healthcare unit as with other multidrug-resistant enterobacteria such as ESBL-positive K. pneumoniae [7] . Obviously, the pace and extent of colonizations are higher in facilities with inadequate infection control practices. Establishment of CP-Kp as part of the intestinal flora depends on the numerous factors determining the host’s resistance to colonization as well as the colonization potential of the microorganism. Once CP-Kp isolates colonize the intestinal tract, carriage may persist for prolonged periods of time ranging from a few weeks to several months [32] . Prolonged duration of colonization results in a large reservoir of colonized patients that will, in turn, exert higher colonization pressure leading to increased rates of cross-transmission among hospitalized patients. Some strains, the so called ‘high-risk clones’, appear to be transmitted more efficiently, as is likely the case with the predominant among the KPC producers ST258 clone. Although it is reasonable to hypothesize that strains belonging to this lineage possess features enhancing transmission and persistence in the patients’ gut flora, relevant studies have not yet been conducted. K. pneumoniae can also be found in various environmental niches. The role of the inanimate environment in CP-Kp acquisition by hospitalized patients is still unclear. However, contamination of the hospital environment with CP-Kps is probably less important than that with nonfermenters such as Acinetobacter baumannii and Pseudomonas aeruginosa. From colonization to infection

Several factors have been associated with an increased risk for colonization and infection with CP-Kps among hospitalized patients (summarized in Table 2 ). It must be pointed out that compilation of the relevant findings poses difficulties since they have been obtained from different study types and settings and, usually, include small numbers of patients. Nevertheless, stay in Table 2. Main risk factors associated with colonization/infection of hospitalized patients with carbapenemase-producing Klebsiella pneumoniae in endemic settings. Stay in intensive care unit

++

Sharing a room with known carrier

++

Prolonged hospitalization

++

Cumulative exposure to antibiotics

++

Poor functional status

++

CP-Kps in the healthcare setting

Malignancy

+

CP-Kp is acquired predominantly in acute-healthcare facilities, although export of this pathogen to long-term care facilities also generates problems to debilitated patients in this setting [31] . The epidemiology of CP-Kps in the healthcare setting appears to be similar to that of other multidrug-resistant Enterobacteriaceae. The gastrointestinal tract is the main colonization site of CP-Kp.

Solid or stem cell transplantation

+

Multiple invasive devices

+

Admission to post-acute care units

+


+: Repeatedly identified as factor facilitating carbapenemase-producing Klebsiella pneumoniae colonization/infection; ++: Consistently associated with carbapenemase-producing Klebsiella pneumoniae colonization/infection.

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an ICU, prolonged hospitalization and poor functional status of the patient have been repeatedly associated with CP-Kp colonization. Also, prior use of various antibiotics such as carbapenems, expanded-spectrum cephalosporins, penicillin-inhibitor combinations, fluorinated quinolones and glycopeptides has been recognized as an independent risk factor for CP-Kp colonization [31,33,34] . The latter findings apparently reflect the adverse effects of antimicrobial use on colonization resistance, depending on the antibiotic type, dosing scheme and duration of therapy. In that respect, cumulative exposure to antibiotics is likely more important for acquisition of CP-Kp than the use of a specific agent alone [35,36] . At this point, it should be noted that most studies assessing risks for CP-Kp colonization have been conducted in endemic settings. Hence, the above mentioned ‘independent’ risk factors are referred to high prevalence settings and largely reflect the ease of CP-Kp transmission in those settings. Indeed, in an interesting cross-sectional survey carried out in post-acute-care facilities in Israel during the KPC-producing K. pneumoniae nationwide epidemic, it was documented that extended length of stay, sharing a room with a known carrier, and increased prevalence of carriers on the ward were the main factors leading to CP-Kp acquisition [37] . A proportion of CP-Kp colonized patients will develop clinical infection with detrimental effects for the host. Bacteremia and pneumonia are the most common infection types caused by CP-Kps among hospitalized patients. The subset of colonized patients that will develop infection may differ in various settings ranging from 10 to 30% [38,39] ; [Daikos GL, Unpublished Data] . A variety of risk factors such as stay in ICU, invasive procedures, exposure to antibiotics and various underlying diseases have been strongly associated with life-threatening CP-Kp infections. Evidently, there is an extensive overlapping between infectionassociated factors and those accounting for CP-Kp colonization. In general, the ICU setting appears to promote the progression from colonization to infection [39] . However, there also seems to be a strong link of developing CP-Kp infection with factors directly related to the host (e.g., solid organ or stem cell transplantation, solid tumors and diabetes mellitus) [39–41] . Experimental data on the interaction of CP-Kps with antibiotics

Virtually all CP-Kps exhibit resistance to multiple antibiotic classes. According to in vitro susceptibility data, β-lactams should be among the last therapeutic options. A significant proportion of CP-Kps, apart from carbapenemases, co-produce potent acquired β-lactamases including various ESBLs (CTXM, SHV and so on) and cephalosporinases such as CMYs, thus precluding the use of the few β-lactam compounds that withstand hydrolysis by carbapenemases such as aztreonam by MβLs and expanded-spectrum cephalosporins by OXA-48. MIC distributions indicate that carbapenems are the most effective β-lactams against CP-Kps. However, based on the current CLSI breakpoints [12] , the vast majority of CP-Kps are classified as resistant to carbapenems. Moreover, some investigators support the view that use of carbapenems against CP-Kps should be avoided even if MICs are within the susceptible range [42] . On the other 1396

hand, there have been studies indicating that the carbapenem MIC itself and not the carbapenemase production should be considered [43,44] . The latter aspect is in line with the findings of pharmacok inetics/pharmacodynamics (PK/PD) studies predicting a beneficial effect of optimized carbapenem treatment schemes, and data from animal infection models suggesting that carbapenems may exert measurable antibacterial activity in vivo even against intermediately susceptible CP-Kps [45–48] . Of the clinically available aminoglycosides, gentamicin appears to be the most active agent against CP-Kps, except NDM producers that commonly produce 16S rRNA methylases [49] . High resistance rates to fluorinated quinolones and other less clinically important antimicrobial agents such as tetracyclines, chloramphenicol and nitrofurantoin, have also been recorded [50] . Colistin, tigecycline and fosfomycin remain active in vitro against the majority of CP-Kps, the former two currently being the preferable choices in the treatment of the respective infections. It must be noted, however, that resistance to colistin and tigecycline is on the rise [50] . Moreover, the clinical effectiveness of the latter drugs in CP-Kp bacteremias is unacceptably low (see the relevant discussion in the next section). The shortage of reliable antibiotics has led to efforts to discover combinations that would enhance our therapeutic potential against severe CP-Kp infections. Assessment of the efficacy of a variety of combinations, occasionally including more than two antibiotics, has been attempted mostly using in vitro time-kill methodologies. Most of the relevant studies have included polymyxins B and E (colistin) at various fractions of the MICs for the tested CP-Kp isolates. Despite some discrepant results, combinations of a polymyxin with drugs such as rifampin, doxycycline, tigecycline, carbapenems and fosfomycin appear to exhibit measurable synergistic effects [51–53] . Also, combinations of fosfomycin (a drug known for its potential to select resistant mutants at high frequencies) [54] with various antibiotics, apart from being synergistic, seem to partly avert emergence of fosfomycin-resistant CP-Kp variants [55] . Findings of in vitro time-kill assays, however, should be considered cautiously since they heavily depend on the MIC fractions of the antibiotics tested and they are often strain dependent. Overview & evaluation of antibiotic regimens against CP-Kp bacteremias

CP-Kps induce a broad spectrum of infections in debilitated patients with various underlying diseases in the acute-healthcare setting [34] . Bacteremias (primary or secondary) represent the more severe forms of CP-Kp infections and constitute the vast majority of them. Recent reports indicate that CP-Kp bloodstream infections are associated with high mortality, ranging from 23.8 to 68.4% [43,56] . Older age, severity of underlying disease, severity of sepsis and resistance to carbapenems, have been shown to be independent predictors of death in these patients [33,43,56–58] . Given that CP-Kp isolates exhibit an extensive drug-resistant phenotype, an additional factor contributing to adverse outcome in bloodstream infections may be the delay in initiating effective therapy during the initial critical hours of the infection process. Expert Rev. Anti Infect. Ther. 10(12), (2012)


Indeed, in a recent study the patients with carbapenem-resistant K. pneumoniae bloodstream infections were four-times more likely to receive inappropriate empiric treatment [43] . In addition to the host- and treatment-related factors, an enhanced virulence of the infecting CP-Kp isolates could also have an impact on the outcome. In view of the high mortality associated with CP-Kp infections, it is tempting to assume that CP-Kps are more virulent than non-carbapenemase-producers. This hypothesis, however, has not yet been thoroughly evaluated. Preliminary data from our laboratory have not shown increased virulence of CP-Kp strains. On the contrary, the authors have observed that the majority of KPC-Kp clones circulating in Athens, Greece, including the widely disseminated strains of the ST258, are rapidly killed after exposure to human serum [Daikos GL, Unpublished Data] . The lack of an important virulence factor such as serum resistance does not fit with the hypothesis of the increased pathogenic potential of these microorganisms. Comparative evaluation of strains belonging to different clonal complexes using various animal infection models may provide some useful clues. While CP-Kp become increasingly prevalent and cause serious infections resulting in high fatality rates, the optimal treatment of the patients infected with such organisms is presently unknown. Clinical experience in the treatment of patients infected with CP-Kp is based on case reports, case series, retrospective and observational studies. In the absence of controlled comparative trials, a critical appraisal of the relevant literature may provide some guidance on the treatment of patients infected with CP-Kp. The authors conducted a systematic review of the literature to identify patients with CP-Kp bloodstream infections (BSIs). All studies available in MEDLINE reporting on BSIs associated with CP-Kp were considered (search terms: Klebsiella pneumoniae, infection, blood, bloodstream, bacteraemia [bacteremia], sepsis, carbapenemase, KPC, metallo-β-lactamase, VIM, IMP, NDM and OXA-48). Thirty-two studies that provided adequate information regarding the treatment schemes, a clear assessment of the outcomes in terms of mortality rates, the in vitro susceptibilities of the infecting organisms to the antimicrobials used and the carbapenemase types were selected for reviewing [14,17,43,56,57,59–85] . A total of 432 patients were identified, 283 (65.5%) infected with KPC-48-producing K. pneumoniae, 146 (33.8%) with MβL-48-producing K. pneumoniae (mainly VIM; n = 142) and three (0.7%) with OXA-48-producing K. pneumoniae. The probable source of bacteremia was identified in 182 patients; 34 had urinary tract infection, 58 intravascular catheter-related, five surgical site infections, 75 pneumonia and ten other infections (mostly intra-abdominal). In 150 instances no definite portal of entry could be detected and those cases were characterized as primary bacteremias, whereas in 100 patients no information was provided by the authors for the source of BSI (Table 3) . Efficacy of various antibiotic regimens used against BSIs caused by MβL- and KPC-producing isolates was assessed by compiling data from 421 cases (30 studies; the two studies reporting on BSIs due to OXA-48 producers were excluded due to the low number of cases [n = 3]). Of the 421 patients infected with CP-Kp, 192 (45.6%) received monotherapy (one drug was active in vitro against the infecting organism), 179 (42.5%) www.expert-reviews.com

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received combination therapy (at least two drugs were active in vitro), while 50 (11.9%) received ‘inappropriate’ therapy (no drug was active in vitro). It should be noted that the susceptibility status to carbapenems was taken as reported in the relevant studies in which the previous CLSI interpretive criteria were applied [86] . Monotherapy with either a carbapenem or an aminoglycoside (mostly gentamicin) resulted in moderate success rates that were higher than those observed with tigecycline or colistin, but no single agent appeared to be considerably superior to ‘inappropriate’ therapy. Colistin and tigecycline were the least effective agents in the monotherapy group as 45.9 and 47.2% of the respective patients were reported as treatment failures. These proportions were similar to that observed in the patients having received antimicrobial agents that were inactive in vitro (Table 4) . Thus, the efficacy of monotherapy was not satisfactory, mainly because of the inferior performance of colistin, which was used in almost half of the patients treated with a single active agent. Among the 179 patients who received multiple drugs, the most frequent combinations included in the regimens, in descending order, were: colistin–aminoglycoside, colistin–carbapenem, colistin–tigecycline and carbapenem–aminoglycoside. Overall, combination therapy seemed to be superior to monotherapy and to ‘inappropriate’ therapy. By dividing the patients who received combination therapy into two groups on the basis of inclusion of a carbapenem in the treatment scheme, it was shown that the carbapenem-containing regimens were more efficacious than the carbapenem-sparing ones (Table 4) . Overall, these observations may be taken as indicating that the superiority of combination therapy to monotherapy is, at least partly, mediated by carbapenems and their potential synergistic activity with aminoglycosides or colistin. The authors should emphasize that the assessment of the available clinical data attempted herein lacks the characteristics of a vigorous meta-analysis since it was not possible to measure and adjust for potential confounders including patients’ age and status, comorbitities, severity of sepsis and time of therapy initiation. Nevertheless, in the absence of controlled studies, our analysis provides important information helping to guide us for the treatment of serious infections caused by CP-Kps. In search of the most effective antibiotic schemes

It is clear from the data presented here that the current approaches in the treatment of CP-Kp infections must be reconsidered. Approximately half of the patients were treated with a single agent, mainly colistin. This was primarily due to the fact that clinicians are left with very few alternative options for the treatment of infections caused by these extensively drug-resistant organisms. It is also possible that, in some instances, colistin monotherapy was deliberately chosen by clinicians who believe that monotherapy is not inferior to combination therapy as has been supported by previous meta-analyses [87–89] . The latter studies, however, were conducted in a context of much lower resistance rates and monotherapy regimens primarily included active β-lactam antibiotics. Most importantly, the authors must emphasize that in 1397

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Table 3. Clinical studies included in the review. Study design

Bloodstream infection patients (n)

Source of bacteremia (n)

Outcome assessment

Outcome Carbapenemase (survived/died) type (n)

Case series

1

PB

In-hospital mortality 1/0

KPC-2

[14]

Case series

1

PB


KPC-2

[17]

Prospective observational study

67

PB (15), CRI (7), LRTI (30) 14-day mortality UTI (4), SSI (4), other (7)

VIM-1

[43]

Case–control study

37

Not defined


KPC-2 (19), VIM-1 (18)

[56]

Case–control study

53

Not defined


KPC-2

[57]

Case series

8

PB (4), UTI (3), not defined (1)

28-day mortality

5/3

KPC-2

[62]

Case series

5

Not defined


VIM-1

[63]

Retrospective study

28

PB (17), CRI (6), LRTI (3), UTI (2)

14-day mortality

VIM-1

[66]

Case series

3

PB (2), UTI (1)


KPC type

[68]

Case series

1

CRI

14-day mortality

IMP-8

[72]

Case series

4

Not defined


KPC type

[75]

Retrospective study

34

PB (6), CRI (11), LRTI (10), 28-day mortality UTI (7)

21/13

KPC type

[76]

Retrospective study

133

PB (75), CRI (13), LRTI (28), UTI (17)

28-day mortality

73/52†

KPC-2 (27), KPC-3 (98)

[77]

Case series

15

PB (8), CRI (4), LRTI (1) SSI (1), other (1)

7-day mortality

12/3

VIM-1

[79]

Case series

14

PB (7), CRI (5), LRTI (1), other (1)

7-day mortality

10/4

KPC-2

[80]

Case series

3

PB (2), CRI (1)


IMP-8

[83]

Case series

1

CRI


OXA-48

[84]


KPC-2 (8), VIM-1 (9) KPC + MβL (5), OXA-48 (2)

51/16

19/9

1/0

Ref.

Collective presentation of case reports Case reports

24

PB (12), CRI (9), LRTI (2), other (1)

[11,59–61, 64,65,67, 69–71,73, 82,85]

† Adequate data for antibiotic schemes used and/or outcome were available for 125 patients. CRI: Catheter-related infection; LRTI: Lower respiratory tract infection; PB: Primary bacteremia; SSI: Surgical site infection; UTI: Urinary tract infection.

CP-Kp bacteremia, colistin monotherapy does not seem to work. A similar conclusion has previously been reached by Hirsch and Tam [90] , who reviewed 15 studies involving 55 KPC-producing K. pneumoniae-infected patients, of whom 18 had been treated with regimens including either colistin or polymyxin B. Several factors may account for the apparently poor therapeutic performance of colistin against these infections. The current dosing schemes of colistin do not attain serum concentrations that would be sufficient for the treatment of infections caused by pathogens with MICs higher than 0.5 mg/l [91] . Moreover, by the standard dosing regimens, the steady-state concentration of colistin is achieved within 2–3 days. This delay, which is likely detrimental 1398

to patient’s outcome, can be overcome by administering a loading dose of the drug [92] . From the available data, it appears that colistin is administered in two or three fractionated doses across the day considering that prolonged exposure of CP-Kp to the drug increases bacterial killing. This assumption has been based on data from animal infection models suggesting that the ratio of the area under the concentration-time curve for the free, unbound fraction of the drug (fAUC) to the MIC is the PK/PD index best correlated with antibacterial effect [93] . On the other hand, several important characteristics of colistin, such as the relatively long half-life, its concentration-dependent killing in vitro as well as the possible Expert Rev. Anti Infect. Ther. 10(12), (2012)


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induction of adaptive resistance [94–96] , Table 4. Efficacy of various antibiotic regimens used to treat clearly favor the administration of this bloodstream infections caused by MβL- and KPC-producing Klebsiella agent in larger dosages at longer intervals pneumoniae. provided that these regimens are not more Outcome (no. of patients Total no. of nephrotoxic. Cumulative experience with Antibiotic(s) that survived, died) patients [survived, colistin against CP-Kp infections clearly for infections caused by: (%) died] (% success) suggests that there is an urgent need for KPC producers MβL producers carefully designed trials that would further elucidate the complex kinetics of this drug Monotherapy and allow establishing the most effective Carbapenem 28 (20, 8) 6 (3, 3) 34 (23, 11) (68.4) and least toxic treatment regimen. In this 35 (24, 11) 63 (29, 34) 98 (53, 45) (54.1) context, similar studies with polymyxin B Colistin 4 (3, 1) 32 (16, 16) 36 (19, 17) (52.8) may prove useful. Although clinical expe- Tigecycline rience with this drug is quite limited as Aminoglycoside 12 (7, 5) 12 (8, 4) 24 (15, 9) (62.5) compared with colistin, there have been Total (% success) 79 (54, 25) (69.2) 113 (56, 57) (48.1) 192 (110, 82) (57.0)† indications that combination schemes containing polymyxin B exhibit some thera- Combination therapy 27 (25, 2) 27 (24, 3) 54 (49, 5) (90.7) ‡ peutic potential against infections caused ≥two active drugs by KPC-producing enterobacteria as well (including an active as other m ultidrug-resistant pathogens [97] . carbapenem) 16 (9, 7) 109 (70, 39) 125 (79, 46) (63.2) ‡ Tigecycline has also been used as a sin- ≥two active drugs gle antimicrobial agent in the treatment of (not including an CP-Kp bacteremias, albeit at a lesser extent. active carbapenem) 43 (34, 9) (77.3) 136 (94, 42) (69.5) 179 (128, 51) (71.5)† The relevant data summarized here, how- Total (% success) ever, clearly suggest that tigecycline mono- Inappropriate therapy therapy must be avoided. Of note, in 2010, Total (% success) 24 (17, 7) (70.8) 26 (10, 16) (38.5) 50 (27, 23) (54.0) the US FDA issued a warning against the 146 (105, 41) (71.9) 275 (160, 115) (58.2) 421 (265, 156) (62.9) use of this agent for serious infections [201] . Total (% success) † Odds ratio: 1.87; 95% CI: 1.21–2.88. Our observations are in line with recent ‡p = 0.005; p MIC). The probabilities of attaining 50% also that tigecycline’s MIC distribution ranges between 1 and T>MIC target for an isolate with a MIC of 4 mg/l is 69% for the 2 mg/l for the majority of contemporary CP-Kp isolates and that traditional dosing regimen (e.g., 30 min infusion of 1 g every 8 h approximately 15% of CP-Kp isolates circulating in Greek hos- for meropenem) and increases to 100% for the high-dose/prolonged pitals exhibit tigecycline MICs of >2 mg/l [Daikos GL, Unpublished infusion regimen (e.g., 3 h infusion of 2 g every 8 h for meroData] , the poor therapeutic efficacy of the drug in bloodstream penem). Even for an MIC of 8 mg/l, the high-dose/prolongedinfections can be explained. Additionally, neither colistin nor infusion regimen displays a relatively high probability (85%) of tigecycline have been evaluated as monotherapy in the setting bactericidal target attainment [44] . of immunosuppressed (i.e., neutropenic) patients who represent Although experience with carbapenems in the therapy of a population very often affected by CP-Kp infections. bacteremias caused by CP-Kps is still limited, the data analyses As discussed previously, therapeutic schemes including a car- presented herein support the notion that carbapenems may be a bapenem were the most efficacious. This partly reflects the fact reasonable treatment option against these infections, provided that a significant number of CP-Kps, especially the MβL-positive that the carbapenem MIC for the infecting organism is ≤4 mg/l; ones, were inhibited by relatively low carbapenem concentrations a high-dose prolonged-infusion regimen is administered to drive www.expert-reviews.com

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MIC of carbapenems

>4 mg/l

≤4 mg/l

AMG susceptible

CARB + AMG

AMG resistance

COL susceptible

AMG susceptible

COL resistance AMG + Other AA

CARB + COL

AMG resistance

CARB + Other AA

COL resistance

COL susceptible

COL + Other AA

Combination of other AAs

Figure 1. Proposed algorithm to be considered as a basis in therapeutic decision-making for bloodstream infections caused by carbapenemase-producing Klebsiella pneumoniae. In case the infecting organism is an MβL-producer and remains susceptible to aztreonam the authors may consider administering this drug in combination with an aminoglycoside or colistin depending on the in vitro susceptibilities. AA: Other in vitro active agents (these may include tigecycline as well as fluorinated quinolones, tetracyclines, fosfomycin and chloramphenicol, which have occasionally been used against carbapenemase-producing Klebsiella pneumoniae); AMG: Aminoglycoside; CARB: Carbapenem; COL: Colistin; MIC: Minimum inhibitory concentration.

the PK/PD profile to acceptable exposures, and this class of agents is administered in combination with another active compound, preferably with an aminoglycoside or colistin. Based on the published studies as interpreted here and on their clinical experience, the authors propose an algorithm that may help clinicians to choose the most effective antimicrobial regimen for the treatment of bloodstream infections caused by CP-Kp (Figure 1) . In selected cases, performance of in vitro synergy studies once the causative agent has been isolated may help in the choice of the most appropriate targeted combination scheme. Expert commentary & five-year view

A public health crisis, like the one caused by CP-Kps, requires actions that would provide immediate solutions or, at least, opportunities to better cope with the situation. It is remarkable that after more than a decade too little has been done to systematically evaluate and, if necessary, to improve our therapeutic approaches. Some new drugs active against carbapenemase-producing Enterobacteriaceae are indeed in an advanced stage of development but very few of them are expected to be clinically available soon. Thus, in the foreseeable future, we shall continue to rely on the currently existing antibiotics. The present attempt to summarize and evaluate clinical and therapeutic data regarding CP-Kp-caused bloodstream infections led us to propose some

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changes in the antibiotic regimens used that may be of help in increasing the unacceptably low success rates. While the aspect of abandoning monotherapy has recently gained ground, we expect that our proposal of using carbapenems as first-line antibiotics against CP-Kps will raise objections by many investigators. Nonetheless, a discussion on this issue would be fruitful. Also, it has to be admitted that our effort lacks some important characteristics of a rigorous meta-analysis mainly due to the insufficiency of information included in the relevant studies. In that respect, a consensus based on the minimal set of clinical data is required. In the meanwhile, public health authorities should take actions to limit the spread of these microorganisms. Fortunately, there are sound studies showing successful containment of carbapenemase producers by implementing a bundle of infection control measures of which the most important were active surveillance cultures, separation of carriers and assignment of dedicated nursing staff [34] . Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Expert Rev. Anti Infect. Ther. 10(12), (2012)


Review

Key issues • Spread of multiresistant carbapenemase-producing Klebsiella pneumoniae (CP-Kp) has caused a public health crisis of global dimensions. • CP-Kps are implicated in life-threatening nosocomial infections such as bacteremia and pneumonia mainly in debilitated patients in the acute-healthcare setting. • Therapeutic options are quite limited, with colistin and tigecycline being the most common choices due to their consistent in vitro activity against CP-Kps. • The available clinical data indicate that the current antibiotic regimens, especially monotherapies with either colistin or tigecycline, are far less than optimal in treating CP-Kp bacteremias. • Antibiotic combinations including an in vitro active carbapenem and an in vitro active aminoglycoside or colistin exhibit the highest therapeutic efficacy. • Colistin dosing schemes for CP-Kp bacteremias must be thoroughly re-assessed and, if feasible, optimized. • Experimental and clinical data suggest that exploitation of the pharmacokinetic/pharmarmacodynamic characteristics of carbapenems would likely allow a more efficacious use of these drugs against CP-Kps.

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