The effect of double-carbapenem therapy on mortality rates and microbiological cure rates in patients diagnosed with carbapenem-resistant Klebsiella pneumoniae infections in comparison to monotherapy and currently used combinations of antibiotics: A meta-analysis

Introduction: Infection with the bacteria carpamenease-producing Klebsiella pneumoniae represents a significant cause of mortality in hospitalised patients. These multidrug resistant bacteria are resistant to currently used antibiotics as a result of carbapenemase production. Dual carbapenem therapy has been proposed as a valid therapeutic option, this therapy combines two carbapenem antibiotics, with one acting as a suicide inhibitor allowing the subsequent carbapenem to exert a bactericidal effect. Aim: The aim of this meta-analysis was to determine if dual carbapenem therapy had a significant effect on mortality rate and microbiological cure rate in patients diagnosed with carbapenemase-producing Klebsiella pneumoniae infections in comparison to standard antibiotic therapies. Methods: The search terms “(dual OR double) carbapenem (therapy OR treatment) AND klebsiella pneumoniae” were used to search databases and inclusion and exclusion criteria were applied to retrieved papers, a total of seven studies were identified for inclusion in the meta-analysis. The quality of included studies was assessed using the cochrane tool for risk of bias assessment and funnel plots were produced to determine the influence of publication bias. A random effects model was used to assess the outcomes; mortality rate and microbiological cure rate. Results: Dual carbapenem therapy had a time dependent effect on patient mortality rates. Dual carbapenem therapy significantly lowered mortality rates in patients in comparison to standard antibiotic therapy, especially in comparison to monotherapy treatment regimens. Additionally, dual carbapenem therapy significantly improved microbiological cure rate in patients when compared to standard antibiotic treatment regimens. Demonstrating the possible clinical applications of a dual carbapenem antibiotic regimen in the treatment of carbapenemase-producing Klebsiella pneumoniae infections.


Carbapenemase-producing Klebsiella pneumoniae infection and dual carbapenem therapy
Klebsiella pneumoniae is one of the most common Gram-negative causes of nosocomial infection (1). Carbapenem antibiotics are usually effective in the treatment of multidrug-resistant bacterial strains. For this reason carbapenem antibiotics are usually the last line of defence to treat infections caused by K. pneumoniae. Recently, however, there has been a growing trend in the number of carbapenem-resistant/producing K. pneumoniae (CR/PKP) isolates. The increasing emergence of CRKP poses a threat to health globally, and has been associated with increased health care costs, prolonged hospital stays, treatment failure and increased mortality, thus the need for novel treatment strategies is evident (1). In an effort to fight this multidrug-resistant bacteria a new treatment was put forward: double carbapenem therapy (DCT) (2). DCT utilizes a dual carbapenem antibiotic combination, the first carbapenem acts as a suicide inhibitor of the carbapenemase enzyme, allowing the second carbapenem to have a bactercidal effect.
1.2 Klebsiella pneumoniae: the emerging threat K. pneumoniae isolates are associated with a variety of infections, including infections of the urinary tract (UTIs) and infections of the bloodstream (BSIs), frequently occurring at multiple body sites concurrently. Infections are also commonly associated with underlying comorbidities such as malignancy or previous organ transplantation (1). CRKP are currently classified as critical according to the World Health Organization's 'priority list of pathogens for research and discovery of new antibiotics', this list describes the bacteria which pose the greatest threat to health, as determined by; the fatality rate associated with their infection, the length of hospital stay, the rate of resistance to current antibiotics, and the availability of current treatments (3). In addition, the European Centre for Disease Prevention and Control reported that currently more than one third of K. pneumoniae isolates are resistant to at least one antibiotic (4). Consequently the need for an effective treatment of CPKP infections is vital.

Current treatments
The antibiotics colistin belonging to the polymyxin antibiotic class, tigecycline belonging to the glycycline antibiotic class, fosfomycin belonging to the phosphonic antibiotic class, and antibiotics form the aminoglycoside class, are currently used to treat infections caused by K. pneumoniae, either in mono-or combination-therapy, other example combination antibiotic strategies include ceftazidime-avibactam and meropenem-vaborbactam (5). However, limitations exist to the wide-spread use of these antibiotics. Due to increased usage, there is an increasing incidence of CPKP resistance to these antibiotics (6). Additionally, the potentially fatal adverse effect, dosedependent nephrotoxicity is commonly associated with colistin administration (7). Carbapenem antibiotics are used as a salvage treatment in K. pneumoniae infections, post failure of other antibiotics.The most common clinically administered carbapenem antibiotics include, imipenem, meropenem, ertapenem, and doripenem. Recently developed carbapenems include; tebipenem the first oral carbapenem, tomopenem whose bactericidal properties appear more potent than older carbapenems such as imipenem and meropenem as evidenced by in vitro and in vivo studies, and santrifenem the first trinem carbapenem possessive of broad spectrum bactericidal activity (8). Trinem carbapenems encompass tricyclic beta-lactams that possess a penicillin, cephalosporin, or carbapenem backbone. Due to the increasing resistance of K. pneumoniae isolates to these antibiotics, new treatment options are of vital importance (9).
1.4 Klebsiella pneumoniae resistance mechanisms CPKP are resistant to carbapenem antibiotics as a result of carbapenemase production. This enzyme is capable of hydrolysing carbapenem antibiotics, thus rendering them inactive (10). The carbapenemase enzyme is encoded for by extended spectrum betalactamase (KPC) (bla(KPC)) genes, evidencing this, Yan., et al., found that 38.5% of CPKP isolates possessed bla-KPC carbapenemase-encoding-genes (11). In accordance, Logan and Weinstein, found similar results, noting that the minimum inhibitory concentration (MIC) of a carbapenem antibiotic was related to bla-KPC copy number (12). Additional CPKP resistance mechanisms include the production of AmpC cephalorinase enzymes. OmpK 35/36 are porins present in the cell membrane of K. pneumoniae isolates, antibiotics exploit these porins to enter the bacterial cell and exert their bactericidal effect. Insertions or deletions in the OmpK 35/36 encoding genes, OmpK35/36, results in the inactivation of, or altered structure of, these porins, thus conferring additional resistance to CPKP isolates. The loss of these porins, particularly ompK 35, increases the MIC of the antibiotic, as reduced concentrations of antibiotic are able to enter the bacterial cell, generating increased resistance as a result of decreased phagocytosis. Additionally, porin loss is able to significantly increase the production of the polysaccharide capsule surrounding the bacterium, which forms a physical barrier against the entry of antimicrobial agents as well as preventing the formation of the membrane attack complex. The absence of functional porins also acts to increase the lipopolysaccharide content in the outer membrane of the CPKP bacteria, aiding in evasion from the host complement system and protecting against phagocytosis (13,14).

Double-Carbapenem therapy
In an effort to fight this multidrug-resistant bacteria a new treatment was put forward: double carbapenem therapy (DCT). Initially proposed by Bulik and Nicolau (2) .DCT has been shown to be an effective treatment for CPKP infections, when other antibiotic regimes have failed, even in cases when single carbapenems used in monotherapy have shown no bactericidal activity. DCT combines two carbapenem antibiotics, ertapenem with either meropenem or doripenem. Ertapenem is administered prior to the second carbapenem. Ertapenem dosage is lower than that of the second carbapenem. The carbapenemase enzyme produced by CPKP has a greater affinity for ertapenem in comparison to other carbapenem antibiotics, this is exploited in DCT (2).
1.6 Importance of this study Much of the research into the effectiveness of DCT is positive. DCT appears to be an effective alternative to monotherapy, lowering the mortality rate of patients, as well as improving both microbiological and clinical outcomes. However, the majority of these studies are case studies, or retrospective observational studies, which are characterized by small sample sizes. Meta-analyses regarding DCT and its effectiveness as a treatment for CPKP infections are currently lacking. The addition of a meta-analysis in this area would allow for the determination of the statistical significance in the effectiveness of DCT in treating infections caused by CPKP, allowing for the grouping together of existing data to generate an increased sample size, addressing the issues posed by previous studies, leading to greater generalisability of findings. Such research could be used to inform clinical decisions regarding the use of DCT. The aim of this meta-analysis is to determine if DCT has a significant effect on mortality rates in patients diagnosed with infections due to CPKP in comparison to monotherapy and alternate antibiotic combination regimens. An additional aim of this meta-analysis is to determine if there is a significant difference in the effect of DCT on mortality rates at different time points post initiation of treatment. Furthermore, this meta-analysis aims to determine if DCT significantly alters the microbiological cure rate in CPKP infected patients in comparison to standard antibiotic regimes.

Study selection
The search terms "(dual OR double) carbapenem (therapy OR treatment) AND klebsiella pneumoniae" were used to search the following databases for relevant papers; pubmed, science direct, web of science, wiley online library, cochrane controlled trials register, and current controlled trials. In addition the search terms were used to search the following conferences; Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) 2011-2019, and the European Congress of Clinical Microbiology and Infectious Diseases 2014-2019. The reference sections of retrieved papers were searched for further relevant papers. The inclusion criteria applied were; patients diagnosed with carbapenem-resistant Klebsiella pneumoniae infection, patients in the experimental group must be receiving double-carbapenem therapy, carbapenemresistant Klebsiella pneumoniae infections at all body sites were included, studies from all countries were included, all patients aged over 18 years of age were included, only studies in which a control group was present were included, and only studies published pre 2020 were included. The exclusion criteria applied were; patients diagnosed with multiple infections caused by bacteria other than Klebsiella pneumoniae, animal studies were excluded, studies lacking a control group were excluded, studies published in languages other than english were excluded, and any study published post 1st January 2020 was excluded.

Data extraction
The following data was extracted for each study; authors, year of publication, treatment received, sample size, number of deaths amongst patients receiving DCT, total number of patients receiving DCT, and either the number of deaths amongst patients receiving monotherapy and the total number of patients receiving monotherapy, or the number of deaths amongst patients receiving combination therapy and the total number of patients receiving combination therapy. The microbiological cure rates in patients treated with DCT and the microbiological cure rates in patients treated with standard antibiotic regimes, were extracted from applicable studies.

Quality assessment of studies
To ensure study quality, all papers included in the meta-analysis were subject to peerreview. To ensure methodological quality, papers selected for inclusion were assessed for risk of bias in accordance with the cochrane tool for assessing the risk of bias in nonrandomized studies of interventions (3). To be determined as having a low overall risk of bias the study must be judged to be at low bias in all domains, and to be determined as having a moderate overall risk of bias the study must be judged to be at low or moderate risk of bias in all domains. Only papers with a low or moderate risk of bias were included in the analysis. Funnel plots were produced to assess the impact of publication bias.

Definitions
Dual carbapenem therapy consisted of an antibiotic regimen containing two carbapenem antibiotics. Monotherapy consisted of a single active antibacterial agent. Combination therapy consisted of two or more active antibacterial agents used in combinations other than a dual carbapenem combination. Standard antibiotic therapy (SAT) consisted of appropriate antibiotic regimens, both monotherapy and combination therapies, exempting DCT. Mortality rate was determined as the number of deaths occurring in the population of patients with CPKP infections post initiation of treatment with DCT, monotherapy, or other antibiotic combination therapies at the following time points (where applicable for each study); 14 day mortality, 28-30 day mortality, 60-90 day mortality, and the mortality rate at the latest follow up time point within each study, termed the overall mortality rate. Microbiological cure was defined as cultures negative for the original pathogen, collected from the original site of infection, post antibacterial treatment.

Data analysis
The outcomes assessed were mortality rate and microbiological cure rate. Microbiological cure rates post antibacterial treatment were assessed. Mortality rates post initiation of treatment at the latest follow up time point within each study were assessed. Mortality rates were then stratified according to the following time points; 14 days, 28-30 days, and 60-90 days, post initiation of treatment. A random effects model was used to assess these outcomes. The odds ratio (OR) and 95% confidence interval (CI) were calculated for all included studies. The overall OR and 95%CI were calculated for each analysis. The overall effect (Z) and significance (p) were also calculated for each analysis.The I² statistic was used as the test of heterogeneity. The I² value was interpreted as follows: I²<50%: low heterogeneity; I² =50-75%: moderate heterogeneity; I² ≥75%: high heterogeneity (4). A p value <0.05 was considered significant.The software Review Manager (RevMan) version 5.3 was utilised to carry out this meta-analysis (5).

Study inclusion
The search strategy of online databases identified 599 studies, an additional study was identified through searching of conference databases. 600 studies were screened for eligibility for inclusion based upon title and abstract content, and the inclusion and exclusion criteria previously outlined were applied. 30 duplicate studies were removed. 30 studies were subject to full text review and the inclusion and exclusion criteria were applied. A total of 7 studies were identified for inclusion in the meta-analysis. ertapenem and meropenem at varying doses. Antibiotics administered in monotherapy regimens included; colistin, gentamicin, tigecycline, aminoglycosides, meropenem, imipenem, cefepime, aztreonam, ceftazidime, and chloramphenicol. Antibiotics administered in combination regimens included; meropenem plus another agent, rifampicin plus another agent, colistin plus another agent, tigecycline plus another agent, and gentamicin plus another agent. As shown in table 1.  (22). Giannella et al (23), and Venugopalan et al (24).

Risk of bias assessment of included studies
The studies selected for inclusion were assessed for risk of bias and all included studies were determined to have a moderate risk of bias, with the exception of the study conducted by Gutierrez-Gutierrez et al., 2017, (20) and that conducted by Venugopalan, et al., 2017 (24) (24), were determined to have a low risk of bias due to confounding. All studies included in the analysis were determined to have a low risk of bias in selection of participants into the study (18,19,20,21,22,23,24). Similarly all included studies were determined to have a low risk of bias due to deviations from intended interventions and in bias due to classification of interventions (18,19,20,21,22,23,24). The study conducted by De Pascale et al., 2017 (18) was determined to have a moderate risk of bias due to missing data, all other included studies were determined to have a low risk of bias due to missing data (19,20,21,22,23,24). In addition, all studies had low risk of bias in both measurements of outcomes and in selection of the reported result (18,19,20,21,22,23,24). As shown in table 2.

Mortality rates in patients treated with DCT in comparison to monotherapy
The studies included in this analysis displayed low heterogeneity (I²=0%). Patients receiving DCT had a lower overall mortality rate in comparison to patients receiving monotherapy (OR= 0.77, 95%CI [0.50,1.19]). However the overall effect of DCT on mortality rates was non-significant (Z=1.19 (p=0.24)). As illustrated in figure 2.

Data shown is number of deaths (events) and total number in group (total),data shown is odds ratio and 95% confidence interval, events refers to mortality,CI-confidence interval, df-degrees of freedom, DCT-dual carbapenem therapy, experimental group received DCT treatment, control group received monotherapy, p<0.05 is significant, De Pascale et al (18), Cancelli et al (19), Gutierrez-Gutierrez et al (20), Tumbarello et al (21), Onal et al (22).
However, stratifying by time post initiation of treatment, revealed a significant effect. DCT significantly lowered the 28-30 day mortality rate in patients in comparison to patients treated with monotherapy regimes (OR=0.44, 95%CI[0.17,1.10], Z=1.76 (P=0.08)). The studies included in this analysis displayed moderate heterogeneity (I²=66%). As illustrated in figure 3.

Mortality rates in patients treated with DCT in comparison to alternative antibiotic combinations
The studies included in the analysis displayed low heterogeneity (I²=8%). Patients receiving DCT had a lower overall mortality rate in comparison to patients receiving alternate antibiotic combinations (OR= 0.71, 95% CI [0.45, 1.14]). However the overall effect of DCT on mortality rate was non-significant (Z=1.41 (P= 0.16)). As illustrated in figure 4.

Figure 4: Overall mortality rates in CPKP infected patients treated with DCT in comparison to patients treated with alternate antibiotic combinations
Data shown is number of deaths (events) and total number in group (total),data shown is odds ratio and 95% confidence interval, events refers to mortality, CI-confidence interval, df-degrees of freedom, DCT-dual carbapenem therapy, experimental group received DCT treatment, control group received alternate antibiotic combinations, p<0.05 is significant. Tumbarello et al (21), Giannella et al (23), and Venugopalan et al (24).
In contrast to the monotherapy subgroup, stratifying the mortality rate by time post initiation of treatment for patients receiving combination therapy in comparison to those receiving DCT did not yield a significant effect (OR=0.77, 95%CI[0.52,1.16], Z=1.23 (p=0.22)). The studies included in this analysis displayed low heterogeneity (I²=0%). As illustrated in figure 5.     Data shown is number of deaths (events) and total number in group (total),data shown is odds ratio and 95% confidence interval, events refers to mortality, CI-confidence interval, df-degrees of freedom, SAT-standard antibiotic therapy, DCT-dual carbapenem therapy, experimental group received DCT treatment, control group received standard antibiotic regimens, p<0.05 is significant. De Pascale et al (18), Cancelli et al (19).

Microbiological cure rates in patients treated with DCT in comparison to standard antibiotic regimes
The studies included in this analysis displayed low heterogeneity (I²=0%). Patients receiving DCT had a higher microbiological cure rate in comparison to patients receiving standard antibiotic regimes (OR= 2.14, 95%CI [1.24, 3.71]). This difference in microbiological cure rate between patients receiving DCT and those receiving standard antibiotic regimens was significant (Z=2.71, (P=0.007)). As illustrated in figure 9.

Publication bias
To investigate potential publication bias funnel plots were produced of the included studies. The funnel plots display symmetry, suggesting that publication bias is not an issue in these analyses. As demonstrated by figures 10 and 11.

OR-odds ratio, SE(log[OR])-standard error (log[odds ratio]), Tumbarello et al (21), Giannella et al (23), and Venugopalan et al (24).
The funnel plot produced for the studies included in the analysis of microbiological cure rate, displays asymmetry, suggesting the possible influence of publication bias. As demonstrated in figure 12.

Impact of the results of the present analysis
The majority of studies included in the analysis displayed homogeneity. The I² statistics were low (<50%), or moderate (66%) as in the case of one analysis, suggesting there is very little inter-study variation in the results. Although the test of heterogeneity was not statistically significant, a random effects model was still selected for this analysis.
Although the test of heterogeneity did not reach statistical significance, this may have been due to low power, the observed effect sizes may still vary across a range in studies with a great deal or error, for example. The odds ratios with respect to each study were subject to variation (OR= 0.11-6.25), and for this reason a random effects model was selected. An additional benefit of utilizing a random effects model is that this model allows greater generalisability of the results, beyond the scope of the studies included in the analysis. Allowing the conclusions drawn from this analysis to be generalised into clinical practice.
The funnel plots produced for the studies included in the analysis of microbiological cure rate displayed asymmetry, suggesting the influence of publication bias in this analysis. Asymmetry may be ascribed to poor methodological study design, typically a feature of studies with a small sample size, resulting in an overestimation of the treatment effect (25). However, all the studies included in the present analysis have relatively large sample sizes, suggesting another factor as the causative agent for the asymmetry. Heterogeneity in the studies is another causative factor of asymmetry in funnel plots, similarly however, the included studies were determined to be homogenous, thus heterogeneity is an unlikely cause of the asymmetry. Funnel plots become unreliable methods of investigating publication bias when the number of studies is small, as is the case with the present analysis, thus uncertainties remain as to the true effect of publication bias in the analysis of the microbiological cure rate.
Patients treated with DCT had a significantly higher microbiological cure rate in comparison to the microbiological cure rate in patients treated with standard antibiotic regimens. Evidencing the symbiotic and bactericidal effects of DCT. Carbapenem antibiotics are beta-lactamase inhibitors, exerting their bactericidal effects through binding of penicillin-binding-proteins present on the bacterial cell wall, inhibiting the synthesis of peptidoglycan, an essential component of the cell wall in many bacterial species including K. pneumoniae, resulting in a weakening, and subsequent lysis of the bacterial cell due to osmotic pressure, and thus cell death (26,27). The synergistic action of the dual carbapenem combination explains the significantly greater microbiological cure rate seen in patients to whom DCT was administered.
DCT significantly lowered the 28-30 day mortality rate in patients in comparison to standard antibiotic therapies, this effect may be explained by the action of ertapenem and the second carbapenem acting synergistically. The carbapenemase enzyme produced by CPKP has a greater affinity for ertapenem in comparison to other carbapenem antibiotics, as such ertapenem is administered first, and due to its high affinity for the carbapenemase enzyme, it binds with ease to the enzyme, resulting in a depletion of the enzyme, sufficient time for this reaction to occur elapses before the second carbapenem, meropenem or doripenem, is administered. Due to depletion of the carbapenemase enzyme in the reaction with ertapenem, higher concentrations of the second carbapenem are established in the environment surrounding the bacteria which would otherwise be concentrated with the carbapenemase enzyme. Alternatively, ertapenem may act as a suicide inhibitor. Ertapenem may bind to the crabapemase enzyme and be hydrolysed. The second carbapenem is then administered, again allowing sufficient time for the reaction between ertapenem and the carabapenemase enzyme to occur. The carbapenemase enzyme is bound to ertapenem, thus there is a lower concentration of enzyme available to hydrolyse the second carbapenem, consequently this carbapenem can exert its bactericidal effect (2,6,26).
DCT did not significantly lower the 60-90 day mortality rate in patients diagnosed with CPKP infections, in comparison to standard antibiotic treatments. The failure of DCT to sustain effectiveness at the 60-90 day time point may be attributed to unmeasured confounders occurring so long post treatment. The fact that all the included studies were retrospective observational studies, and therefore have the possibility to be influenced by confounding variables, such as underlying comorbidities, strengthens this hypothesis.
DCT also had no significant effect on the 14 day mortality rate in comparison to standard antibiotic treatments. This is suggestive of DCT's need for accumulation of efficacy over a prolonged course of therapy in order to have a significant effect. This theory is supported by the findings of Wiskirchen, et al. (28) DCT failed to significantly lower the overall mortality rate in patients diagnosed with CPKP infections in comparison to patients treated with monotherapy antibiotic regimes. Similarly, DCT failed to significantly lower the overall mortality rate in patients diagnosed with CPKP infections in comparison to alternative antibiotic combination regimes. One possible explanation for the failure of DCT to significantly lower the overall mortality rate in patients may be the uncertainty surrounding DCT's mechanism of action. Varying hypothese exist to explain the mechanisms underpinning the possible effectiveness of DCT; the establishment of higher concentrations of the carbapenem antibiotic in the microenvironment of the bacteria which would otherwise be concentrated with carbapenemase enzyme may play a role, alternately the lower concentration of enzyme available to hydrolyse the carbapenem antibiotic may be responsible. Failure to elucidate these mechanisms prevents accurate predictions regarding the effectiveness of a DCT regimen in the treatment of infections due to CPKP.
Nonetheless, DCT did significantly lower the 28-30 day mortality rate, in particular, when compared to monotherapy antibiotic regimens. This effect may be due to the synergism of the two carbapenems antibiotics, which is an advantage in comparison to monotherapy antibiotic regimens. These results are in line with those obtained by Oliva et al., who determined the combination of ertapenem and meropenem to be synergistic and bactericidal in activity against K. pneumoniae (29).
In contrast, DCT failed to significantly lower the 14 day mortality rate in patients in comparison to patients treated with other antibiotic combination regimens. Suggesting that whilst DCT may be significantly more effective in treating CPKP infection than monotherapy regimens, DCT is not more effective than other antibiotic combinations. Opposingly, the causative factor for these results may be the accumulation of efficacy over a prolonged time period required to yield a significant effect within a DCT regimen. These results support the finding that DCT failed to significantly lower the 14 day mortality rate when compared to standard antibiotic regimens, which included both monotherapy and combination regimens. Thus, strengthening the hypothesis that DCT has a time dependent effect on mortality rates.
Such findings indicate that DCT may have a time-dependent effect on mortality rates. Evidencing that whilst DCT may be initially effective at lowering the mortality rate in patients, such a response is not maintained in the long term. However, failure to maintain effectiveness, may be less to do with an inherent flaw in DCT but rather due to the influence of confounding variables not controlled for in the included studies. Thus there is a need for randomised controlled trials to determine if DCT's effectiveness can be sustained when confounding variables are controlled for.
The findings presented here indicate that, up to two weeks post initiation of treatment, there was no significant difference in the mortality rates of patients receiving DCT in comparison to patients receiving standard antibiotic therapy. Interestingly however, 28-30 days post initiation of antibiotic treatment, there was a significantly lower mortality rate in the cohort of patients to whom DCT was administered in comparison to those receiving standard antibiotic therapy. But, 60-90 days post initiation of treatment, this significant difference was absent, and no significant difference existed in the mortality rates in the cohort of patients who had been receiving standard antibiotic therapy, compared to that in the cohort of patients who had received DCT.

Conclusion
DCT significantly improved the microbiological cure rate in CPKP infected patients in comparison to standard antibiotic treatments. DCT failed to significantly lower the overall mortality rate in comparison to the overall mortality rates in patients treated with either monotherapy or alternate combination therapies. However, when stratified by time post initiation of treatment, DCT significantly lowered the 28-30 day mortality rate in patients in comparison to the 28-30 day mortality rate in patients treated with monotherapy. Contrastingly, when stratified according to time post initiation of treatment, DCT still had no significant effect on the 14 day mortality rate in comparison to the 14 day mortality rate in patients treated with alternate combination therapies. DCT did not significantly lower the 14 day mortality rate in comparison to standard antibiotic regimens. DCT did however, significantly lower the 28-30 day mortality rate in patients in comparison to standard antibiotic regimens. DCT did not significantly lower the 60-90 day mortality rate in comparison to standard antibiotic regimens.
These results indicate a time dependent response in the effectiveness of a DCT regimen.
Overall, DCT demonstrated efficacy in the treatment of CPKP infection, significantly lowering the 28-30 day mortality rate and significantly improving the microbiological cure rate, in comparison to standard antibiotic treatments, and thus may be a valid therapeutic option for the treatment of CPKP infections.