Resistant Klebsiella Research Articles

Emergence of High-Level Antibiotic Resistance in Klebsiella pneumoniae: A Narrative Review

In an era marked by remarkable advancements in medicine, the persistent emergence of high-level antibiotic resistance in Klebsiella pneumoniae poses a critical threat to public health globally. As the worldwide spread of extensively drug-resistant (XDR) and pan-drug-resistant (PDR) K. pneumoniae strains continues to grow, a significant shift in how we approach treatment is on the horizon. The complex interaction of genetic factors, which encompasses a wide range of beta-lactamases, aminoglycoside-modifying enzymes, and chromosomal mutations, creates a dynamic resistance mechanism that counters the effects of antibiotics. These intricate adaptations, arising from both gene transfers facilitated by plasmids and changes in the genome itself, present a challenging obstacle to our efforts in managing antimicrobial effectiveness. Klebsiella infections come back stronger armed with molecular tactics that challenge healthcare systems, prolong hospital stays, and increase mortality. Beyond healthcare settings, the economic and social dimensions grow as resources are redirected, intensifying the impact on vulnerable groups. This review delves into the intricate mechanisms behind the high-level antibiotic resistance in K. pneumoniae, examining its epidemiological, molecular, and clinical facets. Highlighting the necessity for coordinated research, medical protocols, and policies, the review underscores the importance of judicious antibiotic utilization, drug innovation, and rigorous infection management.

Extensively Drug-Resistant Klebsiella pneumoniae Associated with Complicated Urinary Tract Infection in Northern India.

Klebsiella pneumoniae (Kp), which is associated with hospital-acquired infections, is extensively drug-resistant (XDR), making treatment difficult. Understanding the genetic epidemiology of XDR-Kp can help determine its potential to be hypervirulent (hv) through the presence of siderophores. We characterized the genomes of 18 colistin-resistant XDR-Kp isolated from 14 patients with complicated tract infection at an Indian healthcare facility. The 18 organisms comprised the following sequence types (STs): ST14 (n = 9), ST147 (n = 5), ST231 (n = 2), ST2096 (n = 1), and ST25 (n = 1). Many patients in each ward were infected with the same ST, suggesting a common source of infection. Some patients had recurrent infections with multiple STs circulating in the ward, providing evidence of hospital transmission. β-lactamase genes (blaCTX-M-1, blaSHV, and blaampH) were present in all isolates. blaNDM-1 was present in 15 isolates, blaOXA-1 in 16 isolates, blaTEM-1D in 13 isolates, and blaOXA-48 in 3 isolates. Disruption of mgrB by various insertion sequences was responsible for colistin resistance in 6 isolates. The most common K-type among isolates was K2 (n = 10). One XDR convergent hvKp ST2096 mutation (iuc+ybt+blaOXA-1+blaOXA-48) was associated with prolonged hospitalization. Convergent XDR-hvKp has outbreak potential, warranting effective antimicrobial stewardship and infection control.

Phased outbreak of Burkholderia cepacia complex and multi-drug resistant Klebsiella pneumoniae causing neonatal sepsis in a tertiary hospital in Benin City, Nigeria: Investigation and mitigation

Phased outbreak of Burkholderia cepacia complex and multi-drug resistant Klebsiella pneumoniae causing neonatal sepsis in a tertiary hospital in Benin City, Nigeria: Investigation and mitigation

Draft genome sequence of multi-drug resistant Klebsiella quasipneumoniae subsp. similipneumoniae isolated from a teaching hospital wastewater in South West, Nigeria.

This broadcast is about the whole genome sequence of Klebsiella quasipneumoniae subsp. similipneumoniae (ST 1422) isolated from a teaching hospital wastewater in South West, Nigeria, in May 2022. This data set compiles information on the DNA size (5,332,183 bp) and GC content (57.91%) in its genome.

Clone dissemination of IncX3 plasmid carrying blaNDM-1 in ST76 carbapenem resistance Klebsiella pneumoniae and bactericidal efficiency of aztreonam combined with avibactam in vitro and in vivo

ObjectivesThe rapid spread of the New Delhi Metal-β-lactamase-1 (NDM-1) gene in Klebsiella pneumoniae poses a substantial challenge to pediatric therapeutic care. Here, we aimed to characterise the IncX3-type plasmid carrying the blaNDM-1 gene in ST76 carbapenem resistance K. pneumoniae (CRKP) strains and assess the in vitro and in vivo bactericidal efficacy of Aztreonam (ATM) combined with Avibactam (AVI) (ATM+AVI) against CRKP. MethodsThe broth microdilution method and PCR were used to detect antimicrobial susceptibility and antibiotic resistance genes. Genetic relatedness was determined using Pulsed-Field Gel Electrophoresis (PFGE) and Multilocus Sequence Typing (MLST). The plasmid conjugation assay was used to verify the transmissibility of drug-resistant plasmids. Whole-Genome Sequencing (WGS) was employed to elucidate the genomic attributes of the genes. The Fractional Inhibitory Concentration (FIC) was calculated based on the checkerboard titration assay to determine the antimicrobial effect of ATM+AVI. The time-kill curve assay and a mouse anti-infection model were used to investigate the in vitro and in vivo bactericidal efficiency of ATM+AVI. ResultsSeven blaNDM-1-producing strains were found to be highly resistant to carbapenems, and they all belonged to the same sequence type (ST76) and were classified into the same PFGE clusters with an 89.1% similarity. The conjugation assay showed that the blaNDM-1-carrying plasmid was successfully transferred to Escherichia coli 600, resulting in transconjugants with carbapenem antibiotic resistance. A 54-kb IncX3 plasmid (pNDM-XZA88) carried the blaNDM-1 gene located on a Tn125 transposon-like element structure, demonstrating the transferability of resistance genes. Genome comparative analysis revealed that pNDM-XZA88 was highly similar to pCQ17 × 3 and pRor-30818cz and had relatively conserved backbones and variable accessory regions compared to the other four plasmids (pC39-334 kb, pNDM-1-DY1928, pNDM-K725, and pNDM-Z244). The checkerboard titration and time-kill curve assays revealed that the ATM+AVI combination therapy exerted significant bactericidal efficacy against the blaNDM-1-producing strains in vitro. The ATM+AVI combination also significantly reduced the bacterial burden in a mouse infection model constructed using the blaNDM-1-producing K. pneumoniae. ConclusionThis study demonstrated the clone dissemination of blaNDM-1-harboring IncX3 plasmids among the ST76 K. pneumoniae isolated from pediatric patients. Therefore, more attention should be paid to preventing this high-risk clone from harming pediatric patients. Moreover, we deduced that the ATM+AVI combination therapy is an effective strategy for treating blaNDM-1-producing K. pneumoniae.

Emergence of carbapenem resistant gram-negative pathogens with high rate of colistin resistance in Egypt: A cross sectional study to assess resistance trends during the COVID-19 pandemic

The current study investigated the temporal phenotypic and genotypic antimicrobial resistance (AMR) trends among multi-drug resistant and carbapenem-resistant Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa recovered from Egyptian clinical settings between 2020 and 2021. Bacterial identification and antimicrobial sensitivity of 111 clinical isolates against a panel of antibiotics were performed. Molecular screening for antibiotic resistance determinants along with integrons and associated gene cassettes was implemented. An alarming rate (98.2%) of these isolates were found to be phenotypically resistant to carbapenem. Although 23.9 % K. pneumoniae isolates were phenotypically resistant to colistin, no mobile colistin resistance (mcr) genes were detected. Among carbapenem-resistant isolates, blaNDM and blaOXA-48-like were the most prevalent genetic determinants and were significantly overrepresented among K. pneumoniae. Furthermore, 84.78% of K. pneumoniae isolates co-produced these two carbapenemase genes. The plasmid-mediated quinolone resistance genes (qnrS and qnrB) were detected among the bacterial species and were significantly more prevalent among K. pneumoniae. Moreover, Class 1 integron was detected in 82% of the bacterial isolates. This study alarmingly reveals elevated resistance to last-resort antibiotics such as carbapenems as well as colistin which impose a considerable burden in the health care settings in Egypt. Our future work will implement high throughput sequencing-based antimicrobial resistance surveillance analysis for characterization of novel AMR determinants. This information could be applied as a step forward to establish a robust antibiotic stewardship program in Egyptian clinical settings, thereby addressing the rising challenges of AMR.

Synergistic effect of tryptamine-urea derivatives to overcome the chromosomally-mediated colistin resistance in Klebsiella pneumoniae

Colistin is considered as the last-resort antibiotics to treat multi-drug resistant Gram-negative bacterial infections in humans. However, the clinical use of colistin was limited because of the apparition of chromosomal mutations and mobile colistin resistance genes in bacterial isolates. One promising strategy is to combine existing antibiotics with promising non-antibiotics to overcome the widespread emergence of antibiotic-resistant pathogens. Moreover, colistin resistance would be regulated by two component systems PhoP/PhoQ which leads to permanent synthesis of cationic groups compensating for Mg2+ deficiency. In this study, the synthesis of a small library of tryptamine urea derivatives was carried out. In addition, antibiotic susceptibility, antibiotic adjuvant screening and checkerboard assays were used to investigate the antibacterial activity of these synthesized compounds and the potential synergistic activity of their combination with colistin. Conformational analysis of the docked binding modes of the active compound in the predicted binding pocket of bacterial response regulator PhoP were carried out, to see if the active compound inhibits PhoP which is involved in colistin resistance. Finally, hemolytic activity studies have been conducted on the most active compound.

Identification and analysis of CRISPR/Cas systems structures in the genomes of antibiotic-resistant strains of <i>Klebsiella pneumoniae</i>

Background. Klebsiella pneumoniae belongs to a group of opportunistic bacteria that can form multiple resistance to antibiotics and transmit it to various types of bacteria through horizontal gene transfer. These studies examine the structural and functional diversity of CRISPR/Cas systems that protect bacteria from foreign DNA. Their analysis using the example of antibiotic-resistant strains of Klebsiella pneumoniae will demonstrate their resistance to certain bacteriophages, which will make it possible to develop approaches to the treatment of complex infectious diseases caused by these microorganisms by creating targeted phage therapy.The aim. To perform a bioinformatics analysis of the identified structural components of CRISPR/Cas systems for screening bacteriophages through CRISPR cassette spacers using the example of antibiotic-resistant strains of Klebsiella pneumoniae.Materials and methods. The article analyzed 29 full-genome sequences of Klebsiella pneumoniae, in the genome of which the structures of CRISPR/Cas systems and antibiotic resistance genes were determined (according to NCBI). To achieve this goal, using software modeling methods, a search was made for Cas genes and CRISPR cassettes, and their structural and functional characteristics were given.Results. Using bioinformatic search algorithms in the genome of antibiotic-resistant strains, functionally active CRISPR/Cas systems with the presence of one or two CRISPR cassettes and belonging to Type I Subtype IE were identified. Groups of resistant strains with identical spacer composition of CRISPR cassettes have been identified. A phylogenetic analysis was carried out confirming their common origin. By analyzing the spacer sequences of CRISPR cassettes, the spectrum of diversity of phages of bacteria of the genus Klebsiella, Salmonella, belonging to the same family Enterobacteriaceae, was determined. Thus, information was obtained about the bacteriophages that are targeted by the action of CRISPR systems of Klebsiella pneumoniae strains that have antibiotic resistance.Conclusions. Analysis of the functional and structural features of the CRISPR/Cas systems of antibiotic resistant Klebsiella pneumoniae strains made it possible to obtain information about their evolutionary history and about the bacteriophages against which their action is directed, that is, about their phage resistance. The approach used in this study may further serve as the basis for the creation of personalized phage therapy

PREVALENCE AND ANTIBIOGRAM OF KLEBSIELLA SPECIES DETECTED IN CLINICAL

Objectives: We evaluated the prevalence rate and antibiogram of Klebsiella species isolated in various clinical samples, for effective management. Methods: The prospective study was undertaken to evaluate various clinical samples received in the microbiology laboratory for culture and sensitivity testing. Culture showing Klebsiella species were further processed for antibiotic susceptibility testing by the Kirby−Bauer disk diffusion test. Results: During the study period, 332 Klebsiella species were isolated in various samples and out of which 98.7% were Klebsiella pneumoniae and were predominately from urine samples (37%). All isolates were processed to determine their antibiogram. The highest antimicrobial resistance was observed for third and fourth-generation cephalosporines (more than 85%). Conclusion: It is concluded from our study that multidrug resistance K. pneumoniae are the emerging superbugs which require close monitoring and should be reported regularly which will guide clinicians in effectful management and thus help in preventing the spread of multidrug resistance Klebsiella and future threat.

Assessment of carbapenem resistant Klebsiella pneumoniae in intensive care unit of Zagazig University Hospitals

Assessment of carbapenem resistant Klebsiella pneumoniae in intensive care unit of Zagazig University Hospitals

Convergence of plasmid-mediated Colistin and Tigecycline resistance in Klebsiella pneumoniae.

The co-occurrence of colistin and tigecycline resistance genes in Klebsiella pneumoniae poses a serious public health problem. This study aimed to characterize a K. pneumoniae strain, K82, co-harboring a colistin resistance gene (CoRG) and tigecycline resistance gene (TRG), and, importantly, investigate the genetic characteristics of the plasmid with CoRG or TRG in GenBank. K. pneumoniae strain K82 was subjected to antimicrobial susceptibility testing, conjugation assay, and whole-genome sequencing (WGS). In addition, comparative genomic analysis of CoRG or TRG-harboring plasmids from K82 and GenBank was conducted. K. pneumoniae strain K82 was resistant to all the tested antimicrobials including colistin and tigecycline, except for carbapenems. WGS and bioinformatic analysis showed that K82 belonged to the ST656 sequence type and carried multiple drug resistance genes, including mcr-1 and tmexCD1-toprJ1, which located on IncFIA/IncHI2/IncHI2A/IncN/IncR-type plasmid pK82-mcr-1 and IncFIB/IncFII-type plasmid pK82-tmexCD-toprJ, respectively. The pK82-mcr-1 plasmid was capable of conjugation. Analysis of the CoRG/TRG-harboring plasmid showed that mcr-8 and tmexCD1-toprJ1 were the most common CoRG and TRG of Klebsiella spp., respectively. These TRG/CoRG-harboring plasmids could be divided into two categories based on mash distance. Moreover, we found an IncFIB/IncHI1B-type plasmid, pSYCC1_tmex_287k, co-harboring mcr-1 and tmexCD1-toprJ1. To the best of our knowledge, this is the first report on the co-occurrence of mcr-1 and tmexCD1-toprJ1 on a single plasmid. Our research expands the known diversity of CoRG and TRG-harboring plasmids in K. pneumoniae. Effective surveillance should be implemented to assess the prevalence of co-harboring CoRG and TRG in a single K. pneumoniae isolate or even a single plasmid.

PCR detection of spreading TEM and CTX-M gene in Klebsiella pneumoniae isolated from urinary tract infection

Mostly, urine is devoid of bacteria, viruses, and fungi, making it sterile. However, an infection may arise when minuscule organisms, mostly bacteria from the digestive system, attach to the urethral opening and proliferate, leading to infections. This research seeks to identify the B-lactam genes responsible for antibiotic resistance in Klebsiella pneumoniae linked with infections, as well as their resistance to treatments. This inquiry specifically focuses on this aspect. The primary focus of the study was identifying bacterial isolates by established diagnostic methods. The secondary objective was to assess the resistance and sensitivity of antibiotics. Lastly, the study used the Polymerase Chain Reaction (PCR) method to ascertain the presence of the blaCTX-M and blaTEM genes. Within the period from November 2022 to June 2023, a 540 clinical samples were gathered from patients with urinary tract infections at Al-Hakim General Hospital, Al-Sadr City Hospital, Al-Furate Al-Awsat Hospital, and Al-Zahra Maternity and Children in AL-Najaf governorate. A total of 120 samples were found to be tainted with Klebsiella pneumoniae. This study assessed the sensitivity of the test using the disk diffusion method. The findings indicated that Klebsiella pneumoniae exhibited high levels of resistance to a road scope of antibiotics, namely Ampicillin/sulbactam, Ampicillin, and Ticarcillin/Clavulanic acid. Additionally, some isolates showed resistance to Cefotaxime. The experiment yielded diverse outcomes for the quinolone, aminoglycoside, and macrolide groups. Among the 120 samples that were examined, 87 of them showed positive results for K. pneumoniae when the PCR technique was used to detect the presence of the blaCTX-M gene. On the other hand, 36 samples tested positive for K. pneumoniae when the blaTEM gene was used. The specimens were obtained from the urine of individuals diagnosed with urinary tract infections.

Expression of transcriptional regulator mgrB is enhanced in colistin-resistant Klebsiella pneumoniae: A report from India

Background: Colistin is regarded as the final option for treating Gram-negative bacteria that are resistant to several drugs. A common resistance mechanism for colistin in Klebsiella pneumoniae is mgrB gene inactivation. Inactivation of mgrB activates the PhoPQ which upregulates the PmrAB leading to resistance by lipopolysaccharide modification. Colistin resistance has been reported in Klebsiella pneumoniae, still, studies related to molecular mechanisms of this resistance are lacking. Aim: Role of mgrB in colistin resistance Methods: In this study, eight colistin-resistant clinical Klebsiella pneumoniae were selected, and performed broth microdilution followed by Rapid polymyxin NP test for screening of colistin resistance. PCR was performed for different types of mcr genes. MgrB was amplified and sequenced. Quantitative real-time PCR was performed for mgrB, PmrA, PmrB, PhoP, and PhoQ genes. Further, clonal analysis by ERIC PCR was done. Results: Colistin MIC of 4μg/ml has been shown by the isolates. No mcr gene was detected. Positive amplification for the mgrB gene was found in all the isolates. Sequence analysis of the mgrB gene found no mutation however, higher expression in the mgrB, PmrA, PmrB, PhoP, and PhoQ genes of all the eight colistin-resistant isolates could be observed when the isolates were exposed to colistin and Mg2+ pressure. Clonal analysis exhibited seven different haplotypes of Klebsiella pneumoniae. Conclusion: This study provides firsthand knowledge about molecular mechanisms of colistin resistance in Klebsiella pneumoniae in this geographical area. Enhancement in mgrB expression in the presence of colistin and Mg2+ pressure regardless of any mutation has a remarkable impact in the context of colistin resistance mechanisms in clinical Klebsiella pneumoniae.

Retrospective Tertiary Care-Based Cohort Study on Clinical Characteristics and Outcomes of Ceftazidime-Avibactam-Resistant Carbapenem-Resistant Klebsiella pneumoniae Infections.

The advent of ceftazidime-avibactam (CAZ-AVI)-resistant carbapenem-resistant Klebsiella pneumoniae (CRKP) isolates has been steadily documented in recent years. We aimed to identify risk factors of CAZ-AVI-resistant CRKP infection and assess clinical outcomes of patients. The study retrospectively examined the clinical and microbiological data of patients with ceftazidime avibactam susceptible and ceftazidime avibactam-resistant Klebsiella pneumonia carbapenem-resistant enterobacteriaceae infection to identify risk factors, clinical features, and outcomes using multivariate logistic regression analysis. A total of 152 patients with CRKP infection were enrolled in this study. Patients with CAZ-AVI-resistant CRKP isolates (20/34 = 58.8%) had prior exposure to carbapenems (p=0.003) and had more tracheostomies (16/34 = 47.1%) (p=0.001). Only 8/28 (28.6%) patients with CAZ-AVI susceptible CRKP isolates died amongst those administered ceftazidime-avibactam compared to 49/90 (54.4%) who did not receive the same (p=0.016). 1/9 (11.1%) patients with CAZ-AVI-resistant CRKP isolates who received colistin died compared to 13/25 (52%) who did not receive colistin (p=0.03). There was no association between presence of CAZ-AVI-resistant CRKP isolates and overall mortality (odds ratio: 0.7; 95% CI: 0.3, 1.6), and no independent predictors of risk factors to overall mortality in the group with CAZ-AVI-resistant CRKP isolates were noted. Early advent of CAZ-AVI resistance in CRE isolates highlights the dynamic necessity of routine CAZ-AVI resistance laboratory testing and antimicrobial stewardship programmes focusing on the utilization of all antibiotics. Consolidating the hospital infection control of tracheostomies may help to prevent CAZ resistance in CRKP. Colistin may aid in decreasing of mortality rates among patients with CAZ-AVI CRKP isolates.

Highly selective organo-gallium hydroxamate mediated inhibition of antibiotic resistant Klebsiella pneumoniae.

Five complexes of gallium derived from hydroxamic acids have been synthesised, characterised, and their anti-bacterial activity and mammalian cell toxicity established. These are three metal-organic complexes; [Ga(BPHA)3] 1, [Ga(BHA-H)3] 2, [Ga(SHA-H2)(SHA-H)3] 3, and two heteroleptic organometallic complexes [GaMe2(BPHA)] 4, and [GaMe(BHA-H)2] 5, along with the iron complex [Fe(BPHA)3] 6 (BPHA-H = N-benzoyl-N-phenylhydroxamic acid, BHA-H2 = phenylhydroxamic acid, and SHA-H3 = salicylhydroxamic acid). Solid-state structures of 1, 4-6 were identified by single-crystal X-ray crystallography. Complexes 1 and 6 adopt an octahedral geometry at the metal centre, while the organometallic complexes 4 and 5 adopt, respectively, tetrahedral and trigonal bipyramidal geometry. The solution and solid-state chemistry of complex 3 was found to differ: the solution state is composed of an equilibrium mixture of the bis-complexed hydroximate-hydroxamate species and the homoleptic tris-hydroxamate species, with the solid state preferring the bis-complexed hydroximate-hydroxamate composition. The methyl gallium complexes 4 and 5 differed in their preferred composition with 4 forming the expected dimethyl hydroxamate complex while 5 stabilises as the methyl bis-hydroxamate complex. Complexes were tested for the anti-microbial activity against a series of Gram-positive and Gram-negative bacteria, with an emphasis on the Gram-negative Klebsiella pneumoniae. While the metal-organic complexes 1, 2, 3 and 6 showed little to no activity towards either the bacteria or mammalian cells, the alkyl gallium complexes 4 and 5 were found to have exceptional activity toward K. pneumoniae in RPMI-HS media with MIC values of 78 nM. Interestingly, [GaMe2(OH)] also showed significant activity with an MIC of 156 nM.

Characterization of four novel bacteriophages targeting multi-drug resistant Klebsiella pneumoniae strains of sequence type 147 and 307.

The global dissemination of multi-drug resistant (MDR) pathogenic bacteria requires the rapid research and development of alternative therapies that can support or replace conventional antibiotics. Among MDR pathogens, carbapenem-resistant Klebsiella pneumoniae (CR-Kp) are of particular concern due to their extensive resistance profiles, global dissemination in hospital environments, and their major role in some life-threatening infections. Phages, or some of their components, are recognized as one of the potential alternatives that might be helpful to treat bacterial infections. In this study, we have isolated and characterized four lytic bacteriophages targeting K. pneumoniae strains of Sequence Type (ST) 307 or ST147, two predominant high-risk clones of CR-Kp. Phages, designated vB_KpS_GP-1, vB_KpP_GP-2, vB_KpP_GP-4, and vB_KpP_GP-5, were isolated from sewage wastewater samples. The vB_KpS_GP-1 phage was a siphovirus unable to establish lysogeny with its host, while the other three were podoviruses. While 85.7% of K. pneumoniae strains of ST307 were selectively lysed by the phages vB_KpS_GP-1 or vB_KpP_GP-5, the other two phages were able to lyse all the tested strains of ST147 (n = 12). Phages were stable over a broad pH and temperature range and were characterized by burst sizes of 10-100 plaque forming units and latency periods of 10-50 minutes. Genome sequencing confirmed the absence of antibiotic resistance genes, virulence factors or toxins and revealed that two phages were likely members of new genera. Given their strictly lytic nature and high selectivity towards two of the major high-risk clones of K. pneumoniae, cocktails of these phages could represent promising candidates for further evaluation in in vivo experimental models of K. pneumoniae infection.

Acute Diarrhea in Early Post-Transplant Period in Living Donor Kidney Transplant Recipients

Background: Acute diarrhea is common in Myanmar. People are so used to diarrhea at least once a year that they do not think diarrhea as an important problem. Acute diarrhea in early post-operative period in renal transplant recipient may result in pre-renal failure and delay graft function. This study aimed to identify the prevalence of diarrhea, its severity and response to treatment in early post-operative period (3 weeks after transplant) in living donor kidney transplant (LDKT) recipients. Patients and Methods: LDKT recipients having acute diarrhea in early post-transplant period at two transplant centers (Mingaladon and Nay Pyi Taw) in Myanmar were analyzed over 10 years period; from 2013 to 2023 September. Acute diarrhea is defined as three or more semisolid or liquid stools per day for a minimum of 1 day duration. It was a hospital based observational study. After obtaining diet history and physical examination, laboratory tests were done. Clinical parameters (diet, fever, features of oral candidiasis, features of dehydration, examination of abdomen), stool examination (stool inspection, stool examination for ova and cyst, stool for Clostridium difficle toxin, stool culture), blood tests (total WBC count, serum creatinine, liver function tests) and blood trough level for Tacrolimus and mycophenolate mofetil were done. Management was given according to algorithm and their response to treatment was recorded. Dose modification of immunosuppressants were done depending on full blood count and blood level of them. Results: A total of 230 LDKT recipients were observed; among them, thirteen percent (30/230) of recipients developed acute diarrhea in early post-operative period. The age ranged from 14 to 73 years. A majority of them had mild form; mild dehydration without significant changes in hemodynamic status. The peak onset of diarrhea was 4 to 5 days after transplant; majority resolved over one week. They did not have oral candidiasis. Abdominal examination was normal except mild tenderness over grafted kidney in all of them. Total WBC count and platelet count were normal except in two cases. Stool examination did not show trophozoite or cyst. Stool for Clostridium difficile toxin was not identified. With dietary modification and oral rehydration solution, their motion was back to normal in sixteen percent (5/30). Folic acid therapy with or without probiotics made resolution of diarrhea in 33.3% (10/30). Anti-infective therapy was given in 10% (3/30) of cases; norfloxacin to 2 cases. Intravenous colistin to one case as he had enterocolitis and septicemia due to Klebsiella pneumonia. His stool culture as well as blood culture showed Carbepenem resistant Klebsiella pneumonia; he was known case of myelodysplastic syndrome. Blood level of mycophenolate mofetil was normal; however, the dose was reduced in 2 cases owing to leucopenia or thrombocytopenia. Blood tacrolimus trough level was normal in two-third (20/30); and, it was high in one-third of them (20/30). They passed formed stool 24 - 48 hours after dose reduction of tacrolimus. Conclusion: In this study, 13% of the LDKT recipients had acute diarrhea in early post-operative period. Majority of them had mild form. Half of them recovered with oral rehydration solution, diet modification, folic acid and probiotics. Only one tenth of them had infective in origin and responded to anti-infective therapy. Raised blood tacrolimus trough level was found in one third of LDKT recipients with acute diarrhea; diarrhea improved dramatically after reduction of tacrolimus dose.

Survey for Carbapenem Resistant Klebsiella Pneumoniae among Patients Attending Aminu Kano Teaching Hospital, Kano, Nigeria

Carbapenem resistant Klebsiella pneumoniae is becoming a more significant pathogen because of the grave clinical risk it poses which affects patient’s treatment outcome. This study aimed to survey for carbapenem resistant Klebsiella pneumoniae (CRKP) among patients attending Aminu Kano Teaching Hospital, Kano State, Nigeria. A total of 600 clinical samples including urine, sputum and swabs were collected and screened. Klebsiella pneumoniae were isolated and confirmed using culture, microscopy and biochemical test according to standard microbiological techniques. Phenotypic carbapenem resistant and carbapenemase production were detected using meropenem discs diffusion method and modified Hodge test respectively. Genotypic carbapenemase productions were confirmed by detecting the presence of blaKPC genes using PCR and Gel electrophoresis. Antibiotics susceptibility profiles of the CRKP isolates were evaluated using disc diffusion method and interpreted using CLSI protocols. The study revealed the incidence of Klebsiella pneumoniae infection as 14% with the highest occurrence in sputum (18%) and the lowest in swab (10%). Of the total number of isolated K. pneumoniae, 14.3% were found to be carbapenem resistant. Up to 75% of CRKP isolates were found to produce carbapenamase and harbor blaKPC genes. Antibiotic susceptibility profile of these isolates revealed colistin and tigecycline as the most active antibiotics in vitro (92%).The isolates were found to be generally resistant to cefepime, ceftriaxone, cefuroxime, cotrimoxazole and ciproflaxin (100%). Up to 8% of the isolates were sensitive to Gentamicin and Nalidixic acid, 25% to Nitrofurantoin, 50% to Minocycline and 17% to Amikacin. This study verifies the existence of carbapenem resistant Klebsiella pneumoniae isolates that are highly resistant to other antibiotics in patients attending AKTH Kano which is an indication of increase in drug resistance. This requires the need for newer tactics in infection control to prevent the spread of carbapenem resistant isolates.

Machine Learning-Led Optimization of Combination Therapy: Confronting the Public Health Threat of Extensively Drug Resistant Gram-Negative Bacteria.

Developing optimized regimens for combination antibiotic therapy is challenging and often performed empirically over many clinical studies. Novel implementation of a hybrid machine-learning pharmacokinetic/pharmacodynamic/toxicodynamic (ML-PK/PD/TD) approach optimizes combination therapy using human PK/TD data along with in vitro PD data. This study utilized human population PK (PopPK) of aztreonam, ceftazidime/avibactam, and polymyxin B along with in vitro PDs from the Hollow Fiber Infection Model (HFIM) to derive optimal multi-drug regimens de novo through implementation of a genetic algorithm (GA). The mechanism-based PD model was constructed based on 7-day HFIM experiments across 4 clinical, extensively drug resistant Klebsiella pneumoniae isolates. GA-led optimization was performed using 13 different fitness functions to compare the effects of different efficacy (60%, 70%, 80%, or 90% of simulated subjects achieving bacterial counts of 102 CFU/mL) and toxicity (66% of simulated subjects having a target polymyxin B area under the concentration-time curve [AUC] of 100 mg·h/L and aztreonam AUC of 1,332 mg·h/L) on the optimized regimen. All regimens, except those most heavily weighted for toxicity prevention, were able to achieve the target efficacy threshold (102 CFU/mL). Overall, GA-based regimen optimization using preclinical data from animal-sparing in vitro studies and human PopPK produced clinically relevant dosage regimens similar to those developed empirically over many years for all three antibiotics. Taken together, these data provide significant insight into new therapeutic approaches incorporating ML to regimen design and treatment of resistant bacterial infections.

Multidrug-resistant organisms may be associated with bed allocation and utilization efficiency in healthcare institutions, based on national monitoring data from China (2014–2020)

Analyzing the influence of the bed allocation and utilization efficiency in healthcare institutions on the isolation proportion of Multidrug-resistant organisms (MDROs) to provide data to support prevention and control of MDROs. In this study, the provincial panel data from 2014 to 2020 in China on health resource indicators, including the number of beds per 1,000 population, hospital bed utilization rate, and average hospital stay from 2014 to 2020 in China were used to analyze the relationship between bed allocation or utilization efficiency and MDROs by the panel data quantile regression model. It was shown that the number of beds per 1,000 population had a negative effect on the isolation proportion of methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis, vancomycin-resistant Enterococcus faecium, penicillin-resistant Streptococcus pneumoniae, methicillin-resistant coagulase-negative Staphylococcus, and cefotaxime or ceftriaxone resistant Escherichia coli (regression coefficient < 0, P < 0.05). The utilization rate of hospital bed had a positive effect on the isolation proportion of methicillin-resistant Staphylococcus aureus, methicillin-resistant coagulase-negative Staphylococcus, vancomycin-resistant Enterococcus faecium, penicillin-resistant Streptococcus pneumoniae, cefotaxime or ceftriaxone resistant Escherichia coli, carbapenem-resistant Escherichia coli, cefotaxime or ceftriaxone resistant Klebsiella pneumoniae, carbapenem-resistant Klebsiella pneumoniae, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii (regression coefficient > 0, P < 0.05). The average hospital stay had a positive effect on the isolation proportion for several antibiotic-resistant organisms, including methicillin-resistant Staphylococcus aureus, methicillin-resistant coagulase-negative Staphylococcus, vancomycin-resistant Enterococcus faecalis, vancomycin-resistant Enterococcus faecium, penicillin-resistant Streptococcus pneumoniae, cefotaxime or ceftriaxone resistant Escherichia coli, carbapenem-resistant Escherichia coli, quinolone-resistant Escherichia coli, cefotaxime or ceftriaxone resistant Klebsiella pneumoniae, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii (regression coefficient > 0, P < 0.05). Bed allocation and utilization efficiency in healthcare institutions may affect the isolation proportion of MDROs in varying degrees.