Special Issue "Stewardship of Antibiotics for Multidrug-Resistant Gram-Negative Bacteria"

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Antibiotics Use and Antimicrobial Stewardship".

Deadline for manuscript submissions: closed (30 November 2019).

Special Issue Editors

Dr. Daniele Roberto Giacobbe
E-Mail Website
Guest Editor
Department of Health Sciences (DISSAL), Università degli Studi di Genova, 16132 Genoa, Italy
Interests: antimicrobial resistance; antimicrobial stewardship; multidrug-resistant Gram-negative bacteria; invasive fungal diseases
Special Issues and Collections in MDPI journals
Dr. Ilias Karaiskos
E-Mail Website
Guest Editor
Department of Internal Medicine – Infectious Diseases, Hygeia Hospital, Athens, Greece
Interests: antimicrobial resistance; multidrug-resistant Gram-negative bacteria; colistin; fosfomycin; prostatitis

Special Issue Information

Dear Colleagues,

In the last decades, multidrug-resistant Gram-negative bacteria (MDR-GNB) have represented an important threat, for several reasons. Above all, the paucity of dependable therapeutic options, which, until just a few years ago, often relied on potentially nephrotoxic drugs and/or on drugs with possible suboptimal efficacy.

Recently, some much awaited novel agents have become available, restoring our ability to effectively counteract some perilous infections due to these organisms. However, it remains imperative to administer novel agents thoughtfully and in line with antimicrobial stewardship principles, in order to: (i) delay the development of resistance to novel agents; (ii) delay the diffusion of resistance to novel agents, since some cases of inherent or acquired resistance have already been reported. In light of this, our efforts to optimize the use of old agents should also not be discontinued, since they still remain essential for treating infection due to MDR-GNB nonsusceptible to novel agents.

The present special issue focuses on stewardship of both old and novel antibiotics for MDR-GNB infections. We especially encourage submission of original articles and reviews. However, case reports describing peculiar stewardship situations and decisions in patients with MDR-GNB infections will also be considered. 

Dr. Daniele Roberto Giacobbe
Dr. Ilias Karaiskos
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibiotics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • antimicrobial resistance
  • MDR
  • antimicrobial stewardship
  • multidrug-resistant Gram-negative bacteria
  • Acinetobacter
  • Pseudomonas
  • Klebsiella
  • KPC
  • OXA
  • NDM
  • IMP
  • VIM
  • ESBL

Published Papers (12 papers)

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Editorial

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Editorial
Stewardship of Antibiotics for Multidrug-Resistant Gram-Negative Bacteria
Antibiotics 2020, 9(4), 206; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9040206 - 24 Apr 2020
Cited by 1 | Viewed by 742
Abstract
Nearly one year ago, we wrote the following introductory note for authors willing to submit their paper to our Special Issue entitled “Stewardship of Antibiotics for Multidrug-Resistant Gram-Negative Bacteria” in Antibiotics: [...] Full article

Research

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Article
Clinical Experience with Ceftazidime-Avibactam for the Treatment of Infections due to Multidrug-Resistant Gram-Negative Bacteria Other than Carbapenem-Resistant Enterobacterales
Antibiotics 2020, 9(2), 71; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9020071 - 09 Feb 2020
Cited by 12 | Viewed by 2035
Abstract
Background: Experience in real clinical practice with ceftazidime-avibactam for the treatment of serious infections due to gram−negative bacteria (GNB) other than carbapenem-resistant Enterobacterales (CRE) is very limited. Methods: We carried out a retrospective multicenter study of patients hospitalized in 13 Italian hospitals who [...] Read more.
Background: Experience in real clinical practice with ceftazidime-avibactam for the treatment of serious infections due to gram−negative bacteria (GNB) other than carbapenem-resistant Enterobacterales (CRE) is very limited. Methods: We carried out a retrospective multicenter study of patients hospitalized in 13 Italian hospitals who received ≥72 h of ceftazidime-avibactam for GNB other than CRE to assess the rates of clinical success, resistance development, and occurrence of adverse events. Results: Ceftazidime-avibactam was used to treat 41 patients with GNB infections other than CRE. Median age was 62 years and 68% of them were male. The main causative agents were P. aeruginosa (33/41; 80.5%) and extended spectrum beta lactamase (ESBL)-producing Enterobacterales (4/41, 9.8%). Four patients had polymicrobial infections. All strains were susceptible to ceftazidime-avibactam. The most common primary infection was nosocomial pneumonia (n = 20; 48.8%), primary bacteremia (n = 7; 17.1%), intra-abdominal infection (n = 4; 9.8%), and bone infection (n = 4; 9.8%). Ceftazidime-avibactam was mainly administered as a combination treatment (n = 33; 80.5%) and the median length of therapy was 13 days. Clinical success at the end of the follow-up period was 90.5%, and the only risk factor for treatment failure at multivariate analysis was receiving continuous renal replacement therapy during ceftazidime-avibactam. There was no association between clinical failures and type of primary infection, microbiological isolates, and monotherapy with ceftazidime-avibactam. Only one patient experienced recurrent infection 5 days after the end of treatment. Development of resistance to ceftazidime-avibactam was not detected in any case during the whole follow-up period. No adverse events related to ceftazidime-avibactam were observed in the study population. Conclusions: Ceftazidime-avibactam may be a valuable therapeutic option for serious infections due to GNB other than CRE. Full article
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Article
How Does Antimicrobial Stewardship Affect Inappropriate Antibiotic Therapy in Urological Patients?
Antibiotics 2020, 9(2), 63; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9020063 - 06 Feb 2020
Cited by 4 | Viewed by 1171
Abstract
Antimicrobial stewardship teams (ASTs) have been well-accepted in recent years; however, their clinical outcomes have not been fully investigated in urological patients. The purpose of this study was to evaluate the outcomes of intervention via a retrospective review of urological patients, as discussed [...] Read more.
Antimicrobial stewardship teams (ASTs) have been well-accepted in recent years; however, their clinical outcomes have not been fully investigated in urological patients. The purpose of this study was to evaluate the outcomes of intervention via a retrospective review of urological patients, as discussed in the AST meetings, who were treated with broad-spectrum antibiotics between 2014 and 2018 at the Department of Urology, Kobe University Hospital in Japan. Interventions were discussed in AST meetings for patients identified by pharmacists as having received inappropriate antibiotic therapy. The annual changes in numbers of inappropriate medications and culture submissions over five years at the urology department were statistically analyzed. Among 1,033 patients audited by pharmacists, inappropriate antibiotic therapy was found in 118 cases (11.4%). The numbers of inappropriate antibiotic use cases and of interventions for indefinite infections had significantly decreased during the study period (p = 0.012 and p = 0.033, respectively). However, the number of blood and drainage culture submissions had significantly increased (p = 0.009 and p = 0.035, respectively). Our findings suggest that urologists have probably become more familiar with infectious disease management through AST intervention, leading to a decrease in inappropriate antibiotic use and an increase in culture submissions. Full article
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Article
Characterisation of Campylobacter spp. Isolated from Poultry in KwaZulu-Natal, South Africa
Antibiotics 2020, 9(2), 42; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9020042 - 21 Jan 2020
Cited by 7 | Viewed by 2030
Abstract
This study investigated the antibiotic resistance, virulence profiles, and clonality of Campylobacter jejuni and Campylobacter coli isolated from an intensive poultry farming system in KwaZulu-Natal, South Africa. Following ethical approval, samples were collected over six weeks using the farm-to-fork approach. Campylobacter spp. were [...] Read more.
This study investigated the antibiotic resistance, virulence profiles, and clonality of Campylobacter jejuni and Campylobacter coli isolated from an intensive poultry farming system in KwaZulu-Natal, South Africa. Following ethical approval, samples were collected over six weeks using the farm-to-fork approach. Campylobacter spp. were identified using culture, confirmed and differentiated to species level by PCR, and subjected to antibiotic susceptibility testing. Selected antibiotic resistance (and mutations) and virulence genes were screened by PCR and confirmed by DNA sequencing. Genetic relatedness amongst the isolates was ascertained using pulsed-field gel electrophoresis. In all, 105 isolates were confirmed as belonging to both Campylobacter coli (60; 57%) and C. jejuni (45; 43%). The highest resistance was recorded against erythromycin and clindamycin. The gyrA mutation, A20175C/A2074G point mutation, tet(O), and cmeB, all associated with antibiotic resistance, were detected. All the virulence genes (pldA, ciaB, cdtA, cdtB, cdtC, dnaJ, except for cadF) were also detected. Isolates were grouped into five pulsotypes displaying 85% similarity, irrespective of their resistance profiles. The numerous permutations of clonality, antibiotic resistance, and virulence profiles evident in Campylobacter spp. pose a challenge to food safety and necessitate a comprehensive understanding of the molecular epidemiology of this organism to decrease its spread in the food chain. Full article
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Article
Antimicrobial Drug Administration and Antimicrobial Resistance of Salmonella Isolates Originating from the Broiler Production Value Chain in Nigeria
Antibiotics 2019, 8(2), 75; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics8020075 - 06 Jun 2019
Cited by 5 | Viewed by 2097
Abstract
Salmonella is among the pathogens on the high global priority lists for monitoring for studies on the discovery of new antimicrobials and understanding of how antimicrobial resistance (AMR) develops. AMR in connection with antibiotic usage patterns has been considered as a strong factor [...] Read more.
Salmonella is among the pathogens on the high global priority lists for monitoring for studies on the discovery of new antimicrobials and understanding of how antimicrobial resistance (AMR) develops. AMR in connection with antibiotic usage patterns has been considered as a strong factor and contributor to the AMR pool. The purposes of use, pattern of antimicrobial drug administration, as well as the prevalence of AMR in Salmonella originating from the Nigeria broiler production value chain (NBPVC) was explored. A well-structured questionnaire on antimicrobial usage (n = 181) was used for sampling that focused on 21 antimicrobials from 151 locations. Simultaneously, AMR testing for 18 commonly used antimicrobials on Salmonella in humans was also carried out. Antimicrobial resistance Salmonella spp. were isolated in 23% of the samples (261 of 1135 samples from the broiler input, products, and the environment) using modified ISO 6579 and invA PCR protocols. Over 80% of the antimicrobials used in the NBPVC were administered without a veterinarian prescription. Prevalence of antimicrobial administration without prescription were as follows: live-bird-market (100%), hatchery (86.7%), grow-out-farm (75%), and breeder (66.7%). Widespread prophylactic and metaphylactic use of antimicrobials were recorded with the highest use seen for enrofloxacin (63% and 24%), tetracycline (58% and 33%), and erythromycin (50% and 17%). Antimicrobial resistance was highest for flumequine (100%), penicillin (95%), and perfloxacin (89%). High levels of use without laboratory support of a newer generation of a class of antibiotics suspected to confer high resistance on older generations of the same class (quinolones) was observed. Full article
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Review

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Review
Carbapenem-Sparing Strategies for ESBL Producers: When and How
Antibiotics 2020, 9(2), 61; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9020061 - 05 Feb 2020
Cited by 22 | Viewed by 2424
Abstract
Extended spectrum β-lactamase (ESBL)-producing bacteria are prevalent worldwide and correlated with hospital infections, but they have been evolving as an increasing cause of community acquired infections. The spread of ESBL constitutes a major threat for public health, and infections with ESBL-producing organisms have [...] Read more.
Extended spectrum β-lactamase (ESBL)-producing bacteria are prevalent worldwide and correlated with hospital infections, but they have been evolving as an increasing cause of community acquired infections. The spread of ESBL constitutes a major threat for public health, and infections with ESBL-producing organisms have been associated with poor outcomes. Established therapeutic options for severe infections caused by ESBL-producing organisms are considered the carbapenems. However, under the pressure of carbapenem overuse and the emergence of resistance, carbapenem-sparing strategies have been implemented. The administration of carbapenem-sparing antibiotics for the treatment of ESBL infections has yielded conflicting results. Herein, the current available knowledge regarding carbapenem-sparing strategies for ESBL producers is reviewed, and the optimal conditions for the “when and how” of carbapenem-sparing agents is discussed. An important point of the review focuses on piperacillin–tazobactam as the agent arousing the most debate. The most available data regarding non-carbapenem β-lactams (i.e., ceftolozane–tazobactam, ceftazidime–avibactam, temocillin, cephamycins and cefepime) are also thoroughly presented as well as non β-lactams (i.e., aminoglycosides, quinolones, tigecycline, eravacycline and fosfomycin). Full article
Review
Ceftazidime/Avibactam and Ceftolozane/Tazobactam for Multidrug-Resistant Gram Negatives in Patients with Hematological Malignancies: Current Experiences
Antibiotics 2020, 9(2), 58; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9020058 - 03 Feb 2020
Cited by 5 | Viewed by 2164
Abstract
Patients suffering from hematological malignancies are at high risk for severe infections, including in particular bloodstream infections, which represent one of the most frequent life-threatening complications for these patients, with reported mortality rates reaching 40%. Furthermore, a worrisome increase in antimicrobial resistance of [...] Read more.
Patients suffering from hematological malignancies are at high risk for severe infections, including in particular bloodstream infections, which represent one of the most frequent life-threatening complications for these patients, with reported mortality rates reaching 40%. Furthermore, a worrisome increase in antimicrobial resistance of Gram-negative bacteria (e.g., cephalosporin- and/or carbapenem-resistant Enterobacteriaceae and multidrug-resistant (MDR) Pseudomonas aeruginosa) involved in severe infectious complications among patients with hematological malignancies has been reported during the last years. The two novel combination of cephalosporins and β-lactamase inhibitors, ceftolozane/tazobactam and ceftazidime/avibactam, were recently approved for treatment of complicated intra-abdominal and urinary tract infections and nosocomial pneumonia and display activity against several MDR Gram-negative strains. Although not specifically approved for neutropenic and/or cancer patients, these drugs are used in this setting due to increasing rates of infections caused by MDR Gram-negative bacteria. The aim of this review is to describe the actual evidence from scientific literature about the “real-life” use of these two novel drugs in patients with hematological malignancies and infections caused by MDR Gram-negative bacteria. Full article
Review
Machine Learning and Multidrug-Resistant Gram-Negative Bacteria: An Interesting Combination for Current and Future Research
Antibiotics 2020, 9(2), 54; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9020054 - 31 Jan 2020
Cited by 4 | Viewed by 1402
Abstract
The dissemination of multidrug-resistant Gram-negative bacteria (MDR-GNB) is associated with increased morbidity and mortality in several countries. Machine learning (ML) is a branch of artificial intelligence that consists of conferring on computers the ability to learn from data. In this narrative review, we [...] Read more.
The dissemination of multidrug-resistant Gram-negative bacteria (MDR-GNB) is associated with increased morbidity and mortality in several countries. Machine learning (ML) is a branch of artificial intelligence that consists of conferring on computers the ability to learn from data. In this narrative review, we discuss three existing examples of the application of ML algorithms for assessing three different types of risk: (i) the risk of developing a MDR-GNB infection, (ii) the risk of MDR-GNB etiology in patients with an already clinically evident infection, and (iii) the risk of anticipating the emergence of MDR in GNB through the misuse of antibiotics. In the next few years, we expect to witness an increasingly large number of research studies perfecting the application of ML techniques in the field of MDR-GNB infections. Very importantly, this cannot be separated from the availability of a continuously refined and updated ethical framework allowing an appropriate use of the large datasets of medical data needed to build efficient ML-based support systems that could be shared through appropriate standard infrastructures. Full article

Other

Brief Report
Carbapenem-Resistant but Cephalosporin-Susceptible Pseudomonas aeruginosa in Urinary Tract Infections: Opportunity for Colistin Sparing
Antibiotics 2020, 9(4), 153; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9040153 - 01 Apr 2020
Cited by 11 | Viewed by 1245
Abstract
This paper briefly reports the occurrence and epidemiology of carbapenem-resistant but cephalosporin-susceptible (Car-R/Ceph-S) Pseudomonas aeruginosa isolates from urinary tract infections (UTIs) in a tertiary-care hospital in the Southern Region of Hungary, and the phenotypic characterization of the possible resistance mechanisms in these isolates. [...] Read more.
This paper briefly reports the occurrence and epidemiology of carbapenem-resistant but cephalosporin-susceptible (Car-R/Ceph-S) Pseudomonas aeruginosa isolates from urinary tract infections (UTIs) in a tertiary-care hospital in the Southern Region of Hungary, and the phenotypic characterization of the possible resistance mechanisms in these isolates. Isolates and data were collected regarding P. aeruginosa UTIs corresponding to the period between 2008 and 2017. Susceptibility testing was performed using the Kirby–Bauer disk diffusion method; minimum inhibitory concentrations (MICs) of the isolates were determined using E-tests. The phenotypic detection of ampicillin C-type (AmpC) β-lactamases, efflux pump overexpression and carbapenemase production was also performed. P. aeruginosa represented n = 575 (2.72% ± 0.64%) from outpatient, and n = 1045 (5.43% ± 0.81%) from inpatient urinary samples, respectively. Based on the disk diffusion test, n = 359 (22.16%) were carbapenem-resistant; in addition to carbapenems, n = (64.34%) were also resistant to ciprofloxacin; n = (60.17%) to gentamicin/tobramycin; n = (58.51%) to levofloxacin; and n = (27.57%) to amikacin. From among the carbapenem-resistant isolates, n = 56 (15.59%) isolates were multidrug-resistant, while n = 16 (4.46%) were extensively drug-resistant. From among the Car-R/Ceph-S isolates (n = 57), overexpression of AmpC was observed in n = 7 cases (12.28%); carbapenemase production in n = 4 (7.02%); while overexpression of efflux pumps was present in n = 31 (54.39%) isolates. To spare last-resort agents, e.g., colistin, the use of broad-spectrum cephalosporins or safe, alternative agents should be considered in these infections. Full article
Concept Paper
Multiple Drug Resistance Patterns in Various Phylogenetic Groups of Hospital-Acquired Uropathogenic E. coli Isolated from Cancer Patients
Antibiotics 2020, 9(3), 108; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9030108 - 02 Mar 2020
Cited by 5 | Viewed by 1458
Abstract
Cancer patients are more susceptible to several bacterial infections, particularly urinary tract infections caused by uropathogenic E. coli (UPEC). The objective of this work was detection and the phylogenetic characterization of hospital-acquired isolates of uropathogenic E. coli in cancer patients and the determination [...] Read more.
Cancer patients are more susceptible to several bacterial infections, particularly urinary tract infections caused by uropathogenic E. coli (UPEC). The objective of this work was detection and the phylogenetic characterization of hospital-acquired isolates of uropathogenic E. coli in cancer patients and the determination of its relation with antibiotic resistance. A total of 110 uropathogenic E. coli responsible for hospital-acquired urinary tract infections in cancer patients were included in this study. A triplex PCR was employed to segregate different isolates into four different phylogenetic groups (A, B1, B2 and D). Drug resistance was evaluated by the disc diffusion method. All of the isolates were multiple drug-resistant (MDR) and 38.18% of all UPEC isolates were extended-spectrum beta-lactamase (ESBL) producers from which 52% were positive for the blaCTX-M gene, 40% for the blaTEM gene, and 17% for the blaSHVgene. Among 42 ESBL-producing uropathogenic E. coli isolates, the majority belonged to phylogenetic group B2 (43%), followed by group D (36%), group A (19%) and group B1 (2%). Our results have shown the emergence of MDR isolates among uropathogenic E. coli with the dominance of phylogenetic group B2. Groups A and B1 were relatively less common. The most effective drug in all phylogenetic groups was imipenem. Full article
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Brief Report
Reduced Incidence of Carbapenem-Resistant Klebsiella pneumoniae Infections in Cardiac Surgery Patients after Implementation of an Antimicrobial Stewardship Project
Antibiotics 2019, 8(3), 132; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics8030132 - 28 Aug 2019
Cited by 5 | Viewed by 2273
Abstract
Infections due to carbapenem-resistant Klebsiella pneumoniae (CR-Kp) are associated with increased mortality in cardiac surgery patients. In this short communication, we report on the changes in the incidence of CR-Kp colonization and CR-Kp infection in cardiac surgery patients from 2014 to 2018 in [...] Read more.
Infections due to carbapenem-resistant Klebsiella pneumoniae (CR-Kp) are associated with increased mortality in cardiac surgery patients. In this short communication, we report on the changes in the incidence of CR-Kp colonization and CR-Kp infection in cardiac surgery patients from 2014 to 2018 in a teaching hospital in Italy, after the implementation of an antimicrobial stewardship project in 2014. During the study period, 2261 patients underwent open-heart surgery. Of them, 130 were found to be colonized by CR-Kp (5.7%) and 52 developed a postoperative CR-Kp infection (2.3%). The crude in-hospital mortality in patients with CR-Kp infections was 48% (25/52). The incidences of both CR-Kp colonization (incidence rate ratio (IRR) 0.82, 95% confidence intervals (CI) 0.78–0.86, p < 0.001) and CR-Kp infection (IRR 0.76, 95% CI 0.69–0.83, p < 0.001) considerably decreased over the study period. This encouraging result should prompt further concerted efforts, directed towards retaining the positive impact of stewardship and infection-control interventions on CR-Kp-related morbidity in the long term. Full article
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Case Report
Use of Ceftolozane/Tazobactam for the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Pneumonia in a Pediatric Patient with Combined Immunodeficiency (CID): A Case Report from a Tertiary Hospital in Saudi Arabia
Antibiotics 2019, 8(2), 67; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics8020067 - 27 May 2019
Cited by 5 | Viewed by 1693
Abstract
Infections, with multidrug-resistant Pseudomonas aeruginosa, are a major concern in the pediatric intensive care unit, especially in immunocompromised patients. Some of these strains are resistant to all beta-lactams, including carbapenems, leaving very limited treatment options remaining. These options include aminoglycosides and colistin, [...] Read more.
Infections, with multidrug-resistant Pseudomonas aeruginosa, are a major concern in the pediatric intensive care unit, especially in immunocompromised patients. Some of these strains are resistant to all beta-lactams, including carbapenems, leaving very limited treatment options remaining. These options include aminoglycosides and colistin, both of which have poor pharmacokinetic profiles with significant toxicities. Newer beta-lactam/beta-lactamase inhibitor combinations offer additional novel options to treat such infections, given their good pharmacokinetic profiles and activity against multi-drug resistant strains. Ceftolozane/tazobactam is a novel cephalosporin/beta-lactamase inhibitor combination approved in 2014. The drug demonstrates good activity against multidrug-resistant P. aeruginosa strains, including those resistant to all other antibiotics. Ceftolozane/tazobactam is currently approved in adult patients 18 years and older only. There are very limited data on its pharmacokinetic profile and clinical utility in the pediatric population. We report the use of ceftolozane/tazobactam to successfully treat pneumonia caused by multidrug-resistant P. aeruginosa in a pediatric patient with combined immunodeficiency syndrome. Full article
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