Health authorities in Pakistan are responding to an ongoing outbreak of dengue fever. This outbreak was first reported on 8 July 2019 by the Khyber Teaching Hospital in Peshawar, Khyber Pakhtunkhwa (KP) province. Since then, three other provinces (Punjab, Balochistan, and Sindh), as well as Islamabad Capital Territory (ICT), and Azad Jammu and Kashmir (AJK; one of the two autonomous territories) have also reported cases of dengue fever.

From 8 July to 12 November 2019, a total of 47,120 confirmed cases of dengue fever, including 75 deaths, were reported from the four provinces (KP, Punjab, Balochistan, and Sindh), Islamabad, and AJK.

On 10 October 2019, the National IHR Focal Point for Sudan notified WHO of 47 suspected cases of Rift Valley Fever (RVF), including two deaths in Arb’aat Area, Towashan Village, in El Qaneb locality, Red Sea State. The suspected cases presented with high-grade fever, headaches, joint pain, vomiting. There were no hemorrhagic signs or symptoms observed. The first case presented to the health facility on 19 September 2019.

On 28 September 2019, a total of 14 samples were sent to the National Public Health Laboratory in Khartoum, and 5 tested positive for RVF by Immunoglobulin M (IgM) enzyme-linked immunosorbent assay (ELISA) and reverse-transcriptase polymerase chain reaction (RT-PCR). These samples were also tested for malaria and were found negative.

Six new confirmed cases were reported in the past week (6 to 12 November) in the ongoing Ebola virus disease (EVD) outbreak in North Kivu and Ituri provinces.

Abstract

Carbapenem-resistant gram-negative bacteria including Enterobacteriaceae as well as nonfermenters, such as Pseudomonas aeruginosa and Acinetobacter baumannii, have emerged as significant global clinical threats. Although new agents have recently been approved, none are active across the entire range of resistance mechanisms presented by carbapenem-resistant gram-negative bacteria. Cefiderocol, a novel siderophore cephalosporin, has been shown in large surveillance programs and independent in vitro studies to be highly active against all key gram-negative causative pathogens isolated from patients with hospital-acquired or ventilator-associated pneumonia, bloodstream infections, or complicated urinary tract infections. The improved structure, the novel mode of entry into bacteria, and its stability against carbapenemases enables cefiderocol to exhibit high potency against isolates that produce carbapenemases of all classes or are resistant due to porin channel mutations and/or efflux pump overexpression. Resistance to cefiderocol is uncommon and appears to be multifactorial.

Abstract

Historically, the regulatory requirements of the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for developing new antibiotics have not addressed pathogen-focused indications for drug approval. The design of the necessary randomized controlled trials traditionally involves the enrollment of patients with site-specific infections caused by susceptible as well as resistant pathogens. Cefiderocol has undergone a streamlined clinical development program to address serious carbapenem-resistant infections. The regulatory approach, and the pivotal clinical trials, differed between the FDA and EMA. In the United States, the APEKS-cUTI (Acinetobacter, Pseudomonas, Escherichia coli, Klebsiella, Stenotrophomonas–complicated urinary tract infection) study was conducted to provide the basis for FDA approval of a site-specific cUTI indication. The EMA, however, preferred the CREDIBLE-CR (A MultiCenter, RandomizED, Open-label ClInical Study of S-649266 or Best AvailabLE Therapy for the Treatment of Severe Infections Caused by Carbapenem-Resistant Gram-negative Pathogens) study, in which patients with nosocomial pneumonia, bloodstream infections, or cUTIs were enrolled if they had a carbapenem-resistant pathogen. The resulting European label will be pathogen focused rather than infection site specific (ie, treatment of gram-negative infection in patients with limited treatment options). The implications and limitations of these different regulatory processes are discussed.

Abstract

The emergence of antimicrobial resistance is a significant public health issue worldwide, particularly for healthcare-associated infections caused by carbapenem-resistant gram-negative pathogens. Cefiderocol is a novel siderophore cephalosporin targeting gram-negative bacteria, including strains with carbapenem resistance. The structural characteristics of cefiderocol show similarity to both ceftazidime and cefepime, which enable cefiderocol to withstand hydrolysis by β-lactamases. The unique chemical component is the addition of a catechol moiety on the C-3 side chain, which chelates iron and mimics naturally occurring siderophore molecules. Following the chelation of iron, cefiderocol is actively transported across the outer membrane of the bacterial cell to the periplasmic space via specialized iron transporter channels. Furthermore, cefiderocol has demonstrated structural stability against hydrolysis by both serine- and metallo-β-lactamases, including clinically relevant carbapenemases such as Klebsiella pneumoniae carbapenemase, oxacillin carbapenemase-48, and New Delhi metallo-β-lactamase. Cefiderocol has demonstrated promising in vitro antibacterial and bactericidal activity, which correlates with its in vivo efficacy in several animal models. This article reviews the discovery and chemistry of cefiderocol, as well as some of the key microbiological and in vivo findings on cefiderocol from recently conducted investigations.