We report a case of resistance development toward cefiderocol in a patient with intra-abdominal and bloodstream infections caused by carbapenemase-producing Enterobacter cloacae within 21 days of cefiderocol therapy. Whole genome sequencing revealed heterogeneous mutations in the cirA gene, encoding a catecholate siderophore receptor, conferring phenotypic resistance to cefiderocol.

Objectives Co-trimoxazole (trimethoprim/sulfamethoxazole) is clinically valuable in treating skin and soft tissue infections (SSTIs) caused by community-associated methicillin-resistant Staphylococcus aureus (MRSA). The genetic basis of emerging trimethoprim/sulfamethoxazole resistance in S. aureus from Africa is unknown. Such knowledge is essential to anticipate its further spread. We investigated the molecular epidemiology of trimethoprim resistance in S. aureus collected in and imported from Africa. Methods Five hundred and ninety-eight human S. aureus isolates collected at five locations across sub-Saharan Africa [Gabon, Namibia, Nigeria (two) and Tanzania] and 47 isolates from travellers treated at six clinics in Europe because of SSTIs on return from Africa were tested for susceptibility to trimethoprim, sulfamethoxazole and trimethoprim/sulfamethoxazole, screened for genes mediating trimethoprim resistance in staphylococci [dfrA (dfrS1), dfrB, dfrG and dfrK] and assigned to spa genotypes and clonal complexes. Results In 313 clinical and 285 colonizing S. aureus from Africa, 54% of isolates were resistant to trimethoprim, 21% to sulfamethoxazole and 19% to trimethoprim/sulfamethoxazole. We found that 94% of trimethoprim resistance was mediated by the dfrG gene. Of the 47 S. aureus isolates from travellers with SSTIs, 27 (57%) were trimethoprim resistant and carried dfrG. Markers of trimethoprim resistance other than dfrG were rare. The presence of dfrG genes in S. aureus was neither geographically nor clonally restricted. Conclusions dfrG, previously perceived to be an uncommon cause of trimethoprim resistance in human S. aureus, is widespread in Africa and abundant in imported S. aureus from ill returning travellers. These findings may foreshadow the loss of trimethoprim/sulfamethoxazole for the empirical treatment of SSTIs caused by community-associated MRSA.

Cefiderocol is a promising novel siderophore cephalosporin for the treatment of multidrug-resistant Gram-negative bacilli and with stability against degradation by metallo-β-lactamases. Nonetheless, the emergence of cefiderocol in metallo-β-lactamase-producing Enterobacterales during therapy has been reported on more than one occasion.

Background. Antibiotic-resistant Staphylococcus aureus is a globally emerging pathogen. Exchangeable virulence factors, such as Panton-Valentine leukocidin (PVL), have been proposed to drive this epidemic. We investigated whether skin infections and nasal colonization in travelers contribute to the global spread of such strains. Methods. We conducted a case-control study of 38 returnees from the tropics and subtropics with S. aureus–positive skin and soft tissue infections (SSTIs) and 124 control patients with other travel-associated disorders. We collected information on travel characteristics, clinical outcomes of SSTIs, antibiotic sensitivity patterns, and genotypes of S. aureus strains isolated from skin lesions and the nares. Results. S. aureus–positive SSTIs were associated with travel duration and purpose and were most common in returnees from Africa (odds ratio, 4.2; P = .005). PVL-positive (PVL⁺) S. aureus was frequent in the lesional and nasal isolates from travelers with SSTIs but could not be found in the nares of the control patients. The presence of PVL in S. aureus in travelers was associated with complicated disease, reduced antibiotic susceptibility, and secondary spread. The genotypes of PVL⁺S. aureus in returnees were reported to be endemic to the visited destination but rarely observed in Europe. Conclusions. Geographic variation in the risk of SSTIs in travelers supports a globally heterogeneous distribution of virulent S. aureus. Complicated SSTIs in returnees from nontemperate climates are associated with PVL⁺S. aureus and promote the emergence and spread of virulent and antibiotic-resistant strains. We propose a network for the surveillance of imported S. aureus (www.staphtrav.eu).

Background. Genetically determined variation in the expression of innate defense molecules may explain differences in the propensity to be colonized with Staphylococcus aureus. Methods. We determined S. aureus nasal carriage in 603 volunteers; analyzed polymorphisms in the DEFB1 promoter at positions −52 G>A (rs1799946), −44 C>G (rs1800972), and −20 G>A (rs11362); and measured the content of human β-defensin 1 (hBD-1) and hBD-3 messenger RNA (mRNA) in 192 samples of healthy and experimentally wounded human skin. Results. Compared with GGG at the positions −52/−44/−20, the ACG haplotype was more common among persistent S. aureus nasal carriers (odds ratio, 1.93; 95% confidence interval [CI], 1.2–3.1; P = .006) and was associated with reduced expression of hBD-1 (GGG>ACG>GCA; P < .001) and hBD-3 (GGG>GCA>ACG; P = .04) in skin when measured 72 hours after wounding. Furthermore, a 50% decrease in hBD-1 and hBD-3 mRNA expression in wounded skin increased the odds of persistent carriage by 1.45 (95% CI, .93–2.26; P = .1) and 1.48 (95% CI, 1.01–2.17; P = .04), respectively. Adjustment for known risk factors of persistent S. aureus carriage did not substantially change the associations of both DEFB1 haplotypes and β-defensin expression with S. aureus colonization. Conclusions. DEFB1 polymorphisms may promote persistent S. aureus colonization by altering β-defensin expression in keratinocytes of human skin.