Stenotrophomonas maltophilia is increasingly emerging as an opportunistic pathogen of global concern. Trimethoprim-sulphamethoxazole (TMP-SMX) is the generally accepted antibiotic of choice for the treatment of infections caused by this organism, but resistance to the drug is increasingly being reported; hence, the need for alternative therapeutic options. In this study, the antimicrobial susceptibility profile of 110 commensal S. maltophilia isolates obtained from Nkonkobe municipality, Eastern Cape Province, Republic of South Africa was investigated. Twenty-one antibiotics including TMP-SMX and the fluoroquinolones; levofloxacin, gatifloxacin and moxifloxacin were included in the antibiotic panel. About 63.4% of the isolates were susceptible to TMP-SMX with a resistance rate of 28.2%. The fluoroquinolones were more effective with susceptibilities ranging from 76% to 94.7%. Levofloxacin was the most effective fluoroquinolone tested. Phenotypic dectection of extended spectrum b-lactamases (ESBLs) showed double disc synergy test (DDST) positivity in 59.5% of the isolates. Isolates exhibited nine different ESBL phenotypes, however, PCR amplification of the bla genes revealed four isolates that possessed genes belonging to the blaCTX-M group (blaCTX-M-1 and blaCTX-M-8 groups). ESBL positive isolates appeared more susceptible to the fluoroquinolones compared to TMP-SMX. The fluoroquinolones are a possible alternative treatment option for S. maltophilia infections in this environment.