In vitro selection of Neisseria gonorrhoeae unveils novel mutations associated with extended-spectrum cephalosporin resistance.

The emergence of Neisseria gonorrhoeae strains resistant to extended-spectrum cephalosporins (ESCs) is a worldwide concern because this class of antibiotics represents the last empirical treatment option for gonorrhea. The abusive use of antimicrobials may be an essential factor for the emergence of ESC resistance in N. gonorrhoeae. Cephalosporin resistance mechanisms have not been fully clarified. In this study, we mapped mutations in the genome of N. gonorrhoeae isolates after resistance induction with cefixime and explored related metabolic pathways. Six clinical isolates with different antimicrobial susceptibility profiles and genotypes and two gonococcal reference strains (WHO F and WHO Y) were induced with increasing concentrations of cefixime. Antimicrobial susceptibility testing was performed against six antimicrobial agents before and after induction. Clinical isolates were whole-genome sequenced before and after induction, whereas reference strains were sequenced after induction only. Cefixime resistance induction was completed after 138 subcultures. Several metabolic pathways were affected by resistance induction. Five isolates showed SNPs in PBP2. The isolates M111 and M128 (ST1407 with mosaic penA-34.001) acquired one and four novel missense mutations in PBP2, respectively. These isolates exhibited the highest minimum inhibitory concentration (MIC) for cefixime among all clinical isolates. Mutations in genes contributing to ESC resistance and in other genes were also observed. Interestingly, M107 and M110 (ST338) showed no mutations in key determinants of ESC resistance despite having a 127-fold increase in the MIC of cefixime. These findings point to the existence of different mechanisms of acquisition of ESC resistance induced by cefixime exposure. Furthermore, the results reinforce the importance of the gonococcal antimicrobial resistance surveillance program in Brazil, given the changes in treatment protocols made in 2017 and the nationwide prevalence of sequence types that can develop resistance to ESC.

Phase II trial evaluating the clinical efficacy of cefixime for treatment of active syphilis in non-pregnant women in Brazil (CeBra).

BACKGROUND: Syphilis is a sexually and vertically transmitted infection caused by the bacteria Treponema pallidum for which there are few proven alternatives to penicillin for treatment. For pregnant women infected with syphilis, penicillin is the only WHO-recommended treatment that will treat the mother and cross the placenta to treat the unborn infant and prevent congenital syphilis. Recent shortages, national level stockouts as well as other barriers to penicillin use call for the urgent identification of alternative therapies to treat pregnant women infected with syphilis. METHODS: This prospective, randomized, non-comparative trial will enroll non-pregnant women aged 18 years and older with active syphilis, defined as a positive rapid treponemal and a positive non-treponemal RPR test with titer ≥1:16. Women will be a, domized in a 2:1 ratio to receive the oral third generation cephalosporin cefixime at a dose of 400 mg two times per day for 10 days (n = 140) or benzathine penicillin G 2.4 million units intramuscularly based on the stage of syphilis infection (n = 70). RPR titers will be collected at enrolment, and at three, six, and nine months following treatment. Participants experiencing a 4-fold (2 titer) decline by 6 months will be considered as having an adequate or curative treatment response. DISCUSSION: Demonstration of efficacy of cefixime in the treatment of active syphilis in this Phase 2 trial among non-pregnant women will inform a proposed randomized controlled trial to evaluate cefixime as an alternative treatment for pregnant women with active syphilis to evaluate prevention of congenital syphilis. TRIAL REGISTRATION: Trial identifier: www.Clinicaltrials.gov, NCT03752112. Registration Date: November 22, 2018.

Resistência de Neisseria gonorrhoeae a antimicrobianos na prática clínica: como está o Brasil? / Antimicrobials resistance of Neisseria gonorrhoeae in clinical practice: where Brazil stands?

Estima-se que um milhão de infecções sexualmente transmissíveis (IST) sejam adquiridas por dia no mundo, segundo a Organização Mundial da Saúde. Elas podem ser causadas por diversos micro-organismos pelo contato sexual. Embora tratáveis, as infecções, como a clamidiana, sífilis, tricomoníase e gonorreia, são responsáveis por 350 milhões de novos casos de IST anualmente no mundo. A gonorreia é a segunda IST bacteriana mais prevalente no planeta e tem chamado atenção nos últimos anos em decorrência da baixa eficácia em seu tratamento. O agente etiológico é a Neisseria gonorrhoeae. Na maioria das mulheres, a infecção por esse micro-organismo é assintomática, dificultando ainda mais seu diagnóstico e tratamento e, portanto, aumentando o risco de desenvolvimento de suas complicações associadas. Mesmo quando diagnosticada, essa infecção está sujeita a um alto índice de insucesso terapêutico que se deve, principalmente, à grande plasticidade genética da N. gonorrhoeae para aquisição de genes cromossômicos ou plasmidiais de resistência. O aumento da resistência desse micro-organismo a antimicrobianos comumente utilizados no tratamento, como penicilina, tetraciclina e ciprofloxacina, tem sido relatado em diversos países. No Brasil, poucos estudos estão disponíveis, mas em alguns estados já foram relatadas linhagens resistentes à ciprofloxacina. Dessa forma, deve-se ressaltar a importância de novos estudos que visem descrever o perfil da resistência da N. gonorrhoeae a antimicrobianos. Tais achados certamente nortearão a implementação de sistemas de vigilância epidemiológica no país visto que, até o momento, as infecções por N. gonorrhoeae sequer estão incluídas na lista nacional de doenças e agravos de notificação compulsória.(AU)

According to the World Health Organization, approximately one million sexually transmitted infections (STI) are acquired daily in the world. These infections can be caused by several microorganisms via contact. The treatable STI, such as chlamydia, syphilis, trichomoniasis and gonorrhea, account for 350 million new cases of STI each year worldwide. Gonorrhoea is caused by Neisseria gonorrhoeae and is the second most common bacterial STI in the world. It has drawn more attention in the last years due to the low efficacy in its treatment. Most women with this infection are asymptomatic, which makes its diagnosis and treatment troublesome increasing the risk for its associated complications. Even when diagnosed, this infection is subject to a high rate of therapeutic failure mainly due to the great genetic plasticity of N. gonorrhoeae for the acquisition of chromosomal or resistance plasmid enes. Increased resistance of this microorganism to antimicrobials commonly used in treatment such as penicillin, tetracycline and ciprofloxacin has been reported in several countries. In Brazil, few studies are available, but in some states strains resistant to ciprofloxacin were alreadyreported. The refore, it is important to highlight the importance of new studies aimed at describing the resistance profile of N. gonorrhoeae to antimicrobials in Brazil context. These findings will certainly guide the implementation of epidemiological surveillance systems in the country, since until now N. gonorrhoeae infections do not figure into the national list of compulsorily notifiable diseases.(AU)

Oral administration of cefixime to lower risk febrile neutropenic children with cancer.

BACKGROUND: Febrile neutropenia is a heterogeneous condition. Recently, several risk factors have been defined, permitting the definition of a lower risk group of patients who may benefit form less aggressive therapy. The use of an oral antibiotic approach was tested in the current trial. METHODS: From May 1997 to March 1998, 154 episodes of lower risk febrile neutropenia in 128 children with a mean age of 62 (range, 8-200) months were enrolled in this randomized, single-institution trial. Inclusion criteria were fever (> 38 degrees C), neutropenia (absolute neutrophil count < 500/mm(3)), lower risk features (i.e., absence of severe comorbidity factors, good clinical condition, negative blood cultures, control of local infection, no fever during the last 24 hours), and compliance of parents. After 3 days of ceftriaxone (100 mg/kg/day administered intravenously [i.v.]) every 12 hours plus amikacin (15 mg/kg/day i.v.) every 24 hours for 3 days, all patients were discharged and randomized to be allocated to 2 treatment arms. Group A (n = 74) received ceftriaxone cefixime (8 mg/kg/day administered orally) every 24 hours for 4 days, whereas Group B (n = 80) was treated with ceftriaxone plus amikacin for 7 days. Failure was defined as the need for second hospitalization during the same episode of neutropenia, or fever during the 7 days after discharge. RESULTS: Most of the patients (49% in Group A and 55% in Group B) had acute leukemia. Fifty-four (72%) children in Group A and 46 (56%) in Group B had fever of unknown origin (P = not significant [NS]). No significant differences were found in the sites of initial infection between the two groups. Overall results were outstanding, with a favorable outcome in 73 of 78 cases (98.6%) in Group A and 78 of 80 cases (97.5%) in Group B (P = NS). Three patients needed a second hospitalization due to failure of the initial therapy: one in Group A and two in Group B. All three did well with secondary treatment. CONCLUSIONS: In lower risk febrile neutropenic children receiving anticancer therapy, the efficacy of oral cefixime, given for 4 days after 72 hours of intravenous ceftriaxone plus amikacin, was similar to that of 7 days of parenteral ceftriaxone plus amikacin. The oral outpatient therapy approach to the treatment of lower risk febrile neutropenia after chemotherapy is safe and may be cost-saving. This strategy might be adopted as standard therapy in the future.