Hubungan Riwayat Terapi Antibiotik Cephalosporin dengan Infeksi Enterobacteriaceae Penghasil AmpC Beta-Laktamase

Stefani Anindita Paramitasanti Pramana Gentur Sutapa, Prof. Dr. dr. Osman Sianipar, DMM., M.Sc., Sp.PK, Subsp. P.I.(K), Subsp. Onk.(K); Dr. dr. Teguh Triyono, M.Kes., Sp.PK, Subsp. B.D.K.T.(K), Subsp. K.V.(K)

2025 | Tesis-Spesialis | S2 Ilmu Patologi Klinik

Latar belakang: Prevalensi infeksi Enterobacteriaceae penghasil AmpC Beta-laktamase dilaporkan beragam 10-30% memiliki makna klinis yaitu kegagalan terapi antimikroba. Tingkat resistensi Enterobacteriaceae penghasil AmpC Beta-laktamase terhadap antibiotik beta laktam, khususnya cephalosporin generasi ketiga dilaporkan mencapai 60-80%. Identifikasi faktor risiko penyebab munculnya infeksi Enterobacteriaceae penghasil AmpC Beta-laktamase dapat membantu mencegah penyebaran infeksi atau resistensi. Beberapa penelitian menyebutkan riwayat terapi antibiotik cephalosporin dalam waktu 1-3 bulan dapat menjadi faktor risiko munculnya AmpC Beta-laktamase. Penelitian tentang hubungan riwayat terapi antibiotik cephalosporin dengan kejadian AmpC Beta-laktamase di Indonesia masih terbatas.

Tujuan: Mengevaluasi riwayat terapi cephalosporin sebagai faktor risiko infeksi Enterobacteriaceae penghasil AmpC Beta-laktamase.

Metode: Penelitian ini merupakan unmatched case-control yang dilakukan di RSUP Dr. Sardjito Yogyakarta. Kelompok kasus adalah pasien rawat inap di RSUP Dr. Sardjito dengan infeksi Enterobacteriaceae (Escherichia coli, Klebsiella pneumoniae, dan Proteus mirabilis) penghasil AmpC Beta-laktamase, sementara kelompok kontrol adalah infeksi oleh isolat yang sama tetapi tidak menghasilkan AmpC ?-laktamase. Identifikasi Enterobacteriaceae menggunakan Vitek 2, dan produksi AmpC Beta-laktamase menggunakan uji inhibisi Phenyl boronic acid (PBA). Kelompok kasus dan kontrol kemudian ditelusuri faktor risiko masing-masing terhadap penggunaan terapi cephalosporin dalam 90 hari sebelumnya. Uji beda median dan proporsi antar kelompok kasus dan kontrol dengan uji Mann Whitney, uji Chi Square dan Fisher Exact test. Hubungan faktor risiko dianalisis menggunakan uji bivariat dan multivariat (regresi logistik). Uji stastistik menggunakan perangkat lunak SPSS v.27 dengan batas kemaknaan p<0>

Hasil: Analisis dilakukan terhadap 72 pasien infeksi Enterobacteriaceae, 36 subjek masing-masing kelompok kasus dan kontrol. Tidak ada perbedaan usia, jenis kelamin, komorbid, tempat perawatan, dan alat intervensi medis yang digunakan antar kedua kelompok. Riwayat terapi cephalosporin dalam 90 hari terakhir berhubungan signifikan dengan infeksi Enterobacteriaceae penghasil AmpC Beta-laktamase (OR = 5,80; IK 95%: 2,01–16,72; p = 0,001). Setelah penyesuaian, riwayat terapi cephalosporin dalam 90 hari terakhir tetap menjadi faktor risiko signifikan (aOR = 5,58; IK 95%: 1,81–17,19; p = 0,003). Analisis lanjutan pada jenis cephalosporin didapatkan peningkatan risiko pada riwayat terapi ceftriaxone OR=6,40 (IK95%: 1,87-21,89, p=0,002) dan cefixime OR 1,77 (IK 95%:0,52-6,05, p=0,358).

Simpulan: Pasien dengan riwayat terapi antibiotik cephalosporin dalam 3 bulan sebelumnya memiliki risiko terinfeksi Enterobacteriaceae penghasil AmpC Beta-laktamase sebesar 5,58 kali dibanding yang tidak memiliki riwayat terapi cephalosporin. Riwayat terapi cephalosporin generasi ketiga, khususnya ceftriaxone memberikan peluang risiko infeksi Enterobacteriaceae penghasil AmpC Beta-laktamase sebesar 6,40 kali.

Background: The prevalence of AmpC Beta-lactamase-producing Enterobacteriaceae infections has been reported to vary between 10-30% and has clinical significance in terms of antimicrobial therapy failure. The level of resistance of AmpC Beta-lactamase-producing Enterobacteriaceae to beta-lactam antibiotics, particularly third-generation cephalosporins, has been reported to reach 60-80%. Identifying risk factors for the emergence of AmpC Beta-lactamase-producing Enterobacteriaceae infections can help prevent the spread of infection or resistance. Several studies have mentioned that a history of cephalosporin antibiotic therapy within 1-3 months can be a risk factor for the emergence of AmpC Beta-lactamase. Research on the relationship between a history of cephalosporin antibiotic therapy and the occurrence of AmpC Beta-lactamase in Indonesia is still limited.

Objective: To evaluate the history of cephalosporin therapy as a risk factor for infection with AmpC Beta-lactamase-producing Enterobacteriaceae.

Methods: An unmatched case-control study conducted at Dr Sardjito General Hospital in Yogyakarta. The case group consisted of inpatients at Dr Sardjito General Hospital with Enterobacteriaceae infections (Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis) producing AmpC Beta-lactamase, while the control group consisted of patients who did not produce AmpC Beta-lactamase. Enterobacteriaceae were identified using Vitek 2, and AmpC Beta-lactamase production was determined using the phenyl boronic acid (PBA) inhibition test. The case and control groups were then traced for risk factors associated with cephalosporin therapy use in the previous 90 days. The difference in median and proportions between the case and control groups was tested using the Mann Whitney test, Chi Square test, and Fisher Exact test. The relationship between risk factors was analysed using bivariate and multivariate tests (logistic regression). Statistical tests were performed using SPSS v.27 software with a significance level of p<0>

Result: The analysis was conducted on 72 patients with Enterobacteriaceae infections, 36 subjects in each case and control group. There were no differences in age, gender, comorbidities, place of care, and medical intervention tools used between the two groups. A history of cephalosporin therapy within the last 90 days was significantly associated with infection of AmpC Beta-lactamase-producing Enterobacteriaceae (OR = 5,80; 95% CI: 2.01–16.72; p = 0.001). After adjustment, a history of cephalosporin therapy within the last 90 days remained a significant risk factor (aOR = 5.58; 95% CI: 1.81–17.19; p = 0.003). Further analysis of cephalosporin types revealed an increased risk in the history of ceftriaxone therapy OR=6.40 (95% CI: 1.87–21.89, p=0.002) and cefixime OR 1.77 (95% CI: 0.52–6.05, p=0.358).

Conclusion: Patients with a history of cephalosporin antibiotic therapy within the previous 3 months had a 5.58 times higher risk of infection with AmpC Beta-lactamase-producing Enterobacteriaceae compared to those without a history of cephalosporin therapy. A history of third-generation cephalosporin therapy, particularly ceftriaxone, increases the risk of infection with AmpC Beta-lactamase-producing Enterobacteriaceae by 6.40 times.

Kata Kunci : Enterobacteriaceae, AmpC Beta-laktamase, riwayat terapi cephalosporin, faktor risiko