!

BAB!1!
PENDAHULUAN!
!
1.1! Latar!Belakang!
Sepsis&&pada&neonatus&atau&septikemia&adalah&sindroma&klinis&yang&
terjadi& dalam& bulan& pertama& kehidupan,& ditandai& dengan& gejala& sistemik&
pada& sistem& peredaran& darah& yang& disebabkan& oleh& invasi& aliran& darah&
oleh& bakteri.1& Sepsis& merupakan& penyebab& tersering& dari& kematian&
neonatus.2& Infeksi& nosokomial& pada& bayi& berat& lahir& sangat& rendah,&
merupakan&penyebab&utama&tingginya&kematian&pada&umur&setelah&5&hari&
kehidupan.&Mortalitas&sepsis&sebagian&besar&dapat&dicegah&dengan&terapi&
anti&mikroba&yang&rasional&dengan&perawatan&suportif&yang&agresif.2&&
Angka& kejadian& sepsis& pada& neonatus& adalah& 1B10& per& 1000&
kelahiran&hidup&dan&mencapai&13B27&per&1000&kelahiran&hidup&pada&bayi&
dengan& berat& <1500& gram.& Insiden& sepsis& di& negara& berkembang& cukup&
tinggi,& menurut& perkiraan& World& Health& Organization& (WHO),& terdapat& 5&
juta&kematian&neonatus&setiap&tahun&dengan&angka&mortalitas&34&per&1000&
kelahiran& hidup& dan& 98%& kematian& tersebut& berasal& dari& negara&
berkembang.3& Data& di& RSUD& dr.& Soetomo& Surabaya& pada& tahun& 2014&
sebanyak& 442& dari& 1855& kelahiran,& sedangkan& untuk& kematian& neonatus&
akibat&infeksi&tahun&2014&sebanyak&61&pasien&dari&184&kematian.4&
Resistensi&terhadap&banyak&jenis&antibiotik&menjadi&masalah&penting&
di&NICU,&diperlukan&evaluasi&penggunaan&antibiotik&pada&infeksi&neonatus&
yang& berat.& Sebagian& besar& bakteri& penyebab& sepsis& pada& neonatus&
sudah&resisten&terhadap&antibiotik&yang&umum&digunakan&seperti&amikasin&
(17.4%)& hingga& ampisilin& (77.7%).& Sedangkan& pada& quinolon& dan&
imipenem&memiliki&resistensi&yang&relatif&rendah.5&
Quinolon& tidak& direkomendasikan& penggunaannya& pada& anak&
dibawah&4&tahun,&akan&tetapi&dapat&diindikasikan&jika&kultur&darah&sensitif,&
sepsis& berat,& dan& jika& suatu& mikroorganisme& tidak& sensitif& terhadap&
antibiotik& lainnya.6& Di& Indonesia,& penggunaan& quinolon& pada& sepsis&
neonatal&yang&berat&masih&terbatas&dan&diperlukan&penelitian&lebih&lanjut.&&

! 1!
&
1.2!!Tujuan!
Tujuan&dari&tinjauan&kepustakaan&ini&adalah&untuk&mempelajari&
keamanan&penggunaan&quinolon&pada&neonatus&

! 2!
&
BAB!2!
SEPSIS!PADA!NEONATUS!
!
2.1!! Sepsis!!pada!neonatus!
Sepsis& pada& neonatus& adalah& penyebab& utama& morbiditas& dan&
mortalitas& pada& NICU.& Dalam& sepuluh& tahun& terakhir& terdapat& beberapa&
perkembangan& baru& mengenai& definisi& sepsis,& The$ International$ Sepsis$
Definition$ Conference$ mendefinisikan& sepsis& sebagai& sindrom& klinis&
dengan& adanya& Systemic$ Infammatory$ Response$ Syndrome$ (SIRS)& dan&
infeksi.& Sepsis& merupakan& suatu& proses& berkelanjutan& mulai& dari& infeksi,&
SIRS,& sepsis& berat,& renjatan& atau& syok& sepsis,& disfungsi& multiorgan,& dan&
akhirnya&kematian.7&
Berdasarkan& waktu& terjadinya,& sepsis& pada& neonatus& dapat&
diklasifikasikan& menjadi& dua& bentuk& yaitu& Early$ Onset$ Sepsis& (EOS)& dan&
Late$Onset$Sepsis$(LOS).&Mortalitas&sepsis&sebagian&besar&dapat&dicegah&
dengan&terapi&antimikroba&yang&rasional&dengan&perawatan&suportif&yang&
agresif.!7&
Bayi& baru& lahir& dengan& EOS& 85%& terjadi& dalam& waktu& 24& jam,& 5%&
pada&24B48&jam,&dan&sisanya&terjadi&dalam&waktu&48B72&jam.&EOS&terjadi&
pada& bayi& prematur.& EOS& dapat& berkaitan& dengan& mikroorganisme& yang&
didapat&dari&ibu.&Pada&keadaan&ini&kolonisasi&patogen&terjadi&pada&periode&
perinatal.& Beberapa& mikroorganisme& penyebab,& seperti& treponema,& virus,&
listeria& dan& candida,& ditransmisikan& ke& janin& melalui& plasenta& secara&
hematogenik.& Cara& lain& masuknya& mikroorganisme& dapat& melalui& proses&
persalinan.& Dengan& pecahnya& selaput& ketuban,& mikroorganisme& dalam&
flora& vagina& atau& bakteri& patogen& lainnnya& secara& asenden& dapat&
mencapai& cairan& amnion& dan& janin.& Hal& ini& memungkinkan& terjadinya&
korioamnionitis& atau& cairan& amnion& yang& telah& terinfeksi& teraspirasi& oleh&
janin&atau&neonatus,&yang&kemudian&berperan&sebagai&penyebab&kelainan&
pernapasan.& Adanya& vernix& atau& mekoneum& merusak& peran& alami&
bakteriostatik& cairan& amnion.& Akhirnya& bayi& dapat& terpapar& flora& vagina&

! 3!
waktu&melalui&jalan&lahir.&Kolonisasi&terutama&terjadi&pada&kulit,&nasofaring,&
orofaring,& konjungtiva,& dan& tali& pusat.& Trauma& pada& permukaan& ini&
mempercepat&proses&infeksi.&Penyakit&dini&ditandai&dengan&kejadian&yang&
mendadak& dan& berat,& yang& berkembang& dengan& cepat& menjadi& syok&
sepsis& dengan& angka& kematian& tinggi.& Insidens& syok& septik& 0,1B& 0,4%&
dengan& mortalitas& 15B45%& dan& morbiditas& kecacatan& saraf.& Umumnya&
terjadi& setelah& bayi& berumur& tujuh& hari& atau& lebih.& Mikroorganisme& yang&
paling&sering&dikaitkan&dengan&awitan&dini&sepsis&adalah&sebagai&berikut:&
Grup$ B$ Streptococcus& (GBS),& Escherichia$ coli,& Staphylococcus$
coagulase?negatif,&Haemophilus$influenzae,&Listeria$monocytogenes.!7&
LOS& terjadi& pada& 4B90& hari& kehidupan& dan& umumnya& diperoleh& dari&
lingkungan& sekitar.& Organisme& yang& terlibat& dalam& awitan& lambat& sepsis&
adalah& sebagai& berikut:& Staphylococcus$ coagulase?negatif,&
Staphylococcus$ aureus,$ E$ coli,$ Klebsiella,$ Pseudomonas,$ Enterobacter,$
Candida,& GBS,& Serratia,$ $Acinetobacter$ anaerob.& Disini& transmisi&
horisontal&memegang&peran.&Insiden&awitan&lambat&sepsis&sekitar&5B25%,&
sedangkan&mortalitas&10B20%&namun&pada&bayi&kurang&bulan&mempunyai&
risiko& lebih& mudah& terinfeksi,& disebabkan& penyakit& utama& dan& imunitas&
yang&imatur.!7&
Kecurigaan&sepsis&adalah&diagnosis&yang&paling&sering&ditegakkan&di&
NICU.& Bagaimanapun& tanda& sepsis& sering& tidak& spesifik& dan& tandaBtanda&
peradangan& non& infeksi& dapat& menyerupai& sepsis& pada& neonatus.&
Kebanyakan& bayi& dengan& kecurigaan& sepsis& pulih& dengan& atau& tanpa&
inisiasi& terapi& antimikrobial.& Tantangan& utama& klinisi& adalah& segera&
mengidentifikasi& neonatus& dengan& kecurigaan& EOS& dan& memulai& terapi&
antimikroba,& membedakan& bayi& yang& tampak& sehat& dengan& resiko& tinggi&
atau&bayi&dengan&tanda&klinis&ke&arah&sepsis&dengan&terapi&yang&tersedia.&
serta&stop&penggunaan&terapi&antimikroba&saat&tidak&terbukti&sepsis.!7&
&

! 4!
 &
Gambar&2.&1& Evaluasi& bayi& <37& minggu& asimptomatik& dengan& faktor& resiko& sepsis&
dilakukan&pada&bayi&dengan&faktor&resiko&berupa&korioamnitis&atau&ketuban&
&
pecah&dini&!&18&jam
Sumber&:&Polin&RA,&Papile&LBA,&Baley&JE,&et&al.&Management&of&neonates&with&suspected&
or&proven&earlyBonset&bacterial&sepsis.&Pediatrics.&2012c129(5)&
&
Evaluasi& bayi& <37& minggu& asimptomatik& dengan& factor& resiko& sepsis&
dilakukan& pada& bayi& dengan& factor& resiko& berupa& korioamnitis& atau&
ketuban&pecah&dini&!&18&jam&atau&diindikasikan&mendapat&terapi&antibiotik&
intrapartum& tapi& tidak& adekuat.& Tes& diagnostik& yang& dilakukan& adalah&
kultur&darah&pada&saat&lahir,&pemeriksaan&sel&darah&putih&atau&hitung&jenis&
dapat& juga& ditambahkan& pemeriksaan& CRP& pada& usia& 6B12& jam,&
manajemen&dengan&antibiotik&spektrum&luas&didasarkan&pada&hasil&kultur&
darah& dan& pemeriksaan& penunjang& lainnya.& Jika& kultur& darah& positif&
lanjutkan& pemberian& antibiotik& dan& lakukan& lumbal& pungsi.& Jika& kultur&
darah& negatif,& bayi& bugar,& namun& data& laboratorium& abnormal& pemberian&
antibiotik& dilanjutkan& jika& ibu& mendapat& antibiotik& selama& proses&

! 5!
persalinanc&jika&kultur&darah&negatif,&bayi&bugar,&data&laboratorium&normal&
maka&pemberian&antibiotik&dihentikan.!7&

&
Gambar&2.2&Evaluasi&bayi&≥37&minggu&asimptomatik&dengan&faktor&&resiko&sepsis&adalah&
&
pada&bayi&dengan&ibu&korioamnitis
Sumber& :& Polin& RA.& Management& of& Neonates& With& Suspected& or& Proven& EarlyBOnset&
Bacterial&Sepsis.&Pediatrics.&2012c129:1006–15.&
&
Evaluasi& bayi& ≥& 37& minggu& asimptomatik& dengan& faktor& resiko& sepsis&
adalah& pada& bayi& dengan& ibu& korioamnitis.& Tes& diagnostik& berupa& kultur&
darah& pada& saat& lahir,& hitung& jenis& dan& jumlah& sel& darah& putih& bisa&
ditambahkan& dengan& pemeriksaan& CRP& pada& usia& 6B12& jam.& Pemberian&
antibiotik& spektrum& luas& didasarkan& pada& kultur& darah& dan& data&
laboratorium.& Jika& kultur& darah& positif& lanjutkan& pemberian& antibiotik& dan&
lakukan& lumbal& pungsi,& jika& kultur& darah& negatif,& bayi& bugar,& namun& data&
laboratorium&abnormal&pemberian&antibiotik&dilanjutkan&jika&ibu&mendapat&
antibiotik& selama& proses& persalinan,& jika& kultur& darah& negatif,& bayi& bugar,&

! 6!
data& laboratorium& normal& maka& pemberian& antibiotik& dihentikan& dan& bayi&
boleh&dipulangkan&setelah&48&jam&observasi.!7&
&

&
Gambar& 2.3& Evaluasi& bayi& ≥& 37& minggu& asimptomatik& dengan& faktor& resiko&&&&&&&
&
sepsis&(tanpa&koriamnitis),&ketuban&pecah&dini&!&18&jam
Sumber&:& Polin& RA.& Management& of& Neonates& With& Suspected& or& Proven&
EarlyBOnset&Bacterial&Sepsis.&Pediatrics.&2012c129:1006–15.&
&
Evaluasi& bayi& ≥& 37& minggu& asimptomatik& dengan& faktor& resiko&
sepsis& (tanpa& koriamnitis),& ketuban& pecah& dini& !& 18& jam,& antibiotik&
profilaksis& intrapartum& diindikasikan& tapi& tidak& adekuat.& Tes& diagnostik&
berupa& hitung& jenis& dan& jumlah& sel& darah& putih& dengan& tambahan&
pemeriksaan& CRP& pada& usia& 6B12& jam,& namun& tidak& diberikan& antibiotik&
maupun& di& observasi.& Jika& data& laboratorium& abnormal,& lanjutkan&
pemeriksaan& kultur& darah,& jika& hasilnya& juga& negatif,& anak& bugar,&
pulangkan& setelah& 48& jam,& jika& data& laboratorium& normal,& bayi& bugar,&
maka&bayi&boleh&dipulangkan&setelah&48&jam&observasi.!7&

! 7!
 Tes& diagnostik& untuk& EOS& (di& luar& kultur& LCS& dan& kultur& darah)&
sangat& berguna& untuk& mengidentifikasi& bayi& dengan& kemungkinan& kecil&
sepsis.& Kultur& dari& bagian& superfisial& sepsis,& aspirat& lambung,& dan& urin&
tidak& memiliki& nilai& diagnosis& pada& EOS.& Lumbal& pungsi& tidak& dibutuhkan&
pada& semua& bayi& dengan& kecurigaan& sepsis& (terutama& pada& bayi& yang&
tampak&sehat)&tetapi&sebaiknya&dilakukan&untuk&bayi&dengan&tanda&sepsis,&
untuk& bayi& dengan& kultur& yang& positif,& bayi& yang& cenderung& mengalami&
bakteremia& (didasarkan& pada& data& laboratorium& dasar),& dan& pada& bayi&
yang&tidak&respon&terhadap&terapi&antimikroba.!7&
Terapi& optimal& pada& bayi& dengan& kecurigaan& awitan& dini& sepsis&
adalah& pemberian& antimikroba& spectrum& luas& (golongan& ampisilin& dan&
aminglikosida).& Jika& pathogen& berhasil& diidentifikasi,& terapi& antimikroba&
harus& dipersempit& sesuai& hasil& kultur.& Terapi& antimikroba& harusnya&
dihentikan& pada& 48& jam& pada& situasi& klinis& dimana& kemungkinan& sepsis&
rendah.8&&
!
2.2! Metabolisme!obat!pada!neonates!
Neonatus& memiliki& perbedaan& yang& bermakna& dalam& hal& absorpsi&
obat,& distribusi& obat,& metabolisme,& dan& eleminasi& obat.9& Variabel& seperti&
usia&kehamilan,&komposisi&tubuh,&usia&postnatal,&penggunaan&obat&secara&
bersamaan,& hipoksemia& atau& asidemia& dan& perfusi& organ& akhir& dapat&
mempengaruhi&terapi&obat&pada&neonatus.8!
Perbedaan& dalam& fisiologi& neonatus& juga& mempengaruhi&
farmakodinamik& obat& yang& menyebabkan& terjadinya& perbedaan& potensi&
obat.& Farmakokinetik& adalah& analisis& kuantitatif& tentang& bagaimana& suatu&
makhluk&hidup&bereaksi&terhadap&bahan&kimia,&yang&digambarkan&dengan&
gambaran&waktu&absorpsi&obat,&distribusi,&metabolisme,&dan&ekskresi.&8&
&
a.&& Absorbsi&Obat&
Absorbsi& diartikan& sebagai& translokasi& suatu& obat& dari& tempat&
pemberian& menuju& ke& pembuluh& darah.10& Obat& yang& diberikan& secara&
intravaskuler& (intravena& atau& intraarterial)& memiliki& bioavailibilitas& yang&

! 8!
cepat& dan& sempurna.& Obat& yang& diberikan& secara& ektravaskuler& (oral,&
rektal,&inhalasi,&topikal,&intramuskular,&subkutaneus)&harus&melewati&barier&
kimia,&fisik,&mekanikal&dan&biologi&untuk&dapat&melewati&banyak&membran&
untuk&mencapai&sirkulasi&sistemik.8,10&
&
b.& Distribusi&Obat&&
Distribusi& diartikan& sebagai& proses& pergerakan& obat& dan& senyawa&
lainnya&dari&sirkulasi&sistemik&ke&berbagai&bagian&tubuh,&jaringan,&dan&sel.&
Distribusi& sebaian& besar& obat& di& dalam& tubuh& dipengaruhi& oleh& berbagai&
faktor& yang& terkait& dengan& usia& termasuk& ikatan& protein,& ukuran& tubuh,&
faktor&hemodinamik&seperti&curah&jantung&dan&aliran&darah&setempat,&serta&
permeabilitas&membran.&10&
Pertumbuhan& neonatus& dihubungkan& dengan& perubahan& yang&
bermakna& pada& komposisi& tubuh.& Persentase& total& cairan& berkurang& dari&
85%& pada& usia& kahamilan& 24& minggu& menjadi& 75%& saat& aterm.& Pada&
waktu& yang& bersamaan& jaringan& lemak& meningkat& 15%.& Perubahan&
komposisi& tubuh& ini& akan& mempengaruhi& dosis& (mg/kg)& obat& yang&
dibutuhkan&untuk&memberikan&efek.&Ikatan&protein&memiliki&dampak&pada&
distribusi& obat,& pembersihan& dan& pada& akhir& aktivitas& farmakologi.& Hanya&
obat&yang&tidak&terikat&yang&memiliki&aktivitas&farmakologi.8&
Bayi& prematur& memiliki& konsentrasi& pengikatan& protein& (albumin,&
lipoprotein,&alpha?1?acid$glycoprotein&dan&beta&globulin)&yang&rendah.&Bayi&
prematur& memiliki& albumin& yang& memiliki& afinitas& yang& rendah& terhadap&
obat,& tingkat& keasaman& plasma& yang& rendah& yang& menyebabkan& ikatan&
protein& yang& rendah& pada& obatBobat& yang& bersifat& asam& dan& adanya&
kompetitor& endogen& terhadap& ikatan& protein& (bilirubin,& free& fatty& acid).&
Apabila& ikatan& protein& berkurang,& maka& volume& distribusi& menjadi&
meningkat& sehingga& membutuhkan& dosis& yang& lebih& besar& untuk&
mencapai& total& konsentrasi& serum& yang& sama.& Adanya& fraksi& obat& bebas&
yang&lebih&tinggi&juga&menyebabkan&efek&toksik&yang&lebih&besar.8& &
&
&

! 9!
c.&& Metabolisme&obat&
Banyak& obatBobatan& memerlukan& biotrasformasi& menjadi& senyawa&
yang& larut& air& untuk& mempermudah& eliminasi.& Biotransformasi& ini& dapat&
terjadi& pada& berbagai& organ& (plasma,& kulit,& paruBparu,& adrenal,& usus,& dan&
ginjal),&namun&sebagian&besar&biotransformasi&terjadi&di&hati&melalui&reaksi&
fase&I&atau&fase&II&untuk&membuat&senyawa&obat&yang&secara&farmakologi&
lebih& lemah& atau& menjadi& inaktif.& Namun& beberapa& obat& ditransformasi&
menjadi& metabolit& aktif& atau& senyawa& antara,& seperti& misalnya& theofilin&
menjadi& kafein.& Ada& beberapa& senyawa& obat& yang& secara& farmakologi&
memiliki& senyawa& awal& inaktif& (atau& disebut& prodrug)& yang& membutuhkan&
biotransformasi& untuk& mejadi& senyawa& yang& aktif& (misal& chloramphenicol&
succinate,&cefuroxime&axetil,&fosphenytoin).&8&
Dampak& maturasi& yang& terjadi& pada& neonatus& terhadap&
biotransformasi&obat&sulit&untuk&diprediksi&hanya&berdasarkan&usia&karena&
beberapa& jalur& metabolik& dapat& diinduksi& dan& beberapa& obat& terpaksa&
melalui& jalur& metabolik& lainnya& yang& memiliki& kecepatan& pembersihan&
yang& berbeda& (clearance$ rate).& Secara& umum& proses& biotransformasi&
berkurang& pada& neonatus& preterm& akibat& dari& kurangnya& pengambilan&
obat& oleh& sel,& rendahnya& kapasitas& enzim& hati,& kurangnya& aliran& darah&
hati,&dan&kurangnya&ekskresi&bilier.18&
Sebelum& biotransformasi& terjadi,& langkah& pertama& adalah&
pengambilan& obat& oleh& sel& hepar& (hepatosit)& oleh& protein& akseptor.&
Neonatus& preterm& memiliki& akseptor& protein& yang& rendah,& bahkan&
beberapa& belum& memiliki& akseptor& protein.& Hal& ini& menyebabkan&
gangguan& pada& kapasitas& clearance& beberapa& obat& (obat& yang& memiliki&
intrinsic$ clearance& yang& rendah).& Konsentrasi& protein& akseptor& akan&
meningkat& secara& bertahap& dalam& 10& hari& setelah& bayi& lahir.& Saat& obat&
sudah& memasuki& hepatosit& maka& obat& tersebut& akan& mengalami&
transformasi& fase& I& atau& fase& II.& Pada& umumnya& obat& akan& menjalani&
reaksi& fase& I& yang& kemudian& akan& diikuti& dengan& reaksi& fase& II.& Reaksi&
fase& I& disebut& dengan& reaksi& persiapan& dan& didalamnyan& termasuk&
oksidasi,& reduksi,& hidrolisis,& dan& hidroxilasi.& Reaksi& ini& mempersiapkan&

! 10!
obat& agar& dapat& masuk& ke& reaksi& fase& II& (glukoronidase,& sulfation,&
acetylation,&dan&methylation).&8&
Sebagian&besar&enzim&yang&dipergunakan&pada&fase&I&sudah&ada&
saat& lahir& bahkan& pada& neonatus& preterm.& Namun& jumlah& enzim& tersebut&
dapat&bervariasi&dan&dapat&dipengaruhi&oleh&senyawa&yang&diberikan&saat&
prenatal& seperti& phenobarbital& pada& ibu,& antiretroviral,& dan& kortikosteroid.&
Kondisi&tertentu&pada&bayi&seperti&menurunnya&curah&jantung,&rendahnya&
perfusi& hati,& pembengkakan& pada& hati,& atau& hipoksia& dapat& menurunkan&
aktivitas&enzim&pada&hati&dan&menyebabkan&rendahnya&pembersihan&obat&
tertentu.&8&
&
c.& Eliminasi&obat&
Ginjal& merupakan& rute& eliminasi& untuk& sebagian& besar& obat.& ObatB
obatan& yang& tidak& mudah& menguap,& larut& dalam& air,& dan& memiliki& berat&
molekul& yang& rendah& secara& umum& dieliminasi& melalui& ginjal.& Renal&
clearance& (bersihan& ginjal)& didefinisikan& sebagai& volume& plasma& yang&
dibersihkan& dari& obatBobatan& per& satuan& waktu& melalui& ginjal.& & Renal&
clearance& merupakan& gabungan& dari& proses& filtrasi& glomerular,& sekresi&
tubular,& dan& reabsorpsi& aktif& maupun& pasif& dari& tubulus,& dimana& hal& ini&
pada&neonatus&preterm&masih&sangat&rendah.&8&
Pematangan& fungsi& ginjal& dimulai& pada& saat& organogenesis& dan&
sempurna& pada& masa& anakBanak.& Nefrogenesis& dimulai& pada& usia&
kehamilan& 9& minggu& dan& sempurna& pada& usia& kehamilan& 34& minggu.8&&
Saat&lahir&fungsi&glomerular&lebih&cepat&berkembang&dibandingkan&fungsi&
tubular,& Neonatus& aterm& mengalami& peningkatan& GFR& dengan& cepat&
dalam& 2& minggu& pertama& kehidupan& kemudian& melambat& hingga&
mencapai& fungsi& dewasa& pada& usia& 6B12& bulan.& Neonatus& preterm&
memiliki& trend& yang& serupa& namun& peningkatan& GFR& awal& lebih& rendah&
akibat& nefrogenesis& yang& belum& sempurna& hingga& usia& kehamilan& 34&
minggu.9&
Fungsi& ginjal& setelah& lahir& dapat& dipengaruhi& oleh& paparan& prenatal&
terhadap& obat& tertentu& seperti& betametason& dan& indometasin.&

! 11!
Betametason&dapat&meningkatkan&GFR&dengan&cara&meningkatkan&fraksi&
filtrasi& sedangkan& indometasin& dapat& menurunkan& GFR& melalui&
penghambatan& sintesis& prostaglandin& yang& kemudian& menyebabkan&
meningkatnya& tahanan& vaskuler& ginjal& dan& pada& akhirnya& akan&
mengurangi&aliran&darah&ginjal.8,9&
Pada&akhirnya,&jumlah&obat&yang&difiltrasi&oleh&ginjal&tergantung&pada&
kapasitas& fungsional& dari& glomerolus,& aliran& darah& ginjal,& dan& berapa&
banyak&ikatan&obat&dan&protein.&& &Sekresi&tubulus&merupakan&suatu&proses&
yang& aktif& dan& tidak& tergantung& pada& ikatan& protein& plasma,& namun&
bergantung&pada&aliran&darah,&ikatan&obat&dengan&protein&pembawa&pada&
tubulus& proksimal,& kecepatan& transport& melewati& membran& tubular,& dan&
kecepatan& obat& untuk& sampai& pada& organ& sekresi& (Neonatal&
pharmacology).&Fungsi&tubulus&pada&bayi&baru&lahir&belum&sempurna&dan&
berkisar& antara& 20B30%& dari& fungsi& tubulus& pada& orang& dewasa.&
Pematangan& fungsi& tubulus& ginjal& terjadi& secara& bertahap& dan& mencapai&
fungsi&seperti&orang&dewasa&pada&usia&7B12&bulan.8&
Reabsorpsi& tubulus& merupakan& suatu& proses& yang& pasif& dan&
tergantung&pada&karakteristik&fisika&dan&kimia&dari&obat&(misalnya&apakah&
obat&larut&dalam&lemak&atau&air,&apakah&obat&tersebut&bersifat&asam&atau&
basa)& dan& tingkat& keasaman& cairan& di& tubulus& proksimal& dan& distal.&
Reabsorpsi&tubulus&masih&belum&sempurna&pada&bayi&baru&lahir&terutama&
pada& neonatus& preterm.& Maturasi& reabsorpsi& tubulus& ginjal& terjadi& secara&
bertahap&sejak&lahir&hingga&remaja&dengan&puncak&pematangan&pada&usia&
1B3&tahun.8,11&

! 12!
 BAB!III!
QUINOLON!
!
3.1!Definisi!Quinolon!
Quinolon& merupakan& antibiotika& spektrum& luas& dengan& aktivitas&
bakterisidal.& Quinolon& tidak& seperti& antibiotika& lainnya& yang& berasal& dari&
organisme& hidup.& Quinolon& merupakan& antibiotika& yang& disintesis& secara&
kimia.& Perkembangan& quinolon& secara& pesat& dimulai& pada& tahun& 1962.&
Penambahan& gugus& fluoro& pada& quinolon& menghasilkan& fluoroquinolon&
dimana& memiliki& spektrum& yang& lebih& luas.& Fluoroquinolon& juga& memiliki&
efek&samping&yang&minimal.&12&
&
&
Tabel&3.I&Empat&generasi&antibiotik&fluoroquinolon.&
Generasi&I& asam&nalidiksat&
Generasi&II& ciprofloxacin,&levofloxacin,&enoxacin,&fleroxacin,&ofloxacin,&
lomefloxacin,&norfloxacin&
Generasi&III& gatifloxacin,&gemifloxacin,&grepafloxacin,&sparfloxacin&
Generasi&IV& moxifloxacin,&trovafloxacin&
Sumber& & :& Schaad& UB.& Fluoroquinolone& antibiotics& in& infants& and& children.& Infect.& Dis.&
Clin.&North&Am.2005c19:617–28&
&
Fluoroquinolon&sensitif&terhadap&berbagai&organisme&gram&positif&dan&
negatif.& pada& generasi& pertama& lebih& sensitif& terhadap& bakteri& gram&
negatif,&namun&pada&generasi&ketiga&dan&keempat&memiliki&spektrum&yang&
lebih&luas&terhadap&kuman&gram&positif.13&
&
&
&
&
&
&
&
&
&

! 13!
 &
&
Gambar&3.1&Golongan&Quionolon
Sumber&:&Schaad&UB.&Fluoroquinolone&antibiotics&in&infants&and&children.&Infect.&Dis.&Clin.&
North&Am.2005c19:617–28&
&
&
3.2!Farmakokinetik!quinolon!
Fluoroquinolon& dapat& diabsorpsi& dengan& baik& dan& didistribusi& secara&
luas& pada& jaringan.& Waktu& paruh& berkisar& antara& 3B10& jam.& Levofloxacin,&
gemifloxacin,&gatifloxacin&dan&moxifloxacin&yang&mempunyaii&waktu&paruh&
yang& relatif& lebih& panjang& sehingga& menyebabkan& pemberiannya& cukup&
satu& kali& sehari.& Konsentrasi& serum& dari& penggunaan& secara& intravena&
hampir& sama& dengan& penggunaan& secara& oral.& Sebagian& besar&
fluoroquinolon& dieliminasi& di& melalui& ginjal,& baik& melalui& sekresi& tubular&
atau& filtrasi& glomerulus.& Penyesuaian& dosis& dibutuhkan& pada& pasienB
pasien& dengan& creatinine$ clearances& kurang& dari& 50& mL/menit,&
penyesuaian& yang& tepat& tergantung& dari& kerusakan& ginjal& dan&
fluoroquisnolon& yang& spesifik& digunakan.& Penyesuaian& dosis& untuk& gagal&
ginjal& tidak& dibutuhkan& untuk& moxifloxacine.& Fluoroquinolon& yang& tidak&
disekresikan&di&renal&memiliki&kecenderungan&kontraindikasi&pada&pasienB
pasien& dengan& gagal& hepar.14& Studi& farmakokinetik& ciprofloxacin&
menunjukkan& bahwa& tingkat& yang& sama& untuk& bayi& <1500& dan& >1500&
gram&dan&untuk&bayi&berusia&<7&dan&>&7&hari.15&
Ciprofloxacin is used in neonates with suspected or documented Gram-
negative serious infections. Currently, its use is off-label partly because of
lack of pharmacokinetic studies. Within the FP7 EU project TINN (Treat

! 14!
Infection in NeoNates), our aim was to evaluate the population
pharmacokinetics of ciprofloxacin in neonates and young infants<3 months
of age and define the appropriate dose in order to optimize ciprofloxacin
treatment in this vulnerable population. Blood samples were collected from
neonates treated with ciprofloxacin and concentrations were quantified by
high-pressure liquid chromatography–mass spec- trometry. Population
pharmacokinetic analysis was performed usingNONMEMsoftware. The
data from 60 newborn infants (postmenstrual age [PMA] range, 24.9 to 47.9
weeks) were available for population pharmacokinetic analysis. A two-
compart- ment model with first-order elimination showed the best fit with
the data. A covariate analysis identified that gestational age, postnatal age,
current weight, serum creatinine concentration, and use of inotropes had a
significant impact on ciprofloxacin pharmacokinetics. Monte Carlo
simulation demonstrated that 90% of hypothetical newborns with
aPMAof<34 weeks treated with 7.5 mg/kg twice daily and 84% of
newborns with aPMA>34 weeks and young infants receiving 12.5 mg/kg
twice daily would reach the AUC/MIC target of 125, using the standard
EUCAST MIC susceptibility breakpoint of 0.5 mg/liter. The associ- ated
risks of overdose for the proposed dosing regimen were<8%. The
population pharmacokinetics of ciprofloxacin was evalu- ated in neonates
and young infants<3 months old, and a dosing regimen was established
based on simulation.C

Dosing regimen and pharmacokinetic sampling. Ciprofloxacin (ge-

neric; Peckforton Pharmaceuticals, Crewe, United Kingdom) was admin-

istered as an intravenous infusion either over either 30 or 60 min by using a
syringepumpconnected to microbore tubing at a dose of 10 mg/kg/dose
twice daily (BID) for neonates with a postmenstrual age (PMA) of ?40

Received

weeks and three times daily (TID) or BID for young infants with aPMAof
?40 weeks.

Ciprofloxacin pharmacokinetics was assessed on day 1 (D1) or D2 of

treatment and again between D5 and D7. The total number of study-
specific blood samples was restricted to six per participant with a maxi-
mum of three on each sampling day. Patients were randomly assigned to
one of the two predefined three-time point schedules (Table 1). Precise
infusion and sample times were recorded. The blood volume of samples
obtained for pharmacokinetic analyses was 0.2 ml per sample. Scavenged
samples were also obtained from blood remaining after routine biochem-
ical tests. Only samples with validated sampling information were in-

! 15!
cluded. Blood samples were refrigerated and centrifuged (2,500?g at 4C for
10 min), and serum or plasma was stored at ?70°C. Samples were
shippedondry ice to the Department of Pediatric Pharmacology at Robert
Debré Hospital, where they were stored at?70°C prior to analysis.
Analytical method of ciprofloxacin and creatinine. The analytical

method of ciprofloxacin has been reported previously (8). Briefly, cipro-

floxacin concentrations were determined using high-performance liquid

chromatography with mass spectrometry with ciprofloxacin-d8 as an in-

ternal standard. The calibration curve ranged from 25 to 3,000 ng/ml. The
inter- and intraday coefficients of variation of controls were 4.1 and 2.4%,
respectively. The lower limit of quantification was 25 ng/ml. Serum cre-
atinine concentrations were measured by an adapted Jaffé method using the
Architect C system (Abbott Diagnostics, Abbott Park, IL). Population wei
zhou

The pharmacokinetics of orally administered ciprofioxacin (CIP) was

studied in seven infants aged 5 to 14

weeks and nine children aged 1 to 5 years, most ofwhom were Sabnonella
carriers. In each case, 15 mg of CIP per kg ofbody weight was given with
water on an empty stomach, and timed serum samples were taken during
the following 12 h. The elimination half-life of CIP was significantly (P <
0.001) longer in the infants (2.73 0.28 h; mean :± standard deviation) than it
was in the children (1.28 + 0.52 h). The area under the serum CIP
concentration-time curve (AUC) from time zero to infinity was 16.1

7.4 mg. h liter-' among the infants

and 5.3 + 3.3 mg- h liter-' in the children (P < 0.01). No significant
differences in the maximum concentration in serum, time to maximum
concentration in serum, or absorption half-life were observed between the
two groups. In contrast, the mean residence time was twofold longer in the
infants (4.6 h) than it was in the children (2.4 h; P < 0.001). The findings
suggest that elimination of CIP is particularly rapid in children whojust
have passed infancy; they may require doses at shorter time intervals than
those required by infants or older children or adults. In general, an oral dose
of 10 to 15 mg of CIP per kg three times daily seems appropriate for
children aged 1 to 5 years.

Changes (peltola)

TABLE 46–2 Pharmacokinetic properties of some fluoroquinolones.

! 16!
 Oral Peak Serum
Drug Half-Life (h) Bioavailability Concentration Oral Dose (mg) Primary Route of Excretion
(%) (mcg/mL)

Ciprofloxacin 3–5 70 2.4 500 Renal

Gatifloxacin 8 98 3.4 400 Renal

Gemifloxacin 8 70 1.6 320 Renal and nonrenal

Levofloxacin 5–7 95 5.7 500 Renal

Lomefloxacin 8 95 2.8 400 Renal

Moxifloxacin 9–10 > 85 3.1 400 Nonrenal

Norfloxacin 3.5–5 80 1.5 400 Renal

Ofloxacin 5–7 95 2.9 400 Renal

katzung

!
3.2.1!Mekanisme!Aksi!Quinolon!
Target&dari&antibiotik&quinolone&adalah&kedua&tipe&IIA&topoisomerase&
bakteri& yaitu:& DNA& gyrase& dan& topoisomerase& IV.& DNA& gyrase& adalah&
suatu& heterotetramer& yang& dikode& oleh& dua& gen& gyrA& (nalA)& dan& gyrB&
(nalC).& GyrA& bersama& GyrB& bekerja& dengan& cara& membentuk& pintu& pada&
DNA& atau& celah& pada& untai& ganda& DNA,& memberi& dampak& negatif&
supercoil& ke& DNA& dan& merelaksasikan& positif& supercoil& yg& terjadi& akibat&
proses& replikasi.& DNA& topoisomerase& IV,& suatu& hetero& tetramer& dikode&
oleh& oleh& dua& gen& yaitu& ParC& dan& ParE& yang& menyerupai& subunit& GyrA&
dan& GyrB& pada& DNA& gyrase,& berperan& dalam& memisahkan& molekul& DNA&
yang& saling& berhubungan& sebagai& hasil& dari& replikasi& DNA.& Bagaimana&
quinolon&bekerja&pada&kedua&tipe&IIA&topoisomeras&masih&diperdebatkan,&
namun& penelitian& menunjukkan& bahwa& molekul& ini& bekerja& dengan& cara&
memblok& kompleks& DNABtopoisomerase& pada& saat& asam& nukleat&
membelah.& Akibat& struktur& dan& fungsi& yang& hampir& serupa& antara& DNA&
gyrase&dan&topoisomerase&IV&maka&kedua&tipe&IIA&topoisomerase&ini&dapat&
dihambat& oleh& quinolon,& sehingga& terjadi& kematian& sel& bakteri& akibat&
fragmentasi& dari& kromosom.& Pada& Escherichia& coli& dan& bakteri& gram&

! 17!
negatif& lainnya,& quinolon& memiliki& target& utama& DNA& gyrase,& sedangkan&
pada& bakteri& gram& positif,& target& utama& quinolon& adalah& hambatan& pada&
topoisomerase& IV.& (Quinolon& from& antibiotic& to& autoinducer,& Mechanisms&
of& quinolone& action& & and& microbial& & response.& Mutasi& dari& gyra& dapat&
membuat&resistensi&terhadapat&obat&ini.16&
!
3.2.2!! Spektrum!antibakterial!
Fluoroquinolones were originally developed because of their excellent
activity against gram-negative aerobic bacteria; they had limited activity
against gram-positive organisms. Several newer agents have improved
activity against gram-positive cocci. This

relative activity against gram-negative versus gram-positive species is

useful for classification of these agents. Norfloxacin is the least active of
the fluoroquinolones against both gram-negative and gram-positive
organisms, with minimum inhibitory concentrations (MICs) fourfold to
eightfold higher than those of ciprofloxacin. Ciprofloxacin, enoxacin,
lomefloxacin, levofloxacin, ofloxacin, and pefloxacin comprise a second
group of similar agents possessing excellent gram-negative activity and
moderate to good activity against gram-positive bacteria. MICs for gram-
negative cocci and bacilli, including Enterobacter sp, P aeruginosa,
Neisseria menin- gitidis, Haemophilus sp, and Campylobacter jejuni, are 1–
2 mcg/mL and often less. Methicillin-susceptible strains of S aureus are
gener- ally susceptible to these fluoroquinolones, but methicillin-resistant
strains of staphylococci are often resistant. Streptococci and entero- cocci
tend to be less susceptible than staphylococci, and efficacy in infections
caused by these organisms is limited. Ciprofloxacin is the most active agent
of this group against gram-negative organisms, P aeruginosa in particular.
Levofloxacin, the L-isomer of ofloxacin, has superior activity against gram-
positive organisms, including Streptococcus pneumoniae.

Gatifloxacin, gemifloxacin, and moxifloxacin make up a third group of

fluoroquinolones with improved activity against gram- positive organisms,
particularly S pneumoniae and some staphylo- cocci. Gemifloxacin is active
in vitro against ciprofloxacin-resistant strains of S pneumoniae, but in vivo
efficacy is unproven. Although MICs of these agents for staphylococci are
lower than those of ciprofloxacin (and the other compounds mentioned in
the para- graph above), it is not known whether the enhanced activity is
sufficient to permit use of these agents for treatment of infections caused by
ciprofloxacin-resistant strains. In general, none of these agents is as active
as ciprofloxacin against gram-negative organ- isms. Fluoroquinolones also
are active against agents of atypical pneumonia (eg, mycoplasmas and

! 18!
chlamydiae) and against intra- cellular pathogens such as Legionella
pneumophila and some myco- bacteria, including Mycobacterium
tuberculosis and Mycobacterium avium complex. Moxifloxacin also has
modest activity against anaerobic bacteria. Because of toxicity, gatifloxacin
is no longer available in the United States.

&
Fluoroquinolon& adalah& agen& bakterisidal& yang& melawan& berbagai&
jenis& mikroorganisme.& Fluoroquinolon& memiliki& senstivitas& yang& baik& bagi&
staphylococcus&tetapi&tidak&pada&strain&&methicillin?resistant.&Terbatasnya&
tipe& quinolone& yang& sensitive& terhadap& Streptococcus,& adapun&
diantaranya& levofloxacine& (Levaquin),& gatifloxacin& (tequin),& dan&
moxifloxacin& (avelox).& Beberapa& bakteri& interselular& yang& dihambat& oleh&
fluoroquinolon,& termasuk& spesies& dari& Chlamydia,$ Mycoplasma,$
Legionella,$ Brucella,$ dan$ Mycobacterium& (termasuk& Mycobacterium$
tuberculosis).& Ciprofloxacine,& ofloxacine& (floxin)& dan& pefloxacine&
menghambat&M.$fortuitum,$M.$kansasii$dan$M.$Tuberculosis.17&
Pada&penelitian&Dhanraj,&2012&menulis&ciprofloxacin,&norfofloxacin,&
sparfloxacin,& ofloxacin,& levfofloxacin& sangat& sensitif& terhadap&
Staphylococcus$aureus.$Ciprofloxacin,&norfofloxacin,&levofloxcacin&sensitif&
tinggi& terhadap& Pseudomonas$ aeruginosa,$ sensitif& sedang& terhadap&
oflloxacin,& resisten& terhadap& sparfloxacin.& Escherichia$ coli$ sensitif& tinggi&
terhadap&ciprofloxacin,&norfloxacin,&sparfloxacin,&sensitif&sedang&terhadap&
levofloxacin,& resisten& terhadap& ofloxacin.& Klebsiella$ pneumonia& sensitif&
terhadap&sparfloxacin,&ciprofloxacin,&norfloxacin,&oflloxacin,&levofloxacin.&18&
&
3.3!Farmokodinamik!Quinolon!(absorpsi!dan!ekskresi)&
Quinolon&diabsorpsi&baik&melalui&oral&dan&didistribusikan&secara&luas.&
Kadar& puncak& dapat& dicapai& dalam& 1B3& jam& dengan& dosis& oral& 400& mg.&
Kadar& Quinolon& yang& rendah& relatif& diperoleh& dengan& norfloxacin& dan&
berguna&untuk&terapi&infeksi&saluran&kemih.&Makanan&tidak&mempengaruhi&
absorpsi& oral& namun& dapat& menghambat& waktu& mencapai& neonatus&
preterm.& Maturasi& reabsorpsi& tubulus& ginjal& terjadi& secara& bertahap& sejak&
lahir&hingga&remaja&dengan&puncak&pematangan&pada&usia&1B3&tahun.&17&

! 19!
 Kosentrasi& puncak.& Bioavaibilitas& dari& fluoroquinolon& lebih& dari& 50%&
hingga&95%&dari&beberapa&agen.&Waktu&paruh&berkisar&antara&3&sampai&5&
jam& untuk& norfloxacine& sedangkan& ciprofloxacine& sampai& 20& jam.&
Sebagian& besar& quinolon& dieksresi& di& ginjal& dan& dosis& harus& disesuaikan&
dengan& penderita& gagal& ginjal.& Pefloxacin& dan& moxifloxacin& sebagian&
besar& dimetabolisme& oleh& hepar& dan& sebisa& mungkin& tidak& dipergunakan&
pada&pasien&dengan&gagal&hepar.15&
!

! 20!
 BAB!IV!
TERAPI!QUINOLON!PADA!SEPSIS!NEONATUS!
! !
Peggunaan& quinolon& pada& anak& dan& neonatus& awalnya& masih&
menjadi& pertentangan& karena& data& awal& menunjukkan& adanya& toksisitas&
pada&sendi.&&&
4.1&Laporan&awal&toksisitas&&
Laporan& pertama& tentang& toksisitas& quinolon& adalah& oleh& Ingham&
dkk& di& tahun& 1977& yang& menemukan& kerusakan& sendi& besar& pada& anjing&
remaja& pada& penggunaan& quinolon& generasi& pertama.19& DataBdata&
berikutnya& menemukan& toksisitas& pada& jenis& hewan& lain& seperti& tikus,&
kuda.20& & Laporan& efek& samping& muskuloskeletal& pada& hewan& mencakup&
kepincangan,& eksudasi& cairan& sendi,& dan& erosi& ulseratif& pada& kartilago&
sendi& pada& sendi& tungkai.& Egerbacher& dkk& tahun& 2000& menemukan&
toksisitas&pada&sel&kondrosit&manusia&dan&tikus&sel&secara&invitro.21&
&
4.2&Keamanan&penggunaan&ciprofloxacin&pada&infeksi&neonatus&
Adanya& kerja& antibakterial& dan& penetrasi& jaringan& yang& baik& telah&
memicu& peneliti& untuk& melakukan& trial& penggunaan& kuinolon& terutama&
ciprofloxacin&pada&pasien&anak.&Penelitian&oleh&Richard&dkk&di&tahun&1997&
membandingkan& penggunaan& ciprofloxacin& oral& dan& ceftazidim& intravena&
pada&kasus&cistic&fibrosis.&&&Perbaikan&klinis&antara&kedua&kelompok&tidak&
banyak& berbeda.& & Penilaian& keamanan& terkait& isu& arthropathy& juga&
menemukan& tidak& ada& laporan& efek& samping& muskoloskeletal& pada&
kelompok&&&ciprofloxacin.(richard)&Hasil&&yang&hampir&sama&juga&dilaporkan&
oleh&Hampel&di&tahun&yang&sama.&(hampel)&
Penggunaan& kuinolon& pada& neonatus& pertama& dilaporkan& oleh&
Bannon& di& tahun& 1987,& melaporkan& penggunaannya& pada& infeksi&
Enterobacter& Cloacae& yang& multiresisten& pada& 6& bayi& prematur.& & Efikasi&
yang&bagus&juga&dicapai&dalam&laporan&kasus&lain&dan&tanpa&laporan&efek&
samping.& (bannon& 1987)& Oever& dkk& tahun& 1997& juga& melaporkan&
penggunaan& ciprofloxacin& pada& bayi& prematur& yang& menderita& infeksi&

! 21!
Enterobacter& cloacae$ diberikan& terapi& quinolone,& setelah& antibiotik& lain&
gagal,&dan&tidak&ada&efek&samping&yang&ditemukan&selama&3&tahun.&&&
&&
&Gurpinal& dkk& melakukan& penelitian& longitudinal$ study& tahun& 1997&
dimana& pertumbuhan& dan& perkembangan& pada& sembilan& neonatus& yang&
diberikan& ciprofloxacin,& fluoroquinolon& dengan& dosis& sebesar& 20&
mg/kg/hari& yang& di& follow?up& hingga& 42& bulan.& Dimana& ciprofloxacin&
digunakan& hanya& sebagai& terapi& pilihan& terakhir& pada& kasus& sepsis& yang&
sudah& terjadi& resistensi& terhadap& golongan& antibiotik& lainnya.& Pada& dua&
kelompok& lain& dari& sembilan& neonatus,& dengan& berat& lahir& dan& usia&
kehamilan& yang& sama& sebagai& kelompok& kontrol:& satu& kelompok& dengan&
sepsis,& yang& secara& diberikan& cefotaksim& dan& satu& kelompok& neonatus&
sehat.& Tidak& ada& perbedaan& statistik& yang& signifikan& dalam& pertumbuhan&
dan& perkembangan& antara& kelompok& yang& di& followBup& selama& 42& bulan.&
Tidak& ada& permasalahan& pada& osteoarticular& atau& deformitas& sendi& yang&
diamati& pada& kelompok& ciprofloxacin.& Ciprofloxacin& diberikan& sebagai&
pilihan&terapi&terakhir&untuk&bayi&yang&baru&lahir&dengan&sepsis.&29&
Chaudhari& dkk& melakukan& penelitian& kasus& kontrol& berpasangan&
untuk& mengevaluasi& efek& samping& ciprofloxacin& sebagai& terapi& sepsis&
pada& neonatus.& Penelitian& ini& dilakukan& di& Neonatal& Intensive& Care& Unit&
dan& klinik& High& Risk& Follow& Up,& Bagian& Anak& King& Edward& Memorial&
Hospital,&Pune&pada&tahun&1999&B&2000.&Sebagai&kelompok&kasus&adalah&
30& neonatus& dengan& sepsis& yang& resisten& terhadap& beberapa& antibiotik&
tetapi& sensitif& terhadap& ciprofloksasin.& Ciprofloksasin& diberikan& secara&
intravena& selama& 14& hari& dengan& dosis& 20& mg/kg/hari& terbagi& menjadi& 2&
dosis.& Kelompok& kontrol& adalah& 30& neonatus& dengan& sepsis& yang&
mendapatkan& terapi& antibiotik& selain& ciprofloxacin.& Tidak& didapatkan&
perbedaan& pada& serum& elektrolit,& fungsi& hati,& fungsi& ginjal,& dan& prameter&
hematologi& antara& kelompok& kontrol& maupun& kelompok& kasus.&
Ultrasonografi& serial& untuk& mengukur& kartilago& sendi& lutut& dilakukan& pada&
bulan& pertama& dan& bulan& ke& enam& setelah& terapi& dihentikan.& Hasil&
ultrasonografi& serial& tidak& berbeda& pada& kedua& kelompok.& Evaluasi&

! 22!
kartilago& tibia& juga& tidak& menunjukkan& perbedaan& peningkatakan& ukuran&
pada& kedua& kelompok& pada& bulan& ke& enam.& Kelemahan& penelitian& ini&
adalah& besar& sampel& yang& kecil& dan& follow$ up& yang& singkat.& Namun&
karena&pertumbuhan&maksimum&kartilago&dan&epifisis&terjadi&pada&6&bulan&
pertama,&maka&dianggap&efek&patologis&pada&sendi&dan&tulang&tidak&akan&
tampak& setelah& usia& ini.& Penelitian& ini& tetap& menyarankan& agar&
penggunaan& ciprofloksasin& hanya& digunakan& pada& sepsis& neonatus&
dengan&resistensi&beberapa&antibiotik&sebagai&pilihan&terakhir.&30&
Pada& penelitian& Agakidou& dkk& tahun& 2004& dengan& metode&
prospektif&observasional&meneliti&efek&dari&pemberian&ciprofloksasin&pada&
sepsis& neonatal.& Pada& 2& kelompok& sepsis& neonatal& terdapat& 116& sample&
diberikan& ciprofloksasin& dan& 100& sample& tidak& diberikan& ciprofloksasin.&
Pada& semua& sample& diperiksa& darah& sebelum& dan& setelah& mulai&
pengobatan.& Diamati& selama& satu& tahun& dan& didapatkan& tidak& adanya&
perbedaan& yang& signifikan& antara& kedua& kelompok& pada& pemeriksaan&
darah&dan&biokimia&serta&pertumbuhan&tidak&ada&bukti&klinis&arthropati.&32&
Ahmed& dkk& pada& tahun& 2006& melakukan& penelitian& di& Bangladesh&
pada&492&neonatus&dengan&usia&gestasi&<&33&minggu&dimana&92&neonatus&
mendapatkan& terapi& dengan& ciprofloxacin& selama& 5& hari& atau& lebih& dan&
400& neonatus& mendapatkan& terapi& dengan& antibiotik& lain& seperti&
cefotaksim,& gentamisin& dan& ampisilin.& Kriteria& inklusi& pada& penelitian& ini&
adalah& neonatus& yang& terdiagnosis& neonatal& sepsis& dan& mendapatkan&
terapi& antibiotik& parenteral& dengan& atau& tanpa& adanya& isolasi& kuman& dari&
kultur&darah&atau&kultur&cairan&serebrospinal.&Tidak&didapatkan&deformitas&
sendi& pada& kelompok& yang& mendapatkan& terapi& dengan& ciprofloxacin.&
Tidak& didapatkan& adanya& perbedaan& pada& tumbuh& kembang& antara&
kelompok& yang& mendapatkan& ciprofloxacin& dan& kelompok& yang&
mendapatkan&antibiotik&lain.&&&Karena&keterbatasan&sumber&daya,&evaluasi&
dengan& USG& ginjal& dan& MRI& tidak& bisa& dilakukan.& & Tingginya& angka&
kematian&juga&menjadi&kelemahan&studi&ini.&&&ahmed&
Pada& penelitian& Duta& dkk& tahun& 2015& dengan& metode& studi& kohort&
retrospektif& penggunaan& ciprofloksasin& pada& berat& bayi& lahir& sangat&

! 23!
rendah& yang& diikuti& hinga& usia& 12& bulan.& Kriteria& eksklusi& bayi& tanpa&
catatan&panjang&badan.&Dari&205&bayi&dalam&penelitian&ini,&ada&61&kasus&
dan& 144& kontrol.& Kelompok& kasus& menerima& ciprofloxacin& intravena& (10&
mg& /& kg& /& dosis& 12Bjam)& selama& minimal& 3& hari& pada& periode& neonatus,&
sedangkan& kontrol& adalah& mereka& yang& tidak& terpapar& ciprofloxacin&
selama& hidup.& Didapakan& hasil& tidak& ada& pengaruhi& pertumbuhan& linier&
mereka&sampai&usia&12&bulan.&35&

4.2.1 Differences in velocity of growth in animals and man: an explanation for the
low risk of quinolone-associated toxicity in children?

The chondrotoxic risk associated with the use of quinolones in children is obviously low.
Some authors even assume that the findings of animal testing are completely irrelevant
for humans. However, a conclusive explanation for the fundamental differ- ence in the
reaction of connective tissues in man and in animals, which could explain the observed
species differences, is not known. No major principal differences between the
morphology or bio- chemical composition of the cartilage in animals and man are known.
Since all animal species tested proved to be susceptible to the quinolone-induced toxic
effects on cartilage and tendon, it is unlikely that these effects cannot occur in humans.
For many compounds the differences between toxic effects observed in ani- mals and
man can be explained by the differences in dose levels or, more precisely, the differences
in exposure based on the AUC. In the case of quinolone-induced chondrotoxicity,
however, it can- not be ignored that the immature joint cartilage in juvenile dogs is
damaged at dose levels (and exposure based on AUC values) that are below those that are
used in children. Also in rats, which rep- resent the species in which, besides dogs, most
experiments were performed, cartilage changes occur at quinolone plasma concentra-
tions that are achievable during therapy. Therefore, the high doses that have been used in
some experiments to induce chondrotoxi- city in juvenile rats are not a good argument to
explain principal species differences.

One aspect that has not been discussed so far in this context is the velocity of growth,
which shows major differences between the animals used in the toxicological evaluation
and in children. The number, location and time of appearance of secondary centres of
ossification varies between species [40]. Animals that are used in toxicological studies
grow rapidly, but human growth extends over much longer periods, exhibits pronounced
individual vari- ability and cannot be viewed as a continuous process. Rather it is
characterised by changing velocity with age. It has been shown

that growth in length occurs by discontinuous, aperiodic salta- tory spurts. These bursts
were separated by periods of 2–63 days duration with no measurable growth. In other
words, 90–95% of normal development during infancy is growth-free [41]. Although
these data have been criticised, it is undisputed that periods of no growth (stasis) are a
common phenomenon in human growth [42–44]. If the assumption is correct that damage
to the imma- ture joint cartilage can only occur during growth periods, then the low
degree of human susceptibility is explainable. It would explain why the quinolone-
induced arthropathies are a rare adverse effect in children whilst immature animals
develop symptoms in a more uniform way. (Judith Sendzik)

! 24!
 !
4.3&Resistansi&
Selama& terapi& fluorokuinolon& dilakukan& secara& kurang& bijaksana,&
organisme& resisten& muncul& dalam& sekitar& satu& dari& setiap& 107B109&
organisme,&terutama&di&kalangan&stafilokokus,&P&aeruginosa,&dan&Serratia&
marcescens.&Resistensi&ini&disebabkan&karena&salah&satu&atau&lebih&terjadi&
mutasi&pada&strain&quinolon&sehingga&terjadi&perubahan&enzim&target&atau&
permeabilitas& organisme.& BaruBbaru& ini& didapatkan& dua& jenis& resistensi&
plasmidBdimediasi.& Tipe& pertama& menggunakan& Qnr& protein,& yang&
melindungi&girase&DNA&dari&fluoroquinolon.&Yang&kedua&adalah&varian&dari&
acetyltransferase& aminoglikosida& mampu& memodifikasi& ciprofloxacin.&
Kedua&mekanisme&resistensi&tingkat&rendah&yang&dapat&memfasilitasi&titik&
merupakan& hasil& mutasi& yang& memberikan& resistensi& tingkat& tinggi.&
Resistensi& terhadap& satu& fluoroquinolon,& terutama& jika& itu& adalah& tingkat&
tinggi,& umumnya& menyebabkan& resistansi& silang& kepada& semua& anggota&
lain&dari&kelas&ini.&katzung&
Perkembangan& resistensi& bakteri,& seperti& disebutkan& sebelumnya&
ada& kekhawatiran& besar& mengenai& dampak& potensial& penggunaan&
fluorokuinolon& secara& luas& pada& anakBanak& dan& neonatus& terhadap&
pengembangan& resistensi& bakteri& [6,15,30,38,39].& Secara& historis,&
penggunaan& antimikroba& telah& menyebabkan& perkembangan& resistensi&
obat.& Penggunaan& yang& berlebihan& (jumlah& antibiotik& yang& digunakan&
pada& manusia& dan& hewan),& penyebaran& klonal& (perjalanan& global,&
kebersihan,& rumah& sakit,& tempat& penitipan& anak,& keluarga,& perubahan&
serotipe),& dan& jenis& antibiotik.& Berlebihan& (misalnya,& untuk& infeksi& virus,&
sebagai& profilaksis,& indikasi& dokter& hewan)& mencerminkan& pengetahuan&
yang& kurang& dari& seorang& dokter& tentang& pemakaian& quinolon& dan& tidak&
tersedianya& metode& diagnostik.& Penggunaan& yang& tepat& untuk&
menghindari& penyalahgunaan,& tidak& hanya& mencakup& pilihan& klasik&
optimasi& yang& optimal,& tetapi& juga& dosis& individu& dan& durasi& terapi.&
kebijakan& yang& didefinisikan& dengan& antibiotik,& langkahBlangkah&
kebersihan& yang& baik,& dan& program& pengendalian& infeksi& yang& kuat&

! 25!
merupakan& poin& penting& untuk& membatasi& penyebaran& resistensi&
antibiotik.& Bakteri& dapat& menjadi& resisten& terhadap& quinolon& oleh& karena&
mutasi& pada& molekul& target& (protein& girase,& topoisomerase).& Berkenaan&
dengan& resistensi& quinolon,& variasi& besar& ada& di& antara& spesies& bakteri,&
pengaturan& klinis,& dan& epidemiologi& lokal.& Resistance& adalah& ekspresi&
fenotipik& yang& sesuai& dengan& perubahan& genetik& yang& disebabkan& oleh&
salah&satu&mutasi&atau&perolehan&informasi&genetik&baru.&Dalam&beberapa&
kasus,&resistensi&terhadap&banyak&obat&terjadi.&Streptococcus&pneumoniae&
merupakan&salah&satu&patogen&pernapasan&yang&paling&penting,&memiliki&
peran&utama&dalam&infeksi&saluran&pernapasan&atas&dan&bawah.&resistensi&
pneumokokus&terhadap&antimikroba&dapat&diperoleh&dengan&cara&transfer&
horisontal& diikuti& oleh& rekombinasi& homolog& dari& materi& genetik& dari& flora&
normal& rongga& mulut& manusia& atau& dengan& cara& mutasi.& Perlawanan& di&
pneumokokus& terhadap& penisilin& dan& makrolida& telah& meningkat& selama&
beberapa&waktu,&tetapi&baruBbaru&ini&resisten&fluoroquinolon&telah&menjadi&
isu& dengan& baik.& [40,41].& resistensi& fluoroquinolon& tidak& terbatas& pada& S&
pneumoniae& dan& telah& didokumentasikan& dalam& patogen& lainnya,&
termasuk& mereka& yang& bertanggung& jawab& infeksi& saluran& kemih,&
pernafasan,&dan&pencernaanc&kulit&dan&jaringan&lunak&serta&infeksi&tulang,&
sendic&penyakit&menular&seksualc&dan&bisul&[38,39]&
Bukti&yang&terkumpul&tentang&terjadinya&resistensi&multidrug&pada&
terapi& pneumokokus& berhubungan& dengan& peresepan& antibiotik& yang&
kurang&bijaksana&pada&anakBanak.&Resistensi&multidrug&lebih&sering&pada&
anakBanak& daripada& orang& dewasa,& hal& ini& disebabkan& oleh& banyaknya&
kolonisasi&kuman&pneumokookus&yang&terdapat&di&nasofaring,&hal&tersebut&
dapat& meningkatkan& potensial& terbentuknya& resistensi.[38].& kepadatan&
penduduk&juga&mempunyai&peranan&terhadap&terjadinya&&transmisi&bakteri&
pada&anakBanak&dan&bayi&yang&masih&rentan&(44).&
Kekhawatiran& baru& tentang& bertambah& banyaknya& penggunaan&
fluoroquinolon& untuk& mengobati& pasien& anakBanak& dan& orang& dewasa&
maka& semakin& meningkatnya& kejadian& reistensi& terhadap& antibiotik&
tersebut.& [45,46]& Ketika& terjadi& resistensi& maka& akan& terjadi& mutasi& strain&

! 26!
kuman.&resistensi&S.$pneumoniae&terhadap&fluorokuinolon&dapat&menyebar&
dengan& mudah& dari& anak& ke& orang& tua,& dan& akhirnya& menyebar& dengan&
luas&pada&populasi&yang&lebih&besar.&(38)&schaad&
!

! 27!
 !
PENELITIAN( METODE( INKLUSI( EKSLUSI( KELEMAHAN( KELEBIHAN( HASIL(

22
Ahmed,(2006 ( cohort( memantau( pertumbuhan(
dan( perkembangan( bayi(
prematur( yang( diberikan(
ciprofloxacin( secara(
intravena( pada( periode(
neonatal(di(Bangladesh(
23
Chaudhari,(1996 ( case( matched( Thirty( neonates( with(
control(study( septicemia( who( were(
already( on( other(
antibiotics,(but(had(shown(
clinical( deterioration( and(
the( blood( culture( had(
grown(multiUdrug(resistant(
organisms( sensitive( to(
ciprofloxacin( were(
selected(for(the(study(
DrossouU observational( 2( groups( of( septic(
24
Agakidou,(2004 ( prospective( neonates( were( studied,(
study( 116( neonates( who(
received(ciprofloxacin(and(
100(neonates(matched(for(
gestational( age( and( birth(
admitting( physician,( based( on( berdasarkan(penilaian(klinis( ( Pemeriksaan(fisik(normal(
clinical(judgment,(thought(would(die( dokter,( pikiran( akan( mati( pada( kedua( kelompok(
within( 48( hoursO( those( who( had( a( dalam( waktu( 48( jamO( selama( follow% up.( Tidak(
major( congenital( anomaly,( hydrops( mereka( yang( memiliki( ada(bukti(toksisitas(pada(
fetalis,( or( generalized( skin( disease( anomali( kongenital,( pembengkakan( sendi(
or( a( structural( defect( of( >5%( body( hydrops( fetalis,( penyakit( akut,( nyeri( atau( gerakan(
surface(areaO(and(those(admitted(to( kulit( umum( atau( cacat( luas( dibatasi( selama( atau(
the(hospital(for(a(major( pada( permukaan( tubuh>( setelah( pengobatan.( Tak(
surgical(procedure( 5%( dan( mereka( yang( satu( pun( dari( anakUanak(
dirawat( di( rumah( sakit( pada( kedua( kelompok(
untuk(prosedur(operasi( memiliki( sejarah(
masalah( osteoarticular(
atau(deformitas(sendi(
30( neonatus( dengan( septikemia( The( main( limitations( of( this( ( Ciprofloxacin( did( not(
yang(telah(diberi(antibiotik( study( are( the( small( sample( show( any( adverse(
size( and( the( short( follow( effects,( especially(
up.( arthropathogenic( toxicity,(
when( used( in( neonates(
with(septicemia(
No( significant( differences( between( Although(no(ultrasound(and( ( No(significant(differences(
the( magnetic( resonance( between(the(
two( groups( were( found( in( the( imaging( of( the( joints( was( two(groups(were(found(in(
hematologic( and( biochemical( performed(in(our(study( the( hematologic( and(
indices(as(well(as(growth(at(the(end( biochemical( indices( as(
of( the( first( year( of( life.( Also( no( well(as(growth(at(the(end(

! 28!
 weight( who( did( not( clinical(evidence(of(arthropathy(was(
receive(ciprofloxacin( observed(
25
Dutta,(2006 ( retrospective( VLBW( babies( followed( up(
cohort(study( until( 12( months( corrected(
age((12UmCA).(
( neonatal(
205( babies( were( included(
in( the( study.( SixtyUone(
babies( had( received(
ciprofloxacin(for(at(least(3(
days( (cases)( and( 144(
were( never( exposed( to(
ciprofloxacin((controls).(
26
Gurpinar,(1997 ( longitudinal( neonates( admitted(
study( between( February( 1993(
and( June( 1994( in( the(
Medical(Faculty(of(Uludag(
University,( Department( of(
Paediatric( Surgery.(
Patients(
of( the( first( year( of( life.(
Also( no( clinical( evidence(
of( arthropathy( was(
observed(
Exclusions( were:( infants( with( no( Being(a(retrospective(study,( ( Our( study( showed( that(
length( record( taken( at( 12UmCA,( we( did( not( have( access( to( adminU( istration( of(
who( received( ciprofloxacin( after( data( on( parental( heights,( Ciprofloxacin( to( VLBW(
period,( were( nutritional(intakes(and(other( babies( in( the( neonatal(
neurologically( abnormal,( growth( determinants( of( infantile( period( did( not( have( any(
retarded( in( utero( or( congenitally( height,( which( may( have( effect( on( the( linear(
malformed,( had( chronic( systemic( otherwise( influenced( the( growth( till( 12( months( of(
illnesses( or( endocrinopathies( in( height( at( 1( year.( This( is( a( corrected(age.(This(
infancy( limitation(of(our(study(
( In( our( study,( children( This( study( No( sideUeffects( were(
received( quinolones( as( enabled( us( to( detected( during(
aIifeU( saving( therapy'( in( evaluate( the( treatment( and(
smaller( doses( and( for( impact( of( interruption( of( treatU(
shorter(periods(of(time.( fluoroquinolone( ment( was( not( necessary(
(ciprofloxacin)( in( any( case.( The( phyU(
adminisU( tration( sical( examination( was(
on( growth( and( normal( in( all( groups( at(
development( in( the(end(of(either(36(or(42(
newU(borns(with( weeks((after(birth).(None(
severe( of( the( children( in( any( of(
infections( the(groups(
had( any( history( of(
osteoarticular( problems(
or( joint( deformities.( No(
statistically( significant(
differences( were(
observed( in( weight,(
height( or( head(

! 29!
 circumference( between(
any( of( the( groups( at( any(
of(the(ages(studied.(
Growth(was(not(impaired(
in(the(ciprofloxacin(group(
and( no( statistically(
significant( differences(
between( the( groups(
were(found.(
choi( ( ( ( ( ( (

vasili( ( ( ( ( ( (

! 30!
!
!

! 31!
!
BAB!V!
RINGKASAN!
!
5.1!Ringkasan!
Quinolon' merupakan' antibiotika' spektrum' luas' dengan' aktivitas'
bakterisidal.' Quinolon' tidak' seperti' antibiotika' lainnya' yang' berasal' dari'
organisme' hidup.' Quinolon' merupakan' antibiotika' yang' disintesis' secara'
kimia.' Ciprofloxacin' merupakan' antibiotik' generasi' ke' dua' dari' golongan'
quinolon,' yang' aktif' melawan' kuman' gram' negatif' dan' positif.' Namun'
tetap' harus' waspada' terhadap' toksik' dari' ciprofloxacin' yaitu' dapat'
menyebabkan'kerusakan'tulang'rawan'dan'ruptur'tendon'achiles.'
Neonatus' memiliki' perbedaan' yang' bermakna' dalam' hal' absorpsi'
obat,' distribusi' obat,' metabolisme,' dan' eleminasi' obat.' (Dosing' in'
neonate).' ' Variabel' seperti' usia' kehamilan,' komposisi' tubuh,' usia'
postnatal,' penggunaan' obat' secara' bersamaan,' hipoksemia/asidemia,'
dan'perfusi'organ'akhir'dapat'mempengaruhi'terapi'obat.'
Sepsis' pada' neonatus' adalah' penyebab' utama' morbiditas' dan'
mortalitas' pada' NICU.' Dalam' sepuluh' tahun' terakhir' terdapat' beberapa'
perkembangan' baru' mengenai' definisi' sepsis,' The$ International$ Sepsis$
Definition$ Conference$ mendefinisikan' sepsis' sebagai' sindrom' klinis'
dengan' adanya' Systemic$ Infammatory$ Response$ Syndrome$ (SIRS)' dan'
infeksi.' Sepsis' merupakan' suatu' proses' berkelanjutan' mulai' dari' infeksi,'
SIRS,' sepsis' berat,' renjatan' atau' syok' sepsis,' disfungsi' multiorgan,' dan'
akhirnya' kematian.' Berdasarkan' waktu' terjadinya,' sepsis' pada' neonatus'
dapat'diklasifikasikan'menjadi'dua'bentuk'yaitu'Early$Onset$Sepsis'(EOS)'
dan' Late$ Onset$ Sepsis$ (LOS).' Mortalitas' sepsis' sebagian' besar' dapat'
dicegah' dengan' terapi' antimikroba' yang' rasional' dengan' perawatan'
suportif'yang'agresif.''
' ' Dua'kekawatiran'terbesar'tentang'penggunaan'fluoroquinolon'pada'
anakNanak' adalah' berkembangnya' resistensi' bakterial' dan' toksisitas'
kartilago' seperti' yang' digambarkan' pada' hewan' coba' usia' muda.' Risiko'
berkembang'cepatnya'resistensi'pada'pneumokokus'dan'bakteri'patogen'

! 32!
lainnya' dihubungkan' dengan' penggunaan' quinolon' yang' luas' dan' tidak'
terkontrol' pada' pasien' anak.' Toksisitas' kartilago' pada' penggunaan'
fluoroquinolon'merupakan'suatu'fenomena'laboratorium'pada'hewan'coba'
usia' muda' dan' tidak' ada' artropati' yang' terdokumentasi' pada' anakNanak'
yang' mendapat' terapi' dengan' fluoroquinolon.' Terlepas' dari' hal' tersebut,'
penggunaan' senyawa' quinolon' yang' baru' masih' memerlukan'
pengamatan.'
' ' Pada' sebagian' besar' negara,' fluoroquinolon' hanya' disetujui'
penggunaannya' pada' anak' dengan' cystic' fibrosis' dan' infeksi' saluran'
kencing'dengan'komplikasi.'Ijin'untuk'indikasi'penggunaan'yang'lebih'luas'
pada' anakNanak' memerlukan' usaha' dari' ahli' di' bidang' mikrobiologi' dan'
penyakit'infeksi,'pemerintah,'dan'pabrik'obat.'Survey'setelah'pemasaran'
harus'termasuk'rencana'tatalaksana'yang'baik'terhadap'risiko'yang'dapat'
terjadi'yang'sesuai'untuk'pasien,'orangtua,'dan'perusahaan'obat.'
' ' Fluoroquinolon' harus' tetap' menjadi' terapi' pilihan' terakhir' pada'
anakNanak' hanya' setelah' kegagalan' terapi' sebelumnya' dan' saat' pilihan'
antibiotik' lainnya' yang' telah' disetujui' penggunaannya' pada' anakNanak'
tidak'dapt'diberikan.'Pedoman'ini'harus'memastikan'bahwa'penggunaan'
fluoroquinolon'tetap'aman'untuk'bayi'dengan'infeksi'yang'sulit'diatasi.'
!
' '
'

! 33!
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BMJ.'2004[329:1277–80.''
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newborn.'Indian'J'Pediatr.'2001[68:1143–7.''
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Geneva:'2005.''
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Surabaya:'2014.''
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antibiotic'resistance'in'neonatal'sepsis.'J'Ayub'Med'Coll'
Abbottabad.'2012[24:131–4.''
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therapeutic'implications.'Pediatr'Indones.'2006[46:25–31.''
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EarlyNOnset'Bacterial'Sepsis.'Pediatrics.'2012[129:1006–15.''
8.'' Tayman'C,'Rayyan'M,'Allegaert'K.'Neonatal'pharmacology:'
extensive'interindividual'variability'despite'limited'size.'J'Pediatr'
Pharmacol'Ther.'2011[16:170–84.''
9.'' Ku'LC,'Smith'PB.'Dosing'in'neonates:'special'considerations'in'
physiology'and'trial'design.'Pediatr'Res.'2015[77:2–9.''
10.'' Kauffman'RE.'Drug'action'and'therapy'in'the'infant'and'child.'In:'
Yaffe'SJ,'Aranda'J'V,'editors.'Neonatal'and'Pediatric'
Pharmacology:'Therapeutic'Principles'in'Practice.'new'york:'
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