- Email: [email protected]
Ceftazidime in the treatment of neonatal infection
~ournal of Hospital Infection (1985) 6, 158-165
Ceftazidime
in the treatment
of neonatal
infection
I. P o l l o c k , * A. M u l h a ' l l a n d J. d e L o u v o i s
Queen Charlotte's Maternity Hospital, Goldhawk Road; London W 6 0 ~ f G 2qccepted for publication 9 October 1984 Summary: T h e efficacy of ceftazidime in the treatment o f neonatal sepsis was s t u d i e d in 42 low b i r t h w e i g h t p r e m a t u r e babies. F o r t y - n i n e courses of ceftazidime (25 m g / k g bd, iv or im were administered. In 19 babies,.treatm e n t was s t o p p e d after 48 h, t h e r e m a i n d e r were treated for 5 days or m o r e . Six neonates h a d bacteriological evidence of infection, one o t h e r was pyrexial and 29 h a d radiological evidence c o m p a t i b l e with respiratory tract infection. Eight of the s t u d y p o p u l a t i o n died. O n l y one death was attributed to infection w h i c h arose 3 days after c o m p l e t i o n o f a 5-day course of ceftazidime. T w o babies d e v e l o p e d clinical signs of necrotizing enterocolitis ( N E C ) . Clostridium diflicile (7) and CI. perfringens (2) were isolated from 34 p o s t - t r e a t m e n t faecal samples b u t not from the two babies ~ i t h N E C . N o faecal s a m p l e contained CI. diflicile toxin. P o s t - t r e a t m e n t cultures from 12 neonates yielded ceftazidime-resistant m i c r o - o r g a n i s m s . C e f t a z i d i m e t h e r a p y was n o t associated with significant alteration in s e r u m alanine aminotransferase, urea, creatinine, p r o t e i n or albumin. F o u r b a b i e s h a d an eosinophilia, three transient and one following two intrauterine transfusions. C o o m b s ' tests were p e r f o r m e d on 17 babies. T h e r e were no false positives. T h e a b n o r m a l clotting studies observed in one baby were n o t due to ceftazidime. I n a c o n c u r r e n t p h a r m a c o k i n e t i c study, the half-life of ceftazidime was 7-4 (so 4-4-1)h following iv administration. O t h e r pharmacokinetic values were C m a x 74 (SD4- 2 0 ) m g 1-~ t r o u g h concentration 20 (sD q- 1 0 ) m g 1-z. T o t a l b o d y clearance ranged f r o m 0-13 tO 2-10 m l m i n - t ' p e r kg a n d increased w i t h increasing postnatal age. Ceftazidime is safe and effective for the t r e a t m e n t of infected neonates achieving fnerapeutic concentrations in blood, u r i n e , cerebrospinal fluid and bronchial aspirates. T h e r e were n o significant side effects. N o major p r o b lems d u e to ceftazidime-resistant bacteria have e m e r g e d following i t s routine use i n the special care baby u n i t for 12 m o n t h s .
Introduction In neonatal medicine, broad-spectrum antibiotics are commonly i/adicated i n h i g h r i s k s i t u a t i o n s b e f o r e a m i c r o b i o l o g i c a l d i a g n o s i s is m a d e . V a r i o u s antibiotics or combinations have been :used--a reflection of the changing pattern of bacteria infecting thenewborn and the individual recluirements o f C l i f f e r e n t n e o n a t a l - U n i t s . A t p r e s e n t , t h e r e is n o i d e a l c h o i c e a n d t h e majority of units usean aminoglycoside together with peniciilin or ampicillin. Increasing resistance to these antibiotics among neonatal * Present address: Paddington Children's Hospital, London W2. 0195-670|/85/020158+08 $03.00/0
1985 T h e Hos;)i~! Infection Societv
58
Ceftazidirne and neonatal infection
159
p a t h o g e n s and the d e v e l o p m e n t of n o n - t o x i c alternatives to the a m i n o g l y c o s i d e s suggests that othe r e q u a l l y efficacious b u t safer r e g i m e n s are n o w available. C e f t a z i d i m e is a n e w derivative of c e p h a l o s p o r i n C w h i c h has the advantage over p r e v i o u s c e p h a l o s p o r i n s of b e i n g h i g h l y active against Pseudomonas aeruginosa as well as the e n t e r i c G r a m - n e g a t i v e rods, wh ile r e t a i n i n g activity against the m a j o r G r a m - p o s i t i v e p a t h o g e n s e n c o u n t e r e d in the neonate. T h i s paper reports the clinical, mic r obiologic a l a n d phaiii~acological results of a prospective s t u d y in a g r o u p of 42 neonates. T h e study was a p p r o v e d by the H o s p i t a l Ethical C o m m i t t e e a n d the D e p a r t m e n t of H e a l t h and Social Security C o m m i t t e e on Safety of M e d i c i n e s . Materials and methods
Study population T h e neonates studied were those a d m i t t e d to the special care b a b y u n i t ( S C B U ) at Q u e e n C h a r l o t t e ' s M a t e r n i t y H o s p i t a l over a pe r iod of 3 m o n t h s . All of the patients h a d clinical signs a nd s y m p t o m s suggestive of infection and w o u l d otherwise have received g e n t a m i c i n a n d penicillin.
Dose C e f t a z i d i m e was a d m i n i s t e r e d by the iv or i m route at a dose of 25 m g k g - , 12 h o u r ly. Prospective clinical assessments were m a d e b y one of us (IP) on each day of t h e r a p y a n d for 3 da ys' p o s t - t r e a t m e n t .
Laboratory investigations Blood, urine, surface swabs a nd a gastric aspirate were collected for bacteriological c u l t u r e before t r e a t m e n t started. Repeat s p e c i m e n s were taken following the isolation of a p a t h o g e n and on o t h e r occasions w h e n c l i n i c a l l y ' i n d i c a t e d . A s s e s s m e n t of the colonization rate w i t h ceftazidimeresistant bacteria of all babies in the u n i t was m a i n t a i n e d t h r o u g h o u t the s t u d y b y c u l t u r i n g all s p e c i m e n s onto 8 % horse blood agar c o n t a i n i n g 10 m g 1-1 ceftazidime. Faecal s a m p l e s c o l l e c t e d at the e n d of t r e a t m e n t were c u l t h r e d for Clostridium difficile a n d tested for the pr e se nc e of CL difficile toxin u s ing the m e t h o d s of Borriello & H o n o u r (1981). D e t e r m i n a t i o n s o f s e r u m urea, creatinine, p r o t e i n , a l b u m i n , a la nin e a m i n o t r a n s f e r a s e , h a e m o g l o b i n and total a nd differential w h i t e cell c o u n t s were u n d e r t a k e n before, d u r i n g a n d a f t e r t r e a t m e n t u s i n g r outin e l a b o r a t o r y m e t h o d s . D i r e c t C o o m b s ' tests w e r e p e r f o r m e d o n m o s t babies receiving phototherapy for h y p e r b i l i r u b i n a e m i a . Clotting~ studies ( p r o t h r o m b i n time, t h r o m b i n time, k a o l i n c e p h a l i n time) were d o n e on six b a b i e s with s i g n s s u g g e s t i v e of a clotting defect.
~narmacokznettc study, Blood s a m p l e s w e r e collected for c e f t a z i d i m e assay ¼, ½, 1,3, 5, 12 h a f t e r t h e first; dose a n d / o r at steady state ( i . e : a f t e r at least f o u r doses),~Timed u r i n e s a m p l e s and p h a r y n g e a l a s p i r a t e s were collected also for assay.
160
I. P o l l o c k e t a l .
Treatment regimen A c c o r d i n g to established practice i n the unit, c e f t a z i d i m e t h e r a p y w a s assessed after 48 h. T r e a t m e n t was stopped if there was a significant i m p r o v e m e n t i n the b a b y ' s c o n d i t i o n a n d p r e - t r e a t m e n t bacteriological cultures were negative or if an alternative positive diagnosis ha d been made. T r e a t m e n t was c o n t i n u e d for 5 days if a significant p a t h o g e n had b e e n isolated or there w ere s t r o n g . c l i n i c a l or :radiological i n d i c a t i o n s of active infection. I f m u l t i p l e chest dr a ins or central lines were in place, t r e a t m e n t was continued. W h e r e the indications for c h e m o t h e r a p y persisted, t r e a t m e n t was c o n t i n u e d for m o r e than 5 d a y s . Results
F o r t y - t w o neonates (23 m a l e s a nd 19 f e ma le s) r e c e i v e d ceftazidime. Gestation ranged f r o m 25 tO 42 ( m e a n 3 2 - 9 ~ 4 " 0 sv) weeks a n d b i r t h w e i g h t f r o m 0"53 to 4-27 ( m e a n 1.944-0-8 s o ) k g . T e n of 42 p a t i e n t s were less t h a n the 10th eentile for b i r t h w e i g h t , head c i r c u m f e r e n c e or le ngth, 12 we igh e d less t h a n 1"5 kg at birth, and 12 were less t h a n 31 weeks' gestation. For ty of 42 patients started t r e a t m e n t on or before the t h i r d postna ta l day. A total of 49 courses of c e f t a z i d i m e w e r e a d m i n i s t e r e d . N i n e t e e n courses were stopped after 48 h, 23 c o n t i n u e d for 5 days a nd seven c o n t i n u e d for 5 to 19 days. T h e p r e s e n t i n g signs and s y m p t o m s of infection together with the m a j o r indication f o r i n i t i a t i n g t h e r a p y are s h o w n in T a b l e I. R e s p i r a t o r y p r o b l e m s , usually with associated radiological changes, were the c o m m o n e s t indications for t r e a t m e n t . M a t e r n a l or ne ona ta l pyrexia or infection was the m a j o r i n d i c a t i o n for 7/49 courses. I n t u b a t i o n , the insertion of long lines and p r e m a t u r i t y were not by t h e m s e l v e s justifications for c h e m o t h e r a p y . T h e final d i a g n o s e s in the 42 patients s t u d i e d are s h o w n in T a b l e I I. F o u r babies w i t h respiratory p r o b l e m s w e n t on to develop b r o n c h o p u l m o n a r y d y s p l a s i a . Seven babies h a d signif ic a nt infection or pyrexia. A n o t h e r b a b y d e v e l o p e d necrotizing ~e n t e r o c o l i t i s ( N E C ) while r e c e i v i n g c e f t a z i d i m e , Retrospective : a sse ssme nt o f t r e a t m e n t c o n c l u d e d t h a t ' i n eight cases there h a d : b e e n no significant p a t h o l o g y , a l t h o u g h at the t i m e o f a d m i s s i o n t o t h e S C B U antibiotic t h e r a v v was t h o u g h t to be warranted. Bacteriological s p e c i m e n s collected prior to t h e i n i t i a t i o n o f t r e a t m e n t y i e l d e d ~a significant isolate: in,six cases ( T a b l e iI I I ) . O n e b a b y o f 27 weeks' g e s t a t i 0 n , ' w e i g h i n g 1 ' 1 6 kg h a d e a r l y onset: G r o u p :B Streptococcal sepsis. T h i s was rapidly cleared w i t h c e f ta z idime a l t h o u g h t h e b a b y s u b s e q u e n t l y d i e d following:~a m a s s i v e intravehtricular: haemorrhage.: C u l t u r e s t a k e n at p 0 s t - r n o r t e m w e r e sterileiPseudomonas aeruginosa isolated f r o m t h e axiUa of one b a b y before a n d d u r i n g t r e a t m e n t !was r e sponsible i f o r e ba c te r a e mia whic deVel0Ped 3 days after C d m p l e t i 0 n o f a 5-day course of ceftazidime. Thei~ p a t i e n t i n f e c t e d W i t h StaphyIococcus epidermidis s h o w e d no ~clinical i m p r o v e m e n t : a f t e r 4 \ days ~ t r e a t m e n t : withal c e f t a z i d i m e : T r e a t m e n t w a s c h a n g e d ~!t011g e n t a t n l c i n ! a n d ~penicill~:i:iBacteriaif r o m t h e other t h r e e babies h a d been::eradi~/itetl breathe:end of :treatment.
Ceftazidime and neonatal infection
161
Table I. Presenting signs and symptoms with major indications for initiating ceftc~idime therapy _ _ .
,H
,,,,,,,
,,,,
i
i
_
Presenting signs and s y m p t o m s
No. of babies
M a j o r indication for t h e r a p y
Respiratory p r o b l e m s L u n g abnormalities on chest X-ray Copious endotracheal secretions Repeated apnoea M e m b r a n e s r u p t u r e d > 10 days Maternal pyrexia Maternal infection (proven) Neonatal pyrexia Neonatal infection (proven) T w i n on ceftazidime Non-specific deterioration Intubation L o n g line catheters < 10th centile for weight etc.
38 29 9 6 8 3 1 3 2 4 3 31 15 10
27 2 2 2 2 1 1 3 2 4 3 0 0 0 i
T a b l e I I. Final diagnosis of 42 neonates treated with ceftazidime ,,i
i,,,,
ii
Hi
i
i
,
iH
Final diagnosis
N o . of babies
Hyaline m e m b r a n e disease B r o n c h o p u l m o n a r y dysplasia M e c o n i u m aspiration T r a n s i e n t tachypnoea of n e w b o r n Focal lung collapse/consolidation Neonatal infection/pyrexia Maternal infection/pyrexia T w i n receiving treatment Necrotizing enterocolitis P u l m o n a r y agenesis Asphyxia
14 4 3 5 1 7 2 2 1 1 2
_
T r e a t m e n t was changed to penicillin and gentamicin in eight babies. T w o babies with s u s p e c t e d or proven N E C also received~metronidazole: Three out '~:of eight; babies were changed empirically or ~because,: of: clinical deterioration within :48 h Of starting ~Ceftazidime. ~Treatment o f one:,baby was'changed:after 5 d a y s followingisolation of Ps.aeruginosa, and treatment of the baby with Staph. epidermidischestl infectionwas changed after.4-days. Finally, a 530 g baby of 24 weeks'::gestation failed to pr0gress following 1~1 days' treatment with ceftazidime and t r e a t m e n t was changed. Blood c l 0 t t ~ g problems, w h i c h ! w e r e f i r s t o b s e r v e d a t the end of ceftazidime therapy, Were shown~subsequently" not! t o be~associated iWith antibiotic therapy. ~The baby died aged 7 weeks With brain infarction c o n s e q u e n t u p o n extreme prematurity,
I . , P o l l o c k e t aL
162
Table I I I . Significant pre-treatment bacterial isolates f r o m 42 babies treated with ceftaMdime Organism
Site
Clinical features
I. G r o u p B streptococci
Blood
2. Ps. aeruginosa Enterobacter spp. 3. Staph. aureus
Axilla
4. Staph. epidermidis
Bronchial aspirate
5. Enterobacter spp.
Blood, bronchial aspirate, surface swabs Umbilicus
L o w birthweight, p r e m a t u r e , twin* Bacteraemia 3/7 posttreatment* Maternal pyrexia, birth asphyxia, P R M 31[7, Respiratory problems* Very severe respiratory problems, no i m p r o v e m e n t , t r e a t m e n t failure Maternal infection, P R M 13/7, Respiratory problems Umbilical sepsis
6. Enterobacter app.
Bronchial aspirate
* Patient died. PRM = prolonged rupture of membranes.
Eight of the study population died (Table IV) and all had p o s t - m o r t e m examinations. T h e death of one baby, referred to above, was attributed to bronchopneumonia due to Ps. aeruginosa and N E C . T h i s baby who had surface colonization with Ps. aeruginosa received ceftazidime for the first 5 days of life. T h r e e days after treatment stopped, the baby showed clinical signs of N E C and was treated with penicillin, gentamicin and metronidazole. A blood culture collected at that t i m e yielded Is. aeruginosa. None of the remaining deaths was attributed to microbial infection, and post-mortem cultures from the cerebrospinal fluid, heart blood and bronchus were all sterile. T h i r t y - f o u r samples of faeces were examined 2-4 days after completion of ceftazidime treatment. Clostridium diflicile was isolated from seven and CI. perfringens from two others. T w o of the isolates of CI. diflicile were toxin producers but toxin could not be detected in any of the 34 faecal samples. Neither Cl. difficile nor Sits toxin could be isolated from two babies with clinical evidence o f N E C . Twelve babies treated with ceftazidime became colonized with resistant organisms (Candidaalbicans, 8; faecal streptococci, 5; Clostridium spp., 3; Staph. aureus, 1;Pseudomonas spp., 1 ) a n d two babies who:did not receive ceftazidime w e r e c o l o n i z e d with ceftazidime-resistant strains of Enterobacterspp. Babies with oral candidiasis received nystatin; none of the other micro-organisms w a s considered t o b e o f clinicalsignificance. No Clinical s i g n s o f local reaction or:allergic p h e n o m e n a were seen in the study group. Ceftazidime t h e r a p y was not responsible for any major changes in hepatic or renal fUnCtion or i n Whitecell count, haemoglobin o r packed cell :volume. One'baby? w h o h a d a n exchange t r a n s f u s i o n had significant b u t transient elevati0n of s e r u m a l a n i n e aminotransferase, creatinine a n d urea which
163
Ceftazidime and neonatal infection
I'able IV. Cause of death in eight babies who received ceftazidime ill
1. 2.
Gestation (weeks)
Birthweight (kg)
27 30
1"17 1"25
Age at death Clinical diagnosis
,
ill
i
,,,
i
~ause of death following postmortem
5 days Severe HMD 11 days Severe HMD ?Infection 19 h Severe HMD--hypoxia 12 h Severe birth asphyxia
Massive IVH--HMD Bronchopneumonia-NEC 3. 27 1-27 Severe HMD 4. 39 3-44 Pulmonary haemorrhage--DIC u Intrapartum asphyxia Brain infarction-5. 24 0-53 48 days Extreme prematurity residual HMD Severe HMD 6. 30 0"88 31 h HMD Subdural and pulmonary haemorrhage--HMD 7. 38 2-00 6 days Severe respiratory Pulmonary agenesis-IUGR--multiple problems malformations Birth asphyxia-8. 40 2.80 12 h Birth asphyxia meconium aspiration Sudden collapse H~VID=Hyalinemembranedisease; iUGR = Intrauterine"gr0wth retardation; Di c = Disseminated intravascular coagulation;NEC = Necrotizingenterocolitis. r a p i d l y r e t u r n e d to n o r m a l after t r e a t m e n t . T w o others h a d slight rises in these values w i t h i n the n o n n a l range. Clotting studies were n o r m a l on 6/7 b a b i e s tested. T h e a b n o r m a l result was on the 530 g b a b y r e f e r r e d to above. E o s i n o p h i l i a was noted in four babies, in three of w h o m it was transient. T h e f o u rth b a b y h a d h a d two i n t r a u t e r i n e transfusions. T h r e e of 17 D i r e c t C o o m b s ' t e s t s w e r e positive, all in b a b i e s with r he sus disease. T h e m e a n p e a k s e r u m c o n c e n t r a t i o n (4-sv) following 25 m g kg -t c e f t a z i d i m e w a s 74 4- 20 (range 41-140) m g 1, t. T r o u g h serum c o n c e n t r a t i o n s were 204- 10 (range 3 - 5 3 ) m g 1-1. T h e e l i m i n a t i o n phase half-life w a s 7-4 (4- 4' 1 ) h in b a b i e s who received iv therapy. I n 6/8 ba bi e s w h o r e c e i v e d i m t h e r a p y , the d r u g half-life was 5"9 (4-1-7) h, I n the r e m a i n i n g two babies , the d r u g half-lives were 35 a n d 4-3 h respectively. Babies in these two g r o u p s were of s i m i l a r postnatal age, gestational age a n d b i r t h w e i g h t . T h e t i m e t o m a x i m u m s e r u m c o n c e n t r a t i o n was 1-5 (4" 0,7) h in b a b i es r e c e i v i n g i m t h e r a p y b u t fin every case s e r u m c o n c e n t r a t i o n s e x c e e d e d 20 m g ! , ! w i t h i n 15 rain o f i n j e c t i o n . T o t a l b o d y clearance of c e f t a z i d i m e ranged f r o m 0"13 to 2 " 1 0 m l rain -I P e r k g a n d i n c r e a s e d with i n c r e a s i n g p o s t n a t a l age. G e s t a t i o n a l age h a d no e f f e c t : on the p h a r m a c o k i n e t i c s of~ c e f t a z i d i m e a n d t h e r e was no d r u g a c c u m u l a t i o n f o l l o w i n g m u l t i p l e injections. Discussion T h i s s t u d y has s h o w n that c e f t a z i d i m e (25 m g k g -~ bd) is efficacious a n d
164
I. P o l l o c k e t a / .
safe for the treatment of neonates with clinical evidence of infection, findings which are in agreement with those of Snelling, H a r t & Cooke (1983). O u r results do not support the view of Prinsloo et al. (1983) that once daily injections of 25 m g kg - l m a y be adequate for neonates. We observed no serious side effects resulting from ceftazidime therapy, a finding in line with m a n y other workers who attest to the low level of toxicity associated with this antibiotic. T h e broad in vitro activity of ceftazidime reported by Wise, A n d r e w s & Bedford (1980) is reflected by the good clinical results when compared with the conventional regimen of penicillin + gentamicin (Snelling et al., 1983). T h e r e remains, however, the problem of org/misms which are resistant to ceftazidime and to gentamicin (Shelling et al., 1983). T h e unpredictable sensitivity of S t a p h . epiderraidis and the resistance of faecal streptococci to ceftazidime pose the most immediate p r o b l e m for neonates but there are already reports of resistance among clinical isolates of enteric G r a m - n e g a t i v e rods (Roos, 1982). In our study, two strains of intrinsically resistant Enterobacter spp. were isolated from babies who were in the same ward as the treatment group but who did not receive ceftazidime. Eight of the 42 babies harboured-Cand, albicans on superficial sites at the end of treatment. T h o s e with clinical signs responded rapidly to nystatin. T h e incidence of superficial candidiasis was the same in the study group as in the general neonatal population. T h e r e was no difference in the rate of intestinal colonization with C1. diflicile between the study group and that reported for neonates who have not received antibiotics (Richardson, Alcock & G r a y , 1983)• T h e incidence of clinical signs of N E C within the S C B U did not change as a result of ceftazidime usage. T r a n s i e n t elevation of s e r u m creatinine was noted in some patients receiving ceftazidime, a finding also reported by Reed et al. (1982) in older children. T h e changes were within t h e normal range for neonates and alteration o f treatment was not considered necessary. O t h e r biochemical changes observed could be a c c o u n t e d for by the clinical condition of the baby. Positive Coombs' tests were not observed in any baby who did not have rhesus d i s e a s e and no baby was found to have abnormal clotting factors attributable to ceftazidime. &s with other cephalosp0rins studied by u s (de Louvois, Mulhall & Hurley, 1982; de L o u v o i s , Mulhall & James, 1983; de:Louvois, James & Mulhall, ::1984) gestational a g e had n o effect on t h e pharmacokinetics of ceftazidime and there :is no justification f0r reducing the daily dose (per kg) f0~ premature~ babies. Tl~is Study a d d s tO: the ~growing e v i d e n c e that ceftazidime is highly effective in the t r e a t m e n t o f infection in neonates a n d infants; that at a dosage of 25 m g kg" I b d therapeutic serum concentrations are maintained t h r o u g h o u t : t h e d o s a g e : i n t e r v a l and that i n c a s e s of: meningitis C S F penetration is good ( F 0 n g & T o m k i n s , 1983). T h e r e is some evidence that,
Ceftazidime and neonatal infection
165
in neonates at least, ceftazidime penetrates also across the non-inflamed meninges (Hawkins, Bechard & Finn, 1983). There remains the problem, e6mmon to all new cephalosporins, that Gram-negative rods will develop or acquire resistance to ceftazidime. The risk of this can be reduced only by the judicious and rational use of these agents. We have used ceftazidime as the first line antibiotic in the SCBU for a year and have not encountered any major problems due to resistant bacteria. We are grateful to Dr D. R. Harvey and Dr R. Dinwiddie, Consultant Paediatricians, for allowing us to study their patients and to the nursing staff of the SCBU for their help and cooperation. Our thanks are due to Dr E. Hughes and Dr J. Meek, Neonatal Biochemistry Unit, Hammersmith Hospital, for undertaking the biochemical investigations, and also to Glaxo Group Research Limited for their support and for funding IP during the course of this study.
References Boriello, S. P. & Honour, P. (1981). Simplified procedure for the routine isolation of Clostridium difficile from faeces, a%urnalof Clinical Pathology 34, 1124-1127. de Louvois, J., Mulhall, A. & Hurley, R. (1982). T h e safety and pharmacokinetics of cefotaxime in the treatment of neonates. Paediatric .Pharmacology 2, 275-284. de Louvois, J., Mulhall, A. & James J. (1983). An evaluation of ceftriaxone in the treatment of neonates. Abstract 74, Proceedings of the 23rd ]nterscience Conference on ~qntimicrobial Agents and Chemotherapy, Las Vegas. de Louvois, J., James, J. & Mulhall, A. (1984). Latamoxef and the neonate. Archives of Disease b~ Childhood 59, 346-350. Fong, I. W. & Tomkins, K. B. (1983). Ceftazidime cerebrospinal fluid penetration in inflamed and non-inflamed meninges. Abstract 828, Proceedings of the 23rd Interscience Confeience :on Antimicrobial ~qgents and Chemotherapy, Las Vegas. Hawkins, S. S., Bechard, D. L. & Finn, A. L. (1983). CSF penetration of ceftazidimeln patients with meningitis. Abstract 831, Proceedings of the 23rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Las Vegas. Prinsloo, J. G., Delport, ' S. D., Moncrieff, J. & Paton, A. M. (1983). A preliminary pharmacokinetic study of ceftazidime in premature, newborn and small infants, a%urnal of Antimicrobial Chemotherapy 12 (Supplement A), 361-364. Reed, M., Murdell, D., O'Brien, C., Aronsff, S. & Blumer, J. (1983). Efficacy and safety of ceftazidime in serious pediatric infections. Abstract 78, Proceedings of the 23rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Las Vegas. Richardson, S. A., Aleock, P, A . & Gray, J. (1983). Clostridium dijOicile and its toxin in healthy neonates. Lancet 2, 878. Roos, J. (1982). Ceftazidime: a questionable alternative to the aminoglycosides. Lancet 2, 551. Shelling, S., Hart, C. A. & Cooke, R. W. I. (1983). Ceftazidime or gentarnicin plus benzylpenicillin in neonates less than forty-eight hours old..~qntimierobial Chemotherapy 12 (Supplement A), 353-356. Wise, R., Andrews. J. M. & Bedford, K. A. (1980). Comparison of the in vitro activity of GR. 20263, a novel cephalosporin derivative with activities of other beta lactam compounds. Antimicrobial Agents and Chemotherapy 17, 884-889.
Ceftazidime
in the treatment
of neonatal
infection
I. P o l l o c k , * A. M u l h a ' l l a n d J. d e L o u v o i s
Queen Charlotte's Maternity Hospital, Goldhawk Road; London W 6 0 ~ f G 2qccepted for publication 9 October 1984 Summary: T h e efficacy of ceftazidime in the treatment o f neonatal sepsis was s t u d i e d in 42 low b i r t h w e i g h t p r e m a t u r e babies. F o r t y - n i n e courses of ceftazidime (25 m g / k g bd, iv or im were administered. In 19 babies,.treatm e n t was s t o p p e d after 48 h, t h e r e m a i n d e r were treated for 5 days or m o r e . Six neonates h a d bacteriological evidence of infection, one o t h e r was pyrexial and 29 h a d radiological evidence c o m p a t i b l e with respiratory tract infection. Eight of the s t u d y p o p u l a t i o n died. O n l y one death was attributed to infection w h i c h arose 3 days after c o m p l e t i o n o f a 5-day course of ceftazidime. T w o babies d e v e l o p e d clinical signs of necrotizing enterocolitis ( N E C ) . Clostridium diflicile (7) and CI. perfringens (2) were isolated from 34 p o s t - t r e a t m e n t faecal samples b u t not from the two babies ~ i t h N E C . N o faecal s a m p l e contained CI. diflicile toxin. P o s t - t r e a t m e n t cultures from 12 neonates yielded ceftazidime-resistant m i c r o - o r g a n i s m s . C e f t a z i d i m e t h e r a p y was n o t associated with significant alteration in s e r u m alanine aminotransferase, urea, creatinine, p r o t e i n or albumin. F o u r b a b i e s h a d an eosinophilia, three transient and one following two intrauterine transfusions. C o o m b s ' tests were p e r f o r m e d on 17 babies. T h e r e were no false positives. T h e a b n o r m a l clotting studies observed in one baby were n o t due to ceftazidime. I n a c o n c u r r e n t p h a r m a c o k i n e t i c study, the half-life of ceftazidime was 7-4 (so 4-4-1)h following iv administration. O t h e r pharmacokinetic values were C m a x 74 (SD4- 2 0 ) m g 1-~ t r o u g h concentration 20 (sD q- 1 0 ) m g 1-z. T o t a l b o d y clearance ranged f r o m 0-13 tO 2-10 m l m i n - t ' p e r kg a n d increased w i t h increasing postnatal age. Ceftazidime is safe and effective for the t r e a t m e n t of infected neonates achieving fnerapeutic concentrations in blood, u r i n e , cerebrospinal fluid and bronchial aspirates. T h e r e were n o significant side effects. N o major p r o b lems d u e to ceftazidime-resistant bacteria have e m e r g e d following i t s routine use i n the special care baby u n i t for 12 m o n t h s .
Introduction In neonatal medicine, broad-spectrum antibiotics are commonly i/adicated i n h i g h r i s k s i t u a t i o n s b e f o r e a m i c r o b i o l o g i c a l d i a g n o s i s is m a d e . V a r i o u s antibiotics or combinations have been :used--a reflection of the changing pattern of bacteria infecting thenewborn and the individual recluirements o f C l i f f e r e n t n e o n a t a l - U n i t s . A t p r e s e n t , t h e r e is n o i d e a l c h o i c e a n d t h e majority of units usean aminoglycoside together with peniciilin or ampicillin. Increasing resistance to these antibiotics among neonatal * Present address: Paddington Children's Hospital, London W2. 0195-670|/85/020158+08 $03.00/0
1985 T h e Hos;)i~! Infection Societv
58
Ceftazidirne and neonatal infection
159
p a t h o g e n s and the d e v e l o p m e n t of n o n - t o x i c alternatives to the a m i n o g l y c o s i d e s suggests that othe r e q u a l l y efficacious b u t safer r e g i m e n s are n o w available. C e f t a z i d i m e is a n e w derivative of c e p h a l o s p o r i n C w h i c h has the advantage over p r e v i o u s c e p h a l o s p o r i n s of b e i n g h i g h l y active against Pseudomonas aeruginosa as well as the e n t e r i c G r a m - n e g a t i v e rods, wh ile r e t a i n i n g activity against the m a j o r G r a m - p o s i t i v e p a t h o g e n s e n c o u n t e r e d in the neonate. T h i s paper reports the clinical, mic r obiologic a l a n d phaiii~acological results of a prospective s t u d y in a g r o u p of 42 neonates. T h e study was a p p r o v e d by the H o s p i t a l Ethical C o m m i t t e e a n d the D e p a r t m e n t of H e a l t h and Social Security C o m m i t t e e on Safety of M e d i c i n e s . Materials and methods
Study population T h e neonates studied were those a d m i t t e d to the special care b a b y u n i t ( S C B U ) at Q u e e n C h a r l o t t e ' s M a t e r n i t y H o s p i t a l over a pe r iod of 3 m o n t h s . All of the patients h a d clinical signs a nd s y m p t o m s suggestive of infection and w o u l d otherwise have received g e n t a m i c i n a n d penicillin.
Dose C e f t a z i d i m e was a d m i n i s t e r e d by the iv or i m route at a dose of 25 m g k g - , 12 h o u r ly. Prospective clinical assessments were m a d e b y one of us (IP) on each day of t h e r a p y a n d for 3 da ys' p o s t - t r e a t m e n t .
Laboratory investigations Blood, urine, surface swabs a nd a gastric aspirate were collected for bacteriological c u l t u r e before t r e a t m e n t started. Repeat s p e c i m e n s were taken following the isolation of a p a t h o g e n and on o t h e r occasions w h e n c l i n i c a l l y ' i n d i c a t e d . A s s e s s m e n t of the colonization rate w i t h ceftazidimeresistant bacteria of all babies in the u n i t was m a i n t a i n e d t h r o u g h o u t the s t u d y b y c u l t u r i n g all s p e c i m e n s onto 8 % horse blood agar c o n t a i n i n g 10 m g 1-1 ceftazidime. Faecal s a m p l e s c o l l e c t e d at the e n d of t r e a t m e n t were c u l t h r e d for Clostridium difficile a n d tested for the pr e se nc e of CL difficile toxin u s ing the m e t h o d s of Borriello & H o n o u r (1981). D e t e r m i n a t i o n s o f s e r u m urea, creatinine, p r o t e i n , a l b u m i n , a la nin e a m i n o t r a n s f e r a s e , h a e m o g l o b i n and total a nd differential w h i t e cell c o u n t s were u n d e r t a k e n before, d u r i n g a n d a f t e r t r e a t m e n t u s i n g r outin e l a b o r a t o r y m e t h o d s . D i r e c t C o o m b s ' tests w e r e p e r f o r m e d o n m o s t babies receiving phototherapy for h y p e r b i l i r u b i n a e m i a . Clotting~ studies ( p r o t h r o m b i n time, t h r o m b i n time, k a o l i n c e p h a l i n time) were d o n e on six b a b i e s with s i g n s s u g g e s t i v e of a clotting defect.
~narmacokznettc study, Blood s a m p l e s w e r e collected for c e f t a z i d i m e assay ¼, ½, 1,3, 5, 12 h a f t e r t h e first; dose a n d / o r at steady state ( i . e : a f t e r at least f o u r doses),~Timed u r i n e s a m p l e s and p h a r y n g e a l a s p i r a t e s were collected also for assay.
160
I. P o l l o c k e t a l .
Treatment regimen A c c o r d i n g to established practice i n the unit, c e f t a z i d i m e t h e r a p y w a s assessed after 48 h. T r e a t m e n t was stopped if there was a significant i m p r o v e m e n t i n the b a b y ' s c o n d i t i o n a n d p r e - t r e a t m e n t bacteriological cultures were negative or if an alternative positive diagnosis ha d been made. T r e a t m e n t was c o n t i n u e d for 5 days if a significant p a t h o g e n had b e e n isolated or there w ere s t r o n g . c l i n i c a l or :radiological i n d i c a t i o n s of active infection. I f m u l t i p l e chest dr a ins or central lines were in place, t r e a t m e n t was continued. W h e r e the indications for c h e m o t h e r a p y persisted, t r e a t m e n t was c o n t i n u e d for m o r e than 5 d a y s . Results
F o r t y - t w o neonates (23 m a l e s a nd 19 f e ma le s) r e c e i v e d ceftazidime. Gestation ranged f r o m 25 tO 42 ( m e a n 3 2 - 9 ~ 4 " 0 sv) weeks a n d b i r t h w e i g h t f r o m 0"53 to 4-27 ( m e a n 1.944-0-8 s o ) k g . T e n of 42 p a t i e n t s were less t h a n the 10th eentile for b i r t h w e i g h t , head c i r c u m f e r e n c e or le ngth, 12 we igh e d less t h a n 1"5 kg at birth, and 12 were less t h a n 31 weeks' gestation. For ty of 42 patients started t r e a t m e n t on or before the t h i r d postna ta l day. A total of 49 courses of c e f t a z i d i m e w e r e a d m i n i s t e r e d . N i n e t e e n courses were stopped after 48 h, 23 c o n t i n u e d for 5 days a nd seven c o n t i n u e d for 5 to 19 days. T h e p r e s e n t i n g signs and s y m p t o m s of infection together with the m a j o r indication f o r i n i t i a t i n g t h e r a p y are s h o w n in T a b l e I. R e s p i r a t o r y p r o b l e m s , usually with associated radiological changes, were the c o m m o n e s t indications for t r e a t m e n t . M a t e r n a l or ne ona ta l pyrexia or infection was the m a j o r i n d i c a t i o n for 7/49 courses. I n t u b a t i o n , the insertion of long lines and p r e m a t u r i t y were not by t h e m s e l v e s justifications for c h e m o t h e r a p y . T h e final d i a g n o s e s in the 42 patients s t u d i e d are s h o w n in T a b l e I I. F o u r babies w i t h respiratory p r o b l e m s w e n t on to develop b r o n c h o p u l m o n a r y d y s p l a s i a . Seven babies h a d signif ic a nt infection or pyrexia. A n o t h e r b a b y d e v e l o p e d necrotizing ~e n t e r o c o l i t i s ( N E C ) while r e c e i v i n g c e f t a z i d i m e , Retrospective : a sse ssme nt o f t r e a t m e n t c o n c l u d e d t h a t ' i n eight cases there h a d : b e e n no significant p a t h o l o g y , a l t h o u g h at the t i m e o f a d m i s s i o n t o t h e S C B U antibiotic t h e r a v v was t h o u g h t to be warranted. Bacteriological s p e c i m e n s collected prior to t h e i n i t i a t i o n o f t r e a t m e n t y i e l d e d ~a significant isolate: in,six cases ( T a b l e iI I I ) . O n e b a b y o f 27 weeks' g e s t a t i 0 n , ' w e i g h i n g 1 ' 1 6 kg h a d e a r l y onset: G r o u p :B Streptococcal sepsis. T h i s was rapidly cleared w i t h c e f ta z idime a l t h o u g h t h e b a b y s u b s e q u e n t l y d i e d following:~a m a s s i v e intravehtricular: haemorrhage.: C u l t u r e s t a k e n at p 0 s t - r n o r t e m w e r e sterileiPseudomonas aeruginosa isolated f r o m t h e axiUa of one b a b y before a n d d u r i n g t r e a t m e n t !was r e sponsible i f o r e ba c te r a e mia whic deVel0Ped 3 days after C d m p l e t i 0 n o f a 5-day course of ceftazidime. Thei~ p a t i e n t i n f e c t e d W i t h StaphyIococcus epidermidis s h o w e d no ~clinical i m p r o v e m e n t : a f t e r 4 \ days ~ t r e a t m e n t : withal c e f t a z i d i m e : T r e a t m e n t w a s c h a n g e d ~!t011g e n t a t n l c i n ! a n d ~penicill~:i:iBacteriaif r o m t h e other t h r e e babies h a d been::eradi~/itetl breathe:end of :treatment.
Ceftazidime and neonatal infection
161
Table I. Presenting signs and symptoms with major indications for initiating ceftc~idime therapy _ _ .
,H
,,,,,,,
,,,,
i
i
_
Presenting signs and s y m p t o m s
No. of babies
M a j o r indication for t h e r a p y
Respiratory p r o b l e m s L u n g abnormalities on chest X-ray Copious endotracheal secretions Repeated apnoea M e m b r a n e s r u p t u r e d > 10 days Maternal pyrexia Maternal infection (proven) Neonatal pyrexia Neonatal infection (proven) T w i n on ceftazidime Non-specific deterioration Intubation L o n g line catheters < 10th centile for weight etc.
38 29 9 6 8 3 1 3 2 4 3 31 15 10
27 2 2 2 2 1 1 3 2 4 3 0 0 0 i
T a b l e I I. Final diagnosis of 42 neonates treated with ceftazidime ,,i
i,,,,
ii
Hi
i
i
,
iH
Final diagnosis
N o . of babies
Hyaline m e m b r a n e disease B r o n c h o p u l m o n a r y dysplasia M e c o n i u m aspiration T r a n s i e n t tachypnoea of n e w b o r n Focal lung collapse/consolidation Neonatal infection/pyrexia Maternal infection/pyrexia T w i n receiving treatment Necrotizing enterocolitis P u l m o n a r y agenesis Asphyxia
14 4 3 5 1 7 2 2 1 1 2
_
T r e a t m e n t was changed to penicillin and gentamicin in eight babies. T w o babies with s u s p e c t e d or proven N E C also received~metronidazole: Three out '~:of eight; babies were changed empirically or ~because,: of: clinical deterioration within :48 h Of starting ~Ceftazidime. ~Treatment o f one:,baby was'changed:after 5 d a y s followingisolation of Ps.aeruginosa, and treatment of the baby with Staph. epidermidischestl infectionwas changed after.4-days. Finally, a 530 g baby of 24 weeks'::gestation failed to pr0gress following 1~1 days' treatment with ceftazidime and t r e a t m e n t was changed. Blood c l 0 t t ~ g problems, w h i c h ! w e r e f i r s t o b s e r v e d a t the end of ceftazidime therapy, Were shown~subsequently" not! t o be~associated iWith antibiotic therapy. ~The baby died aged 7 weeks With brain infarction c o n s e q u e n t u p o n extreme prematurity,
I . , P o l l o c k e t aL
162
Table I I I . Significant pre-treatment bacterial isolates f r o m 42 babies treated with ceftaMdime Organism
Site
Clinical features
I. G r o u p B streptococci
Blood
2. Ps. aeruginosa Enterobacter spp. 3. Staph. aureus
Axilla
4. Staph. epidermidis
Bronchial aspirate
5. Enterobacter spp.
Blood, bronchial aspirate, surface swabs Umbilicus
L o w birthweight, p r e m a t u r e , twin* Bacteraemia 3/7 posttreatment* Maternal pyrexia, birth asphyxia, P R M 31[7, Respiratory problems* Very severe respiratory problems, no i m p r o v e m e n t , t r e a t m e n t failure Maternal infection, P R M 13/7, Respiratory problems Umbilical sepsis
6. Enterobacter app.
Bronchial aspirate
* Patient died. PRM = prolonged rupture of membranes.
Eight of the study population died (Table IV) and all had p o s t - m o r t e m examinations. T h e death of one baby, referred to above, was attributed to bronchopneumonia due to Ps. aeruginosa and N E C . T h i s baby who had surface colonization with Ps. aeruginosa received ceftazidime for the first 5 days of life. T h r e e days after treatment stopped, the baby showed clinical signs of N E C and was treated with penicillin, gentamicin and metronidazole. A blood culture collected at that t i m e yielded Is. aeruginosa. None of the remaining deaths was attributed to microbial infection, and post-mortem cultures from the cerebrospinal fluid, heart blood and bronchus were all sterile. T h i r t y - f o u r samples of faeces were examined 2-4 days after completion of ceftazidime treatment. Clostridium diflicile was isolated from seven and CI. perfringens from two others. T w o of the isolates of CI. diflicile were toxin producers but toxin could not be detected in any of the 34 faecal samples. Neither Cl. difficile nor Sits toxin could be isolated from two babies with clinical evidence o f N E C . Twelve babies treated with ceftazidime became colonized with resistant organisms (Candidaalbicans, 8; faecal streptococci, 5; Clostridium spp., 3; Staph. aureus, 1;Pseudomonas spp., 1 ) a n d two babies who:did not receive ceftazidime w e r e c o l o n i z e d with ceftazidime-resistant strains of Enterobacterspp. Babies with oral candidiasis received nystatin; none of the other micro-organisms w a s considered t o b e o f clinicalsignificance. No Clinical s i g n s o f local reaction or:allergic p h e n o m e n a were seen in the study group. Ceftazidime t h e r a p y was not responsible for any major changes in hepatic or renal fUnCtion or i n Whitecell count, haemoglobin o r packed cell :volume. One'baby? w h o h a d a n exchange t r a n s f u s i o n had significant b u t transient elevati0n of s e r u m a l a n i n e aminotransferase, creatinine a n d urea which
163
Ceftazidime and neonatal infection
I'able IV. Cause of death in eight babies who received ceftazidime ill
1. 2.
Gestation (weeks)
Birthweight (kg)
27 30
1"17 1"25
Age at death Clinical diagnosis
,
ill
i
,,,
i
~ause of death following postmortem
5 days Severe HMD 11 days Severe HMD ?Infection 19 h Severe HMD--hypoxia 12 h Severe birth asphyxia
Massive IVH--HMD Bronchopneumonia-NEC 3. 27 1-27 Severe HMD 4. 39 3-44 Pulmonary haemorrhage--DIC u Intrapartum asphyxia Brain infarction-5. 24 0-53 48 days Extreme prematurity residual HMD Severe HMD 6. 30 0"88 31 h HMD Subdural and pulmonary haemorrhage--HMD 7. 38 2-00 6 days Severe respiratory Pulmonary agenesis-IUGR--multiple problems malformations Birth asphyxia-8. 40 2.80 12 h Birth asphyxia meconium aspiration Sudden collapse H~VID=Hyalinemembranedisease; iUGR = Intrauterine"gr0wth retardation; Di c = Disseminated intravascular coagulation;NEC = Necrotizingenterocolitis. r a p i d l y r e t u r n e d to n o r m a l after t r e a t m e n t . T w o others h a d slight rises in these values w i t h i n the n o n n a l range. Clotting studies were n o r m a l on 6/7 b a b i e s tested. T h e a b n o r m a l result was on the 530 g b a b y r e f e r r e d to above. E o s i n o p h i l i a was noted in four babies, in three of w h o m it was transient. T h e f o u rth b a b y h a d h a d two i n t r a u t e r i n e transfusions. T h r e e of 17 D i r e c t C o o m b s ' t e s t s w e r e positive, all in b a b i e s with r he sus disease. T h e m e a n p e a k s e r u m c o n c e n t r a t i o n (4-sv) following 25 m g kg -t c e f t a z i d i m e w a s 74 4- 20 (range 41-140) m g 1, t. T r o u g h serum c o n c e n t r a t i o n s were 204- 10 (range 3 - 5 3 ) m g 1-1. T h e e l i m i n a t i o n phase half-life w a s 7-4 (4- 4' 1 ) h in b a b i e s who received iv therapy. I n 6/8 ba bi e s w h o r e c e i v e d i m t h e r a p y , the d r u g half-life was 5"9 (4-1-7) h, I n the r e m a i n i n g two babies , the d r u g half-lives were 35 a n d 4-3 h respectively. Babies in these two g r o u p s were of s i m i l a r postnatal age, gestational age a n d b i r t h w e i g h t . T h e t i m e t o m a x i m u m s e r u m c o n c e n t r a t i o n was 1-5 (4" 0,7) h in b a b i es r e c e i v i n g i m t h e r a p y b u t fin every case s e r u m c o n c e n t r a t i o n s e x c e e d e d 20 m g ! , ! w i t h i n 15 rain o f i n j e c t i o n . T o t a l b o d y clearance of c e f t a z i d i m e ranged f r o m 0"13 to 2 " 1 0 m l rain -I P e r k g a n d i n c r e a s e d with i n c r e a s i n g p o s t n a t a l age. G e s t a t i o n a l age h a d no e f f e c t : on the p h a r m a c o k i n e t i c s of~ c e f t a z i d i m e a n d t h e r e was no d r u g a c c u m u l a t i o n f o l l o w i n g m u l t i p l e injections. Discussion T h i s s t u d y has s h o w n that c e f t a z i d i m e (25 m g k g -~ bd) is efficacious a n d
164
I. P o l l o c k e t a / .
safe for the treatment of neonates with clinical evidence of infection, findings which are in agreement with those of Snelling, H a r t & Cooke (1983). O u r results do not support the view of Prinsloo et al. (1983) that once daily injections of 25 m g kg - l m a y be adequate for neonates. We observed no serious side effects resulting from ceftazidime therapy, a finding in line with m a n y other workers who attest to the low level of toxicity associated with this antibiotic. T h e broad in vitro activity of ceftazidime reported by Wise, A n d r e w s & Bedford (1980) is reflected by the good clinical results when compared with the conventional regimen of penicillin + gentamicin (Snelling et al., 1983). T h e r e remains, however, the problem of org/misms which are resistant to ceftazidime and to gentamicin (Shelling et al., 1983). T h e unpredictable sensitivity of S t a p h . epiderraidis and the resistance of faecal streptococci to ceftazidime pose the most immediate p r o b l e m for neonates but there are already reports of resistance among clinical isolates of enteric G r a m - n e g a t i v e rods (Roos, 1982). In our study, two strains of intrinsically resistant Enterobacter spp. were isolated from babies who were in the same ward as the treatment group but who did not receive ceftazidime. Eight of the 42 babies harboured-Cand, albicans on superficial sites at the end of treatment. T h o s e with clinical signs responded rapidly to nystatin. T h e incidence of superficial candidiasis was the same in the study group as in the general neonatal population. T h e r e was no difference in the rate of intestinal colonization with C1. diflicile between the study group and that reported for neonates who have not received antibiotics (Richardson, Alcock & G r a y , 1983)• T h e incidence of clinical signs of N E C within the S C B U did not change as a result of ceftazidime usage. T r a n s i e n t elevation of s e r u m creatinine was noted in some patients receiving ceftazidime, a finding also reported by Reed et al. (1982) in older children. T h e changes were within t h e normal range for neonates and alteration o f treatment was not considered necessary. O t h e r biochemical changes observed could be a c c o u n t e d for by the clinical condition of the baby. Positive Coombs' tests were not observed in any baby who did not have rhesus d i s e a s e and no baby was found to have abnormal clotting factors attributable to ceftazidime. &s with other cephalosp0rins studied by u s (de Louvois, Mulhall & Hurley, 1982; de L o u v o i s , Mulhall & James, 1983; de:Louvois, James & Mulhall, ::1984) gestational a g e had n o effect on t h e pharmacokinetics of ceftazidime and there :is no justification f0r reducing the daily dose (per kg) f0~ premature~ babies. Tl~is Study a d d s tO: the ~growing e v i d e n c e that ceftazidime is highly effective in the t r e a t m e n t o f infection in neonates a n d infants; that at a dosage of 25 m g kg" I b d therapeutic serum concentrations are maintained t h r o u g h o u t : t h e d o s a g e : i n t e r v a l and that i n c a s e s of: meningitis C S F penetration is good ( F 0 n g & T o m k i n s , 1983). T h e r e is some evidence that,
Ceftazidime and neonatal infection
165
in neonates at least, ceftazidime penetrates also across the non-inflamed meninges (Hawkins, Bechard & Finn, 1983). There remains the problem, e6mmon to all new cephalosporins, that Gram-negative rods will develop or acquire resistance to ceftazidime. The risk of this can be reduced only by the judicious and rational use of these agents. We have used ceftazidime as the first line antibiotic in the SCBU for a year and have not encountered any major problems due to resistant bacteria. We are grateful to Dr D. R. Harvey and Dr R. Dinwiddie, Consultant Paediatricians, for allowing us to study their patients and to the nursing staff of the SCBU for their help and cooperation. Our thanks are due to Dr E. Hughes and Dr J. Meek, Neonatal Biochemistry Unit, Hammersmith Hospital, for undertaking the biochemical investigations, and also to Glaxo Group Research Limited for their support and for funding IP during the course of this study.
References Boriello, S. P. & Honour, P. (1981). Simplified procedure for the routine isolation of Clostridium difficile from faeces, a%urnalof Clinical Pathology 34, 1124-1127. de Louvois, J., Mulhall, A. & Hurley, R. (1982). T h e safety and pharmacokinetics of cefotaxime in the treatment of neonates. Paediatric .Pharmacology 2, 275-284. de Louvois, J., Mulhall, A. & James J. (1983). An evaluation of ceftriaxone in the treatment of neonates. Abstract 74, Proceedings of the 23rd ]nterscience Conference on ~qntimicrobial Agents and Chemotherapy, Las Vegas. de Louvois, J., James, J. & Mulhall, A. (1984). Latamoxef and the neonate. Archives of Disease b~ Childhood 59, 346-350. Fong, I. W. & Tomkins, K. B. (1983). Ceftazidime cerebrospinal fluid penetration in inflamed and non-inflamed meninges. Abstract 828, Proceedings of the 23rd Interscience Confeience :on Antimicrobial ~qgents and Chemotherapy, Las Vegas. Hawkins, S. S., Bechard, D. L. & Finn, A. L. (1983). CSF penetration of ceftazidimeln patients with meningitis. Abstract 831, Proceedings of the 23rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Las Vegas. Prinsloo, J. G., Delport, ' S. D., Moncrieff, J. & Paton, A. M. (1983). A preliminary pharmacokinetic study of ceftazidime in premature, newborn and small infants, a%urnal of Antimicrobial Chemotherapy 12 (Supplement A), 361-364. Reed, M., Murdell, D., O'Brien, C., Aronsff, S. & Blumer, J. (1983). Efficacy and safety of ceftazidime in serious pediatric infections. Abstract 78, Proceedings of the 23rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Las Vegas. Richardson, S. A., Aleock, P, A . & Gray, J. (1983). Clostridium dijOicile and its toxin in healthy neonates. Lancet 2, 878. Roos, J. (1982). Ceftazidime: a questionable alternative to the aminoglycosides. Lancet 2, 551. Shelling, S., Hart, C. A. & Cooke, R. W. I. (1983). Ceftazidime or gentarnicin plus benzylpenicillin in neonates less than forty-eight hours old..~qntimierobial Chemotherapy 12 (Supplement A), 353-356. Wise, R., Andrews. J. M. & Bedford, K. A. (1980). Comparison of the in vitro activity of GR. 20263, a novel cephalosporin derivative with activities of other beta lactam compounds. Antimicrobial Agents and Chemotherapy 17, 884-889.