cefoperazone sulbactam en rn

Original Articleped_3458 60..63

Use of Cefoperazone/sulbactam in neonates

Fahri Ovali, Tugba Gursoy, Ilkay Sari, Demet Divrikli and Alev Aktas

Neonatal Intensive Care Unit, Zeynep Kamil Maternity and Children’s Training and Research Hospital, Istanbul, Turkey

Abstract Background: Neonates are at high risk for nosocomial infections due to multidrug-resistant pathogens. The use ofb-lactamase inhibitors in combination with b-lactam antibiotics broadens the antimicrobial spectrum. Cefoperazone/sulbactam is used in children but there are limited data on its usage in neonates. The purpose of the present study wastherefore to evaluate the use of cefoperazone/sulbactam in the treatment of neonatal infections caused by multidrug-resistant pathogens.Methods: The records of neonates who were hospitalized and who received cefoperazone/sulbactam were reviewed.Results: There were 90 infants who received cefoperazone/sulbactam. A pathogen could be isolated in 41 (45.6%) of theinfants. In total, 17.1% of isolated pathogens were resistant to cefoperazone/sulbactam. Side-effects were seen in fourof the infants. Two infants had cholestasis, one infant had neutropenia and one had superinfection with candida.Conclusion: Cefoperazone/sulbactam can be used in the treatment of nosocomial infections caused by multidrug-resistant pathogens in neonates.

Key words cefoperazone/sulbactam, infection, multidrug-resistant microorganism, neonate, nosocomial infection.

In spite of the advances in the diagnosis and treatment of sepsis inrecent years, sepsis is still an important cause of morbidity andmortality in neonatal intensive care units (NICUs). Furthermore,these are units that are at utmost risk for nosocomial infectionscaused by multidrug-resistant pathogens in hospitals.1–3 Cefopera-zone has a broad spectrum activity against both Gram-positive andGram-negative bacteria,4 which may make it a suitable choice forthe treatment of sepsis acquired in NICU. The use of b-lactamaseinhibitors in combination with b-lactam antibiotics is currentlyone of the most successful strategies to combat a specific resis-tance mechanism. Sulbactam, a b-lactamase inhibitor, has beenshown to enhance the in vitro spectrum of cefoperazone.5

Cefoperazone/sulbactam is widely used in older children andadults, but there are limited data on its use in neonates. The aim ofthe present study was therefore to evaluate the use and the side-effects of cefoperazone/sulbactam in the treatment of nosocomialinfections caused by multidrug-resistant pathogens.

Methods

The records of 90 neonates hospitalized at the NICU of ZeynepKamil Maternity and Children’s Hospital between May 2007and December 2007 and who received cefoperazone/sulbactamwith the diagnosis of sepsis, pneumonia, urinary tract infectionand osteomyelitis were reviewed. Thermal instability (fever,

hypothermia), not doing well, not sucking well, irritability,hypotonia, lethargy, tachypnea, grunting, retractions, cyanosis,apnea, jaundice, hepatomegaly, vomiting, abdominal distensionand seizures were accepted as signs of sepsis.1,3,6 Peripheralblood smear, complete blood count, C-reactive protein andblood culture were obtained from these babies. If a microor-ganism was isolated from the blood culture, culture-provensepsis was diagnosed. The diagnosis of clinical sepsis wasmade in neonates having the aforementioned signs of sepsissupported by laboratory findings, but who had no bacterialgrowth in their cultures. Nosocomial sepsis was diagnosed inneonates who had the aforementioned clinical and laboratoryfindings after the third postnatal day or after an invasive pro-cedure. Upon isolation of carbapenem-resistant microorganismsin the blood culture of neonates with nosocomial sepsis,empiric antibiotic protocol for suspected nosocomial infection,which was meropenem plus vancomycin, was changed tocefoperazone/sulbactam and vancomycin (10 mg/kg per dose,dosing interval dependent on the gestational age of the patient).Before changing the protocol, the resistance pattern of the iso-lated pathogens against cefoperazone/sulbactam was evaluated,and they were found to be susceptible to this agent.

Cefoperazone/sulbactam was given to babies if (i) the baby’sclinical signs deteriorated under first-line therapy, which wasampisillin and gentamicin (n = 44); (ii) the baby had no sign ofinfection in the first postnatal day, but had an invasive proce-dure such as umbilical catheterization and deteriorated after-wards (n = 2); or (iii) the baby developed nosocomial infectionduring follow up in NICU (n = 44). Those patients who hadclinical and laboratory findings of sepsis received 150 mg/kgcefoperazone/sulbactam per day in two divided doses together

Correspondence: Tugba Gursoy, MD, Neonatology, Zeynep KamilMaternity and Children’s Training and Research Hospital, NeonatalIntensive Care Unit, Uskudar, Istanbul 34662, Turkey. Email:[email protected]

Received 3 February 2011; revised 11 August 2011; accepted 17August 2011.

Pediatrics International (2012) 54, 60–63 doi: 10.1111/j.1442-200X.2011.03458.x

© 2011 The AuthorsPediatrics International © 2011 Japan Pediatric Society

with vancomycin in order to obtain full coverage of both Gram-positive and Gram-negative microorganisms. If cultures indi-cated Gram-positive microorganisms, cefoperazone/sulbactamtreatment was discontinued. Response to treatment was evalu-ated according to the changes observed in clinical and labora-tory findings. The course of each baby was monitored for side-effects of cefoperazone/sulbactam such as nausea, vomiting,diarrhea, urticaria, drug-induced fever, hypersensitivity syn-drome, reversible neutropenia, positive direct Coombs test,anemia, eosinophilia, thrombocytopenia, hypoprothrombinemia,elevated liver enzymes, jaundice and superinfection. Blood cul-tures were drawn into Bactec bottles and resistance to micro-organisms was evaluated using the disk diffusion method(Becton, Dickinson & Company, Sparks, MD, USA; mero-penem disks contained 10 mg meropenem; cefoperazone/sulbactam disks contained 30 mg sulbactam and 75 mgcefoperazone). Resistance was detected according to Clinicaland Laboratory Standards Institute standards. Parental consentwas obtained for all therapies.

Statistical analysis

Data are given as percentages for categorical variables, as mean1SD for approximately normally distributed continuous vari-ables, and as medians (min–max) for skewed continuous vari-ables. The McNemar test was used to compare the resistancepattern of the antibiotics. When accompanied by a clinicallysignificant difference, P < 0.1 was interpreted as reflectingchanges that were not due to chance.

Results

There were 90 newborns (41 female, 49 male) with a meangestational age of 30.3 1 4.1 weeks (23–40 weeks) and a meanbirthweight of 1392 1 557 g (510–3250 g) who receivedcefoperazone/sulbactam started at a median of 6.5 postnatal days(range, 3–87 days) for a duration of 12.2 1 6.6 days (1–30 days).The diagnoses were as follows: sepsis confirmed with clinicalfindings and/or sepsis work-up, n = 80; pneumonia, n = 8; urinarytract infection, n = 1; or osteomyelitis, n = 1. Forty-four (48.9%) ofthe babies received antibiotics prior to cefoperazone/sulbactamfor a mean duration of 7.6 1 7.9 days.Apathogen could be isolatedin 41 (45.6%) of the infants. One of the pathogens was isolatedfrom the urine culture and 40 of them were isolated from bloodcultures. The isolated pathogens were staphyloccocal species (n =20; three of them were S. epidermidis, 17 of them were S. aureus),

Klebsiella (n = 11); streptococcal species (n = 3; one of them wasS. agalactiae whereas species were not defined in the remainingtwo); Escherichia coli (n = 3), enterobacteria (n = 3) andPseudomonas (n = 1). In total, 17.5% of isolated pathogens (7/40)were resistant to cefoperazone/sulbactam (four of the staphyloc-cocal species, one of the streptococcal species, one K. pneumonia,one enterobacteria; Table 1). All the other pathogens (82.5%)were sensitive to this antibiotic. Side-effects were seen in four(4.4%) of the infants. Two infants had cholestasis, one infant hadneutropenia and one had superinfection with candida. The babywith candida superinfection died because of candida sepsis. Thebaby with Klebsiella sepsis that was resistant to cefoperazone/sulbactam died in the first day of therapy before we could obtainthe results of the antibiogram. The baby with enterobacteria sepsisthat was resistant to cefoperazone/sulbactam, however, was clini-cally better when the result of the antibiogram was obtained. Thecontrol blood culture was sterile and she was discharged after 14days of therapy.

A total of 24 patients (26.6%) died. Seven (29.2%) of thepatients died due to sepsis with Gram-positive microorganisms.Four (16.7%) of the patients died in the first 72 h of therapy soefficacy of treatment could not be evaluated in these patients. Onepatient (4.2%) died because of candida superinfection. Theremaining 12 patients (50%) who were all premature died afterclinical and laboratory improvement, due to reasons other thansepsis such as bronchopulmonary dysplasia, grade 3–4 intraven-tricular hemorrhage and metabolic disease.

Fifteen (36.6%) of 41 isolated pathogens (six Klebsiella, eightstaphyloccocal species, one enterobacteria) were resistant to car-bapenems, 38.9% of them (14/36 because only 36 of the isolatedpathogens had aminoglycoside disk used in the antibiogram)were resistant to aminoglycosides (three K. pneumoniae, nineof the staphyloccocal species, two of the streptococcal species)and 35.1% (13/37) of them were resistant to third-generationcephalosporins (three K. pneumoniae, six of the staphyloccocalspecies, two of E. coli, two of enterobacteria; Table 1). When wecompared the resistance pattern of cefoperazone/sulbactam withcarbapenems and aminoglycosides, more pathogens were resis-tant to carbapenems and aminoglycosides and the difference wasstatistically significant (P = 0.09 and 0.06 respectively). Butalthough more organisms were resistant to third-generationcephalosporins when compared with cefoperazone/sulbactam,the difference was not statistically significant (P = 0.18).

No resistance to vancomycin was observed in staphylococcalor streptococcal species.

Table 1 Resistance patterns (%)

Carbapenems Aminoglycosides Third-generationcephalosporins

Cefoperazone/sulbactam

Klebsiella 54.5 30 37.5 10E. coli – – 66.7 –Enterobacteria 33.3 – 66.7 33.3Pseudomonas – – – –Staphylococcus spp 40 52.9 31.6 20Streptococcus spp – 66.7 – 33.3

Cefoperazone/sulbactam and neonates 61


Discussion

Infections cause significant mortality and long-term morbidity inneonates, especially for very low-birthweight premature infants.The total number of neonates who develop nosocomial infectionper admission varies from 6.24% to 33% or, when reported as totalinfections per 1000 patient days, from 4.84 to 22.6.7 The variabil-ity in infection rates depends on the gestational age, environmentalfeatures and care practices. In the Stoll et al. study done at theacademic centers of the National Institute of Child Health andHuman Development (NICHD) Neonatal Research Network, thevast majority (70%) of late-onset infections were caused byGram-positive organisms (coagulase-negative Staphylococcus,S. aureus, Enterococcus spp., and group B Streptococcus). Gram-negative pathogens (E. coli, Klebsiella, Pseudomonas, Entero-bacter, and Serratia) were responsible for 22% of the infections,8

a finding similar to the present one.Because cefoperazone can be used efficiently for the treat-

ment of infections caused by both Gram-negative and positivemicroorganisms, it seems logical to use it for nosocomial infec-tions observed in NICUs. Cefoperazone possesses acceptableb-lactamase stability, especially against Gram-positive andchromosome-mediated Gram-negative enzymes.5 Some morefrequently isolated b-lactamases found in members of theEnterobacteriaceae family, however, can efficiently destroycefoperazone.5 Also, the cephalosporinases produced by theBacteroides fragilis group hydrolyze this newer cephalosporin.Sulbactam combined with cefoperazone prevents its destructionby some clinically prevalent b-lactamases, especially those pro-duced by E. coli and the anaerobes.5 The addition of sulbactamto cefoperazone inhibits hydrolytic activity of b-lactamasesirreversibly and increases its in vitro spectrum of antimicrobialactivity, principally among members of the Enterobacteria-ceae and Bacteroides species. In one study it was shown thatthe presence of sulbactam converted 22 of 63 cefoperazone-resistant enteric bacilli to cefoperazone susceptible.9

There has been no study done in neonates on cefoperazone/sulbactam so far. In a study in adults comparing the effects ofcefoperazone/sulbactam plus vancomycin therapy with imi-penem plus vancomycin therapy, the frequency of side-effectswas significantly higher for imipenem plus vancomycin, due totherapy-associated nausea and vomiting.10 The overall fre-quency of superinfections was similar with both regimens, butClostridium difficile colitis occurred significantly more often inpatients receiving imipenem plus vancomycin.10 In that study itwas concluded that cefoperazone-sulbactam plus vancomycinwas an effective alternative to imipenem plus vancomycin forinitial therapy of fever in neutropenic patients.10

In the present study we have shown that the resistanceobserved against cefoperazone/sulbactam was lower than theresistance observed against other antibiotics (carbapenems, ami-noglycosides and third-generation cefalosporins) used in theNICU at Zeynep Kamil Maternity and Children’s Training andResearch Hospital. Therefore cefoperazone/sulbactam can beproposed as an alternative agent to carbapenems in the treatmentof nosocomial sepsis in NICUs.

The reported side-effects of cefoperazone/sulbactam werenausea, vomiting, diarrhea, urticaria, drug-induced fever, hyper-sensitivity syndrome-reversible neutropenia, positive directCoombs test, anemia, eosinophilia, thrombocytopenia, hypopro-thrombinemia, elevated liver enzymes, jaundice and superinfec-tion.5 We could not, however, find any study done or casereported on the neonatal period concerning the side-effectsof cefoperazone/sulbactam. In the present study, neutro-penia, thrombocytopenia, hypoprothrombinemia, elevated liverenzymes and jaundice were thought to be side-effects ofcefoperazone/sulbactam, if they were absent at the beginning ofthe therapy when the diagnosis of sepsis was made and devel-oped after starting the therapy. These were observed only infour patients (4.4%). In one study the incidence of treatment-related adverse events was reported to be 6.5%, and 3.2% hadto discontinue the therapy due to treatment-related adverseevents.11 In another study adverse reactions were noted in twoout of 39 patients (5%), and in one of them urticaria requiringdiscontinuation of the drug was seen.12 Both of these studieswere done in adults. The number of side-effects observed in thepresent study was lower than that reported in these studies.Therefore, cefoperazone/sulbactam can be used in NICUs forthe treatment of nosocomial infections caused by multidrug-resistant pathogens without any apparent adverse effects. Themajor limitation of the present study, however, is that it wasretrospective, but because the drug is not approved for use inneonates, a randomized controlled study could not be per-formed. Also, blood concentrations of the drug were notobtained and this is not a pharmakokinetic study but a clini-cal one.

In the study by Pfaller et al. the sensitivity of 823 bacteriaisolated in 11 Colombian hospital laboratories to six broad spec-trum b-lactam antimicrobial agents were determined in 1998, andthese data were compared with results of a similar study con-ducted in 1997. It was shown that the sensitivity of isolatedpathogens to imipenem decreased from 96.6% to 93.2%, tocefoperazone/sulbactam from 90.5% to 84.1%, to cefepime from93.6% to 80.9% and to cefotaxime from 74.9% to 65.6%.13 Inshort, gradual increase in antibiotic resistance was observed.

In the study by Iregbu et al. Acinetobacter species that causenosocomial infections showed multiple resistance to the range ofantibiotics tested and all the isolates produced b-lactamase.14 Onehundred percent of the isolates were susceptible to cefoperazone-sulbactam, 77.6% were susceptible to cefotaxime, 84.5% toampicillin-sulbactam, 58.6% to ceftazidime, 65.6% to ticarcillin-clavulanic acid and 70.7% to ciprofloxacin.

In the present study 82.5% of the isolated pathogens weresensitive to cefoperazone/sulbactam, 64.9% were sensitive tothird-generation cephalosporins, 63.4% were sensitive to carbap-enems and 61.1% were sensitive to aminoglycosides. Isolatedpathogens showed more resistance to carbapenems and ami-noglycosides when compared with cefoperazone/sulbactam andthe difference was statistically significant. There was no statisti-cally significant difference, however, between the resistancepatterns of cefoperazone/sulbactam and third-generation cepha-losporins and this might be due to the low number of cases.

62 F Ovali et al.


Broad spectrum antibiotics are well shown to cause candidasuperinfection. In a NICU where meropenem was used, candidasuperinfection was seen in 20% of patients and Candida albicanscolonization was reported in 10% of patients.15 Whereas, in thepresent study candida superinfection was detected in only one ofthe babies (1.1%). Furthermore, carbapenems were suggested tocontribute to increased detection of metallo-b-lactamase (MBL)-producing Pseudomonas aeruginosa isolates, which are resistantto almost all broad spectrum b-lactams and carbapenems.16 Wehad only one P. aeruginosa among the isolated pathogens,however, and it was sensitive to all the antibiotics tested.

In order to study the pharmacokinetics and efficacy of a drug,it should be used alone on the subject. Starting two antibiotics forgreater coverage of microorganisms (both for Gram-negative andGram-positive), however, is a common practice in neonatal unitsand we had to start vancomycin and cefaperazon/sulbactam in therelevant patients. Vancomycin was discontinued usually on thethird day of the regimen, once a Gram-negative organism wasidentified. Starting two antibiotics together may complicate theeffect of the other, but otherwise, starting only one drug empiri-cally is not ethically justified. In contrast, we believe that givingvancomycin for 3 days in a patient with Gram-negative sepsiswill not have any significant effect on the efficacy of cef-operazon/sulbactam, which is used for much longer periodsbecause, as it is well known, Gram-negative organisms are resis-tant to vancomycin. We conclude that cefoperazone/sulbactamcan be an alternative in the treatment of nosocomial infectionscaused by multidrug-resistant pathogens in NICUs and, whencompared with carbapenems reported in literature, they causeless candida superinfection. Before making any further recom-mendation, however, prospective randomized controlled studiesneed to be done to compare its safety and efficacy with otherantibiotics. We also emphasize the need to update the antibioticregimens used in NICUs according to the resistance patterns ofthe isolated pathogens.

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Cefoperazone/sulbactam and neonates 63


cefoperazone sulbactam en rn

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