Keywords: C-reactive protein, Newborn, Sepsis.

Neonatal septicemia remains a significant cause of neonatal morbidity and mortality. The incidence of neonatal sepsis varies between 11 to 24.5 per thousand live births in India(1). Its clinical manifestations vary from being specific to subtle, testing the very skills of a pediatrician. The inability to be certain of infection, coupled with non-specific signs of the life threatening illness in neonates have resulted in widespread use of antibiotics, aggravating the problem of antibiotic resistance. There is an increasing need for careful evaluation of indications and duration of treatment, which in turn would shorten the length and cost of hospital stay and diminish the trauma and side effects of antibiotics.

C-reactive protein (CRP), an acute phase reactant, is synthesized in the liver in response to inflammatory cytokines and may rise more than 1000 times during an acute phase response. It falls quickly after efficient elimination of microbial stimulus, due to its short half-life of 19 hours(2). Thus CRP may be used as a parameter to identify the time period when antibiotics therapy can safely be discontinued in case of suspected neonatal septicemia, which was the aim of the present study.

The present study was conducted in the Department of Pediatrics, IGMC, Shimla from June 2000 to May 2001. Fifty consecutive neonates up to 4 weeks of age with birth weight more than 1500 g and suspected septicemia were studied prospectively. Septicemia was suspected with "sepsis score" which included following signs and symptoms such as refusal for feed, abdominal distention, vomiting, lethargy, jaundice, poor cry, seizures, diarrhea, apnea, tachypnea, poor capillary refill, hypo-thermia, fever and umbilical discharge(3). If baby had three or more than three of above signs or symptoms septicemia was suspected. Neonates who had undergone surgery and those with diagnosis of meningitis were excluded from the study because they require longer duration of treatment regimen. Serum CRP, micro ESR, blood culture and sensitivity was done in all the cases along with other investigations such as hemogram, X-ray chest, swabs for culture and sensitivity as and when required.

CRP value was estimated by latex agglutination method with CRP kit manu-factured by SPAN Diagnostics Ltd. as per instructions in the manual provided by the company. The CRP value of more than 6 mg% was taken as abnormal. Serum CRP was estimated again 48 hours after initiation of therapy. If it was less than 6 mg%, antibiotics were stopped and patients were assigned to Group 1. Neonates with CRP more than 6 mg% were assigned to Group 2. Group 2 was further subdivided into 2a and 2b depending upon whether CRP was done every other alternative day (2a) or only on the 7th day after commencing of antibiotic therapy (2b). Antibiotics were stopped when CRP levels returned to normal (<6 mg%). After stopping the treatment babies were observed for 48 hours in the hospital and followed upto 4 weeks for any relapse.

In the present study, out of fifty neonates 11 weighed between 1500-2000 g, 8 weighed between 2001-2499 g and 31 neo-nates weighed >2500 g. Fifty eight percent (n = 29) of the total neonates were male; 20% (n = 10) were preterm. Twenty six percent (n = 13) presented within 72 hours of life (early onset septicemia) and 74% (n = 37) after 72 hours (late onset septicemia). Table I shows the presenting symptoms and signs.

Symptoms*

N

(%)

Refusal for feed

33

(66)

Lethargy

21

(42)

Poor cry

10

(20)

Diarrhea

3

(6)

Vomitting

3

(6)

Fever

3

(6)

Excessive crying

1

(2)

Signs*

N

(%)

Jaundice

15

(30)

Pyoderma

8

(16)

Hypothermia

7

(14)

Cyanosis

6

(12)

Abdominal distention

5

(10)

Seizures

4

(8)

Conjunctivitis

4

(8)

Vomiting

3

(6)

Fever

3

(6)

Apnea

2

(4)

Tachypnea

2

(4)

Excessive crying

1

(2)

Poor capillary refill

1

(2)

*More than one sign or symptom were present together.

Refusal for feeds, lethargy, and jaundice were the main presenting features followed by poor cry, pyoderma and hypothermia. Incidence of blood culture positivity was 42%, out of which 47.62% were gram positive and 52.48% gram negative. Amongst gram negative, Klebsiella was the commonest organism (23.8%) followed by E. coli (19.04%) and Acinetobacter (9.52%). Amongst gram positive, coagulase positive Staphylococci accounted for 28.27% cases. CRP was positive in 50% and raised micro ESR in 48% cases.

Table II shows the CRP guided distribution of treatment, relapse rate in various groups and correlation with blood culture results. Out of 50 cases of suspected neonatal septicemia CRP was negative after 48 hours in 44% (n = 22) cases and antibiotics were stopped, no relapse was observed within 4 weeks (Group 1). In remaining 56% (n = 28) cases where CRP was raised after 48 hours antibiotics were stopped on the 5th day in 2% (n = 1) and continued for more than 7 days in 26% (n =13) cases as CRP was raised even on the 7th day (Group 2a). In Group 2b antibiotics were stopped in 6% (n = 3) on 7th day and in 22% (n = 11) continued for more than 7 days. CRP was not done beyond 7 days in any group.

There was no relapse in any group within 4 weeks of discontinuation of antibiotics (negative predictive value of 100%). The anti-biotics were required for more than 7 days in all neonates with raised CRP and positive blood culture.

Bacterial infection stimulates the hepato-cytes to produce CRP: a nonspecific immune response, which is a useful clinical marker for the individual host-pathogen interaction. Since the half life of CRP is less than 3 days, a rapid fall is seen with successful therapy, as demonstrated in the present study.

The most common symptoms, by which 66% of these patients presented were refusal for feed, followed by lethargy and jaundice which is similar to the observation of Guha, et al.(4). Fever was not a prominent feature in the present study as demonstrated by other workers(4,5); instead hypothermia was more common (14% vs 6%). It could be related to cold climate of this region.

The incidence of blood culture positivity was 42% in the present study, which is similar to other studies(5,6). The pattern of bacterial isolates was different in different studies due to geographical variations and use of different antibiotics at different centers.

Positive CRP and raised micro-ESR was similar to that reported by Bhartia, et al.(6). Similarly, CRP was positive in all culture positive cases. However, micro ESR was not included in other studies. The comparison of both CRP and micro-ESR with positive blood cultures was statistically significant (p <0.05). There was no relapse in any of the cases in which antibiotics were stopped following normalization of CRP giving a negative predictive value of 100%, which is similar to the observation claimed by Stephen, et al.(8). A similar study by Squire, et al.(9) revealed that authors were able to stop antibiotics in 66.5% of cases within 72 hours and could reduce the duration of treatment by 20% in suspected neonatal septicemia cases(9).

Twenty-one out of 24 (87.5%) cases that required longer duration of antibiotic therapy (>7 days) had positive blood culture suggesting that, those with positive blood culture and raised CRP needed longer duration of antibiotics therapy. No study comparing the blood culture positivity and raised CRP with duration of treatment is available. Further studies are required to determine the duration of antibiotics therapy in neonatal septicemia with raised CRP levels even after 7 days of therapy.

Contributors: AG and RKK supervised the study which was conducted by RSJ and KP. All authors were involved in study design, and writing the paper. RKK shall stand guarantor for the study.

Funding: None.

Competing interests: None stated.

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9. Squire EN, Reich HM, Merestein GB, Favara BE, Todd J. Critria for the discontinuation of antibiotic therapy during presumptive treat-ment of suspected neonatal infection. Pediatr Infect Dis 1982; 1: 85-90.