Indian Pediatr 2011; 48:
How Long Do You Treat Clinically Diagnosed
Neonatal Sepsis With Negative Cultures?
Robert S Baltimore
Professor of Pediatrics and Epidemiology, Yale University
School of Medicine, Associate Hospital Epidemiologist for Pediatrics,
Yale-New Haven Hospital, New Haven Connecticut, USA.
s a Pediatric Infectious Diseases
specialist it is very common for me to be asked to comment on how long a
child with a particular illness should be treated with antibiotics. While
I do have some opinions based upon experience, it is usually very
difficult to apply Evidenced-Based Medicine to this situation. Once an
infection is defined, one can look up the opinions of experts in textbooks
and medical reviews for guidance but often it is either difficult to
categorize the infection status of a particular patient with complex or
unique findings, or the recommendations are vague. Why is this?
It is necessary to know what duration of treatment is
unacceptably short, in order to really know the optimal amount of time to
treat a certain infection. Consider the possibility of conducting a
prospective study to treat a specific infection in which a suitable number
of patients are randomized to treatment groups with a duration of
antibiotics of 5, 7, 10, 12, or 14 days. If the outcome is satisfactory
for 5% of those treated for 5 days, 15% for those treated for 7 days, and
95% for those treated for 10, 12 or 14 days it would be easy to judge that
treatment for 10 days is recommended. Fewer than 10 days may cause the
patient unacceptable risk and longer than 10 days is associated with an
excess of exposure to antibiotics. If the only published clinical study
used treatment for 14 days, we might never know that a shorter duration is
acceptable. Indeed there may be some concern about the ethics of putting
patients to unacceptable risk by performing a study to shorten the
duration of treatment.
Saini, et al. , in this issue, recognized
that the recommendations for treatment of neonates who are suspected of
having sepsis but who have negative cultures are not based on strong
evidence. Indeed there is a lack of information regarding whether such
infants actually have infection. In all the studies of neonatal sepsis in
which I have participated, we require culture of a pathogen from blood, an
organ, or pus from a closed space [2-4]. This requires exclusion of
patients diagnosed as having "clinical sepsis" with negative cultures.
Saini, et al.  have shown equivalent outcomes
for infants with negative cultures and whose symptoms have remitted
whether they are treated for 48-96 hours or 7 days. This is gratifying as
I have recommended 2-3 days of antibiotics for infants suspected of having
sepsis but whose cultures were all sterile [5,6]. It is necessary to note
some limitations of how this study was conducted and any conclusions must
take into consideration that the sample size was small. First, the infants
were all over 30 weeks gestation age and over 1000 grams birth weight.
Since the rate of sepsis is highest for infants <1000 grams birthweight,
the infants in this study were not at maximum risk for sepsis. Second,
there were only a small number of infants whose mothers received
antibiotics before delivery (10 in all). Since one of the most vexing
areas for management of infants with suspected sepsis is whether negative
cultures can be trusted if the infant has already been exposed to
antibiotics by mother’s treatment, this study does not provide guidance
for such infants. Finally, it is doubtful that I could persuade
neonatologists who routinely treat for 7 days to shorten to 2-3 days based
on a study with only 26 infants in each arm. However, it might allow such
neonatologists to participate in a much larger study aimed at reducing the
length of treatment for infants with negative cultures. Our own data
suggest the decision to start antibiotic treatment in low birth weight
infants is most frequently made on the day of birth [2,3]. If a
sufficiently-sized study confirms that antibiotics can be discontinued
after 2-3 days it would save unnecessary treatment in a considerable
number of infants.
Competing interests: None stated.
1. Saini SS, Dutta S, Ray P, Narang A. Short course
versus 7-day course of intravenous antibiotics for probably neonatal
septicemia: A pilot open-label randomized controlled trial. Indian Pediatr.
2. Almuneef MA, Baltimore RS, Farrel PA, Reagan-Cirincione
P, Dembry L-M. Molecular typing demonstrating transmission of
gram-negative rods in a neonatal intensive care unit in the absence of a
recognized epidemic. Clin Infect Dis. 2001;32:221-7.
3. Fonseca, SNS, Ehrenkranz RA, Baltimore RS.
Epidemiology of antibiotic use in a neonatal intensive care unit. Infect
Control Hosp Epidemiol. 1994;15: 156-62.
4. Bizzarro MJ, Raskind C, Baltimore RS, Gallagher PG.
Seventy-five years of neonatal sepsis at Yale: 1928-2003. Pediatrics.
5. Baltimore RS. Perinatal bacterial and fungal
infections. In: Jenson HB, Baltimore RS, editors. Pediatric
Infectious Diseases. Principles and Practice. Second Edition.
Philadelphia: WB Saunders Co; 2002. p.1119-34.
6. Baltimore RS. Neonatal sepsis: epidemiology and management. Pediatr