<p>Amongst the common reasons of admission to NICUs is possible bacterial infection. Many neonates admitted to the NICU's carry a discharge diagnosis of “rule out sepsis”, and these infants account for up to 25% of NICU days in some units (<xref ref-type="bibr" rid="bib001">1</xref>). The signs and symptoms of neonatal sepsis are protean and nonspecific and it caries a high risk of mortality. There is a fear factor in clinician's mind that to delay treatment raises the risk of mortality, also the presumptive treatment with antibiotics based on subtle laboratory or clinical findings results in overtreatment (<xref ref-type="bibr" rid="bib002">2</xref>). Historically between 11 and 23 non-infected newborns were treated with antibiotics for every one with proven sepsis (<xref ref-type="bibr" rid="bib003">3</xref>,<xref ref-type="bibr" rid="bib004">4</xref>). There is also a wide variation of practice in the length of stay for term infants with sepsis evaluations but negative cultures, ranging from a few days to more than a week (<xref ref-type="bibr" rid="bib002">2</xref>).</p></sec><sec id="sec001"><title>The problem

Journal of Neonatology

0973-21870973-2179

National Neonatology Forum

jn-20-1-004

REVIEW ARTICLE

Use and misuse of antibiotics in neonatal septicaemia

Saili

Arvind

*Saili

Ashima Malik

Department of Pediatrics, Lady Hardinge Medical College, New Delhi - 110 001

*E-mail: sailiarvind@gmail.com

1–32006

2012427

<p>Amongst the common reasons of admission to NICUs is possible bacterial infection. Many neonates admitted to the NICU's carry a discharge diagnosis of “rule out sepsis”, and these infants account for up to 25% of NICU days in some units (<xref ref-type="bibr" rid="bib001">1</xref>). The signs and symptoms of neonatal sepsis are protean and nonspecific and it caries a high risk of mortality. There is a fear factor in clinician's mind that to delay treatment raises the risk of mortality, also the presumptive treatment with antibiotics based on subtle laboratory or clinical findings results in overtreatment (<xref ref-type="bibr" rid="bib002">2</xref>). Historically between 11 and 23 non-infected newborns were treated with antibiotics for every one with proven sepsis (<xref ref-type="bibr" rid="bib003">3</xref>,<xref ref-type="bibr" rid="bib004">4</xref>). There is also a wide variation of practice in the length of stay for term infants with sepsis evaluations but negative cultures, ranging from a few days to more than a week (<xref ref-type="bibr" rid="bib002">2</xref>).</p></sec><sec id="sec001"><title>The problem

Although the mainstay of therapy in neonatal sepsis is an early initiation of appropriate antibiotic therapy, the treatment of neonates with suspected sepsis is increasingly blurring the line demarcating appropriate use and the misuse of antibiotics in neonates. The inappropriate and unnecessary use of antibiotics may lead to alterations in normal flora (5), medication errors, intravenous infiltrates along with financial and emotional costs to the parents. Excessive use of antibiotics selects for antibiotic resistant bacteria. The problem is more with broad spectrum antibiotics. The commonly used ampicillin and third generation cephalosporins select for extended spectrum beta lactamases producing gram negative organisms (6–8). The extensive use of imipenem and meropenem selects for beta lactamese producing organisms as well as organisms resistant to imipenem (9).

Dilemma: To treat or not to treat

Due to the constraints of good laboratory support, many neonatal physicians in India face difficulty in drawing a clear line between over-treatment and risk of missing sepsis in neonates. The burden of infection is also large and a trend towards aggressive management of sick neonates is resorted to. Gram negative septicaemia particularly with Klebsiella and E. Coli is more common. Greater reliance on a limited sepsis screen viz. CRP and WBC count contributes to over treatment.

Misuse of antibioticsProphylactic antibiotics

The practice to intake antibiotic therapy in neonates without significant risk factors for infections is common. The presence of an invasive device such as an umbilical artery or venous catheter, intercostal drain, or an endotracheal tube, does not mandate the use of antibiotics (10). Such use of prophylactic antibiotics does not prevent sepsis but may lead to select for multi-resistant organisms. Antibiotic prophylaxis in the delivery room has contributed to the rapidly increasing use of antibiotics in delivery wards which can lead to emergence of resistant bacteria.

Treating colonization

Antibiotics are often prescribed when bacilli are isolated from endotracheal tube aspirates. In the absence of pneumonia, this is treating colonization, not the disease. In a study on neonates with late onset pneumonia, potential pathogens could be cultured as frequently from endotracheal tubes of ventilated babies without pneumonia as from those with pneumonia.

Combination antibiotic therapy

This has been used as a strategy to check the emergence of bacterial resistance. However, no convincing data exists to prove that such treatment for nosocomial infection prevents the subsequent emergency of antibiotic resistance. Combination therapy has the potential risk of increasing overall resistance if not properly controlled, leading to greater overall use of antibiotics. At the same time the combination therapy may be more efficient at producing clinical and microbiological responses thereby limiting the horizontal transmission of inadequately treated antibiotic resistant pathogens.

Use of broad spectrum antibiotics

Empiric therapy with broad spectrum antibiotics is practiced to cover more organisms. This is a fallacy and can lead to selection for resistant organisms (9). The use of third generation cephalosporins to start or initiate treatment in ‘sick looking’ neonates must be discouraged.

Duration of therapy

A trend towards use of antibiotics for long periods is often noted. Continuation of therapy is resorted to if acute phase reactants (CRP) are still positive despite negative cultures. This leads to therapy being extended beyond recommended duration and even after clearance of infection.

Rational antibiotic therapy

A systematic but clinically realistic approach to the diagnosis of neonatal sepsis that would miss no cases, minimize duration of therapy to those uninfected, provides a safe observation protocol for at risk infants who are not treated should be followed. The ability to rule out sepsis with 100% negative predictive accuracy has been achieved with several sepsis screen strategies. In clinical use, 100% ability to rule out sepsis can be achieved if the screens are obtained 12–24 hours after birth (2). Once the decision to initiate therapy is made, the microbiology of neonatal sepsis drives the choice of antimicrobial agents; the duration of therapy is driven by type and location of physiologic condition of the patient.

Rationing antibiotic use

Rational therapy involves rationing antibiotic usage. Narrow spectrum antibiotics must be used whenever possible. The broad spectrum antibiotics should be restricted and used for specific situations when warranted. Some infections such as community acquired pneumonia and urinary tract infections can usually be successfully treated with narrow spectrum antibiotics. Quantitative cultures and assessment of infection risk can reduce prolonged antibiotic use in many neonates with suspected infection. Culture samples should be taken with appropriate technique before starting antibiotics and antibiotics stopped after 72 hours if cultures are negative (12,13). A period of 36 hours is enough to rule out sepsis in the asymptomatic neonate, and a three day incubation period is sufficient to detect infections using the Bac Tec/Alert microbial detection system.

Antibiotic cycling and scheduled changes

Antibiotic class cycling has been advocated as a potential strategy for reducing antimicrobial resistance. A class of antibiotic is withdrawn from use for a defined period and is re-introduced at a later time in an attempt to limit bacterial resistance (14,15). Further, withdrawing an antibiotic from use can potentially restore its effectiveness.

Choice of antibiotics

The best choice is a penicillin with an aminoglycoside (16–18). To cover for Staphylococcal infection, Cloxacillin or Oxacillin may be the right choice. The use of Vancomycin should be restricted to MRSA infection. The emergence of strains of Vancomycin resistant enterococci and staphylococcus aureus is worrisome. Some countries have introduced guidelines in hospitals to restrict the use of Vancomycin to a minimum. The selection of aminoglycoside should be dependant on the sensitivity pattern in the unit. If the organisms are resistant to Gentamycin, a choice between Netilmicin and Amikacin should be made. Cephalosporins (third generation) are active against gram negative and many gram positive organisms. Their prolonged use is associated with fungal infection and selection of cephalosporin resistant gram negative bacilli (20).

With increasing resistance to Ampicillin, a combination of Piperacillin-Tazobactum might be appropriate in Gram negative predominant sepsis. For treatment of meningitis third generation cephalosporin Cefotaxime may be considered in view of its superior CSF penetration. The extended spectrum beta lactamase producing strains of Gram negative bacteria should be managed with carbapenems, Imipenem and Meropenem.

The Way Ahead

A rational approach in management of neonatal sepsis should be followed. To prevent the misuse of antibiotics strict protocols must be pursued. Prescription practices guided by culture reports and use of narrow spectrum antibiotics, as far as possible would go a long way in preventing the emergence of resistant organisms.

References1

Escobar

The neonatal “sepsis work up” personal reflections on the development of an evidence based approach toward newborn infections in a managed care organization. Pediatrics1999; 103910: 360–373.2

Gerdes

Diagnosis and management of bacterial infections in the neonate. Pediatr Clin N Am2004; 51: 939–959.3

Hammerschlag

Klein

Herschel

Patterns of use of antibiotics in two newborn nurseries. N Engl J Med1977; 235: 1268–1269.4

Phillips

AGS

Hewitt

Early diagnosis of neonatal sepsis. Peditrics1980; 65: 1036–1041.5

Bennet

Eriksson

Nord

Fecal bacterialmicroflora of newborn infants during intensive care management and treatment with five antibiotic regimen. Pediatr Infect Dis J1986; 5: 533–539.6

Gordon

Isaacs

Late onset infection and therole of antibiotic prescribing policies. Curr opin Infect Dis2004; 17: 231–236.7

Pessoa-Silva

Moreira

B Meurer

Camara

Alemeida

Extended spectrum beta lactamaseproducing Klebsiella pneumoniae in a neonatal intensive care unit : Risk factors for infection and colonization. J Hosp Infect2003; 53: 198–206.8

Jain

Roy

Gupta

Prevalence of extended-spectrum betalactamase-producing Gram-negative bacteria in septicaemic neonates in a tertiary care hospital. J Med Microbiol2003; 52: 421–425.9

Isaacs

Neonatal Sepsis:The Antibiotic crisis. Ind Pediatr2005; 42: 9–13.10

Isaacs

Moxon

Handbook of neonatal infections. A practical guide. LondonWB Saunders, 1999: 57–60.11

Webber

Wilkinson

Lindsell

Neonatal pneumonia. Arch Dis Child1990; 65: 207–211.12

Isaacs

Wilkinson

Moxon

Duration of antibiotic courses for neonates. Arch Dis Child1987; 62: 727–728.13

Kaiser

Cassat

Lewno

Should antibioticsbe discontinued at 48 hours for negative late onset sepsis evaluations in the neonatal intensive care unit. J Perinatol2002; 2: 445–447.14

Isaacs

Wilkinson

Moxon

Surveillance of colonization and late onset septicaemia in neonates. J Hosp Infect1987; 10: 114–119.15

Gruson

Hilbert

Vargas

Strategy of antibiotic rotation: Long term effect on incidence and susceptibilities of Gram negative bacilli responsible for ventilator associated pneumonia. Crit Care Med2003; 31: 1908–1914.16

Carling

Fung

Kilion

Favourableimpact of a multidisciplinary antibiotic management program conducted during 7 years. Infect Control Hosp Epidemiol2003; 24: 699–706.17

Gould

A review of the role of antibioticpolicies in the control of antibiotic resistance. J Antimicrob Chemother1999; 43: 459–465.18

Tiley

Mac Donald

Doherty

Activepromotion of antibiotic guidelines: An intensive program. Commun Dis Intell2003; 27: S13–S18.19

Tablan

Tenover

Martone

Recommendations for preventing the spread of Vancomyc in resistance. Recommendation of the Hospital Infection Control. Practices Advisory Committee Morbid Mortal Weekly Rep1994; 44 (RR-12): 1–13.20

Modi

Damjanovic

Cooke

Outbreak of cephalospor in resistant Enterobacter cloacae infection in a neonatan intensive care unit. Arch Dis Child1987; 62; 148–151.