MANAGEMENT OF NEONATAL

SEPSIS

BY DR ASIM Rustaq Hospital

NEONATAL SEPSIS

Clinical syndrome of bacteremia with systemic signs and symptoms of

infection in the first four weeks of life .

OBJECTIVES

1/ evalution of newborn2/septic work up3/GBS screening 4/antibiotics5/prevension

SEPSIS

-SIRS: temp,cardiac ,resp,perfusion

-Sepsis as SIRS plus infection

- Severe sepsis: as sepsis associated with organ

dysfunction, hypo perfusion or hypotension ,

-:Septic shocksepsis with arterial hypotension despite fluid resuscitation

NEONATAL SEPSIS“Early onset” 0-3 days (~75% cases)

90% show within 12 hours

Usually septicaemia and pneumonia

11% mortality, 7% morbidity

90% preventable IV Penicillin

“Late onset” 3-90 days (~25% cases)Usually meningitis and septicaemia

8% mortality, 21% morbidity (up to 50% with meningitis)

No current prevention: good hygiene/education

Vaccine: future hope for both late & early onset

NICE GUIDLE LINES –RISK FACTORS

Risk factor with Red flag

1/Invasive group B streptococcal infection in a previous baby2/Maternal group B streptococcal colonisation, bacteriuria or

infection in the current pregnancy3/Prelabour rupture of membranes

4/Preterm birth following spontaneous labour (before 37 weeks' gestation)

5/Suspected or confirmed rupture of membranes for more than 18 hours in a preterm birth

6/Intrapartum fever higher than 38°C, or confirmed or suspected chorioamnionitis

7/Parenteral antibiotic treatment given to the woman for confirmed or suspected invasive bacterial infection (such as septicaemia) at any time during labour, or in the 24-hour periods before and after the birth [This does not refer to intrapartum antibiotic prophylaxis].

8/Suspected or confirmed infection in another baby in the case of a multiple pregnancy.

RISKS - LOS

1/ immature immune responses.2/ poorly developed skin and mucosal barriers to infection.3/ numerous entry portals for organisms via cannulae, catheters and endotracheal tubes.4/ continuing exposure to oppurtunistic organisms during often a prolonged hospital stay

MOTHER TO INFANT TRANSMISSION OF GBS -CDC

GBS colonized mother

Non-colonized newborn

50%

Colonized newborn

50%

Asymptomatic

98%Early-onset sepsis, pneumonia, meningitis

2%

SEPSIS EVALUATION Blood Culture

CSF C/SUrine C/S (LOS)CBC and DEFFRENTIALCRPMicro ESRProcalcitoninothers

BLOOD CULTURE-Volume of 0.5 ml or more (ideally 1 ml or more)

: False –ve c/sMaternal antibioticsSmall blood sample

study of nearly 300 blood c/s , 55% of culture vials contained less than 0.5 ml of blood

Bacteria load, timing of sampling >90% of positive cultures occur within 48 hrs of

incubation. In a 1999, autopsy study of ELBW infantsinfection was primary cause of death by pathologists in (56 of 111)sepsis was not diagnosed prior to death for 61% of these 56 neonates

SEPSIS SCREEN

Consists of 5 items:

1 .C-reactive protein (CRP) ,

2 .Total leukocyte count

3 .Absolute neutrophil count (ANC)

4 .Immature to total neutrophil ratio

( ITR )

5 .Micro-erythrocyte sedimentation rate

( μ-ESR .)

CBC WITH DIFFERENTIALNo agreement on what constitutes

“normal”WBC < 4k or >25 to 30 KImmature:Total neutrophil ration > 0.2

Serial values, 8-12 hrs apart have high NPVBand count

The total neutrophil count reference range in the first 60 hours of life for a group of term neonates. Points represent single values; numbers represent the number of values at the same point;(From Manroe BL: The neonatal blood count in health and disease I: Reference values for neutrophilic cells. J Pediatr 95:91, 1979.)     

Reference ranges for total neutrophil values in very low birthweight neonates from birth to 60 hours of life (A) and 61 hours to 28 days of life (B). (From Mouzinho A et al: Revised reference ranges for circulatingneutrophils in very-low-birth-weight neonates. Pediatrics 94:78, 1994.)

Neutropenia is more predictive of neonatal sepsis than neutrophilia

: it may be present inmaternal hypertension ,birth asphyxia and periventricular hemorrhage .

IT RATIO

= Immature neutrophils (band forms, metamyelocytes, myelocytes)

Mature + immature neutrophils

early predictor of sepsis.

N value = 0.16 in first 24 hours, decreasing to 0.12 by 60 hours .

Upper limit > 0.2 .

Limitation- many noninfectious processes, including prolonged induction with oxytocin, stressful labor, and even prolonged crying, are associated with increased I:T ratios.

CRP

Weitkamp, J-H and Aschner, J.L. Neoreviews, 2005, 6(11):e508-15

Acute phase reactant, stimulated by IL-6Production occurs ~ 4-6 hrs after stimulationPeaks at 36-48 hrsHalf Life of ~ 19 hrs

CRP - Single level often not helpful in determining infection-Serial measurements may be beneficial in determining

duration of antibiotics in certain cases (eg: maternal incomplete antibiotic treatment, high index of suspicion for sepsis but negative cultures)

-Two CRP levels < 10 mg/L taken at least 8 hrs after presentation and 24 hrs apart have high NPV. (Benitz,

W. et al. Pediatrics 1998, 102(e41):1-10)

-Sensitivity of serial CRP testing is lower for bacteremia due to gram-positive than to gram-negative bacteria

elevated CRP on day 1 and/or day2, identify most case of sepsis

sensitivity (90.2%)

MICRO-ESR: Positive Value (mm in first hour) > 3+ age in days (first

week of life) > 10 thereafter

Limitation- increased in noninfectious (anemia,

hyperglycemia)

-Values vary inversely with the

•superficial infection

•-noninfectious processes, including asphyxia ,

aspiration pneumonia, and respiratory distress syndrome .

PCR

Sensitivity 90%Specificity 96% positive predictive value

88.9%negative predictive value

99.8%

POLYMERASE CHAIN REACTION (PCR)

PCR: under investigation for bacterial and fungal infectionamplification of 16S rRNA ,

a gene universally present in bacteria but absent in humans

Results in 9 h of sample acquisition

LUMBAR PUNCTUREIncidence of neonatal meningitis 0.25 to 1 per 1000 live birthsBlood culture negative in up to 50% of meningitis casesDoes not seem warranted in routine evaluations (for perinatal risk factors, mild symptoms)Useful for those with evidence of sepsis (who can tolerate procedure and in those whom longer courses of antibiotics planned)

LP CONSIDERATIONSTraumatic LP: > 1000 RBC/mm3

1 WBC:100 to 500 RBC in normal spinal fluidDifficult to InterpretWBC:RBC ratioObserved:Predicted WBC Ratio based on peripheral blood ratio.O:P <0.01, WBC:RBC < 1:100 and absence of pleocytosis high PPV for absence of meningitis

Mazor, S. et al. Pediatrics 2003, 111:525-8.

LUMBER PUNCTURE Indication :

1/In EOS - a positive blood culture or clinical

picture consistent with septicemia.

2/In late onset sepsis, LP should be done in

all infants prior to starting antibiotics

INTERPRETATION OF CSF FINDINGS

> 32 WBC/mm3

>60% PMN

glucose < 50% - 75% of serum

protein > 150 mg/dl

organisms on gram stain

ROLE OF PROCALCITONIN

detectable within 2 to 4 hours after a trigger

peaks by 12 to 24 hours .

parallels -closely the severity of the

inflammatory higher levels associated with

more severe disease

declining levels with resolution of illness.

In the absence of an ongoing stimulus, ProCT is

eliminated with a half-life of 24 to 35 hours,

making it suitable for serial monitoring.

ProCT level of >2.0 ng/mL ---predicts sepsis and

> 10 ng/mL ---septic shock .

> 20 ng/mL --- guarded prognosis .

The higher the ProCT level -----worse the prognosis.

When sepsis has been successfully treated, ProCT levels

should fall with a half-life of 24 to 35 hours.

 

Identification of secondary septic events –

elevated noninfectious ProCT level, ProCT levels should

fall at a predictable pace in the absence of secondary

infection.

Limitation - ProCT levels that are elevated in

noninfectious conditions like after cesearean section,

resuscitation at birth, perinatal steroid exposure

BUT should start falling within 48 hours . Persistent high

levels or secondary peaks suggest secondary infection.

Protocol on Sepsis

INVESTIGATIONS DURING ANTIBIOTIC TREATMENT

 

1/In babies given antibiotics because of risk factors for infection or clinical indicators of possible infection, measure the C-reactive protein concentration 18–24 hours after presentation.2/ lumbar puncture to obtain a cerebrospinal fluid sample in a baby who did not have a lumbar puncture at presentation who is receiving antibiotics, if it is safe to do so and if the baby:a/has a C-reactive protein concentration of 10 mg/litre or greater, orb/has a positive blood culture, orc/does not respond satisfactorily to antibiotic treatment.

ANTIBIOTICS THERAPY

●The choice of empirical antibiotics is dependent on: Protocols, Organsim/local prev c/s,●The duration of therapy is dependent upon culture results, clinical course, and organism.

 1/The combination of ampicillin  and gentamicin  is effective in treating most of the common pathogens(GBS/ E.COLI)2/Serum gentamicin levels are not required if renal function is normal and a treatment course of only 48 hours is anticipated

THERAPEUTIC DRUG MONITORING FOR GENTAMICIN-NICE

*If a 2nd gentamicin is to be given measure the trough blood gentamicin concentration immediately before giving the second dose. Consider before 3rd dose.* Hospital services should make it available in time to inform the next dosage decision (e.g, within 30 hours of sampling).

PEAK BLOOD GENTAMICIN CONCENTRATIONSConsider in selected babies :1/oedema2/macrosomia (BW more than 4.5 kg)3/ unsatisfactory response to treatment4/proven Gram-negative infection. Measure peak concentrations 1 hour after starting the gentamicin infusion.If a baby has a Gram-negative or staphylococcal infection, consider increasing the dose of gentamicin if the peak concentration is less than 8 mg/litre.

(LP) should be performed:*+ve c/s* TRT more than 48 hours without a positive blood culture (presumed sepsis). 3/If treatment is continued longer than 48 hours, and meningitis has been excluded, the ampicillin regimen can be changed to 75 mg/kg every 12 hours3/ If treatment is continued longer than 48 hours, and no LP has been performed (or if the infant has meningitis), the ampicillin dose should be changed to 75 mg/kg 6/hrly.

AMPI -GENTA VS AMPI -CP ampicillin + cefotaxime :1/is not more effective

2/cephalosporin-resistant strains (eg, Enterobacter cloacae, Klebsiella, and Serratia specie. 3/ 1.5-fold increase in mortality rate (4.2 versus 1.9 percent, adjusted odds ratio 1.5, 95% CI 1.4-1.7)

EOSPositive culture *duration of therapy is generally 10 days . *most improve clinically within 24 to 48 hours. *The (I/T ratio) usually are abnormal for the first few days and begin to normalize by 72 hours . *(CRP), to monitor treatment. Serum CRP initially rises 24 to 48 hours and begins to decrease after 48 to 72 hours in responsive infants .Negative culture — *automated blood c/s systems identify 97% at 24 hours, and 99 percent at 36 hours . Thus, empiric antibiotic therapy should be discontinued in the well-appearing infant after 48 hours .*clinical condition remains concerning , ABS can be extended until anothr diagnosis/ or to complete a 10-days trt . *CRP measurements can be useful in identifying infants who are more likely to have clinincal sepsis and –ve c/s.Follow-up testing — A repeat blood c/s after 24 to 48 hours of therapy is obtained to determine the response. Failure to sterilize the bloodstream suggests that the antimicrobial(s) chosen are not active against the infecting pathogen or that there is an unrecognized focus of infection

QUICK REVIEW OF ANTIBIOTICS--

LATE-ONSET SEPSIS -ANTIBIOTICS

Rehospitalized from home-*low risk of resistance*Ampi genta is empirical treatmet. (study from the HPA voluntary surveillance scheme in 96 percent of isolates from late-onset bacteremia were susceptible to the combination of amoxicillin and gentamicin )

Policy for nosocomial sepsis It is not possible to suggest a single antibiotic

policy for use in all newborn units. Every newborn unit must have its own

antibiotic policy based on the local sensitivity patterns and the profile of pathogens.

Preferably choose Penicillin + Aminoglycoside BE Aware--Cephalosporins rapidly induce the

production of extended spectrum β-lactamases (ESBL), cephalosporinases and fungal colonization.

LOS-EMPIRIC TRT

*Empiric antibiotic treatment varies between neonatal intensive care units and countries*no consensus guidelines on the choice of empiric antibiotics. *There are also no definitive guidelines on classification of CoNS as true sepsis or contaminant, the removal of indwelling catheters or the duration of antibiotics for late onset sepsis*The initial choice

1/ likely pathogens, 2/ susceptibility patterns in particular nursery 3/ presence of an apparent source of infection (eg, skin, joint, central line, or bone involvement).

ANTIBIOTIC RESISTANCE  There has been an increasing emergence of infections in preterm

infants caused by antibiotic-resistant gram-negative bacteria . As an example, in one study from the National Institute of Child

Health and Human Development (NICHHD) Neonatal Research

Network, 85 percent of early-onset Escherichia coli (E coli) infections were resistant to ampicillin .

Risk factors: 1/very low birth weight (birth weight <1500 g) 2/ exposure to third generation cephalosporins. Two mechanisms : a/●Chromosomally-encoded or plasmid-derived AmpC beta-

lactamases. b/●Plasmid-mediated extended-spectrum beta-lactamases (ESBLs)

. Organisms that produce ESBLs, primarily E Coli and Klebsiella

species, are resistant to penicillins, cephalosporins, and monobactams, and can be resistant to aminoglycosides.

ORGANISM –SPECIFIC ANTI -BIOTS Guidelines for the treatment of the most common causative organisms of neonatal sepsis are provided below.● (GBS) is uniformly susceptible to penicillin. Thus, when GBS is identified as the sole causative organism, we recommend that antimicrobial therapy be changed to penicillin G alone . ●Escherichia coli – In (E. coli) sepsis sensitive to ampicillin who have improved clinically and in whom meningitis has been excluded, ampicillin monotherapy is administered for a 10- to 14-day course. For patients with ampicillin-resistant E. coli, the choice of definitive therapy includes an aminoglycoside, such as gentamicin, or cefotaxime. However, in our practice, we prefer the use of cefotaxime over gentamicin in patients with ampicillin-resistant E. coli because of the potential ototoxicity and nephrotoxicity associated with gentamicin and the need to monitor gentamicin levels. *meropenem  - extended-spectrum beta-lactamase producing organisms.

-Other gram-negative bacilli – Nonmeningeal infections caused by E. coli, Klebsiella, Proteus, Salmonella, or Shigella can be treated with a single agent, such as ampicillin or cefotaxime, based upon the antimicrobial susceptibility profile. -Many experts suggest treatment with both a beta-lactam antimicrobial agent (eg, ampicillin or piperacillin-tazobactam) and an aminoglycoside for bacteremic infections caused by Enterobacter, Serratia, or Pseudomonas. Infections due to ESBL organisms, or those with hyperproduction of beta-lactamases, should be treated with meropenem.-Listeria monocytogenes –  ampicillin and gentamicin is more effective than ampicillin alone in vitro and in animal models of Listeria infection, and is used for initial therapy.

ORGANISM AND DRUGSGBS – ampicillin or penicillinE .coli –cefotaxime or ampicillin + gentamycinCONS –VancomycinKlebsiella - cefotaxime or meropenam +gentamycinEnterococcus –ampicillin or vancomycin + gentamycinListeria – ampicillin + gentamycinPsudomonas – ceftazidime or piperacillin-tazobactum + gentamycinStaph. Aureas – nafcillinMRSA - Vancomycin

ABS FOR LOS BETA LACTAM VS BETA LACTAM + AMINOGLYCOSIDE COCHRANE LIBERARY.

Implications for researchThere is a lack of studies that compare different antibiotic for treating suspected LOS.

narrow versus broad spectrum antibiotic regimens for suspected LOS.

In developed countries where CONS is the commonest late onset infection, trials may wish to compare regimens with and without vancomycin plus an aminoglycoside.

In developing countries where broad spectrum antibiotic cover is common, ongoing surveillance of types of organisms and increasing antibiotic resistance is particularly important to then direct randomised trials.

Any future research also needs to assess cost effectiveness and the impact of antibiotics in different settings such as developed or developing countries and lower gestational age groups.

There is no evidence from randomised trials in favour of any particular antibiotic regimen for the treatment of suspected late onset neonatal sepsis

CONS1/As skin commensals, these organisms are also common blood culture contaminants, and there is a lack of consensus as to how to interpret CoNS positive results. 2/In the intensive care setting the vast majority of CoNS are resistant to methicillin and thus infants with suspected late onset infection are typically treated with empiric broad spectrum antibiotics that include vancomycin (Rubin 2002).3/ There are concerns regarding unrestricted vancomycin use as a risk factor for the development of resistant organisms, particularly enterococci (HICPAC 1995). 4/The majority of pathogens associated with fulminant late onset sepsis (lethal within 48 hours) have been shown to be gram negative organisms with pseudomonas leading the table (Karlowicz 2000; Gordon 2004 (a)).

RUSTAG HOSPITAL -SCBUIN 2013BLOOD C/S

*Acinobacter 1*Staph epidermidis 12

*Kleps 1*Staph a 2

*Strep viridans 1*Strep pn 1

*Psudomon 1

ADJUNCTIVE THERAPIES:Intravenous immunoglobulins (IVIG):

The currently available evidence does not support the use of IVIG .

b) Colony stimulating factors: There is currently no evidence to support the use of colony stimulating factors either as a treatment modality or as a prophylaxis therapy.

LACTOFERRINLactoferrin is an iron-binding glycoprotein. It has broad-spectrum antimicrobial activity.A multicenter, randomized, placebo controlled trial involving VLBW infants who received daily orally administered Bovine lactoferrin alone (n=99, dose = 100 mg/day), in combination with Lactobacillus GG (n=99, dose = 106 CFU/day), or placebo (n=104) for 30–45 days show that the incidence of culture-proven sepsis was lower in the groups that received lactoferrin.

Final and complete results from this study are pending.

GLUTAMINEGlutamine -- most abundant amino acid in plasma and

human milk .Studies in immunocompromised adults have

suggested that intravenous parenteral nutrition supplemented with glutamine decreases the risk of

sepsis and mortality .A recently published Cochrane systematic review

examined the effect of enteral or parenteral glutamine supplementation on the incidence of culture-proven invasive infection from 5 clinical trials (n= 2,240). The meta-analysis did not reveal a statistically significant difference between the glutamine supplemented and control groups (RR 1.01; 95% CI 0.91, 1.13).

RECOMBINANT HUMAN PROTEIN CActivated protein C is an endogenous compound that promotes anticoagulation and modulates the inflammatory response.

During severe systemic infections, the levels and degree of protein C activation are decreased;

In one study, decreased activity of activated protein C was associated with increase mortality among neonates with sepsis.The largest randomized controlled-trial of recombinant activated protein C in children (n=477);approximately 6% young infants) failed to show an improvement in the clinical score used at the primary outcome and in the 28-day mortality when the drug was compared to placebo

SUPERFICIAL INFECTIONS Superficial infections can be treated with local application of antimicrobial agents .

Pustules can be punctured with sterile needles and cleaned with spirit or betadine .

Purulent conjunctivitis can be treated with neosporin or chloramphenicol ophthalmic drops.Oral thrush responds to local application of clotrimazole or nystatin (200,000 units per ml) and hygienic precautions .

Superficial infections must be adequately managed; if neglected they can lead to sepsis or

even an epidemic .

PREVENTION OF INFECTIONS A good antenatal care goes a long way in decreasing the incidence, morbidity and mortality from neonatal sepsis .

All mothers should be immunized against tetanus .

All types of infections should be diagnosed early and treated vigorously in pregnant mothers .

Babies should be fed early and exclusively with expressed breast milk (or breastfed) without any prelacteal feeds .

Cord should be kept clean and dry. Unnecessary interventions should be avoided .

HAND WASHING This is the simplest and the most effective method for control of infection in the hospital.All persons taking care of the baby should strictly follow hand washing policies before touching any baby.The sleeves should be rolled above the elbows .

Rings, watches and jewellery should be removed .

Wash hands up to elbows with a thorough scrub for 2 minutes with soap and water taking care to cover all areas including the under surface of well trimmed nails .

Rinse thoroughly with running water. Dry hands with sterile hand towel/paper towel .

Wash hands up to the wrist for 20 seconds in between patients .

Hands should be rewashed after touching contaminated material like one’s face, hair, papers etc .

It is preferable to use bar soaps rather than liquid soaps as the latter tend to harbor organisms after storage .

In emergency situations bactericidal and virucidal solutions like Sterillium can be used to clean hands before touching babies .

Surgical, elbow- operated taps should be used in the hospitals for hand washing .

PREVENTION OF INFECTION IN HOSPITAL The nursery environment should be clean and dry with 24 hour water supply and electricity.There should be adequate ventilation and lighting .

The nursery temperature should be maintained between 30+2°C .Overcrowding should be avoided .

All procedures should be performed after wearing mask and gloves .

Unnecessary invasive interventions such as needle pricks and setting up of intravenous lines should be kept to the barest minimum .

There should be no compromise in the use of disposables. Stock solutions for rinsing should be avoided .

Every baby must have separate thermometer and stethoscope and all barrier nursing measures must be followed .

Strict house-keeping routines for washing, disinfection, cleaning of cots and incubators should be ensured and these policy guidelines should be available in the form of a manual in the nursery .

The use of prophylactic antibiotics for prevention of nosocomial infections is strongly condemned .

They are not only useless but also dangerous because of the potential risk of emergence of resistant strains of bacteria .

CONTROL OF OUTBREAK General measures for the control of an outbreak include detailed epidemiological investigations ,increased emphasis on hand washing ,review of protocols ,procedures and techniques ,disinfection and sterilization of nursery assessment of the need for additional measures .

The nursery may be fumigated using formalin 40% and potassium permanganate (70 gms of KMNO4 with 170 ml of formalin for 1000 cubic feet area) .

Alternatively, bacillocid spray for 1-2 hours may be used. Linen and cotton should be washed thoroughly, dried and autoclaved .

-Use of disposable items for invasive and non- invasive interventions (catheters, probes, cannulae, chest tubes etc.) though costly, reduces the risk of infection .

Depending upon the pathogen and type of outbreak, culture surveys of susceptible patients, cohorting of infants in nursery and a review of antibiotic policy may be necessary .

Most of the times a scrupulous reinforcement of general control measures may be sufficient to stop the outbreak .

THANKS