Rational antibiotic use in newborn. Objectives Neonatal infections categories Challenges of...

Rational antibiotic use in newborn

Objectives

• Neonatal infections categories• Challenges of antibiotic therapy in the NICU• Reasons for continuation of antibiotic therapy

in the neonate• Advers effects of prolonged empirical

antibiotic therapy• Revaluating the antibiotic regimen• Improve rational use of medicines

Definition

• Rational use of medicines refers to the correct, proper and appropriate use of medicines.

• Rational use requires that patients receive the

appropriate medicine, in the proper dose, for an adequate period of time, and at the lowest cost to them and their community. (WHO,1985)

Rational use of medicines, at the 60th World Health Assembly, 2007

Neonatal infections categories

1. Potential infection

2. Presumed infection

3. Proven infection

Journal of Perinatology (2011) 31, 514 – 518


1 . Potential infection: termed colloquially “at risk of sepsis ”

• This category included:– Rule-out sepsis course :In whom with minimal

symptoms but no objective finding for infection – Perioperative course:Those at risk to be or

become infected base on exposure or surgery• Discontinued treatment within 4 days


Neonatal infections categories2. Presumed infection:

termed colloquially “Clinical Sepsis”•Finding of infection presumed the physician to continue antibiotic therapy without of positive culture or local infection

• Abn WBC count &I/T neutrophil ratio• Serial CRP• Radiograpic finding• Change in physical exam

•This category included:• Ventilator associated pneumonia• Difficult to make a diagnosis• An episodes of abdominal dysfunction(from feeding

intolerance to NEC)•Course lasting ≥ 5 days(-/+ antibitics change)



3. Proven infection:termed colloquially “Definite Sepsis”

•This category included:– To trate infections assiciated with positive

cultures from:• Blood(CLABSI/BSI)• Other steril sites

(CSF,peritoneum,abscess,pleura,urin,ect)• Local infection(cellulitis,thrombophlebitis,etc)


Type of antibiotics therapy in neonates

I. Empiric therapy(when infection is suspected but cultures are pending)

II. Definitive therapy (when an organism has been identified)

III. Prophylactic therapy(eg, prevention of postoperative infections).

Semin Perinatol 36:431-436 © 2012 Elsevier

Duration of empirical antibiotic

• We defined initial empirical antibiotic treatment as days of initial empirical antibiotic treatment with sterile culture results

• The infants were categorized into 2 groups: I. Limited antibiotics tx :

1-4 days of initial antibiotic therapy

II. prolonged antibiotics tx :≥5 days of initial antibiotic therapy.


What are the challenges of antibiotic

prescriptions in the NICU?

Unique Challenges in AntibioticPrescribing in the NICU

• NICU clinicians often treat infants with negative cultures for "presumed late-onset sepsis"

• In a retrospective review of 754 patients from 2 NICUs, antibiotic therapy to treat presumed infection was shown to be 8.8-fold higher than antibiotic use to treat culture-proven infection.


What are the reasons for continuation of antibiotic therapy?

Reason for continuation of antibiotic therapy

I. Baby looked sick– A commonly stated reason for continuation of

antibiotic therapy is the infant’s severity of illness.

II. Cultures unreliable– When cultures reveal growth of coagulase-negative

staphylococcal species, distinguishing between infection and colonization or contamination may be difficult.


Reason for continuation of antibiotic therapy

III. Acute phase reactants elevated

IV. Cultures might be false negatives

V. Treatment guidelines are often not established for

infants, particularly for preterm neonates


Risk factors for continuation of antibiotic therapy

• Kuppula et al do report that infants in the prolonged antibiotic group were significantly more likely to have– lower birth weight and gestational age– An Apgar score <6 at 5 minutes of age– Endotracheal intubation and surfactant treatment– More ventilator days– Higher oxygen concentration at 7 days of age– Birth to mothers with chorioamnionitis.

Kuppala et al . J Pediatr.2011


• Cotton et al, reported that

– Using mechanical ventilation for the first 7 days of age as a surrogate marker for severity of illness.


• Afjeh et al reported that infants in the prolonged antibiotic group were significantly more likely to have – Maternal disease – Chorioamnionitis – Multiple gestation– Low birth weight – Non invasive ventilation– Mechanical ventilation

Table 1 – Patients’ characteristics Duration of antibiotic

administration

Total

≤2w (62)>2w(83)

Hosp.course_32w10 (100%)0 (0%)10 (6.9%)

3-4w29 (61.7%)18 (38.3%)47 (32.41%)

+5w23 (26.14%)65 (73.86%)88 (60.69%)

Birth weight (3c)1251-150038 (59.38%)26 (40.63%)64 (44.14%)

1001-125022 (41.51%)31 (58.49%)53 (36.55%)

<=10002 (7.14%)26 (92.86%)28 (19.31%)

Gestational age (3c)<=28 w8 (18.18%)36 (81.82%)44 (30.34%)

29-32 w36 (46.75%)41 (53.25%)77 (53.1%)

>32 w18 (75%)6 (25%)24 (16.55%)

IV.day 14.29±5.3228.67±10.0522.52±10.98

Free.Ab.day 14.90±8.7914.89±10.4914.9±9.77

Total.Ab.day 10.00±2.3525.52±10.5918.88±11.2

Table 2- Association of different neonatal outcomes with

duration of antibiotic therapy. Duration of antibiotic

administration

p-Value

≤2w>2w

Death after 7th day of life (DOL 7)

Survive62 (100%)71 (85.54%)0.002

Expire0 (0%)12 (14.46%)

Death/NEC(>=2) after 7th day of life (DOL 7)

No61 (98.39%)68 (81.93%)0.002

Death/NEC(>=2)1 (1.61%)15 (18.07%)

Death/NEC(>=2)/LOS after 7th day of life (DOL 7)

No59 (95.16%)18 (21.69%)<0.001

Death/NEC(>=2)/LOS3 (4.84%)65 (78.31%)

NECGrade<261 (98.39%)79 (95.18%)0.39

Grade>=21 (1.61%)4 (4.82%)

Late onset sepsis (LOS)No57 (91.94%)18 (21.69%)<0.001

Yes5 (8.06%)65 (78.31%)

Age of Late Onset SepsisNever57 (91.94%)18 (21.69%)<0.001

During 14 days5 (8.06%)42 (50.6%)

After day 140 (0%)23 (27.71%)

Table 4 – Multiple logistic regression with forward stepwise method

CharacteristicsAdjusted OR95% CI for ORp-Value

Birth weight (gr)

1001-1250 vs. ≤ 10000.020.001 - 0.16<0.001

1251-1500 vs. ≤ 10000.040.004 - 0.380.005

NCPAP.NIV vs. none13.933.97- 48.88<0.001

MV ± Surf + NCPAP/ NIV vs. none67.6515.44 - 296.52<0.001

Maternal .disease0.150.05 - 0.520.003

PROM ± Chorioamnionitis5.721.02 - 32.150.048

Multiple . Pregnancy

Twin vs. single1.230.39 - 3.870.72

Triplet and more vs. single0160.03-0.820.03

Factors that confer a greater risk for LOS in the neonate.

NeoReviews Vol.13 No.2 February 2012 e95

What are the adverse effects with prolonged

empirical antibiotic therapy ?

Adverse effects with prolonged antibiotic therapy (>5 days)

– Increased risk of NEC and death– Cotten et al .Pediatrics. 2009;123(1):58–66 – A 19-center study of 5693 ELBW – 4% increase risk of NEC and death with each additional day of

initial empiric antibiotics

– Increased risk of NEC , LOS, and death– Kuppala et al . J Pediatr. 2011;159(5):720–725– 300 neonates of less than 32 weeks’ gestation and less than

1,500 g birthweight– who survived for 7 days with no NEC or sepsis. – They found that prolonged (>5 days) initial empiric antimicrobial

therapy was associated with a higher incidence of NEC, LOS, and death.


– Invasive candidiasis by Cotten et al. Pediatrics. 2006;118(2):717–722

– 3,700 ELBW neonates who survived past 72 hours. – The neonates were treated in 12 different country– The investigators found that use of broad-spectrum

antibiotics (most often a third-generation cephalosporin) was associated with increased risk of invasive candidiasis, the incidence of which ranged widely (2.4%–20.4%) across different centers.


– Increased hospital length of stay– Bacterial resistance.

de Man etal. Lancet. 2000;355(9208):973–978

• Resistance is usually to multiple drugs with a higher mortality

What can be done to improve rational use

of medicines?

• Clark et al : – 98% of preterm infants who received empiric

antibiotics were culture negative

• Cordero and Ayres reported that – prolongation of antibiotic therapy in extremely

low birth weight infants was not associated with severity of illness, but was more associated with institutional decisions.

• Such ‘‘thinking’’ needs to change!

How best to accomplish the seemingly elusive goal of dis-continuation of antibiotics?

First – A full diagnostic evaluation is mandatory for all infants

with sus-pected sepsis in the NICU. obtaining blood cultures at 2 separate sites should

improve the yield and reduce the likelihood of treat-ing contaminants.

lumbar puncture Obtaining urine culture

THE JOURNAL OFPEDIATRICS 2012 :159(5)


Finally–One does need to trust the culture results. Sterile

blood culture results should be inter-preted as no active infection at that site, and antibiotics should be stopped by 36 and 48 hours in suspected early-and late-onset infections, respectively.

– Pneumonia, however, is often a reason for prolonged use of antibiotic therapy be-cause it occurs despite sterile blood and cerebrospinal fluid cultures. Although the likelihood of a noninfectious etiology for the respiratory distress should be strongly considered,shorter courses of antibiotic therapy need to be studied.



Ultimately– The use of biomarkers may help clinicians

feel more comfortable with stopping antibiotic therapy


Why antibiotic regimen should be evaluated again?

Revaluating the Antibiotic Regimen

• However, in a critically ill infant, prolonged courses of antibiotics are often used. It is important in these cases of presumed “culture-negative sepsis” to avoid erroneous attribution and to reevaluate the infant for possible noninfectious etiologies for their clinical worsening

NeoReviews Vol.13 No.2 February 2012


First– The body site from which the positive culture was

isolated should be reviewed.• Growth at nonsterile body sites (such as tracheal

aspirates) may be colonizing flora, particularly when the clinical course is not suggestive of infection..



Second– susceptibility results provide the opportunity to

treat with a narrow spectrum, less toxic, and more efficacious antibiotic.

• For example, highly relevant to the NICU, oxacillin is more effective than vancomycin for the treatment of methicillin-susceptible Staphylococcus aureus infections

• Empiric antibiotics should be promptly stopped if the pathogens are resistant to that agent (eg, discontinue vancomycin when gram-negative bacilli are isolated).


Revaluating the Antibiotic Regimen Third

– The date and time of the microbiology report provide an opportunity for timely discontinuation of therapy when infection is not suspected.

• Nearly all blood cultures (97%) with clinically meaningful bacterial growth will be positive within 48 hours.

• Cultures with growth after 48 hours are more likely to be contaminants or colonizing organisms,as these microbes are generally present at a lower inoculum.


Upgradation of empirical antibiotics :

• No expected clinical improvement with ongoing line of antibiotics.

• At least 48-72 hours period of observation should be allowed before declaring Failure.

• Current evidence does not support the use of serial quantitative CRP as a guide for deciding whether or not antibiotics should be upgraded empirically


• A decision may be taken to bypass the first line of antibiotics and start with the second-line of antibiotics in case – The neonate is extremely sick or – Deteriorating very rapidly and – The treating team feels that the neonate may not

able to survive 48 hours in the absence of appropriate antibiotics

Journal of Antimicrobial Chemotherapy (2008) 61, 743 – 745

Conclusion about duration of antibiotics• Culture positive sepsis :

– The standard antibiotic treatment length for blood culture-positive EOS is 7 days.

– Consider a longer duration if the baby has not fully recovered or if advisable based on the isolated pathogen

Conclusion about duration of antibiotics • Culture negative sepsis :

– If the blood culture is reported sterile at 48 hours, the following guidelines must be adhered to: • Asymptomatic neonate at risk of EOS:

stop antibiotics• Suspected EOS or LOS and the neonate

becomes completely asymptomatic over time: stop antibiotics

Conclusion about duration of antibiotics • Culture negative sepsis :

– If the blood culture is reported sterile at 48 hours, the following guidelines must be adhered to:

• Suspected EOS or LOS and the neonate have not improved or have worsened:

upgrade antibiotics as per the empiric antibiotic policy.

• Simultaneously, alternative explanations for the clinical signs must be actively sought for.

Duration of antibiotic treatment • Consider stopping after 36 hours If

– initial clinical suspicion of infection was not strong and

– CRP < 10mg/l on both tests and– Blood culture is negative and– The baby is well with no clinical indicators of

possible infection • Treat for 5 days if

– Strong clinical suggestion of infection– Continued clinical concerns about infection at 36

hours– CRP > 10 mg/l on either measurement – Positive blood culture

Duration of antibiotic treatment

• Continue antibiotics beyond 5 days if – The baby did not fully recovered at 5 days or– This is advisable based on the blood culture result

and expert microbiological advice if necessary

What is the most appropriate antibiotic?

Empirical Antimicrobial Therapy forNeonatal Sepsis(EOS)

• In developed countries – Ampicillin and gentamicin is an appropriate choice for

empirical therapy of EOS in neonates, where GBS and E. coli continue to be the predominant organisms.

– Ampicillin + cefotaxime were more likely to die and less likely to ultimately be discharged from the NICU compared with those neonates treated with ampicillin + gentamicin (By Clark et al)

• In developing countries– Empiric antibiotic therapy should be based individualized

for each hospital or region.


Empirical Antimicrobial Therapy forNeonatal Sepsis(LOS)

• In a stable neonate: Cloxacillin and gentamicin• In an unstable neonate:(cardiorespiratory

instability and in areas MRSA ) Vancomycin and cefotaxime

The dangers of starting vancomycin as the initial therapy1. The risk of emergence of vancomycin- resistant enterococci 2. Its overuse in cases where CoNS isolates represent mere contaminants.


Antimicrobial Stewardship in NICU :

lessons we have learned

Antimicrobial Stewardship After confirming that the patient has a indication for

antimicrobial therapy, antimicrobial stewardship is the 8 R’s:

1. Right drug2. Right time 3. Right dose 4. Right route 5. Right resident 6. Right documentation 7. Right reason8. Right response


Antimicrobial Stewardship1. On the basis of this evidence, it is critical to emphasize the

rational use of antibiotics.2. Based on current available evidence, the combination of

ampicillin and gentamicin is an appropriate choice for empirical therapy of EOS in neonates

3. It seems that oxacillin/nafcillin plus gentamicin is a reasonable regimen for empirical antibiotic therapy in LOS, although the specific agents chosen should take into account local resistance patterns.

4. The use of vancomycin should be initiated if, in the judgment of the clinician, the infant is critically ill and the postulated infecting organism may be a methicillin-resistant strain of a Gram-positive organism.

5. Third-generation cephalosporin use should be discouraged outside of suspected meningitis.


Antimicrobial Stewardship6. Antibiotic therapy should be narrowed as much

as possible once an organism is identified. 7. In addition to careful selection of what agent to

use, duration of empirical antibiotic therapy should be limited to 2 to 3 days if cultures are negative.

8. It is also important to avoid – Treating colonization (positive endotracheal cultures without

evidence of pneumonia) – Prophylactic antibiotic use for invasive devices.




Thanks for all your excellent care on the

NICU!


• Second-line policies for EOS Of 75% of NICU policies (151/202) that advised empirical change of antibiotics for cases that failed to respond to first-line therapy, 49% (74/202) recommended cephalosporins second-line and 18% (27/202) recommended vancomycin.

Journal of Antimicrobial Chemotherapy(2008)61, 743 – 745


• Empirical second-line policies for LOS, reported from 46% of NICUs (93/202), varied even more widely, with the most common regimen (cefotaxime and vancomycin) accounting for only 8% and other recommendations including meropenem, tei-coplanin, piperacillin/tazobactam and aztreonam.

Journal of Antimicrobial Chemotherapy(2008)61, 743 – 745


• Antifungal recommendations– Guidance for use of antifungal prophylaxis was

specified in only one-third of NNUs (32%; 64/202), but twice as many specified indications for antifungal treatment (65%; 131/202). Fluconazole and amphotericin were recommended equally (66 and 65 U, respectively)..

Criteria for Change• A regimen such as ampicillin and g entamicin should

remain the empirical therapy of choice for presumed EOS until – a correlation between antibiotic resistance and treatment

failure has been observed.• Cefotaxime and ampicillin are commonly used as a substitute for

ampicillin and gentamicin for the presumptive treatment of EOS. – However, there appears to be an increased risk of death with the use of

ampicillin and cefo-taxime.– third generation c ephalosporinuse is probably a risk factor for invasive

candidiasis.– Finally, rates of cephalosporin resistance are increasing.

• Third generation cephalosporins should be used judiciously. NeoReviews Vol.13 No.2 February 2012

To avoid prolonged empiric use of antibiotics

• Providers may now rely more on alternative modes of infection identification.

• Not all sepsis-like syndromes will yield a bacterial organism, and with a critically ill neonate, it can be difficult to discontinue antibiotics in the face of negative culture results.

• However, advances in rapid viral pathogen identification through the use of polymerase chain reaction microarray systems may make it possible to limit the amount of empiric antibiotics given for presumed bacterial sepsis.

Reducing the Need for Antibiotics• Antimicrobial stewardship efforts directed at

infection prevention and optimal drug dosing are two ways in which antimicrobial misuse can be abated in the NICU.– Successful infection prevention efforts have focused

on the appropriate insertion, maintenance, and timely remova l of central venous catheters (CVCs), prevention of colonization and decolonization of potential pathogens, microbiology laboratory surveillance and local antibiogram use, and containment of isolated infections.

– Decreasing the number of health-care–associated infections reduces the need for empiric antibiotic use.

Red Flag Signs Suggestive of Neonatal Infection

• Systemic antibiotics given to mother for suspected bacterial infection within 24 hours of birth

• Seizures • Signs of shock • Need for mechanical ventilation in a term

baby • Suspected or confirmed infection in a co-twin

Actions

First situation Any red flags or no red flags but 2 or more risk

factors or clinical indicators:perform investigations including blood cultures

and start antibiotics

Actions• Second situation

No red flag or clinical indicators but one risk factor or no red flags or risk factors but one clinical indicator

1. Use clinical judgement and consider withholding antibiotics 2. Monitor baby for clinical indicators of possible infection,

including the vital signs 3. Monitor for at least 12 hours from birth (at 1 hors, 2 hours

and then 2 hourly for 10 hours) 4. If further clinical concerns perform investigations including

blood cultures and start antibiotics

Choice and Duration of Antimicrobial Therapy for Neonatal Sepsis and Meningitis

International Journal of Pediatrics Volume 2011 (2011) • Based on current available evidence, the combination

of ampicillin and gentamicin is an appropriate choice for empirical therapy of EOS in neonates, where GBS and E. coli continue to be the predominant organisms.

• Expansion of antimicrobial spectrum and also offers synergistic bacterial killing.

• Low cost and low rates of emergence of bacterial resistance.

• In developing countries, empiric antibiotic therapy should be based individualized for each hospital or region.

Prophylactic antibiotics

• They are given to prevent infection. • Not indicated in almost all situations in

neonatology. • High level evidence: not useful for the

prevention of infection following umbilical vessel or central venous catheterisation

• Antibiotics for all infants receiving mechanical ventilation not supported by evidence from randomised controlled trials.

Prophylactic antibiotics

• The only prophylactic use of antimicrobials: fungal prophylaxis in preterm infants on broad spectrum antibiotics or with central arterial or venous lines.

• A Cochrane systematic review: antifungals reduce the incidence of systemic fungal infections.

• To date there is no evidence that use of oral prophylactic antifungal agents has changed the susceptibility of infecting organisms.

Selecting Appropriate Empiric Antibiotics

• This antimicrobial-specific approach was illustrated in a study by Chiu et al (21) in which a vancomycin clinical use guideline was published and implemented in two tertiary care NICUs in Boston.

• The study yielded a statistically significant reduction in vancomycin start rates (by 35%–62%), as well as an overall reduction (40%–49%) in the number of infants exposed to vancomycin at all. This reduction in vancomycin use occurred with no evidence of increased deleterious effects of untreated sepsis or other infections.

Risc Factors- Early onset sepsis: • Risc Factors- Early onset sepsis

– Low birth weight (<2500 grams) or prematurity – Febrile illness in the mother with evidence of bacterial

infection within 2 weeks prior to delivery. – Foul smelling and/or meconium stained liquor.– Rupture of membranes > 18 hours. – Single unclean or > 3 sterile vaginal examination(s)

during labor – Prolonged labor (sum of 1st and 2nd stage of labor >

24 hrs) – Perinatal asphyxia ( Apgar score <4 at 1 minute)

Risk factors -Late onset sepsis: • Nosocomial (hospital-acquired)

• low birth weight• Prematurity• Admission in intensive care unit• Mechanical ventilation • Invasive procedures• Administration of parenteral fluids

• Community-acquired • Poor hygiene• Poor cord care• bottle-feeding• Prelacteal feeds

Rationale use of antibiotics:

• If the organism is sensitive to an antibiotic with a narrower spectrum or lower cost, therapy must be changed to such an antibiotic.

• If possible, a single sensitive antibiotic must be used, the exception being Pseudomonas for which two sensitive antibiotics must be used.

• 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

Date post:	28-Dec-2015
Category:	Documents
Upload:	fay-conley
View:	216 times
Download:	0 times

Rational antibiotic use in newborn. Objectives Neonatal infections categories Challenges of...

Documents