Brief review of commonly used antibiotics in the NICU followed by clinical applications and sepsis workup

1. Prepared By
M A G E D Z A K A R I A
Neonatologist
Antibiotics
2013

2. Bacterial pathogens of human
are classified as Gram-
positive or Gram-
negative, some notable
exceptions being the
mycoplasmas, chlamydiae, spi
rochetes and the
mycobacteria.
Medically Important Bacteria

3. Cocci
Gram POS Bacteria
Aerobic Anaerobic Aerobic Anaerobic
Staphylococci
Streptococci
Enterococci
Listeria Clostridium
Rods
Medically Important Bacteria

4. Cocci
Gram NEG Bacteria
Aerobic
(Facultative Anaerobic)
Anaerobic Anaerobic
Neisseria
Rods
Aerobic
(Facultative Anaerobic)
Enterobacteriaceae
(Lactose Fermenters)
E coli
Klebsiella
(Non-Lactose Fermenters)
Salmonella
Shigella
Bacteroides
Pseudomonas
Vibrio
Hemophilus
Medically Important Bacteria

5. Intracellular Bacteria
Chlamydia
Rickettsia
Miscellaneous / Poorly
Staining Species
Acid Fast Stain
Mycobacteria
Poorly Staining
Mycoplasma
Legionella
Medically Important Bacteria

6. Mechanism of Action of Antibiotics

7. Mechanism of Action of Antibiotics
Antibacterial agents are directed
against specific targets not
present in human cells to limit
toxicity to the host and maximize
chemotherapeutic activity
affecting invading microbes only.

10. • Bactericidal drugs KILL the bacteria that are within their
spectrum of activity; bacteriostatic drugs only INHIBIT
bacterial growth.
• Bactericidal activity is necessary for patients with altered
immune systems (e.g., neutropenia), protected infectious foci
(e.g., endocarditis or meningitis), or specific infections
(e.g., complicated Staphylococcus aureus bacteremia).
Mechanism of Action of Antibiotics

11. Inhibition of Cell-wall Synthesis
One major difference between
bacterial and human cells is the
presence of a rigid CELL WALL
external to the cell membrane in
bacteria protecting the usually
hyperosmolar bacterial cells (relative
to the host environment) from
osmotic rupture.

12. • Antibiotics act at any step of the synthesis of cell wall units
(peptidoglycans) lead to inhibition of bacterial cell growth and, in most
cases, to CELL DEATH (bactericidal).
• Antibacterial agents act to inhibit cell-wall synthesis are:
o β-Lactam antibiotics acting on penicillin-binding proteins (PBPs) (penicillins,
cephalosporins, and carbapenems).
o Glycopeptides (vancomycin and teicoplanin).
o Bacitracin.
Inhibition of Cell-wall Synthesis

13. Inhibition of Protein Synthesis
• Most of protein synthesis inhibitors selectively interact with bacterial
ribosomes that are different in composition between bacterial and human
cells.
o Aminoglycosides (gentamicin, tobramycin, and amikacin).
o Macrolide antibiotics (erythromycin, clarithromycin, and azithromycin).
o Lincosamides (clindamycin).
o Linezolid.

14. Inhibition of Bacterial Metabolism
oSulfonamides (sulfisoxazole, sulfadiazine, and
sulfamethoxazole).
oTrimethoprim.
For infants > 6 wks of age

15. Inhibition of Nucleic Acid Synthesis
oQuinolones (nalidixic acid and its fluorinated derivatives
(ciprofloxacin, and levofloxacin).
oRifampin.
oMetronidazole (active only against anaerobic bacteria and
protozoa).

16. CHEMOTHERAPEUTICS MONOGRAPH

17. Penicillins
• BACTERICIDAL cell wall synthesis inhibitors.
• Poorly penetrate into CSF UNLESS meninges are inflamed.
• Destroyed by β-lactamase enzyme produced by many
bacteria including Staph., E. coli and H. influenzae.
• β-lactamase is overcomed by adding a β-lactamase
inhibitor (sulbactam, clavulanate or tazobactam).

18. Ampicillin
+
Sulbactam
Amoxycillin
+
Clavulanate
Piperacillin
+
Tazobactam

19. Broad Spectrum Penicillin
o AMPICILLIN is the preferred penicillin for
initial EMPIRICAL THERAPY for neonatal
septicemia and meningitis because it provides
broader antimicrobial activity with good safety.
o Side effects include nonspecific rashes, 
transaminases,  creatinine, alteration of
intestinal flora, and diarrhea.
UNASYN

20. Broad Spectrum Penicillin
o For therapy for bacterial meningitis, a dose
of at least 200 mg/kg/day should be
used, although some consultants use
dosages as high as 300 mg/kg/day.
o CSF concentrations is inhibitory to group B
streptococci (GBS) and L. monocytogenes
but not E. coli.
UNASYN
Ampicillin + Sulbactam

21. Augmentin
Amoxacillin + Clavulanate
Broad Spectrum Penicillin

22. Broad Spectrum Penicillin
o Amoxicillin has similar properties to ampicillin, and there is little to choose
between the two antibiotics when given IV, although amoxicillin is said to be
more rapidly “bactericidal”.
o Clavulanic acid has no antibiotic properties of its own but inhibits many b-
lactamase enzymes.
o Administration to women in preterm labor is associated with a higher risk
of neonatal NEC.
o Amoxicillin shows better bioavailability than ampicillin when taken by mouth
Gras-Le Guen C, Boscher C, Godon N, et al. Therapeutic amoxicillin levels achieved with oral
administration in term neonates. Eur J Clin Pharmacol 2007;63:657–62.

23. Piperacillin / Tazobactam
USES
Non-CNS infections, caused by
susceptible β-lactamase producing
bacteria (e.g. E. coli, Enterobacter,
Klebsiella, H. Influenzae, Proteus,
Pseudomonas and Staph. as well as GBS.
Na content is 2.35 mEq per gram of piperacillin

24. Advantages and Disadvantages of the Aminoglycosides
Advantages Disadvantages
Familiarity among physicians Relatively narrow therapeutic ratio
Broad spectrum of activity
Toxicities: nephrotoxicity, ototoxicity,
neuromuscular blockade (rare)
Rapid bactericidal action
Poor penetration into certain body
fluids such as CSF and bile
Relatively low cost Lack of enteral absorption
Chemical stability Inactivity against anaerobes reactions
Rare association with allergic reactions
Synergism with b-lactam antibiotics and
vancomycin
Aminoglycosides
• Include gentamycin, tobramycin and amikacin.

25. Aminoglycosides Ototoxicity
• Ototoxicity can be cochlear and/or vestibular damage.
• Gentamicin causes more vestibular damage while amikacin causes
more auditory damage.
• Reports on hearing loss in children who received gentamicin as
neonates are scanty. Aminoglycoside induced hearing loss contributes
to only a small proportion of the deafness in the community.
• Individuals with certain mutations in mitochondrial DNA (seen in
up to 50% of cases and are exclusively maternally inherited), have
higher susceptibility to aminoglycoside induced hearing loss.

26. • Approximately 8-26% of patients who receive aminoglycosides for
>7-10 days develop mild renal impairment which is almost always
reversible.
• It usually presents as gradually worsening non-oliguric renal failure.
• Severe acute tubular necrosis may occur rarely.
• Toxicity is increased by use of other nephrotoxic drugs e.g. lasix
and vancomycin, hypokalemia, hypovolemia and hypomagnesemia.
Aminoglycosides Nephrotoxicity

27. Gentamicin Amikacin
Amikacin has almost similar spectrum to gentamicin and is safe in children. It may be
effective against some gentamicin-resistant bacteria and so is more suitable when
gentamicin resistance rates are high.
Comparative Information on Aminoglycoside Toxicity (Australian
Medicines Handbook)
Vestibular Cochlear Nephrotoxicity
Amikacin + ++ ++
Gentamicin ++ ++ ++

28. Neither ototoxicity nor
nephrotoxicity were noted
in a Cochrane review done
to assess safety and
efficacy of once daily
dosing of gentamicin,
based on 11 studies (n=
574) in neonates with
sepsis
2006

29. • Serum-aminoglycoside concentration should be measured in all
children receiving parenteral aminoglycosides and must be
determined in neonates or if there is renal impairment.
• Blood samples should be taken just before the next dose is
administered (‘trough’ concentration). If the trough concentration is
high, the interval between doses must be increased.
• Blood samples should also be taken ~1 hour after IM or IV
administration (‘peak’ concentration). If the peak concentration is
high, the dose must be decreased.

31. • Urea and creatinine should be monitored prior to
treatment with aminoglycosides and twice weekly
thereafter in stable patients (more often if renal
impairment is present at baseline or develops during
therapy).
• The dose interval is determined by the serum gentamicin
trough level measured at 22 hours from commencement of
the dose.

32. Third Generation CephalosporinsCephalosporins
The third generation cephalosporins have excellent activity against Gram–ve organisms
Cephalosporins are not effective against Listeria and Enterococci.
Theoretical advantages of third-generation cephalosporins
1. Low toxicity
2. Unnecessary measurement of serum level

33. Cefoperazone / Sulbactam
Claforan
Cefotaxime
Fortum
Ceftazidime
Third Generation Cephalosporins

34. • Cefotaxime is typically not used alone for initial
therapy in suspected sepsis because of its poor
activity against L. monocytogenes and enterococci.
• The addition of ampicillin provides antibacterial
coverage against these organisms.
• One potential problem associated with the routine use
of this drug is the possible emergence of
cefotaxime-resistant gram-negative bacteria in the
NICU.
Claforan
Cefotaxime

35. • There’s a higher neonatal mortality rate with the
use of cefotaxime compared with gentamicin.
• Resistance develops rapidly when cefotaxime is
used for empiric therapy.
• So, it seems wise to restrict its use to infants
with meningitis due to susceptible organisms.
Clark RE, Bloom BT, Spitzer AR, Gerstmann DR: empiric use of ampicillin and
cefotaxime compared to ampicillin and gentamicin is associated with an increased risk of
Claforan
Cefotaxime

36. Ceftriaxone
Neonatal sepsis and meningitis by G-
ve organisms (e.g. E. coli,
Pseudomonas, Klebsiella and H.
influenza).
Gonococcal infections.
Not recommended for use with
hyperbilirubinemia, hypoalbuminemia, acidosis
and impaired bilirubin binding; it displaces
bilirubin from albumin binding sites.
Concurrent use of Ca-Containing solutions in
not recommended within 48h of the last
administration of ceftriaxone.

37. Fourth Generation Cephalosporins
USES
G-ve organisms (e.g. E.coli, H.influenza,
Enterobacter, Klebsiella, Morganella, Neisseria,
Serratia and Proteus species), esp. Pseudomonas
aeruginosa that is resistant to 3rd generation
cephalosporins.
G+ve organisms (e.g. Strep pneumonia, Strep
pyogenes, Strep agalactiae and Staph aureus).
ADVERSE EFFECTS
Rash, Eosinophilia
Diarrhea,  ALT, AST.
Positive Coombs’ test

38. Carbapenems (Imipenem and Meropenem)
• Carbapenems are structurally related to
β-lactam antibiotics but resistant to β-
lactamases. They are effective against
streptococci, enterococci, pneumococci, m
ethicillin-sensitive S aureus, gram-negative
rods except stenotrophomonas.
• They treat both aerobic and anaerobic
bacteria.
• MRSA is not susceptible.

39. • Both Tienam and Meronem
penetrate well into the CSF.
• Tienam treatment in infants
with bacterial meningitis was
possibly associated with drug-
related seizure activity, that is
not seen with Meronem.
• Lastly, they can increase the risk
of superficial or invasive fungal
disease because of their broad
spectrum of activity.

40. Glycopeptides
• Include Vancomycin and Teicoplanin.
• BACTERICIDAL.
• Synergistic bacterial killing has been
demonstrated with aminoglycosides.

41. Vancomycin
MONITOR Renal function during treatment.
ADVERSE EFFECTS
Nephrotoxicity and ototoxicity.
Rash and hypotension (red man syndrome),
resolves within minutes to hours  slow the
rate of infusion.
Neutropenia (if administrated > 3 wks).
Vancomycin does not readily penetrate the CSF
unless the meninges are inflamed.
Excreted unchanged in the urine.
Bactericidal

42. Teicoplanin
USES
Active against
1. Many G+ve anaerobes (particularly Clostridium)
2. Most Listeria, enterococci and staphylococci (including MRSA)
Rifampicin may sometimes be synergistic in the management of
staphylococcal infection.
Vancomycin resistant organisms are sometimes sensitive to teicoplanin.
ADVERSE EFFECTS
Leucopenia and thrombocytopenia.
Disturbances of liver function.

43. Linezolid
Only used to treat VRSA, and VRE
Thrombocytopenia occurs in 2% of patients
who were on the drug for > 2 wks
CBC should be obtained weekly while on linezolid
Linezolid is a last resort drug and its use is limited
to prevent development of resistance
Bacteriostatic
Rapid and nearly complete
absorption after oral
dosing.

44. Macrolides
• Include erythromycin, clarithromycin and azithromycin.
• Effective in atypical pneumonia caused by mycoplasma,
chlamydia and legionella.

45. Azithromycin
ADVERSE EFFECTS / PRECAUTIONS
Diarrhea and/or vomiting (5-12%).
Irritability, rash and blood in stool.
Pyloric stenosis ?!
Pertussis: 10 mg/kg/dose PO Q24h (5 d)
Chlamydia trachomatis Conjunctivitis and Pneumonitis: 20 mg/kg/dose PO Q24h
(3 d)
IV Dose: 5 mg/kg/dose Q24h over 60 min.

46. Clindamycin
Pseudomembranous colitis is rare in pediatric practice
No significant activity against gram –ve bacteria
Effective against gram +ve aerobes and
anaerobes.
Should NOT be used in ttt of meningitis (poor CSF penetration)
Eliminated primarily by the liver
Widely distributed throughout the body
including pleural fluid, ascites, bone, and bile

47. Metronidazole
USES
Meningitis, ventriculitis and endocarditis caused
by Bacteroides fragilis and other anaerobes
resistant to penicillin.
Serious intra-abdominal infections and C. difficile
colitis.
T. vaginalis infections.
ADVERSE EFFECTS PRECAUTIONS
Carcinogenic?!!
Seizures, sensory polyneuropathy.
Brownish discoloration of urine.

48. Rifampin
ADVERSE EFFECTS / PRECAUTIONS
Orange/red discoloration of body secretions.
Potent CP450 enzyme inducer;  Effect of aminophylline, fluconazole,
morphine, phenobarbital, phenytoin, propranolol.
Used in combination with vancomycin or
aminoglycosides for ttt of persistent systemic
staphylococcal bacteremia or ventriculitis in high
risk neonates.
Eliminated in bile
Bacteriocidal

49. Ciprofloxacin
Most anaerobes are not susceptible.
Avoid use with MRSA (resistant).

50. ADVERSE EFFECTS PRECAUTIONS
Fluoroquinolones may damage growing cartilage causing
arthropathy thus not routinely recommended for patients
under 18 years of age.
However, the arthropathy is reversible and there is a growing
agreement that fluoroquinolones may be used in children in
some cases (eg, for treatment of pseudomonal infections in
patients with cystic fibrosis).
Ciprofloxacin

51. PRINCIPLES OF ANTIBACTERIAL CHEMOTHERAPY

52. Although both ampicillin and gentamicin are still
used frequently for treating sepsis, antibiotics
should be prescribed according to the bacterial
prevalence and resistance patterns of each unit.
It is more important to know the antibiotics
resistance patterns of one's own NICU.
Information on resistance pattern can usually be
obtained from hospital microbiology laboratories.

54. GET SMART principles can be applied to
empiric use (when infection is suspected
but cultures are pending), definitive use
(when an organism has been identified), or
for prophylaxis (e.g. prevention of
postoperative infections).

55. Principles and Strategies of Antimicrobial
Stewardship in the Neonatal Intensive Care Unit
Semin Perinatol 36:431-436 © 2012 Elsevier Inc.

56. Get Smart for Health Care Campaign for the NICU
Get Smart Principles Examples
Accurately identify patients who
need antibiotic therapy
Obtain 2 blood cultures for evaluation of LOS
before starting antibiotics
Use local and regional
antibiograms
Avoid use of meropenem for empiric treatment of
suspected LOS if rates of multidrug-resistant
gram-negative bacilli are low
Avoid therapy with overlapping
activity
Avoid simultaneous use of metronidazole and
meropenem to treat NEC
Give the right dose and interval
of drug
Target vancomycin trough to 15-20 mg/L to treat
pneumonia caused by MRSA

57. Get Smart for Health Care Campaign for the NICU
Get Smart Principles Examples
Review culture results and adjust
antibiotics
Review microbiology results at transitions of
care (eg, sign out, weekend crosscoverage) and
narrow antibiotic coverage promptly
Monitor for toxicity and adjust
therapy accordingly
Adjust antibiotic dose for patients with
deteriorating renal function
Stop therapy promptly if indicated
by culture results
Discontinue antibiotics after 48 hours if blood
cultures are negative and ongoing infection is
not suspected

58. • We first must do everything possible to ascertain whether the
infant truly has an infection that requires antibiotic
therapy.
• Culture of blood is performed routinely, but 2 blood cultures of
at least 0.5 mL each should be obtained before antibiotic
initiation. A larger volume of blood (1-2 mL) may further
increase organism recovery and reduce the likelihood of
treating contaminants.
Before Starting
Antibiotics—Diagnostic Strategies

59. • The need for a lumbar puncture is often debated because
meningitis is a rare occurrence among otherwise stable preterm
infants with RDS.
• However, meningitis can be present at birth, and when sepsis is
strongly suspected, a lumbar puncture should be performed. As
the incidence of early-onset E coli infection increases in preterm
infants, performance of a lumbar puncture is even more important
to help guide antibiotic therapy.
• Knowing that the CSF culture is sterile before initiation of
antibiotic therapy can help shorten the duration of treatment.
Stoll BJ, Hansen NI, Sanchez PJ, Faix RG, Poindexter BB, Van Meurs KP, et al. Early onset neonatal sepsis: the
burden of group B Streptococcal and E coli disease continues. Pediatrics 2011;127:817-26.
Weiss MG, Ionides SP and Anderson CL (1991): Meningitis in premature infants with respiratory distress: role of
admission lumbar puncture. J Pediatr ;119:973-5.

60. • Sterile blood culture results should be
interpreted 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 because it occurs despite sterile blood
and CSF cultures.
Finally, one does need to trust the culture results

61. Before Starting
Antibiotics—Diagnostic Strategies
• Obtaining urine for culture is not
recommended at birth because urinary tract
infections do not occur so early.
However, with a lumbar puncture, a urine
culture is a necessary part of the evaluation
for possible late-onset sepsis.

63. Evaluation of asymptomatic infants <37 weeks’
gestation with risk factors for sepsis
AAP 2012

64. Evaluation of asymptomatic infants ≥37 weeks’
gestation with risk factors for sepsis
AAP 2012

65. Evaluation of asymptomatic infants ≥37 weeks’
gestation with risk factors for sepsis
Inadequate treatment is defined as the use of
an antibiotic other than penicillin, ampicillin,
or cefazolin or if the duration of antibiotics
before delivery was <4 h.
AAP 2012

66. • Antibiotics are disposed of by hepatic elimination
(metabolism or biliary elimination), by renal excretion of the
unchanged or metabolized form, or by a combination of the
two processes.
• The most practical application of the mode of excretion of an
antibiotic is in adjusting dosage when elimination capability is
impaired.
Pharmacokinetics of Antibiotics

67. Antibiotics Dose Adjustments In Renal Impairment
Antibiotic Major route of excretion Dose adjustment with renal impairment
Aminoglycosides Renal Yes
Azithromycin Biliary No
Cefepime Renal Yes
Ceftazidime Renal Yes
Ceftriaxone Renal/Biliary Modest reduction in severe renal impairment
Ciprofloxacin Renal/Biliary Only in severe renal impairment
Clarithromycin Renal/Biliary Only in severe renal impairment
Linezolid Metabolism No
Metronidazole Biliary No
Piperacillin Renal Only with ClCr of < 40 mL/min
TMP-SMX Renal/biliary Only in severe renal Insufficiency
Vancomycin Renal Yes

68. Dose in Renal Impairment
Cr Cl 26-50 mL/min/1.73m2  use normal dose Q12h
Cr Cl 10-25 mL/min/1.73m2  use half normal dose Q12h
Cr Cl <10 mL/min/1.73m2  use half normal dose Q24h
DOSE IN SEPSIS:
20 mg/kg/dose IVI Q12h
An empirically derived formula to estimate CrCl:
In Preterm neonates =
In Term neonates =
Antibiotics Dose Adjustments In Renal Impairment

69. Early-onset Sepsis (GBS - E.coli - Listeria)
• Unasyn + Amikin ± 3rd generation cephalosporin (Claforan or
Fortum; if patient is critically ill).
Late-onset Sepsis
• CONS - MRSA: Vancomycin – Targocid – Zyvox.
• Enterococci (associated with indwelling catheters, meningitis,
NEC): are usually resistant to cephalosporins, penicillins.
Treatment requires the synergistic effect of an aminoglycoside
with ampicillin or vancomycin. Zyvox is also effective.
Choosing the Right Antibiotics

70. • Pseudomonas: treatment requires the
combination of 2 agents active against
pseudomonas; Fortum – Tazocin – Gentamicin
– Tobramycin (best aminoglycoside activity).
• Enterobacter: Maxipime or Meronem and
Gentamicin.
• Klebsiella: Claforan – Meronem – Gentamicin.
Choosing the Right Antibiotics

71. • When adding a second antibacterial agent, it should be
acting through a different mechanism of action from that of
the first is added to prevent the emergence of these resistant
mutants (e.g., imipenem plus an aminoglycoside or a
fluoroquinolone for systemic Pseudomonas infections).
• However, since resistant mutants have emerged after
combination chemotherapy, this approach clearly is not
uniformly successful.
Antibiotic Combinations

72. • Antibiotics may be combined to extend
their antimicrobial spectrum:
1. Penicillin + Third generation Cephalosporin
2. Meronem + Vancomycin
3. Penicillin + Aminoglycoside + Flagyl or Dalacin-C
Antibiotic Combinations

73. Drugs Not Routinely Used in Neonates
Drug Potential Adverse Effect
Tetracycline Depressed bone growth and teeth abnormalities
Chloramphenicol
Circulatory collapse, impaired mitochondrial protein
synthesis, bone marrow aplasia; gray baby Syndrome
Sulfonamide
Bilirubin displacement with rare but possible kernicterus;
increased risk of hemolysis in G6PD-deficient infants
Trimethoprim/
sulfamethoxazole
Same as sulfonamide; bilirubin displacement with rare but
possible kernicterus; increased risk of hemolysis in G6PD-
deficient infants
Ceftriaxone
Highly protein bound, potential to displace bilirubin;
cannot be co-administered with calcium containing fluids

74. Duration of Therapy
• Duration of antibiotics therapy differs according to the site
of infection and the causative organism.
• For bacteremia, most organisms require treatment with
antibiotics for at least 7 days (e.g. for CONS) up to 14 days
(e.g. for Pseudomonas).
• For Meningitis, the usual treatment course is 14-21 days.
• Duration of therapy is 3-4 weeks for osteomyelitis.

78. Biomarkers as a Guide For Antimicrobial Therapy

79. • Biomarkers, such as procalcitonin and B-natriuretic
peptide, used for the early detection of bacterial infection
could guide treatment and reduce misuse of antibiotics.
• CRP is an acute phase protein synthesized by the liver. The
plasma half-life of CRP is constant (~19h) with the sole
determinant of circulating CRP concentration is its synthesis
rate.
• Serum levels of CRP increase ~4-6 h after the start of the
inflammatory process, peaking by 48h and eventually
subsiding once the stimulus disappears, often prior to the
clinical resolution of sepsis.

80. • In septic patients, an increase in CRP
concentrations in the first 48 h was associated
with ineffective antimicrobial therapy.
• Persistently increased serum CRP
concentrations after antimicrobial therapy were
indicative of poor outcome and inadequate
prescription of antibiotics in critically ill
patients.