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The Rational Use of Antibiotics in
Neurosurgery
Dr. P Maharaj
Moderator: Mr. E Kiratu
20 February 2015
The Rational Use of Antibiotics in Neurosurgery
Dr. P Maharaj
Moderator: Mr. E Kiratu
20/02/2015
The current practice of modern neurosurgery relies of the rational use of antibiotics.1
Treatment of infection is part of every neurosurgical practice irrespective of whether
infection lies intra-axial, extra-axial or in soft tissue spaces – neurosurgeons are called
on to provide definitive management and treatment. Additionally, we are responsible
for prevention of post-operative infection following cranial and spinal surgery as well as
immediate recognition and treatment. 2
The use of antibiotics has advanced many areas of surgical practice including the
treatment of infections of the meninges, brain and surgical site so as to reduce harmful
infectious complications. The legendary results of Harvey Cushing 0.7% infectious
complications have clearly defined careful surgical technique overcomes almost all
sources of infection. Nonetheless, antibiotics are an essential part of daily Neurosurgical
practice.2
Each medical or surgical intervention to benefit patients carries an inherent risk –
hence the excessive, inappropriate, and ineffective use and misuse should be avoided so
in successful neurosurgical practice. The natural ability of species to evolve poses the
current challenge of antibiotic resistance.4, 10
An Antibiotic is an imprecisely applied term, generally used to describe natural
compound that inhibits the growth of, or actively kills, bacteria.
Antimicrobials are (natural or synthetic) agents that kill or inhibit the growth of
microorganisms inclusive of bacteria, fungi, viruses and parasites.3
Bacterial Classification
It is fundamental that the appropriate use of anti-bacterial agents should be directed the
most likely or appropriately identified offending bacteria. The contributions of Christian
Gram and Paul Ehrlich for discovery of staining for bacteria and mycobacteria continue
to benefit the practice of medicine.4
Bacteria may be classified according to:3
 Morphology: cocci vs. rod/bacilli vs. coccobacilli
 Gram stain: positive vs. negative vs. variable
 Growth requirements: aerobic vs. anaerobic
 Biochemical reactions: lactose fermenting vs. non-fermenting
 Serotype e.g. Group A vs. B vs. D Streptococcus
 Antibiotic resistance patterns e.g. MSSA vs. MRSA
 rRNA sequence analysis
Relevant Microbiological tests that may have clinical importance:3
 Coagulase test: to differentiate Staphylococcus sp. (Particularly S. aureus is
coagulase positive)

Haemolysis Test: to differentiate Streptococcus sp.: alpha haemolytic – partial (S.
pneumonia/viridans), Beta haemolytic (S. pyogenes/agalactiae) and Gamma
haemolytic – no haemolysis (Enterococcus)
 Lancefield Serotypes: sometimes grouped according to specific carbohydrates
present on bacterial cell wall: Group A - S. pyogenes, Group B – S. agalactiae,
Group D – Enterococcus, S. Bovis. S. pneumonia and viridans have no Lancefields
antigens to categorise
 Lactose Fermentation: used to differentiate for gram negative rods: Lactose
positive (E. coli, Klebsiella and Enterbacter), Lactose negative (most other gram
negative rods), Lactose slow-fermenters (Citrobacter, Serratia)
Additionally on bacteria:3
 Anaerobes: all bacteria which grow and reproduce only in the absence of oxygen,
predominantly found in GI Tract e.g. Clostridium, Bacteroides,
Peptostreptococcus, Actinomyces
 Atypicals: an inexact term referring to bacteria which are considered “unusual”
in cellular structure, morphology, biochemistry or life-cycle e.g. Mycoplasma,
Chlamydia, Rickettsia, Legionella
Figure 1. A Practical Classification of Bacteria 3
Classification of Bacteria
Gram
Positive
Cocci
Coccobacilli
Clusters
Pairs, Chains
Staphylcocci
Streptococci,
Entercocci
Coagulase Test
Gram Negative
Haemolysis
Test, Lancefield
Serotyping
Cocci
Anaerobic
"Atypicals"
Gram Variable
Clostridium,
Bacteroides,
Peptostreptococ
cus,
Actinomyces
Mycoplasma,
Chlamydia,
Rickettsia,
Legionella
Acinetobacter
Rod
Listeria
Lactose
Fermenting
Lactose Slow
Fermenting
E.coli,
Klebsiella,
Enterobacter
Serratia,
Citrobacter
Neisseria,
Moraxella
Lactose Nonfermenting
Classification of Antibiotics
Bactericidal and Bacteriostatic antimicrobials4, 6, 7
Bactericidal actively kills bacteria.
Bacteriostatic inhibits bacterial reproduction but doesn’t otherwise kill.
In reality, there is no sharp distinction between the two as categorization depends upon
drug concentration and bacterial species. There are specific situations where
bactericidal agents are preferred over bacteriostatic: neutropaenia, meningitis,
osteomyelitis and endocarditis. However there is no evidence that bactericidal
antibiotics are, on average better than bacteriostatic in most clinical situations.
Mechanism of Action2, 4
Antimicrobials may be classified by mechanism of action
 Interfere with cell wall synthesis e.g. Beta lactams
 Interfere with nucleic acid synthesis e.g. quinolones
 Interfere with protein synthesis e.g. aminoglycosides
Figure 2. Mechanism of Action of Antibiotics – as adapted3
Inhibitors of
Nucleic Acid
Synthesis
Inhibitors of Cell
wall synthesis
Beta Lactams
Vancomycin
Daptomycin
Polypeptides e.g.
Colisten
Inhibitor DNA
Gyrase +/Topoisomerase:
Quinolones
Inhibits Folate
Synthesis:
Trimethoprim/Sul
famethoxazole
Inhibitors of
Protein Synthesis
Create Free
Radicals:
Metronidazole,
Nitrofurantoin
Inhibit 50S
subunit
Inhibit 30S
subunit
Penecillins
Macrolides
Aminoglycosides
Cephalosporins
Clindamycin
Tetracyclines
Carbapenems
Linezolid
Tigecycline
Monobactams
Streptogramins
Chloramphenicol
Newer Antimicrobial Agents relevant to Neurosurgical Practice:1, 2, 3, 4, 22
In the last decade, a number of newer antibacterial agents introduced have become
prominent as novel therapies for resistant infections.
Linezolid is a member of the oxazolidinone class of antibiotics; mechanism involves
binding to the bacterial 23S ribosomal RNA of 50S subunit, thereby inhibiting bacterial
protein translation. The clinical spectrum demonstrates effectiveness against a broadrange of gram-positive organisms including Methicillin-resistant Staphylococcus aureus
(MRSA) as well as Vancomycin-resistant Enterococcus (VRE) and penicillin-resistant
Streptococcus pneumonia.
Quinupristin-Dalfopristin is a combination streptogramin (from Streptomyces
pristinaspiralis) antibiotic that works synergistically to inhibit protein synthesis on two
separate locations on the bacterial 50S ribosomal subunit. The clinical spectrum
includes most gram-positive organisms, MRSA and Vancomycin-resistant Enterococcus
faecium however use is limited by poor central nervous system penetration. The drug is
known to have a considerable post-antibiotic effect.
Telithromycin is the first drug in the class of semisynthetic ketolide family and shares
its mechanism with macrolide by bonding directly to 50S subunit of bacterial
ribosomes. In addition, the structure of Telithromycin makes it less susceptible to both
erm-mediated ribosomal methylation and active efflux forms of antibacterial resistance.
The clinical spectrum demonstrated effectiveness against penicillin and erythromycinresistant Pneumococcus, Strep. Pyogenes and MRSA. It is also extended to gram
negative and atypical respiratory pathogens.
Carbapenems are a class of beta lactam antibiotics, which inhibit bacterial cell wall
synthesis and are metabolized through hydrolysis of beta lactam ring (and renal
elimination). Carbapenems are relatively resistant to beta lactamases thereby allowing
for an extended clinical spectrum. The clinical spectrum includes bacterial meningitis,
pneumonia and complicated intra-abdominal/pelvic infections due to efficacy against
gram negative, gram positive and anaerobes. However, carbapenems are uniformly
poorly effective against Enterococcus, MRSA and atypical pathogens. Notably seizure
potential is significantly lower for meropenem (0.5%) than imipenem-cilastin (2-7%).
Fluroquinolones inhibit bacterial DNA gyrase and topoisomerase IV thus interfering
with bacterial DNA replication and repair. Gatifloxacin, gemifloxacin and moxifloxacin
are new additions to the fluroquinolone family (fourth generation). These newer
fluroquinolones exhibit improved gram-positive cover including penicillin-resistant
pneumococcus, and continued activity against gram-negative, atypical, anaerobes and
Enterococcus. They are not effective against MRSA, Pseudomonas and C.difficile. The
clinical spectrum of the newer generation fluroquinolones includes nosocomial
respiratory tract infections. Its use is limited by lowered seizure threshold,
neurotoxicity and Q-T prolongation.
Ceftaroline is fifth generation cephalosporin, which shows activity against MRSA,
gram-positive bacteria. It retains the activity against gram-negative bacteria of the later
generation cephalosporins. Current evidence shows non-inferior performance on
comparison with Ceftriaxone for community-acquired pneumonia.
Risks associated with Antibiotic Administration 1, 2, 3
Antibiotics therapy in Neurosurgical patients is commenced for prophylaxis for
procedures, empirical treatment of a presumed infection or treatment of specific
neurosurgical and non-neurosurgical infection. Adverse reactions to antimicrobials,
specifically neuro-toxicity provides a particular problem in neurosurgical management.
Systemic side effects, drug-drug reactions (particularly with anti-epileptic drugs) and
allergic reactions also require consideration when commencing antimicrobial therapy.
Risks associated with specific antimicrobials commonly used in Neurosurgery:
Sulfonamides
Neuro-toxicity may occur in premature and newborn infants due to kernicterus, in
addition ataxia and psychiatric symptoms have also been described.
Quinolones
Neuro-toxicity related to exacerbation of myasthenia gravis, and demyelinating
polyneuropathy is well documented. Lowering of seizure threshold and prolonged Q-T
syndrome may also occur in a dose-related relationship.
Penicillins
Encephalopathy is related to alterations in blood brain barrier and patients with renal
insufficiency. Hoigne’s syndrome may occur following intravascular injection
General Principles of Antimicrobial Use in Neurosurgery23
11 key considerations when prescribing an antimicrobial:
1. Does this patient have an infection or is there an indication for prophylaxis?
2. At what anatomical site is the infection present or prophylaxis required?
3. Where is the infection acquired – community or health facility?
4. What are the common pathogens causing this infection?
5. To which antimicrobials are the normally sensitive?
6. Does the antimicrobial penetrate the anatomical site of sepsis?
7. Are they any contraindications to the drug(s) proposed?
8. Is there an indication for more than one antimicrobial?
9. What route and dose are indicated?
10. How long should the antimicrobial be administered?
11. Can a specimen be obtained?
The Blood-Brain Barrier and Blood Cerebrospinal Fluid Barriers2
The Blood brain barrier (BBB) is formed by endothelial cell of cerebral vasculature supported by astrocytes and pericytes with tight junctions between the endothelial cells
and minimal fenestrations or bulk transport across the cells. For the Blood-brain and
Blood-cerebrospinal fluid barriers, this barrier is located at the epithelial layer of the
choroid plexus (not endothelium but similar in that there are tight junctions between
epithelial cells). Regarding both barriers, active influx and efflux transporters located on
the endothelial/epithelial cell surface may drastically after distribution of an antibiotic
into the desired compartment. Many factors can contribute to the permeability of a
substance across the BBB:
 Molecular weight
 Lipophilicity (i.e. octanol/water partition co-efficient)
 Ionization
 Presence of transport mechanisms (influx or efflux)
 Plasma Protein binding



Inflammation
pH
Metabolism at the barrier
Increasing molecular weight, ionization, plasma protein binding, and metabolism at the
barrier and the presence of efflux transporters are factors that decrease the
permeability of the barriers to antibiotics. Increased lipophilicity, influx transporters
and inflammation can increase the permeability of barriers to antibiotics.
The inflammation related to infections may decrease over the course of and in response
to treatment. Antibiotics may cross over into CSF or brain parenchyma readily on
commencement of therapy but as the inflammatory response to the infection subsides –
the ability of the antimicrobial to cross the BBB is reduced. This response generally does
not alter overall outcomes.
Pharmacokinetics of Antibiotic Delivery to Central Nervous System1, 2
Delivery of adequate levels of anti-microbial drugs outside the central nervous system
(CNS) is generally less complicated. Pharmacokinetics of antimicrobials directed at
central nervous system infections depends both on systemic pharmacokinetics and
behaviour of the antimicrobial in its access to and elimination from the CNS. Most data
that exist regarding CNS pharmacokinetics is as a result of studies on CSF and
meningitis (rather than brain parenchyma). The most valuable data are derived from
using plasma – CSF AUC (area under the drug concentration-versus time curve) ratios.
For Beta-lactam antibiotics the ratio ranges from 0.01 to 0.1 and may be higher in less
hydrophilic drugs (Rifampicin, Co-trimoxazole, fluro-quinolones). Vancomycin and
aminoglycosides demonstrate poor CSF penetration (ratios <0.1).
Ventricular CSF has lower concentrations of protein (and therefore drug) in
comparison to lumbar CSF; CSF in ventricles has not mixed with exuded extracellular
fluid from brain parenchyma.
Penetration through blood-lesion brain barrier (in particular cerebral abscess) is
heavily dependent on the stage of formation of the abscess/lesion, its relative
vascularity and sometimes its cause. It is inappropriate to associate CSF drug
concentrations around with antibiotic levels within the abscesses.
The relative half-life of drugs may be altered due to alteration in BBB and BCSFB during
infection as well as CSF shunts and external CSF drains. CSF half-life is considered
longer than blood half-life.
Table 1. Adequacy of Central Nervous System Penetration for Selected Antimicrobials –
as adapted1
Adequate
Ampicillin
Cefepime
Cefotaxime
Ceftazidime
Ceftriaxone
Cefuroxime
Chloramphenicol
Ciprofloxacin
Imipenem
Levofloxacin
Meropenem
Metronidazole
Nafcillin
Ofloxacin
Penicillin G
Rifampicin
Sulfasoxazole
Trimethoprimsulfamethoxazole
Vancomycin
Piperacillin
Fluconazole
Flucytosine
Voriconazole
Caspofungin
Acyclovir
Gancyclovir
Intermediate
Aztreonam
Cefoxitin
Ticarcillin
Inadequate
Aminoglycosides
Azithromycin
Cefazolin
Clarithromycin
Clindamycin
Erythromycin
Amphoteracin B
Itraconazole
Not yet Established
Ertapenem
Gemifloxacin
Moxifloxacin
Quinupristinedalfopristin
Sparfloxacin
Telithromycin
Trovafloxacin
Valacyclovir
In critically ill patients, volume of distribution is a serious consideration. 5, 6, 8 The
hydrodynamic or “bathtub” model conceptualizes the distribution of drug in the
critically ill. A fixed amount of dye added to a bathtub of known volume, a large bathtub
will yield a small concentration than a small bathtub if the same amount of dye is
consistently used in each one. An inverse relationship exists between protein binding
and volume of distribution – high level of serum protein produce high peak serum
concentrations exhibits a slower rate of elimination from the body (if elimination mode
is by glomerulofiltration).
Pharmacodynamics 4, 5,
The Minimum inhibitory concentration (MIC) is the lowest concentration of an
antimicrobial that completely inhibits growth of a micro-organism in-vitro.
Graph 1. Representation of Pharmacokinetic Parameters 5
“Time dependent” antibiotics –killing dependent on time serum concentration of
remain above the MIC hence regular dosing intervals are required to maintain serum
concentrations above MIC. E.g. Beta Lactams, Clindamycin, Erythromycin,
Clarithromycin, Linezolid and Vancomycin. 4, 5, 6, 8
 Continuous Infusion of B-lactams: current evidence shows potential benefit in
that it translates to better attainment of pharmacokinetic parameters but is
limited by clinical data, which does not always show earlier clinical cure and
mortality benefit.7
“Concentration Dependent” antibiotics – killing is dependent when their serum
concentrations are appreciably above their MIC for organisms – AUC/MIC and
Cmax/MIC ratios. Best responses occur when their concentrations are greater than or
equal to 10 times above the MIC for their target organisms at the site of infection. Single
(high) daily dosing is most effective (as opposed to divided doses). E.g. Fluroquinolones,
Aminoglycosides, Metronidazole, Amphoteracin, Daptomycin.4, 5, 6, 8
Post Anti-biotic Effect – describes persistent suppression of bacterial growth following
exposure of a micro-organism to an antibiotic – most pronounced with antibiotics that
interfere with protein synthesis (aminoglycosides, chloramphenicol, macrolides,
tetracylines) or DNA replication (fluroquinolones). Drugs that interfere with cell wall
synthesis (most Beta lactams) demonstrate little if any post-antibiotic effect with the
exception of the carbapenems. 5, 6
Intra-ventricular Antimicrobials24
Intra-ventricular antimicrobial therapy may facilitate higher levels of antimicrobial in
cerebrospinal fluid. Vancomycin for gram-positive and Gentamycin for gram-negative
infections are the two antimicrobials for which there is the most extensive experience.1,
24
The following agents are currently available locally:
 Vancomycin 10 mg daily
 Amikacin 30 mg daily
 Colistin 10mg
Antimicrobial Resistance2, 3, 4, 10, 11, 12
Antimicrobial resistance is a process of loss of susceptibility of an organism to an
antimicrobial agent. This may be due to:
 Production of enzymes: -lactamases, modifying enzymes etc.
 Change in metabolic pathways: sulphonamides – folic acid
 Change in cell wall/membrane/target site.
Mechanisms of gene transfer that may bring about some of the above mechanisms
include Conjugation (DNA transfer with cell to cell contact), Transduction (DNA transfer
with bacteriophage) and Transformation (DNA transfer from environment).
-De-escalation Therapy10, 11, 12: mechanism whereby the provision of effective initial
antibiotic treatment, particularly in cases of severe sepsis, is achieved while avoiding
unnecessary antibiotic use that would promote the development of resistance. It
includes:
 Intent to narrow spectrum of antimicrobial coverage depending on clinical
response, culture results and susceptibilities of pathogens identified
 Commitment to stop antimicrobial treatment if no infection is established
In clinical practice, this is challenging to apply given the paucity of convincing trial
evidence demonstrating that de-escalation does not result in poorer clinic outcome.
The anticipated benefit in De-escalation: reduction in antibiotic related adverse events
including incidence of C. diff infection/super-infection with resistant bacteria and
Candida, beneficial impact of surveillance on antimicrobial resistance profile and
reduction in overall antimicrobial costs.
-Surveillance11, 12 is the hallmark of infection control; it involves tracking the incidence
of certain antimicrobial-resistant pathogens, such as MRSA, VRE and ESBL producing
organisms.
-Antibiotic stewardship4, 11, 12 is a strategy to optimize proper antibiotic use for
inpatients with goals of improved clinical outcomes in addition to minimizing the
emergence and spread of multi-drug resistant organisms. It incorporates multiple
strategies comprising of antibiotic restriction, decreasing unnecessary or inappropriate
antimicrobial use, de-escalation of therapy, clinical decision support and anti-biograms.
-Conservative Initiation9: in critically ill patients without septic shock but suspected of
having an ICU-acquired infection may be able to have antibiotics withheld until
infection is confirmed using a combination of laboratory, radiologic, and microbiological
data. This concept is controversial and may conflict with aspects of the Surviving Sepsis
Campaign Guidelines.
Antibiotic Prophylaxis2
Surgical Site Infection (SSI) Classification:2
Wound Class
Clean
Description
Examples
Uninflamed,
Craniotomy for tumour
uncontaminated, no trauma
or infection, primarily
closed with no break in
sterile technique
Clean-contaminated
Entry into alimentary,
Transnasal
respiratory or genitoHypophysectomy
urinary tract under
controlled circumstances;
no contamination; minor
break in sterile technique
Contaminated
Non-purulent
Depressed skull fracture
inflammation, recent
with overlying laceration,
trauma, gastro-intestinal
Dropped bone flap
tract contamination, major
break in sterile technique
Dirty
Purulent inflammation,
Opened depressed skull
perforated viscus, faecal
fracture with in-driven
contamination, trauma with foreign bodies, Epidural
devitalized tissue, foreign
abscess, Brain Abscess
bodies or gross
contamination
Table 2. As adapted Youmans Neurological Surgery 6th Edition2
-Specific Agents for Prophylaxis25
1. Cephalosporins
Agents of choice where skin flora (coagulase positive/negative staphylococci) are the
likeliest pathogens e.g. Cefazolin: prophylactic dose 1-2g or 25mg/kg IV 60 minutes
prior to surgery then 6 hourly for 24 hours postoperatively – reaches therapeutic levels
in brain tissue after systemic administration.
2. Vancomycin
Alternative if cephalosporins are contraindicated: dose 15mg/kg IV pre-operatively
then 10mg/kg 8 hourly for 24 hours post-operatively.
External Ventricular drains2
Systemic antibiotic prophylaxis does not reduce infection rate in patients with external
ventricular drains.
CSF Fistula 2
Antibiotic prophylaxis is not advocated in preventing meningitis in patients with skull
base fractures.
CSF Shunts2
Wound irrigation and antimicrobial impregnation of shunt catheters are commonly
used for prophylaxis for which the later is supported by current evidence.
-Infection Control in Theatre15
It is impossible to remove all microbes from the surgical field but there are various
strategies with varying levels of evidence to support implementation.
Timing
Pre-op
Focus
Antibiotics
Pre-op
Skin Prep
Pre-op
Checklist
Intra-op
Gloving
Intra-op
Antibiotics
Post-op
Antibiotics
Intervention
Administration
prior to surgery
Insufficient
research examining
antiseptics preoperative to allow
comparative effects
on post-op surgical
wound infections;
no evidence of
benefit of Iodophorimpregnated drapes
Reduced
complications in
non-cardiac surgery
in patients >16
years
No direct evidence
that additional
glove protection
reduces SSI – but
studies were not
well powered
Intra-op. re-dosing
of antibiotics
reduces overall risk
of SSI
Antibiotics
administered >48
hours post-op are
ineffective and
increase
antimicrobial
resistance
Level of Evidence
II
I
II
I
III
III
Table 3. As adapted from Walcott et al. Infection following operations on central
nervous system: deconstructing the myth of the sterile field- Neurosurgical Focus15
Table 5. Current Antimicrobial Policy – as per Medical Microbiology IALCH (Dr. Y Mahabeer)
BRAIN ABSCESS
Microbes: Rhinogenic
Streptococcus anginosus
Anaerobes
Microbes: Otogenic
Above plus
Enterobacteriacae eg Proteus mirabilis, E.coli, Pseudomonas aeruginosa
Microbes: Haematogenous
Staphylococcus aureus
Microbes: Post-traumatic
Staphylococcus aureus
Enteric gram negative bacilli eg Klebsiella pneumoniae, E.coli, Proteus mirabilis
Anaerobes
Pseudomonas aeruginosa
Empiric antimicrobials:
Ceftriaxone plus metronidazole
Post-trauma/Neurosurgery: Vancomycin plus ceftriaxone or Meropenem plus vancomycin
if hospital-acquired
VP SHUNT SEPSIS
Microbes:
Staphylococcus epidermidis or other spp from skin
Staphylococcus aureus
Gram negative bacteria uncommon
Empiric antimicrobials:
Vancomycin
Can add Ceftiraxone if infection at abdominal end.
EVD-RELATED MENINGITIS
Microbes:
Enteric gram negative bacilli eg Klebsiella pneumoniae, E.coli, Proteus mirabilis
Pseudomonas aeruginosa
Acinetobacter spp (usually multi-drug resistant)
Staphylococcus epidermidis or other spp from skin
Staphylococcus aureus
Empiric antimicrobials:
Meropenem plus Vancomycin
De-escalate ASAP
NOSOCOMIAL PNEUMONIA
Organisms
Enterobacteriacae eg Klebsiella pneumoniae, E.coli, Enterobacter spp
Pseudomonas aeruginosa
Staph aureus (MRSA) not common
Empiric choice :
Piperacillin/tazobactam plus amikacin
INTRAVENTRICULAR ANTIMICROBIALS
Use in combination with intravenous antimicrobials
Vancomycin 10 mg daily
Amikacin 30 mg daily
Colistin 10mg
Antibiotic Treatment
Soft Tissue Infections (Scalp)2
Most likely offending organisms are gram-positive cocci: Staphylococci and Streptococci
for which 1st generation Cephalosporin, a semisynthetic Penecillin, clindamycin or
erythromycin should be considered. If MRSA is suspected, Vancomycin is drug of choice
(should be based on culture/sensitivity). Duration of therapy is dependent on response
(usually 7-10days).
If infection is necrotizing, aetiology is polymicrobial in nature and empirical treatment
(broad spectrum antibiotics) is advocated. Gram positive/negative and anaerobic is
required – Penicillin or 3rd Generation Cephalosporin in combination with
Metronidazole.
Meningitis2
First line therapy as per recommendations above for meningitis involves a third
generation Cephalosporin; however there is an emergence of resistant gram-negative
organisms: Enterobacter and Acinetobacter species with plasmid-encoded or inducible
chromosomal -lactamases that hydrolyze extended spectrum Cephalosporins.
Carbapenems in particular provide coverage for these pathogens but requires judicious
use as resistance has been reported. Some centers use intravenous and intra-thecal
Colistin.
Table 6. Practice guidelines from the Infectious Disease Society of America2
Pre-disposing
Factors
<1 month
1-23 months
Common Bacterial Pathogens
Antimicrobial Therapy
Group B Strep (agalactiae), E.coli,
Listeria, Klebsiella sp.
Strep. Pneumonia, Neisseria Menigitidis,
S. agalactiae, H. influenza, E.coli
Ampicillin + Cefotaxime or
aminoglycoside
3rd Generation
Cephalosporin +
Vancomycin
3rd Generation
Cephalosporin +
Vancomycin and Ampicillin
3rd Generation
Cephalosporin +
Vancomycin
Vancomycin + 2nd
Generation Cephalosporin
or Meropenem
2-50yr
N.meningitidis, S. pneumonia
Basilar Skull
Fracture
S.pneumoniae, H.influenzae, Group A βhaemolytic Strep
Penetrating
Trauma
Staphylococcus aureus, coagulase
negative staphylococci, aerobic gram
negative bacilli (rods) – incl.
Pseudomonas aeruginosa
Neurosurgery
CSF Shunt
Aerobic gram-negative bacilli (rods)
including Pseudomonas aeruginosa, S.
aureus, Coagulase negative Staph.
Coagulase negative Staph, S. aureus,
Aerobic gram-negative bacilli (rods)
including Pseudomonas aeruginosa,
Propionibacterium acnes
Vancomycin + 2nd
Generation Cephalosporin
or Meropenem
Vancomycin + 2nd
Generation Cephalosporin
or Meropenem
Cerebral abscess 19
Medical management may be used in select circumstances for brain abscesses: single
abscess less than 2cm in diameter, with multiple abscesses, with critical illness at a
terminal stage, or if abscess is not accessible localization. Empiric treatment is
advocated until positive culture identifies offending organism or if none identified.
Duration of antibiotic therapy: 6-8 weeks parenterally then 2-3 months orally still
controversial.
Table 7. Pre-disposing Factors for Cerebral abscess and suggested Empiric Regimen20
Predisposing Condition
Empiric Antimicrobial Therapy
Otitis media/mastoiditis
Third Generation Cephalosporin +
Metronidazole
Sinusitis
Third Generation Cephalosporin +
Metronidazole +/- Vancomycin
Dental Infection
Penicillin + Metronidazole
Penetrating trauma or secondary to
Third/Fourth Generation Cephalosporin +
neurosurgery
Vancomycin
Lung abscess/empyema thoracis or
Penicillin + Metronidazole + Sulfonamide
bronchiectasis
Bacterial Endocarditis
Vancomycin + Gentamycin
Congenital Heart Disease
Third Generation Cephalosporin
Unknown
Third/Fourth Generation Cephalosporin +
Vancomycin + Metronidazole
Table 8. Evaluation of Microbiology Results from 2014 – Sample March –May 2014 at
Inkosi Albert Luthuli Central Hospital – Department of Neurosurgery
Empyema2
Initial broad-spectrum antibiotic cover against Streptococci, Staphylococci and
anaerobes – traditional regimen26 used by Nathoo et al penicillin, chloramphenicol and
metronidazole for 2 weeks parenterally then 4 weeks orally but must be de-escalated
based on culture results.
Shunt Infections2
Empiric therapy should ensure coverage for MRSA, Staphyloccus Epidermidis with
resistant gram-negative organsims – Vancomycin with anti-pseudomonal antibiotic (e.g.
Cefepime or Ceftazidime). An alternative regimen includes Linezolid (parental) – which
may prove to be an attractive option based on early studies.
CSF data conclusion:
Empiric choice Vancomycin for VPS sepsis
Empiric choice Vancomycin plus Meropenem for EVD-related meningitis
Fluid data conclusion
For empyaema ff rhinogenic infections, Amoxicillin/clavulanate
If brain abscess ff rhinogenic infections, Cefotaxime plus metronidazole (chloramphenicol
would work as well)
Tissue/swabs as above but:
Hospital-related infections need Vancomycin plus Meropenem
ETA
Early onset pneumonia (within 5 days) and antibiotic naïve patient- Amoxicillin/clavulanate
Late onset pneumonia & previous abt exposure - Piperacillin/tazobactam plus amikacin
Blood culture - very low positivity
Piperacillin/tazobactam plus amikacin
Infection with Spinal Instrumentation2
Empirical antimicrobial therapy should include coverage against Staphylococcal sp. as well
as gram-negative organisms – 3rd Generation Cephalosporin and Vancomycin. Surgical
management may be required as part of source control – includes drainage of abscess,
debridement and occasionally removal of hardware. 2
In a review 817 patients who underwent posterior instrumented lumbar fusion for
degenerative spine disease: older age, diabetes mellitus, obesity, prior spine surgery and
length of hospital stay were each independently identified as risk factors for development
of infection (4.5%). Notably the overwhelming majority (92%) of patients (with infection)
were managed successfully without hardware removal. 21
Conclusion
The rational use of antimicrobials forms a fundamental part of current Neurosurgical
practice. Knowledge of new developments in antimicrobial therapy support updating of
protocols for empiric treatment, surgical site infection prophylaxis and management of
sepsis; using the most appropriate drug in the appropriate context will result less need for
de-escalation, lower risk of antimicrobial resistance and effective management of infection.
Greater coverage is not necessarily better, antimicrobials carry inherent risk of neurotoxicity (“It can’t hurt”)2 and adequate penetration of drug to affected neural tissue must
always be considered.
References:
1. Parag G. Patil, Zimee Zaas, Daniel Sexton et al. Newer Antimicrobials for
Neurosurgery. Contemporary Neurosurgery. Volume 24: Number 23. November
15, 2002
2. H. Richard Winn et al. Youmans Neurological Surgery. Sixth edition 2011.
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of Antimicrobial Agents. 30(2007): 11-18.
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treatment in ICU patients with suspected ICU-acquired infection: more haste less
speed. Current Opinion Critical Care. 2013, 19:461-464.
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8: 2433-2440.
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12. Deverick J. Anderson, Keith S. Kaye. Controlling Antimicrobial Resistance in the
Hospital. Infectious Disease Clinics of North America. 23(2009) 847-864.
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intracranial infection following craniotomy. Neurosurgical Focus. 24 (6):E10,
June 2008.
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the central nervous system: deconstructing the myth of the sterile field.
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16. Kelly Wright, Polly Young, Cristina Brickman et al. Rates and determinants of
ventriculostomy-related infections during a hospital transition to use of
antibiotic-coated external ventricular drains. Neurosurgical Focus. 34 (5):E12,
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17. Ersin Erdogan, Tufan Cansever. Pyogenic Abscess. Neurosurgical Focus. 24 (6):
E2, June 2008.
18. Ranjith K. Moorthy, Vedantam Rajshekhar. Management of brain abscess: an
overview. Neurosurgical Focus. 24 (6): E3, June 2008.
19. Tayfun Hakan. Management of bacterial brain abscess. Neurosurgical Focus. 24
(6): E4, June 2008.
20. James L. Frazier, Edward S. Ahn, George I. Jallo. Management of brain abscesses
in children. Neurosurgical Focus. 24(6):E8, June 2008.
21. Kaisorn L. Chaichana, Mohamad Bydon, David R. Santiago-Dieppa. Risk of
infection following instrumented lumbar fusion for degeneration spine disease in
817 consecutive cases. Journal of Neurosurgery: Spine. 20:45-52, January 2014.
22. P Eckberg, Friedland HD et al. FOCUS 1 and 2 Randomized, Double-blinded,
Multicenter Phase 3 Trials of the Efficacy and Safety of Ceftaroline vs. Ceftriaxone
in Community-acquired pneumonia. 2009 Interscience Conference on
Antimicrobial Agents and Chemotherapy/Infectious Disease Society of America
Conference.
23. DJJ Muckart. Antimicrobial Guidelines – Trauma ICU. 2014
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1: Anticonvulsants, Chemotherapy, Antibiotics. Contemporary Neurosurgery.
Volume 18, Number 9, May 1996.
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Appendix:
1. Evaluation of Microbiology results 2014 - March to May at IALCH
CSF
MICROBES:
Staph aureus
Methicillin
susceptible
Methicillin resistant
Staph spp
Streptcoccus
anginosus
Streptococcus
pyogenes
Enterococcus spp
Strep viridans
Streptococcus
pneumoniae
Haemophilus
influenzae
Enterobacteriacae
E.coli
Klebsiella
pneumoniae
Enterobacter cloacae
Proteus mirabilis
Seratia marscesens
Citrobacter spp
Acinetobacter spp
Pseudomonas
aeruginosa
Stenotrophomonas
maltophila
FLUID
TISSUE/SWABS
BLOOD
CULTURE
ETA
0
4
11
3
1
0
0
18 (17
resistant to
cloxacillin)
3
1
9
2
2
1
1
0
0
0
0
0
0
4
2
0
0
0
2
2
1
2
0
4
5
0
0
0
0
0
0
0
1
0
0
0
3
0
14
4 (All ESBL
producers)
4 (3 ESBL
producers)
2
2
4
0
14
0
4
4
8
0
3
2 (1 ESBL
producer)
5
0
3 (1 ESBL
producer)
1
3
1
0
3
0
1
6 (3 MDR)
1
0
0
2 (2
MDR)
1
2 (2 ESBL
producer)
0
1 (1 ESBL
producer)
0
0
1
0
3 (3 MDR)
0
2
7
0
3
1
0
0
0
1
1
2
1
2
1