update chapter 2012

1. Antibiotic use in an Intensive care setting.
Dr.(Mrs.) Arundhati G. Diwan MD *, Dr. Jignesh Shah MD, DNB, EDIC **, Dr. Sachin A. Adukia MBBS ***
* Professor and Head, Dept. of Internal Medicine- Bharati hospital and Research Centre (BHRC), Pune
**Intensivist and Assistant Professor, Dept. of Anaeathesia, BHRC, Pune.
***Resident, Second year- Dept. of Medicine, BHRC, Pune.
A decade earlier antibiotic resistance was emerging as
a growing threat to medical therapeutics. We always relied on
the stream of higher more powerful antibiotics to flow out of
major pharmaceutical companies till the day has come that this
stream is reduced to a trickle and almost dried up. Today the
Indian physician faces a plethora of resistant microbes which
are spilling out of the intensive care into the community. A few
examples are multidrug resistant (MDR)-TB, Methicillin
resistant Staph. Aures (MRSA), Vancomycin resistant Staph.
Aures(VRSA), the extended spectrum beta lactamase(ESBL)
bacteria and more recently the New Delhi Metallo beta
lactamase-1 (NDM-1) producing bacteria.
The Extended Prevalence of Infection in Intensive Care (EPIC
II) study concluded that infections are common in patients in
contemporary ICUs, and risk of infection increases with
duration of ICU stay(1)
.Closer to home, a recent study on
antibiotic use in a tertiary care centre in an Indian city reveals
that approximately Rs.39000 is spent on antimicrobial therapy
alone to make one patient of disease from infection requiring
ICU survive(2)
. It implies that infections can cost the patient
money and life due to subjective irrational dispensing of
antibiotics in ICU.
CLASSIFICATION OF ANTIBIOTICS(3)
Cell wall synthesis inhibitors
Beta-lactams -penicillins,cephalosporins,
aztreonam , carbapenems
Poly-peptides -bacitracin , vancomycin,
cycloserine
Protein synthesis inhibitors
Bacterostatic :Tetracyclines, Macrolides,
Chloramphenicol, Clindamycin, Linezolid
Bacteriocidal: Aminoglycosides
Antimetabolite- Sulfonamides, Trimethoprim
Topoisomerase inhibitors- quinolones
Membranotoxic compound – Polymyxin,
daptomycin
RNA polymerase inhibitors- rifampin,
rifabutin.
PROPHYLACTIC ANTIBIOTICS:-
1. Antibiotic prophylaxis is not required in percutaneous
arterial and central venous catheters for insertion or while
indwelling. Same applies for indwelling drains as it increases
the risk of later infection by MDR pathogen (4)
.
2. Selective digestive decontamination (SDD) with topical and
parenteral antibiotics decreases the incidence of respiratory
tract infections by 65% and death. However prolonged
prophylaxis is associated with postoperative pneumonia,(5)
catheter sepsis and catheter-related blood stream infection(6)
and
infection by MRSA(4)
. Risk of Clostridium difficile-related
disease (antibiotic-assoiated colitis) goes up fivefold(7)
.
3. In hepatic cirrhosis with portal hypertension and variceal
hemorrhage antibiotic prophylaxis is of clear benefit(8)
. It
reduces risk of infection, recurrent hemorrhage and death (9)
.
4. Systemic antibiotic prophylaxis shows reduction in
nosocomial pneumonia and also a 20% reduction in overall
mortality(10)
.
EMPIRICAL ANTIBIOTICS:
Factors to be considered when selecting empiric antimicrobial
therapy(11)
:
1. Select empiric monotherapy based on coverage of
predictable pathogens as per focus (organ) of infection
(blood/urine/intra-abdominal).
2. Select antibiotic with low resistance potential (locally).
3. Select antibiotic with a good safety profile (eg. least
nephrotoxic).
Combination therapy is more appropriate for those prone to
MDR pathogens (table 1). Therefore, initial coverage should
include agents from different classes. Gram-negative coverage
typically involves a β-lactam, quinolone or aminoglycoside(11)
.
For patients with severe sepsis, intravenous antibiotic therapy
should be started within the first hour of recognition of severe
sepsis, after taking appropriate culture samples(12)
.
Table1. Risk Factors for MDR Organisms(13)
:
Exposure
 History of MDRO(multidrug resistant organisms)
 Colonization pressure (facility rates of MDRO
infection/colonization)
 Recent antibiotics
 Recent hospitalization
 Comorbidity/Dependency (need for contact care)
 Dialysis
“Fertile Ground” For Bacterial Proliferation
 Wounds
 Indwelling devices
 Dental plaque
 Structural lung disease (bronchiectasis, COPD)
THERAPEUTIC USE ANTIBIOTICS:
Pneumonia:-
1. Community acquired pneumonia:- Penicillins remain
effective despite increasing resistance of S. pneumoniae. They
are given for a period of 10 days, or for 14-21 days in cases
caused by Legionella, S. Aureus or gram-negative enteric
bacilli.

2. 2. Hospital acquired pneumonia and ventilator associated
pnenmonia:- For infections developing within four days of
hospital admission, in patients with no other risk factors for
resistant pathogens (Table 2), appropriate agents are co-
amoxiclav, cefuroxime or a fluoroquinolone. For late-onset
cases and those with previous antibiotic exposure or other risk
factors, treatment with an antipseudomonal beta-lactam
(piperacillin / tazobactam, ceftazidime or a carbapenem) or an
antipseudomonal fluoroquinolone (ciprofloxacin/ levofloxacin)
is recommended. Addition of a glycopeptide or linezolid should
be considered if the risk of MRSA is judged to be high. Short
courses of antibiotics appear to be be as effective as longer
ones, and may reduce the risk of bacterial resistance(14)
.
Table 2. Risk factors for multidrug-resistant
pathogens causing hospital-acquired pneumonia
(HAP), healthcare-associated pneumonia
(HCAP), and Ventilator -associated pneumonia
(VAP)(15)
 Antimicrobial therapy in preceding 90 d
 Current hospitalization of 5 d or more
 High frequency of antibiotic resistance in the
community or
 in the specific hospital unit
 Presence of risk factors for HCAP:
 Hospitalization for 2 d or more in the preceding 90 d
 Residence in a nursing home or extended care facility
 Home infusion therapy (including antibiotics)
 Chronic dialysis within 30 d
 Home wound care
 Family member with multidrug-resistant pathogen
 Immunosuppressive disease and/or therapy
Selective decontamination of the digestivetract (SDD):-
Non-absorbable antibiotics, commonly a combination of
polymyxin, amphotericinB and aminoglycoside, are applied
via nasogastric tube and, as a paste, to the oropharynx.
Systemic antibiotics, cefotaxime and ciprofloxacin, may be
added during the first four days in the ICU to prevent early
infections(14)
.
Pulmonary aspiration:-
Antibiotic treatment should be restricted to patients with
clinical evidence of infection, and should follow standard
guidelines for community or hospital-acquired pneumonia(14)
.
Complicated intra-abdominal sepsis:
Empirical treatment of community-acquired infections includes
narrow spectrum agents eg metronidazole plus cephalosporin
(cefuroxime)/ fluoroquinolone (ciprofloxacin). Severe
infections or in immunosuppressed hosts warrant broader
spectrum treatment with carbapenems, piperacillin/ tazobactam,
or a combination of metronidazole and a 3rd or 4th-gen.
cephalosporin or Tigecycline. Hospital-acquired infections
involve resistant organisms such as Enterobacteriaceae.
Commonly used regimens incorporate an aminoglycoside plus
an anti-pseudomonal b-lactam such as piperacillin/ tazobactam.
3rd and 4th-generation cephalosporins, carbapenems, and
extended-spectrum penicillins such as piperacillin/ tazobactam
are all effective. Addition of glycopeptide should be considered
when there is a high risk of infection with MRSA. Five to seven
days treatment is usually adequate (14)
.
Meningitis and meningococcal septicaemia: Community
acquired meningitis involves S. pneumoniae and
N.meningitides. with the occasional L. monocytogenes, S.
aureus, M.tuberculosis and E. coli. Lumbar puncture should not
delay administration of antibiotics because this may reduce the
chances of survival. Initial treatment is intravenous
cefotaxime, 2 g 6-hourly, or ceftriaxone, 2 g 12-hourly.
Therapy should further be guided by gram staining of CSF or
by culture reports(14)
.
Methicillin-resistant S. aureus (MRSA): Glycopeptides or
linezolid are the agents of choice for MRSA bacteraemia and
pneumonia, and for skin and soft tissue infections where the
risk of bacteraemia is high. Minimum duration of treatment is
14 days for bacteraemia (14)
.
It must be noted that the eventual choice of antibiotics has to be
guided by knowledge of institutional antibiograms and
susceptibility patterns.
Table 3: Empiric Antibiotic Selection in suspect
causatives(16)
.
Organism Antibiotic Alternative
Gram-positive organisms
Staphylococci
aureus
Cefazolin or
Vancomycin
Linezolid
Coagulase-
negative
staphylococci
Vancomycin Linezolid…….
S.pneumoniae Ceftriaxone Moxifloxacin
Enterococcus
faecalis
Ampicillin +/-
Gentamicin
Vancomycin +/-
Gentamicin
Enterococcus
faecium
Linezolid Quinupristin
/ dalfopristin
Gram-negative organisms
Serratia Piperacillin/tazobacta
m / Gentamicin
β-lactam /
Ciprofloxacin
or
Ciprofloxacin /
aminoglycoside
Pseudomonas
aeruginosa
Piperacillin /
tazobactam /
Tobramycin
Acinetobacter Cefepime
/Gentamicin
Citrobacter Cefepime
/Gentamicin
Enterobacter Piperacillin/tazobacta
m / Gentamicin
E. coli (non-ESBL
isolate)
Cefazolin Gentamicin
Klebsiella (non-
ESBL isolate)
Cefazolin Gentamicin or
Quinolone
Haemophilus
influenzae
Azithromycin Cefuroxime
E. coli or
Klebsiella (ESBL
producer)
Meropenem
--
Stenotrophomonas
maltophilia
Trimethoprim/sulfa
methoxazole
Ticarcillin /
clavulanic acid

3. ALTERATIONS IN PHARMACOKINETICS (PK) AND
PHARMACODYNAMICS (PD) IN A CRITICALLY ILL
PATIENT (17)
:-
Different antibiotic classes have been shown to have different
kill characteristics on bacteria (Fig. 1 and Table 4).
Y axis
Cmax/MIC
T >MIC
================ MIC
X Axis
Fig. 1:- X Axis- time in hours; Y Axis- concentration (mg/dl).
PK and PD parameters of antibiotics on a concentration vs. time curve.
Key: T >MIC = Time for which a drug’s plasma concentration remains
above the minimum inhibitory concentration (MIC) for a dosing
period; Cmax/MIC, the ratio of the maximum plasma antibiotic
concentration (Cmax) to MIC; AUC/MIC, the ratio of the area under the
concentration time curve during a 24-hour period (AUC0–24) to MIC.
(Adapted from Pharmacokinetic issues for antibiotics in the critically
ill patient - Critical Care Medicine 2009 Vol. 37, No. 3.)
Table 4:- Antibiotics with pharmacodynamic kill
characteristics(17)
:-
Time-dependent Concentration-
dependent
Concentration-
dependent with
time-dependence
β-lactams
Carbapenems
Linezolid
Erythromycin
Clarithromycin
Lincosamides
Aminoglycosides
Metronidazole
Fluoroquinolones
Telithromycin
Daptomycin
Quinupristin-
dalfopristin
Fluoroquinolones
Aminoglycosides
Azithromycin
Tetracyclines
Glycopeptides
Tigecycline
Quinupristin-
dalfopristin
Linezolid
Changes in Volume of distribution (Vd):- Endotoxins result
in vasoconstriction or vasodilatation with maldistribution of
blood flow, endothelial damage and increased capillary
permeability. This capillary leak would increase the Vd of
hydrophilic drugs which decreases their plasma drug
concentration. Vd is also increased by mechanical ventilation,
significant burn injuries, hypoalbuminaemia (increased
capillary leakage) extracorporeal circuits (e.g., plasma
exchange, cardiopulmonary bypass), postsurgical drains.
Lipophilic drugs have a large Vd because of their partitioning
into adipose tissue, and as such the increased Vd that results
from third-spacing is likely to cause insignificant increases in
drug Vd(17)
.
Changes in Antibiotic Half-Life: Drug elimination half-life
(T1/2) is represented by the equation:
T 1/2 = 0.693 x Vd/ CL
Standard initial management of hypotension in critically ill
patients is administration of intravenous fluids (to increase
Vd). When hypotension persists, vasopressor agents are added
(to increase peripheral vascular resistance which reduces renal
perfusion and hence CL= creatinine clearance). Dose
adjustment for hydrophilic antibiotics can be guided by
measures of creatinine clearance whereas equations such as the
Cockroft-Gault and Modified Diet in Renal Disease equations
are likely to be unreliable and, if possible, should not be
substituted for urinary creatinine clearance data(17)
.
Hypoalbuminemia: Protein binding influence the Vd and CL
of many antibiotics. A notable example is of ceftriaxone, which
is 95% bound to albumin in normal ward patients. In
hypoalbuminemic states, as common in critically ill patients,
this can result in a higher unbound concentration that has a
100% increased CL and 90% greater Vd(17)
.
Development of End-Organ Dysfunction: Multiple organ
dysfunction syndrome, which includes renal and/or hepatic
dysfunction results in decreased antibiotic CL, prolonged T1/2,
and potential toxicity from elevated antibiotic concentrations
and/or accumulation of metabolites(17)
.
Fig 2 identifies the above pathophysiological effects.
Fig 2. Schematic representation of the basic pathophysiological
changes that occur during sepsis and their subsequent pharmacokinetic
effects; Key-CL creatinine clearance; Vd, volume of distribution.
(Adapted from Pharmacokinetic issues for antibiotics in the critically
ill patient - Critical Care Medicine 2009 Vol. 37, No. 3.)
General Dosing Consideration: Selection of effective dosing
regimens translates into effective antibiotic therapy in the
critically ill. Table 5(vide infra) proposes some general dosing
recommendations to this end with consideration especially for
the altered renal function.
ANTIBIOTIC RESIISTANCE (18)
:
Mechanisms of drug resistance:-
First, via acquisition by bacteria of genes encoding enzymes,
such as beta-lactamases, that destroy the antibacterial agent
Concentration dependent
e.g. Aminoglycosides
AUC/MIC
e.g. fluoroquinolones
Time-dependant
e.g. β-lactams

4. Table 5 Broad guidelines that can be used for antibiotic dosing adjustment in critically ill patients (17)
Antibiotic Class
Suggested Dosing Adjustment for Critically Ill Patients
Normal Renal Function Moderate to Severe Renal Dysfunction
Comments
Aminoglycosides Use high doses (e.g., gentamicin 7 mg/kg) where
possible to target Cmax:MIC ratio of 10
Use high doses where possible and monitor Cmin
thereafter (36 to 48 hourly extended interval dosing
acceptable); dosing can be guided by MIC data if
available
β-lactams/
Carbapenems
Consider extended or continuous infusion or
more frequent dosing to ensure T > MIC;
If intermitted dosing used, dosing can occur at
reduced dose or frequency (not both); err toward
larger doses as β-lactams have large therapeutic
window.
Glycopeptides Dosing at 30–40 mg/kg/day (vancomycin), may be
increased according to Cmin plasma concentrations (aim
for 15–20 mg/L)
High dosing on day 1 may be required to ensure
adequate distribution; dose adjustments should
occur according to Cmin
Fluoroquinolones Doses that achieve high Cmax:MIC ratio should be
targeted (e.g. ciprofloxacin 1200 mg/day); levofloxacin
may require 500 mg 12-hourly in some patients with
high creatinine clearance; where high doses used,
monitor for toxicity (seizures)
Dose adjustment is required in renal impairment for
levofloxacin, gatifloxacin and ciprofloxacin
Tigecycline 100 mg loading dose then 50 mg 12 hourly No dose adjustment required in renal failure or
dialysisa
Linezolid 600 mg 12 hourly No dose adjustment required in renal failure or
dialysis
Colistin Use 5 mg/kg/day of colistin base (75,000 international
units/kg/day colistimethate sodium)b
intravenously in 3
divided doses
Reduce dose or frequency (not both)
MIC, minimum inhibitory concentration; Cmax, maximum concentration; Cmin, minimum concentration.
a-if severe cholestasis present then tigecycline should be dosed with 50-mg loading dose, then 25 mg 12 hourly;
b-1 mg colistimethate sodium is equivalent to 12,500 international units.
(Adapted from Pharmacokinetic issues for antibiotics in the critically ill patient - Critical Care Medicine 2009 Vol. 37, No. 3.)
before it can have an effect (e.g., erythromycin ribosomal
methylase in staphylococci).
Second, acquisition of efflux pumps that extrude the
antibacterial agent from the cell before it can reach its
target site and exert its effect (efflux of fluoroquinolones in
S aureus).
Third, by acquiring several genes for a metabolic pathway
which produces altered bacterial cell walls that no longer
contain the binding site of the antimicrobial agent or
acquiring mutations that limit access of antimicrobial
agents to the intracellular target site via downregulation of
porin genes(e.g., OmpF in E coli).
Through genetic exchange mechanisms including
transformation, conjugation, or transduction, many bacteria
become resistant to multiple classes of antibacterial agents,
and are labeled as multidrug resistant (defined as resistance
to 3 or more antibacterial drug classes).
Highlighted below are select examples of resistance
acquisition and identification with treatment options
amongst commom resistant ICU setting pathogens.
Methicillin-resistant S. aureus (MRSA): has acquired
genes for generation of PBP’2 (Penicillin binding protein-
2) which does not bind to any β lactam antibiotic making it
resistant to all penicillins, cephalosporins and
carbapenems.
MRSA can be identified on culture report by looking at
resistance to methicilin, oxacillin or cefoxitin.
Treatment options include glycopeptides like vancomycin
& teicoplanin, linezolid, Daptomycin, Quinopristin-
Dalfopristin and Tigecycline(19)
.
Multiresistant gram-negativee nterobacteriaceae-
Those causing HAI include E.Coli, Klebsiella and Proteus.
They produce β lactamases to defend themselves against β
lactam antibiotics.
Three such β lactamases are TEM-1, AmpC and ESBL’s.
1) TEM-1 is plasmid encoded and confers absolute
resistance to ampicillin and amoxicillin
2) AmpC is chromosomally encoded and inducible. They
confer resistance to penicillin, first generation
cephalosporins. Mutant AmpC are resistant to β lactams, β
lactamase inhibitor (BL-BLI) combinations but are
susceptible to carbapenems.

5. 3) ESBL-is plasmid encoded. They confer resistance to all
BL-BLI’s. ESBL strains are resistant to many other non β
lactam antibiotics through plasmid mediated resistance.
Carbapenem resistance is also growing amongst ESBL
organisms.
Microbiological identification is by looking at the activity
of extended-spectrum beta-lactams, including cefotaxime
and ceftazidime alone and in presence of clavulinic acid.
For ESBL producers activity is restored in the presence of
clavulanic acid.
Treatment is carbapenems – Meropenem/ Imipenem.
For Carbapenemase producing organisms, options are
Colistin, Polymixixn B, Tigecycline.
ESBL producers are often resistant to aminoglycosides,
fluoroquinolones, and trimethoprim-sulfamethoxazole.
They must be reported as resistant to all penicillins,
cephalosporins (but not cefoxitin or cefotetan), and
aztreonam regardless of the in vitro result(19)
.
P. aeruginosa: is intrinsically resistant to narrow-spectrum
penicillins, first- and second-generation cephalosporins,
trimethoprim, and sulfonamides.
It has a characteristic grape-like odour and contains the
pigment pyocyanin, imparting a bluish-green color on
culture media.
The antipseudomonal agents include extended-spectrum
penicillins, such as ticarcillin and piperacillin; extended -
spectrum cephalosporins, such as ceftazidime and
cefepime; carbapenems; aminoglycosides; and
fluoroquinolones. However, P. aeruginosa isolates that are
resistant to one or more of these agents, particularly
aminoglycoside and fluroquinolones(19)
.
Acinetobacter spp. Treatment is according to local
sensitivity patterns- empirical treatment will be
carbapenems. For carbapenem resistant strains colistin or
polymyxin B or tigecyline are alternatives(19)
.
Clostridium difficile- Treatment is stopping the causative
antibiotic if possible and administration of anticlostridial
antibiotic.The agent of choice of oral metronidazole .Oral
Vancomycin is an alternative agent(19)
.
Vancomycin-resistant enterococci-
Because of altered PBP (penicillin binding protein)
enterococcus are inherently resistant to cephalosporins,
Some enterococci have become resistant to vancomycin
due to change in peptide side chain. These vancomycin
resistant enterococci (VRE) infections are harder to treat
because of their antibiotic resistance.
Treatment options for VRE are limited and include
Linezolid, Daptomycin, tigecycline and Quinopristin –
Dalfopristin(19)
.
ANTIMICROBIAL STEWARDSHIP (20)
:
It is the rational, systematic approach to the use of
antimicrobial agents in order to achieve optimal outcomes.
Recommendations by Infectious Disease Society of
America/ Society developing an institutional programme to
enhance stewardship involves a close working between
several members.
a. Core committee;
1. Infectious disease physician,
2. Clinical pharmacist with infectious disease
training,
3. Health care epidemiologist,
4. Clinical microbiologist,
b. Close collaboration with the hospital infection
prevention and control programme and the pharmacy and
therapeutics committee.
c. Support and collaboration of;
Hospital administration,
Quality assurance and patient safety programs,
d. Negotiate for adequate authority for outcomes;
e. Hospital administrative support for necessary
infrastructure;
f. Monitoring of the impact and outcomes.
When antibiotic usage is mandatory following guidelines
are recommended;
a. Risk stratification of the patient is done;
1. Patient type 1 (Community-acquired infection).
2. Patient type 2 ( Health-care infection)
3. Patient type 3 (Nosocomial infection)
b. Establish the common microbial flora and antibiotic
susceptibility prevalent in the area of the hospital regarding
the site of infection.
c. The prevalent data may be indicative of the trends
prevalent for the last approximately 6 months collected by
the clinical microbiologist updated at regular fixed
intervals or modified on priority basis should an outbreak
is likely o occur.
d. Depending on the clinical condition of the patient, site/
source of infection and laboratory parameters empirical
antibiotic is selected, awaiting culture and antibiotic
sensitivity report is available.
e. Once antibiotic sensitivity report is available, empirical
antibiotics if sensitive, then they are continued, otherwise
specific antimicrobial therapy is commenced as per culture
sensitivity report.
f. De-escalation or stopping of the antibiotics are done
onceclinical and laboratory parameters show recovery
g. Escalation of therapy is considered if MRSA, ESBL,
VRE or Carbapenemase producing organism or add
antifungals if fungal isolates are obtained(20)
.
PREVENTIVE STRATEGIES AGAINST
ANTIBIOTIC RESISTANCE (21)
:
These include interventions aimed at improving antibiotic
use such as antibiotic rotation, antibiotic restriction, de-
escalation therapy. Area-specific therapy( i.e. according to

6. local prevalence of pathogens) and combination therapy
(discussed above) are other easily applicable strategies.
Contact precautions(19)
is the most often overlooked
strategy to aid this cause. Standard precautions include:-
1. Hand hygiene-Hands must be cleansed before and
after every patient contact
2. Appropriate use of gloves, aprons & PPE when
exposure to body secretions or blood is considered
possible.
3. Appropriate handling and disposal of waste and
sharps.
4. Appropriate handling and management of clean &
soiled linens
5. Isolation precautions for certain infections
6. Terminal disinfection and decontamination of
healthcare equipments
Antibiotic rotation: involves withdrawal a class of
antibiotics or a specific antibiotic drug from use for a
defined time period and reintroduced at a later point in
time in an attempt to limit bacterial resistance to the cycled
antimicrobial agents(21)
.
De-escalation: of antibiotic therapy is a strategy to balance
the need to provide adequate initial antibiotic treatment of
high-risk patients with the avoidance of unnecessary
antibiotic utilization, which promotes resistance. Risk
stratification according to Table 1(13)
should be employed
and those at high risk for infection with antibiotic-resistant
bacteria should be treated initially with a combination of
antibiotics providing coverage for the most likely
pathogens to be encountered in that specific intensive care
unit/clinical setting. Therapy should be modified once the
agent of infection is identified or discontinued altogether if
the diagnosis of infection becomes unlikely(21)
.
Restricting the hospital formulary (Antibiotic
restriction) : for use of certain antibiotics or classes of
antibiotics reduces the adverse drug reactions from the
restricted drug. This approach is generally applied to drugs
with broad spectrums of action (such as imipenem), where
antibiotic resistance emerges rapidly (as with third-
generation cephalosporins) and where toxicity is readily
identified. It has been difficult to demonstrate that
restricting hospital formularies is effective in curbing the
emergence of resistance or improving antimicrobial
efficacy. However, the restrictions have been successful in
outbreaks of infection with antibiotic- resistant bacteria,
particularly in conjunction with infection control practices
and antibiotic educational activities(21)
.
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