BACTERICIDAL ACTIVITY OF DIFFERENT BRANDS OF CEFEPIME ... · Bano and Arsalan, 2018). The...

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Pakistan Journal of Pharmacology ORIGINAL ARTICLE Vol.36, No.1 & 2, January-July,2019, pp.53-67 BACTERICIDAL ACTIVITY OF DIFFERENT BRANDS OF CEFEPIME MARKETED IN PAKISTAN AGAINST GRAM- POSITIVE AND GRAM-NEGATIVE CLINICAL ISOLATES ADEEL ARSALAN 1 *, MIRZA TASAWER BAIG 1 , SYED ABID ALI 2 , AND MUDASSAR HUSSAIN 3 1 Faculty of Pharmacy, Ziauddin University, 4/B, Shahrah-e-Ghalib, Clifton, Karachi, Pakistan 2 HEJ Research Institute of Chemistry, ICCBS, University of Karachi, Karachi, Pakistan 3 Faculty of Pharmacy, University of Karachi, Karachi, Pakistan ABSTRACT An important issue is the hesitation of patients or physicians receiving antibiotics about the quality of a generic medicine is equal to, greater than or less than its innovator one. This present study has been carried out to evaluate the bactericidal activity of parenteral cefepime (500 mg) against clinical isolates. A number of 62 clinical isolates of Gram-positive Staphylococcus aureus (n=33) and Gram-negative Escherichia coli (n=29) were collected from different hospitals in Karachi, Pakistan. The minimum inhibitory concentration 90% (MIC 90 ) of the pathogens was determined by broth dilution method, according to clinical and laboratory standards institute (CLSI) guidelines. Cefepime (standard) was tested against E. coli standard (ATCC=25922) with (MIC 90 ; 0.015-0.25μg/ml) and compared with different seven different brand of cefepime injection 500mg with (MIC 90 ; 0.015-64.0μg/ml). While in the case with Gram-positive S. aureus standard (ATCC=25923) sensitivity against cefepime (standard) was (MIC 90 ; 1.0-4.0μg/ml) and similarly when it was compared with same parentral cefepime (MIC 90 ; 1.0-64.0μg/ml). It has been revealed that in vitro antimicrobial analysis had shown that both the innovator ones and me-too (generics) products have not any significant statistical variability. Now it is very important to conclude by evidence that all commercialized drugs were appropriate for therapeutic use. Keywords: Antimicobial resistance, cephalosporin, in-vitro, bactericidal activity, clinical isolates. INTRODUCTION Microorganisms are found everywhere in nature (Arsalan et al., 2010, 2013a, 2013b; 2014a). It has been found there is increase in resistance of microorganisms with the span of time (Ventola, 2015; Banerjee et al., 2018; Bano and Arsalan, 2018). The resistance of antibioticis one of the most critical problems encountered by health-associated professionals (Arsalan et al., 2014b; Sommer et al., 2017). It has been observed a number of root cause for the resistance among them lack of information about antibiotics, inadequate diagnosis of infections among prescribing doctors (Ayukekbong et al., 2017). Some of the prescribed medicines by practitioners are of incorrect antibiotics or dose, route and/or duration of treatment (Rezal et al., 2015; Davidoff et al., 2015). This may often occur in response to pressure from companies or patients and the desire for profit (WHO, 1999). It has been known that medical representatives or commercially oriented publications were the main sources of information about medicines (Silva et al., 2010; Arsalan et al., 2015). Moreover, the quality of raw material has been also play an significant role in resistance that‟s why some physicians consider that generic drugs are not as valuable as innovator *Corresponding author: e-mail: [email protected]

Transcript of BACTERICIDAL ACTIVITY OF DIFFERENT BRANDS OF CEFEPIME ... · Bano and Arsalan, 2018). The...

Page 1: BACTERICIDAL ACTIVITY OF DIFFERENT BRANDS OF CEFEPIME ... · Bano and Arsalan, 2018). The resistance of antibioticis one of the most critical problems encountered by health-associated

Pakistan Journal of Pharmacology ORIGINAL ARTICLE

Vol.36, No.1 & 2, January-July,2019, pp.53-67

BACTERICIDAL ACTIVITY OF DIFFERENT BRANDS OF

CEFEPIME MARKETED IN PAKISTAN AGAINST GRAM-

POSITIVE AND GRAM-NEGATIVE CLINICAL ISOLATES

ADEEL ARSALAN1*, MIRZA TASAWER BAIG

1, SYED ABID ALI

2,

AND MUDASSAR HUSSAIN3

1Faculty of Pharmacy, Ziauddin University, 4/B, Shahrah-e-Ghalib, Clifton, Karachi, Pakistan 2HEJ Research Institute of Chemistry, ICCBS, University of Karachi, Karachi, Pakistan

3Faculty of Pharmacy, University of Karachi, Karachi, Pakistan

ABSTRACT

An important issue is the hesitation of patients or physicians receiving antibiotics about the

quality of a generic medicine is equal to, greater than or less than its innovator one. This

present study has been carried out to evaluate the bactericidal activity of parenteral cefepime

(500 mg) against clinical isolates. A number of 62 clinical isolates of Gram-positive

Staphylococcus aureus (n=33) and Gram-negative Escherichia coli (n=29) were collected

from different hospitals in Karachi, Pakistan. The minimum inhibitory concentration 90%

(MIC90) of the pathogens was determined by broth dilution method, according to clinical and

laboratory standards institute (CLSI) guidelines. Cefepime (standard) was tested against E.

coli standard (ATCC=25922) with (MIC90; 0.015-0.25µg/ml) and compared with different

seven different brand of cefepime injection 500mg with (MIC90; 0.015-64.0µg/ml). While in

the case with Gram-positive S. aureus standard (ATCC=25923) sensitivity against cefepime

(standard) was (MIC90; 1.0-4.0µg/ml) and similarly when it was compared with same

parentral cefepime (MIC90; 1.0-64.0µg/ml). It has been revealed that in vitro antimicrobial

analysis had shown that both the innovator ones and me-too (generics) products have not

any significant statistical variability. Now it is very important to conclude by evidence that

all commercialized drugs were appropriate for therapeutic use.

Keywords: Antimicobial resistance, cephalosporin, in-vitro, bactericidal activity, clinical

isolates.

INTRODUCTION

Microorganisms are found everywhere in

nature (Arsalan et al., 2010, 2013a, 2013b;

2014a). It has been found there is increase in

resistance of microorganisms with the span of

time (Ventola, 2015; Banerjee et al., 2018;

Bano and Arsalan, 2018). The resistance of

antibioticis one of the most critical problems

encountered by health-associated professionals

(Arsalan et al., 2014b; Sommer et al., 2017). It

has been observed a number of root cause for

the resistance among them lack of information

about antibiotics, inadequate diagnosis of

infections among prescribing doctors

(Ayukekbong et al., 2017). Some of the

prescribed medicines by practitioners are of

incorrect antibiotics or dose, route and/or

duration of treatment (Rezal et al., 2015;

Davidoff et al., 2015). This may often occur in

response to pressure from companies or

patients and the desire for profit (WHO, 1999).

It has been known that medical representatives

or commercially oriented publications were

the main sources of information about

medicines (Silva et al., 2010; Arsalan et al.,

2015).

Moreover, the quality of raw material has

been also play an significant role in resistance

that‟s why some physicians consider that

generic drugs are not as valuable as innovator

*Corresponding author: e-mail: [email protected]

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Bactericidal activity of different brands of cefepime 54

ones, so it is very important to show that all

commercialized drugs are suitable for

therapeutic use (Goff et al., 2017). Antibiotics

are measured by their potency or biological

activity compared against an international

standard. Therefore, the commercial products

should meet the biological assays and other

analytical procedures according to

international reference standard (Russel, 1996;

Diaz et al., 2011).

It has been the prime objective of

pharmaceutical industry to comply with

standards of quality, efficacy, and consistency,

aspects as predetermined by various regulatory

authorities (ICH, 2005; Diaz et al., 2011;

Pezzola and Sweet, 2016; Lamanna et al.,

2018). In recent years, discussions about the

quality and efficacy of generic antibiotics has

taken place in conferences and workshops and

a number of workers have been concluded that

some generics do not meet regulatory

standards and even no similar effect of drugs

has been observed in animal model (Jones et

al., 2008; Zuluaga et al., 2009; Giovagnoli et

al., 2017). It has been mystified by some

workers that some innovator ones are “gold

standard” which are recognized for purposes

of bioequivalence and bioavailability studies

while in the case of intravenous antibiotics, the

bioavailability is 100%, and therefore,

pharmacodynamic studies must be supported

with validated analytical results (Diaz et al.,

2011).

Globally infectious diseases are the

second foremost reason of death after

cardiovascular disease and one of the top

causes of death by the World Health

Organization in 2008. Under developed

countries are severely affected by infectious

diseases because of low-income, high cost of

antibiotics, irrational use of antibiotics, lacking

of follow-up, self-medication (Shi et al., 2017;

Ayukekbong et al., 2017; Bano and Arsalan,

2018). It has been found low level of antibiotic

concentration in tissue and plasma the chances

of resistance is increased many folds (Tangden

et al., 2017). Due to more bioavailability and

rapid onset of action, the parenteral antibiotics

are currently commonly used in severe

infections (Fauci, 2001; Bryant and Katz,

2018). Since last two decades, the use of broad

spectrum antibiotic has been doubled because

of wide-spectra and less chances of

antimicrobial resistance (Craig, 1998; Martens

and Demain, 2017) adverse reactions, drug-

drug interactions and cost (Stanley et al.,

1996; Martens and Demain, 2017). Thus,

broad spectrum has permitted the option of

monotherapy to over-come the hazards to

decrease the risk for toxicity and drug

interactions, reduced drug expenditures, and

other pharmacoeconomic benefits (Badaro et

al., 2002; Singh and Yeh, 2017).

The most favorable efficacy of beta-

lactams against microbes and adequate plasma

levels for as long as possible through the

dosing interval for prolong span (Davies et al.,

2000; Grupper et al., 2016). It has not being

surprising that dosing regimens for beta-

lactam antibiotics has been reevaluated to

maintain plasma levels above MICs for longer

periods of the dosing period and even in

continuous infusions (Turnidge, 1998;

Crokaert, 2001; Veiga and Paiva, 2018).

Cefepime is a zwitterionic, anti-

pseudomonal fourth generation cephalosporin,

having broad-spectrum activity even against

resistant strains (Marwa et al., 2015; Lee et al.,

2017). Cefepime have a low propensity toward

the development of resistance and low affinity

for most beta-lactamases. Due to good safety

profile and wide spectrum of activity, it is

commonly used as empirical therapy of

critically-ill patients (Lipman et al., 2003; Lee

et al., 2017). Since late 1990s, cefepime has

been introduced into clinical practice and

approved for the treatment of moderate-to-

severe infections, such as pneumonia,

uncomplicated and complicated urinary tract

infections (UTIs), skin and soft tissue

infections, intra-abdominal infections and

febrile neutropenia (Endimiani, 2008; Kalil,

2011; Nakane et al., 2015). Konstantinou with

his colleagues (2004) have been observed

cefepime has lower resistance as compared to

other extended spectrum cephalosporins.

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Adeel Arsalan et al 55

Infectious Disease Society of America (IDSA)

has been included cefepime as one of the anti-

pseudomonal antibiotics. It has also been used

against extended spectrum beta-lactamase

producing Escherichia coli (Nguyen et al.,

2009; Nakane et al., 2015; Wang et al., 2016).

Since the last two decades, resistant Gram-

positive and Gram-negative microbes are

mainly involved in the community, long-term

care, and hospital settings, posing serious

problems in the choice of an appropriate

antibiotic for treatment (Exner et al., 2017;

Cerceo et al., 2017). Gram-positive

Staphylococcus aureus, is resistant to many

antibiotics. While Gram-negative Escherichia

coli and Klebsiella species are resistance to

beta-lactam antibiotic by producing class A

extended-spectrum β-lactamases (ESBLs)

(Maglio et al., 2004; Diaz et al., 2011).

Globally it has been observed Gram-positive

Staphylococcus aureus and its resistant sera

has been one of the most commonly isolated

bacteria, Gram-negative bacilli especially E.

coli is major causes of infection (Isais-

Agdeppa and Bravo 2005; Diaz et al., 2011).

MATERIALS AND METHODS

Materials and reagents

Reference cefepime was a kind gift

sample from M/s Barrett Hodgson

Pakistan (Pvt) Ltd. Seven different brands of

cefepime were purchased from retail

pharmacies of Karachi (Pakistan) market.

Representative Gram positive (S. aureus,

ATCC=25923) and Gram-negative (E. coli,

ATCC=25922) standard organism has been

obtained. The clinical isolates were obtained

from July 2018 to March 2019 from different

sources and tertiary care hospitals at Karachi.

Mueller Hilton broth (Merck Germany),

distilled water were prepared freshly to

prepare different dilution (Wiegand et al.,

2008).

Instrumentation

For the determination of MICs of

cefepime content in raw material and their

dosage form a Shimadzu UV-1601

spectrophotometer was utilized for quantitative

calculation, where as for visual observation

laminar hood with light box was used.

Broth dilution method

A Complete protocol for performing these

tests is found in the Clinical and Laboratory

Standards Institute (CLSI) publication, for

broth dilution methods, decreasing

concentrations of the antimicrobial agents(s) to

be tested, usually prepared in serial two fold

dilution, are place and tubes of a broth

medium that has been supported the growth of

the test microorganism (Wiegand et al., 2008).

Preparation of macfarland standard

First we prepared 1% sulfuric acid in

1.175% aqueous solution of barium chloride.

Slowly, and with constant agitation, add the

designated amounts of the two solutions to the

tubes make a total of 10ml per tube. The

suspended barium sulfate precipitate

corresponds approximately to homogenous E.

coli cell densities per ml throughout the range

of standard (Wiegand et al., 2008).

Preparation of inoculums

These suspensions were prepared by using

the top of the colonies of the standard and

isolated microorganisms. Standard E. coli

(ATCC 25922) and S aureus (ATCC 25923)

and clinical isolates of E. coli, and S. aureus

were incubated in test tubes at 37oC for 2-8

hours until the turbidity exceeds that of 0.5

McFarland standards (Wiegand et al., 2008).

Preparation of antibiotic stock solution

Accurately weighed for a required amount

of standard antibiotic powder (standard

powder of cefepime and its different brands).

Prepare stock solution using the formula

(Wiegand et al., 2008).

P

1000CVW

Where P is potency of the antibiotic base,

V is volume in ml required,

C is final concentration of solution and

W is weight of the antimicrobial to be dissolved in V.

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Bactericidal activity of different brands of cefepime 56

Fig. 1: Resistance pattern of gram-negative clinical isolates against different brands of cefepime

injection (500 mg)

Fig. 2: Resistance pattern of gram-positive clinical isolates against different brands of cefepime

injection (500 mg).

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Adeel Arsalan et al 57

Preparation of antibiotic dilution range

Usually prepared a series of varying

concentrations two fold serial dilutions (0.015,

0.03, 0.06, 0.12, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64

g/ml). Equal volume of inoculums has been

added in test tubes (Wiegand et al., 2008).

Procedure

Prepared Mueller Hilton broth, arranged

sufficient sterile test tubes for each antibiotic

to cover the range of antibiotic dilutions.

Transferred 9 ml of broth and 1 ml of each

antimicrobial agents dilution in separate broth

tubes. Now inoculums have been added to

each anti-microbial containing tube in the

dilution series. The tubes have been incubated

at 37oC for 12 to 18 hours. Examined the tubes

with visually and with spectrophotometer (546

nm) for the presence or absence of growth and

compared the result with the growth in the

control tube (Wiegand et al., 2008).

RESULTS AND DISCUSSION

During the present study, antibacterial

activity of seven different brands of cefepime

has been evaluated against Gram-positive and

Gram-negative pathogens. The study has

revealed that among Gram-positive and Gram-

negative, S. aureus and E. coli are the most

frequent clinical isolates in various infections.

A total 62 clinical isolates (S. aureus and E.

coli) have been collected from July 2017 till

March 2018 from different tertiary care

Fig. 3: Overall resistance pattern of clinical isolates against marketed cefepime

Table 1: Summary of clinical isolates

Clinical Isolates Source of isolates Number of

isolates

Gender

Male Female

Staphylococcus

aureus

Surgical, Burn and Accidental

wound pus (Skin and soft tissue

infections)

33 19 (57.57%) 14 (42.42%)

Escherichia coli Stool and Urine (Intra-abdominal

and urinary tract infections) 29 23 (79.31%) 06 (20.68%)

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Bactericidal activity of different brands of cefepime 58

Table 2: Comparison of Standard Cefepime and Different Brands of Cefepime against Standard

Escherichia coli & Different Clinical isolates of Escherichia coli

STD CF CF 01 CF 02 CF 03 CF 04 CF 05 CF 06 CF 07

STD E. coli

ATCC 25922 0.015 0.12 0.015 0.03 0.03 0.015 0.12 0.03

Ec 01 1 1 1 2 2 1 2 4

Ec 02 4 16 32 4 2 64 16 32

Ec 03 2 2 8 16 16 16 64 16

Ec 04 1 1 2 2 8 1 4 2

Ec 05 2 4 2 64 2 2 64 1

Ec 06 4 16 64 16 64 1 64 64

Ec 07 2 16 2 4 64 4 2 32

Ec 08 1 1 64 2 1 2 64 2

Ec 09 1 4 8 8 2 16 2 1

Ec 10 4 16 64 32 16 64 32 64

Ec 11 1 1 16 2 2 2 8 4

Ec 12 1 2 16 64 4 4 32 16

Ec 13 4 32 32 64 16 64 8 16

Ec 14 2 4 32 16 2 8 32 1

Ec 15 1 1 64 4 64 4 4 4

Ec 16 1 4 4 2 1 64 8 16

Ec 17 1 16 2 16 1 2 4 8

Ec 18 2 2 8 2 2 4 4 4

Ec 19 4 64 16 64 32 16 32 16

Ec 20 2 16 4 4 2 2 4 2

Ec 21 4 64 64 16 32 16 64 16

Ec 21 2 4 64 2 16 8 2 64

Ec 23 1 4 2 2 64 2 2 2

Ec 24 8 64 64 32 64 64 32 64

Ec 25 2 2 32 16 2 1 64 2

Ec 26 1 4 16 2 64 2 1 2

Ec 27 2 2 2 16 1 16 2 8

Ec 28 4 16 64 16 64 1 64 64

Ec 29 1 1 4 1 4 4 4 1

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Adeel Arsalan et al 59

Table 3: Comparison of standard cefepime and different brands of cefepime against standard

Staphylococcus aureus and different clinical isolates of Staphylococcus aureus

STD CF CF 01 CF 02 CF 03 CF 04 CF 05 CF 06 CF 07

STD. S. aureus

ATCC 25923 1 1 4 1 2 2 4 1

Sa 01 1 4 2 1 4 4 32 2

Sa 02 1 1 4 64 64 4 1 16

Sa 03 1 4 8 2 1 1 16 1

Sa 04 2 32 8 1 8 4 32 64

Sa 05 1 32 16 64 1 1 1 64

Sa 06 2 8 1 1 8 2 64 1

Sa 07 4 16 64 4 16 32 2 16

Sa 08 1 1 16 64 64 1 1 1

Sa 09 1 2 2 1 2 32 64 1

Sa 10 2 16 1 2 64 1 64 32

Sa 11 1 1 64 32 8 4 4 16

Sa 12 1 1 1 64 16 8 1 8

Sa 13 4 64 32 1 16 64 8 1

Sa 14 2 16 16 32 64 32 1 64

Sa 15 4 64 64 16 32 64 64 2

Sa 16 4 32 64 16 64 64 32 64

Sa 17 1 2 16 16 4 2 8 1

Sa 18 1 4 2 64 1 1 64 64

Sa 19 2 16 32 1 4 64 4 16

Sa 20 4 64 64 16 64 32 64 64

Sa 21 1 8 16 64 8 64 1 1

Sa 21 1 16 32 4 2 1 2 1

Sa 23 2 1 4 64 8 16 64 4

Sa 24 2 32 16 8 16 64 1 16

Sa 25 1 4 1 2 2 2 64 1

Sa 26 1 16 4 64 1 16 1 2

Sa 27 2 16 16 8 16 4 32 1

Sa 28 4 64 64 64 64 1 64 32

Sa 29 1 64 16 1 1 32 1 1

Sa 30 1 1 2 16 64 1 64 16

Sa 31 8 64 64 64 32 16 1 1

Sa 32 2 32 1 8 8 1 2 64

Sa 33 4 16 64 64 64 64 64 1

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Bactericidal activity of different brands of cefepime 60

Table 4: Resistance pattern of clinical isolates of Escherichia coli against Different Brands of

Cefepime injection (500mg)

Marketed cefepime code Susceptible Intermediate Resistant

CF 01 18 (62.06%) 8 (27.58%) 3 (10.34%)

CF 02 13 (44.82%) 8 (27.58%) 8 (27.58%)

CF 03 15 (51.72%) 10 (34.48%) 4 (13.79%)

CF 04 16 (55.17%) 6 (20.69%) 7 (24.13%)

CF 05 19 (65.51%) 5 (17.24%) 5 (17.24%)

CF 06 16 (55.17%) 6 (20.69%) 7 (24.13%)

CF 07 16 (55.17%) 8 (27.58%) 5 (17.24%)

Table 5: Resistance pattern of clinical isolates of Staphylococcus aureus against different brands

of cefepime injection (500 mg)

Marketed cefepime code Susceptible Intermediate Resistant

CF 01 14 (42.42%) 13 (39.39%) 6 (18.18%)

CF 02 14 (42.42%) 11 (33.33%) 8 (24.24%)

CF 03 15 (45.45%) 7 (21.21%) 11 (33.33%)

CF 04 17 (51.51%) 7 (21.21%) 9 (27.27%)

CF 05 18 (54.54%) 8 (24.24%) 7 (21.21%)

CF 06 17 (51.51%) 5 (15.15%) 11 (33.33%)

CF 07 18 (54.54%) 8 (24.24%) 7 (21.21%)

Table 6: Resistance pattern of clinical isolates against cefepime

S.

No Country Year

% Resistance of

Staphylococcus aureus

% Resistance of

Escherichia coli Reference

1 Canada 1997 21.0% – Halpern et al., 1997

2 USA 1996-1997 – 0.4% Jones et al., 1998

3 Brazil 1997-1999 44% 4% Sader et al., 2001

4 Romania 2005 – 22% Vlad, 2005

5 North

America 2005 – 6% Sader et al., 2005

6 Taiwan 2006 – 33% Liao et al., 2006

7 Pakistan 2002 – 19% Iqbal et al., 2002

8 Pakistan 2010 15% 7% Ale-Zehra et al., 2010

9 Pakistan 2013 30% 18% Nasiri et al., 2013

10 Pakistan 2013 8% 22% Siddiqui et al., 2013

11 Pakistan 2012-2013 37% 26% Arsalan et al., 2015

12 Pakistan 2015 38% 27% Arsalan et al., 2016

13 Hungary 2004-2015 – 1-8% Magyar et al., 2017

14 Ethiopia 2016 1% – Deyno et al. 2017

15 United

Kingdom 2013-2014 0% – Xu et al., 2018

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Adeel Arsalan et al 61

hospitals at Karachi, Pakistan as shown in

table 1. The anti-bacterial sensitivity of

reference and different brands of cefepime

against clinical isolates has been shown in

tables 2-3. The resistance pattern of E. coli

clinical isolates has been revealed in table 4

and fig. 1 while Gram-positive S. aureus

susceptibility has been shown in table 5 and

fig. 2 against cefepime marketed in Pakistan.

The overall resistance pattern of clinical

isolates has been shown in fig. 3. Due to

irrational use of cefepime and change in

serotype and source of microbes, there is a

change in resistance pattern of clinical isolates

as shown in various studies table 6.

Cefepime is fourth generation

cephalosporin, possessing good activity

against Gram-positive and Gram-negative.

Because of its wide spectra even against

resistant pathogens, it has been recommended

in severe infections (Nguyen et al., 2009; Lin

et al., 2018). The susceptibility test has

indicated that the MIC90 of reference cefepime

(gifted by M/s. Barrett Hodgson Pakistan

(Pvt.), Ltd.) against standard E. coli (ATCC®

25922) with range of (MIC90 = 0.015–

0.25µg/ml). Moreover, for standard S. aureus

(ATCC® 25923) MIC90 with range of

(MIC90=1-4µg/ml) According to CLSI (2011),

for both pathogens MIC90less than 8μg/ml is

considered as susceptible and 16μg/ml and

more than 32μg/ml is considered as

intermediate and resistance respectively.

Seven different brand of cefepime injection

500mg have been compared with clinical

isolates of Gram-negative E. coli and Gram-

positive S. aureus with (MIC90; 0.015-

64.0µg/ml) and (MIC90; 1.0-64.0µg/ml)

respectively.

The generics should be identical to

innovator ones in purity, quality, and strength

while in the case with parenteral preparations

sterility of medicines along with dissolution of

drug have become the prime object (WHO,

1998; Vega et al., 2015). Any considerable

dissimilarity, in the dissolution profiles among

same generics show lacking in the entire drug

formulations. Solubility and dispersibility of

drug in parenteral preparation plays an

important role as a quality control tool to

monitor batch to batch consistency of drug

release (Kumar and Palmieri, 2010). Taylor et

al. (2009) have been found that some

medicines do not meet the quality

specifications as claimed by manufacturers.

Several workers have reported treatment

failure cases and economic burden due to

substandard medicines (Petralanda, 1995;

Johnston and Holt, 2014; Sammons and,

Choonara, 2017; Ozawa et al., 2018). The

evaluation of the antibacterial activity of an

antibiotic, the inhibition of the multiplication

of pathogenic bacteria by recognized

concentrations of antibiotic with a reference

standard, bring into being meaningful results

by well illustrated procedures (Mendez et al.,

2005).

It has been observed that urinary tract

infections were common in female patients as

supported by Kodner and Gupton (2010),

while S. aureus has been mainly isolated from

pus secretions and male patients (Kaleem et

al., 2010). It has been proposed by several

workers that the bactericidal activity of many

generic antibiotics have showed lesser extent

as compared to innovator against pathogenic

microorganisms (Rodriguez et al., 2004;

Zuluaga et al., 2009; Venkatesh et al., 2011;

Silver 2011; Exner et al., 2017). It can be

probably possible that certain generics have

not fulfilled the quality standards for that

pharmaceutical product (purity, content, etc.)

especially in active pharmaceutical ingredients

due to low in cost (Mallu et al., 2015;

Valverde and Pisani, 2016). These active

pharmaceutical ingredients may be

contaminated which may interfere antibacterial

activities of antibiotics (Zuluaga et al., 2009;

Han et al., 2016; Richardson, 2017).

In the last two decades, there has been a

constant increased in the use of cefepime for

the treatment of severe bacterial infections.

The continuous use and often abuse of

cefepime have led to increase in resistance

against cefepime (Endimiani et al., 2008;

Chong et al., 2010). A number of factors have

been involved in the quality by design of

medicine like manufacturing technology,

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Bactericidal activity of different brands of cefepime 62

quality of excipients, production processes,

overall quality, and release proficiency of

medicament. To ensure the requisite quality

certain tests have been performed during and

after manufacturing even during the shelf life

(Chow, 1997; Pifferi et al., 1999; Newton et

al., 2010; Xu et al., 2017).

The results has obtained after application of

ANOVA has been confirmed that the brands

of cefepime purchased from the local market

produce same antibacterial effect in

comparison to the standard cefepime. It has

been noticed in the present study that there

were no significant variations found in MIC90

values of different brands of cefepime. It has

been indicated that cefepime has been good

choice of drug against S. aureus and E. coli

associated infections.

CONCLUSIONS

Nearly all the pharmaceutical industries

fulfill the requirements of drug regulatory

authorities of their respective countries. It

should be considered that all generics are

pharmaceutical equivalent to innovator ones.

The MIC90 values of the cefepime against each

strain have tested behave approximately same

bactericidal activity. It has been revealed from

the present study that there is no significant

variations have been observed between the

me-too (generics) and trademarks (innovator

ones). The faith should be discouraged by

doctors, pharmacist, and microbiologist to

patients that expensive or innovator ones are

better as compared to generics.

ACKNOWLEDGEMENT

We would like to thank Mr. Shamim

Mumtaz for his keen interest and valuable

suggestions during the preparation of

manuscript.

REFERENCES

Ale-Zehra, Naqvi BS, Bushra R and Ali SQ

(2013). Comparative study on resistance

pattern of different pathogens against

cefixime and cefepime. Jord. J. Pharm.

Sci., 3(2): 145-156.

Arsalan A, Anwar Z, Ahmad I, Saba A and

Naqvi SBS (2013b). Microbes in pediatric

infant formula. Annals. Food Sci. Technol.

14(1): 90-99.

Arsalan A, Anwar Z, Ahmad I, Shad Z and

Ahmed S (2013a). Cronobacter sakazakii:

An emerging contaminant in Pediatric

infant milk formula. Int. Res. J. Pharm.,

4(4): 17-22.

Arsalan A, Naqvi SBS, Ali SA, Ahmed S and

Shakeel O (2015). In vitro bactericidal

activity of cefepime and cefpirome against

clinical isolates at Karachi. Pak. J. Pharm.

Sci., 28(3): 841-847.

Arsalan A, Naqvi SBS, Iqbal A and Shakeel O

(2014b). Temperature monitoring of

vaccines‟ storage compartments in different

health centres and pharmacies at Karachi,

Pakistan. Int. J. Pharm. Teach. Pract., 5(3):

984-988.

Arsalan A, Naqvi SBS, Sabah A, Bano R and

Ali SI (2014). Resistance pattern of clinical

isolates involved in surgical site infections.

Pak. J. Pharm. Sci., 27(1): 97-102.

Arsalan A, Qureshi S, Alam M, Ahmed S,

Shakeel O, Ali A and Jabeen W (2015).

Errors in patients‟ information leaflets of

marketed medicines in Pakistan. J. Appl.

Pharm. Sci., 5(5): 68-74.

Arsalan A, Sabah A, Ahmad I, Naqvi SBS and

Ali SI (2010). The role of antiseptic in

surgery. J. Baqai Med. Uni., 13(2): 47-54.

Arsalan A, Shayam SB, Pasha R and Shakeel

O (2016). First generation and fourth

generation cephalosporin susceptibility

against clinical isolates. J. Uni. Med. Dent.

College, 7(2): 52-58.

Ayukekbong JA, Ntemgwa M and Atabe AN

(2017). The threat of antimicrobial

resistance in developing countries: Causes

and control strategies. Antimicrob. Res.

Infect. Cont., 6: Article No. 47.

Badaro R, Molinar F, Seas C, Stamboulian D,

Mendonca J, Massud J, Nascimento LO

and Latin American Antibiotic Research

Group (LAARG) (2002). A multicenter

comparative study of cefepime versus

Page 11: BACTERICIDAL ACTIVITY OF DIFFERENT BRANDS OF CEFEPIME ... · Bano and Arsalan, 2018). The resistance of antibioticis one of the most critical problems encountered by health-associated

Adeel Arsalan et al 63

broad-spectrum antibacterial therapy in

moderate and severe bacterial infections.

Braz. J. Infect. Dis., 6(5): 206-218.

Banerjee T, Mishra A, Das A, Sharma S,

Barman H and Yadav G (2018). High

prevalence and endemicity of multidrug

resistant Acinetobacter spp. in intensive

care unit of a tertiary care hospital,

Varanasi, India. J. Pathog., Article ID

9129083, 8 pages.

Bano R and Arsalan A (2018). In vitro anti

bacterial susceptibility of different brands of

oral levofloxacin 250 mg against

Staphylococcus aureus and Escherichia coli.

Pak. J. Pharm. Sci., 31(6): 2529-2535.

Bryant PA and Katz NT (2018). Inpatient

versus outpatient parenteral antibiotic

therapy at home for acute infections in

children: a systematic review. Lancet Infect.

Dis., 18(2):e45-e54.

Cerceo E, Deitelzweig SB, Sherman BM and

Amin AN (2016). Multidrug-Resistant

Gram-Negative Bacterial Infections in the

Hospital Setting: Overview, Implications

for Clinical Practice, and Emerging

Treatment Options. Microbial Drug Resis.,

22(5): 412-431.

Chong Y, Yakushiji H, Ito Y and Kamimura T

(2010). Cefepime-resistant Gram-negative

bacteremia in febrile neutropenic patients

with hematological malignancies. Int. J.

Infect. Dis., 14(3):e171-175.

Chow SJ (1997). Pharmaceutical validation

and process controls in drug development.

Therapeutic Innov. Regulat. Sci., 31: 1195-

1201.

Clinical and Laboratory Standards Institute

(CLSI). Performance Standards for

Antimicrobial Susceptibility Testing;

Twenty-First Informational Supplement.

Approved standard Approved standard

M100-S21, Wayne, PA, USA. 2011.

Craig WA (1998). Pharmacokinetic/

pharmacodynamic parameters: rationale for

antibacterial dosing of mice and men.

Clinical Infect. Dis., 26(1): 1-12.

Crokaert F (2001). Pharmacodynamics, a tool

for a better use of antibiotics. Intens. Care

Med., 27(2): 340-343.

Davies J, Wendon J, Wyncoll D and Wade J

(2000). Antibiotic infusions reduce the

incidence of resistant organisms in liver

intensive care. Intensive Care Med., 26:

s269.

Deyno S, Toma A, Worku M and Bekele M

(2017). Antimicrobial resistance profile of

Staphylococcus aureus isolates isolated

from ear discharges of patients at University

of Hawassa comprehensive specialized

hospital. BMC Pharmacol. Toxicol., 18(1):

35.

Diaz JA, Silva E, Arias MJ and Garzon M

(2011). Comparative in vitro study of the

antimicrobial activities of different

commercial antibiotic products of

vancomycin. BMC Clin. Pharmacol., 11: 9.

Endimiani A, Perez F and Bonomo RA (2008).

Cefepime: A reappraisal in an era of

increasing antimicrobial resistance. Expert

Rev. Anti-infect. Ther., 6(6): 805-824.

Exner M, Bhattacharya S, Christiansen B and

Gebel J et al (2017). Antibiotic resistance:

What is so special about multidrug-resistant

Gram-negative bacteria? GMS Hyg. Infect.

Cont., 12: Doc. 05.

Fauci AS (2001). Infectious diseases:

Considerations for the 21st century. Clinical

Infect. Dis., 32(5): 675-685.

Giovagnoli S, Pietrella D, Barberini L, Santi

C, Carotti A, di Michele A and Ricci M

(2017). Reshaping antibiotics through

hydrophobic drug-bile acid ionic

complexation enhances activity against

Staphylococcus aureus biofilms. Int. J.

Pharm., 528(1-2): 144-162.

Goff DA, Kullar R, Goldstein EJC and

Gilchrist M et al. (2017). A global call from

five countries to collaborate in antibiotic

stewardship: United we succeed, divided we

might fail. Lancet Infect. Dis., 17(2): e56-

e63.

Grupper M, Kuti JL and Nicolau DP (2016).

Continuous and prolonged intravenous β-

lactam dosing: Implications for the clinical

laboratory. Clinical Microbiol. Rev., 29(4):

759-772.

Halpern MT, Brown RE, Drolet M, Sorensen

SV and Mandell LA (1997). Decision

analysis modeling of costs and outcomes

Page 12: BACTERICIDAL ACTIVITY OF DIFFERENT BRANDS OF CEFEPIME ... · Bano and Arsalan, 2018). The resistance of antibioticis one of the most critical problems encountered by health-associated

Bactericidal activity of different brands of cefepime 64

following cefepime monotherapy in

Canada. Can. J. Infect. Dis., 8: 19-27

Han SM, Kim JM, Hong IP, Woo SO, Kim

SG, Jang HR and Pak SC (2016).

Antibacterial activity and antibiotic-

enhancing effects of honeybee venom

against methicillin-resistant Staphylococcus

aureus. Molecules, 21(1): 79.

International Conference on Harmonisation

(ICH) of Technical requirements for

registration of Pharmaceuticals for human

use. Validation of analytical procedures:

Text and methodology. Q2 (R1). Current

Step 4 version. Parent guideline dated 27

October 1994 (Complementary Guideline

on Methodology dated 6 November 1996

incorporated in November 2005). 2005.

Iqbal M, Patel IK, Ain Q, Barney N, Kiani Q,

Rabbani KZ, Zaidi G and Mehdi B (2002).

Susceptibility patterns of Escherichia coli:

Prevalence of multidrug-resistant isolates

and extended spectrum beta-lactamase

phenotype. J. Pak. Med. Assoc., 52(9): 407-

411.

Isais-Agdeppa AT and Bravo L (2005). A five-

year retrospective study on the common

Microbial isolates and sensitivity pattern on

blood culture of pediatric cancer patients

admitted at the Philippine general hospital

for febrile neutropenia. PIDSP Journal,

9(2): 19-24.

Johnston A and Holt DW (2014). Substandard

drugs: a potential crisis for public health.

Bri. J. Clin. Pharmacol., 78(2): 218-243.

Jones RN, Fritsche TR and Moet GJ (2008). In

vitro potency evaluations of various

piperacillin/tazobactam generic products

compared with the contemporary branded

(Zosyn®, Wyeth) formulation. Diagnostic

Microbiol. Infect. Dis., 61(1): 76-79.

Jones RN, Pfaller MA, Doern GV, Erwin ME

and Hollis RJ (1998). Antimicrobial activity

and spectrum investigation of eight broad-

spectrum beta-lactam drugs: A 1997

surveillance trial in 102 medical centers in

the United States. Cefepime Study Group.

Diag. Microbiol. Infect. Dis., 30(3): 215-

228

Kaleem F, Usman J, Hassan A, Omair M,

Khalid A and Uddin R (2010). Sensitivity

pattern of methicillin resistant

Staphylococcus aureus isolated from

patients admitted in a tertiary care hospital

of Pakistan. Iran. J. Microbiol., 2(3): 143-

146

Kalil AC (2011). Is cefepime safe for clinical

use? A Bayesian viewpoint. J.

Antimicrobial Chemother., 66(6): 1207-

1 2 09.

Kodner CM and Gupton ET (2010). Recurrent

urinary tract infections in women:

Diagnosis and management. Amr. Family

Physician, 82(6): 638-643.

Konstantinou K, Baddam K, Lanka A, Reddy

K and Zervos M (2004). Cefepime versus

ceftazidime for treatment of pneumonia. J.

Int. Med. Res., 32(1): 84-93

Kumar R and Palmieri Jr MJ (2010). Points to

consider when establishing drug product

specifications for parenteral microspheres.

AAPSJ., 12(1): 27-32.

Lamanna WC, Holzmann J, Cohen HP, Guo

X, Schweigler M, Stangler T, Seidl A and

Schiestl M (2018). Maintaining consistent

quality and clinical performance of

biopharmaceuticals. Expert Opin. Biol.

Ther., 18(4): 369-379.

Lee CH, Su TY, Ye JJ, Hsu PC, Kuo AJ, Chia

JH and Lee MH (2017). Risk factors and

clinical significance of bacteremia caused

by Pseudomonas aeruginosa resistant only

to carbapenems. J. Microbiol. Immunol.

Infect., 50(5): 677-683.

Liao CH, Sheng WH, Wang JT, Sun HY,

Wang HK, Hsueh PR, Chen YC and Chang

SC (2006). In vitro activities of 16

antimicrobial agents against clinical isolates

of extended-spectrum beta-lactamase-

producing Escherichia coli and Klebsiella

pneumoniae in two regional hospitals in

Taiwan. J. Microbiol. Immunol. Infect.,

39(1): 59-66.

Lin Z, Chen T and Fu X (2018). Correlational

study between discontinuation of the fourth-

generation cephalosporin and the dosage of

broad-spectrum antibacterial agents as well

as resistance rates of Pseudomonas

aeruginosa against antimicrobials. Int. J.

Clin. Exper. Med., 11(3): 2256-2263.

Page 13: BACTERICIDAL ACTIVITY OF DIFFERENT BRANDS OF CEFEPIME ... · Bano and Arsalan, 2018). The resistance of antibioticis one of the most critical problems encountered by health-associated

Adeel Arsalan et al 65

Lipman J, Wallis SC and Boots RJ (2003).

Cefepime Versus cefpirome: The

importance of creatinine clearance. Anest.

Analg., 97(4): 1149-1154.

Maglio D, Ong C, Banevicius MA, Geng Q,

Nightingale CH and Nicola DP (2004).

Determination of the In vivo

pharmacodynamic profile of cefepime

against extended spectrum beta-lactamase

producing Escherichia coli at various

inocula. Antimicrol. Agents Chemother.,

48(6): 1941-1947.

Magyar A, Koves B, Nagy K, Dobak A,

Arthanareeswaran VKA, Balint P,

Wagenlehner F and Tenke P (2017).

Spectrum and antibiotic resistance of

uropathogens between 2004 and 2015 in a

tertiary care hospital in Hungary. J. Med.

Microbiol., 66(6):788-797.

Mallu UR, Nair AK, Sankar J, Bapatu HR,

Kumar MP, Narla S, Bhanap TA, Thamma

NK and Raman NVVSS (2015). Impact of

API (Active Pharmaceutical Ingredient)

source selection on generic drug products.

Pharm. Regul. Affairs, 4(2): 135.

Martens E and Demain AL (2017). The

antibiotic resistance crisis, with a focus on

the United States. J. Antib. (Tokyo), 70(5):

520-526.

Martinez JL (2017). Effect of antibiotics on

bacterial populations: A multi-hierachical

selection process. Version 1. F1000

Research, 6: 51.

Marwa JM, Ngayomela IH, Seni J and Mshana

SE (2015). Cefepime versus ceftriaxone for

perioperative systemic antibiotic

prophylaxis in elective orthopedic surgery

at Bugando Medical Centre Mwanza,

Tanzania: A randomized clinical study.

BMC Pharmacol. Toxicol., 16: 42.

Mendez ASL, Weisheimer V, Oppe TP,

Steppe M and Schapoval E (2005).

Microbiological assay for the determination

of meropenem in pharmaceutical dosage

form. J. Pharm. Biomed. Anal., 37(4): 649-

653.

Muhia J, Waithera L and Songole R (2017).

Factors affecting the procurement of

pharmaceutical drugs: a case study of narok

county referral hospital, Kenya. Med. Clin.

Rev., 3: 20.

Nakane T, Tamura K, Hino M, Tamaki T,

Yoshida I, Fukushima T, Tatsumi Y,

Nakagawa Y, Hatanaka K, Takahashi T,

Akiyama N, Tanimoto M, Ohyashiki K,

Urabe A, Masaoka T, Kanamaru A; Japan

Febrile Neutropenia Study Group. (2015).

Cefozopran, meropenem, or imipenem-

cilastatin compared with cefepime as

empirical therapy in febrile neutropenic

adult patients: A multicenter prospective

randomized trial. J. Infect. Chemother.,

21(1): 16-22.

Nasiri MI, Naqvi SB, Zaidi AA, Saeed R and

Raza G (2013). Comparative study on

resistant pattern of clinical isolates against

levofloxacin and cefepime. Pak. J. Pharm.

Sci., 26(2): 415-419.

Newton PL, Green MD and Fernandez FM

(2010). Impact of poor-quality medicines in

the „developing‟ world. Trend. Pharmacol.

Sci., 31(3-3): 99-101.

Nguyen TD, Williams B and Trang E (2009).

Cefepime therapy and all-cause mortality.

Clin. Infect. Dis., 48(7): 902-904.

Ozawa S, Evans DR, Bessias S, Haynie

DG, Yemeke TT, Laing SK and

Herrington JE (2018). Prevalence and

estimated economic burden of substandard

and falsified medicines in low- and middle-

income countriesa systematic review and

meta-analysis. JAMA Network Open, 1(4):

e181662

Pestotnik SL, Classen DC, Evans RS and

Burke JP (1996). Implementing antibiotic

practice guidelines through computer-

assisted decision support: Clinical and

financial outcomes. Annals Intern. Med.,

124(10): 884-890.

Petralanda I (1995). Quality of antimalarial

drugs and resistance to plasmodium vivax

in amazonian region. Lancet, 345(8962):

1433.

Pezzola A and Sweet CM (2016). Global

pharmaceutical regulation: The challenge of

integration for developing states. Global

Health. 12(1): 85.

Page 14: BACTERICIDAL ACTIVITY OF DIFFERENT BRANDS OF CEFEPIME ... · Bano and Arsalan, 2018). The resistance of antibioticis one of the most critical problems encountered by health-associated

Bactericidal activity of different brands of cefepime 66

Pifferi G, Santoro P and Pedrani M (1999).

Quality and functionality of excipients.

Farm., 54(1-2): 1-14.

Rezal RS Md, Hassali MA, Alrasheedy AA,

Saleem F, Md Yusof FA and Godman B

(2015). Physicians' knowledge, perceptions

and behaviour towards antibiotic

prescribing: A systematic review of the

literature. Expert Rev. Anti-infect. Ther.,

13(5): 665-680.

Richardson LA (2017). Understanding and

overcoming antibiotic resistance. PLoS

Biol., 15(8): e2003775.

Rodriguez CA, Zuluaga AF, Salazar BE,

Agudelo M and Sga O (2004). Experimental

comparison of 11 generic products (GP) of

oxacillin (OXA) with the original

compound (OC) in terms of concentration

of active principle (CAP), in vitro activity

and in vivo efficacy, using the neutropenic

murine thigh infection model (NMTIM).

Abstr. A-1305. 44th

Interscience Conference

on Antimicrobial Agents and Chemotherapy

(ICAAC), Washington, D.C.USA.

Russel M (1996). Microbiological control of

raw materials. In: Baird R, Bloomfield SF

(eds.) Microbial Quality Assurance in

Pharmaceuticals, Cosmetics, and Toiletries.

1st ed., CRC Press, London, Chapter 3.

Sader HS, Fritsche TR and Jones RN (2005).

Potency and spectrum trends for cefepime

tested against 65746 clinical bacterial

isolates collected in North American

medical centers: Results from the Sentry

Antimicrobial Surveillance Program (1998-

2003). Diag. Microb. Infect. Dis., 52(3):

265-273.

Sader HS, Gales AC, Pfaller MA, Mendes RE,

Zoccoli C, Barth A and Jones RN (2001).

Pathogen frequency and resistance patterns

in Brazilian hospitals: Summary of results

from three years of the Sentry

Antimicrobial Surveillance Program. Braz.

J. Infect. Dis., 5(4): 200-214.

Sammons HM and Choonara I (2017).

Substandard medicines: A greater problem

than counterfeit medicines? BMJ

Paediatrics Open 1(1): e000007

Shi T, McAllister DA, O'Brien KL et al.

(2017). Global, regional, and national

disease burden estimates of acute lower

respiratory infections due to respiratory

syncytial virus in young children in 2015: a

systematic review and modelling study.

Lancet, 390(10098): 946-958.

Siddiqui T, Naqvi BS, Alam N, Bashir L, Naz

S, Naqvi G, Baig MT and Tasleem S

(2013). Antimicrobial susceptibility testing

of ciprofloxacin & cefepime against

Staphylococcus aureus & Escherichia coli.

Int. J. Sci. Eng. Res., 4(12): 1386-1389.

Silva E, Jorge A, Diaz JA, Arias MJ,

Hernandez AP and de la Torre A (2010).

Comparative in vitro study of the

antimicrobial activities of different

commercial antibiotic products for

intravenous administration. BMC Clin.

Pharmacol., 10: 3.

Silver LL (2011). Challenges of antibacterial

discovery. Clin. Microbiol. Rev., 24(1): 71-

109.

Singh N and Yeh PJ (2017). Suppressive drug

combinations and their potential to combat

antibiotic resistance. J. Antib. (Tokyo),

70(11): 1033-1042.

Sommer MOA, Munck C, Toft-Kehler RV and

Andersson DI (2017). Prediction of

antibiotic resistance: time for a new

preclinical paradigm? Nat. Rev. Microbiol.,

15(11): 689-696.

Tangden T, Martin VR, Felton TW and

Nielsen EI (2017). The role of infection

models and PK/PD modelling for

optimising care of critically ill patients with

severe infections. Intens. Care Med., 43(7):

1021-1032.

Taylor RB, Shakoor O, Behrens RH, Everad

M, Slow A, Wangboonskul J, Reid RG and

Kolawole JA (2009). Pharmaopoeial quality

of drugs supplied by Nigerian pharmacies.

Lancet, 357: 1933-1936.

Turnidge JD (1998). The pharmacodynamics

of beta-lactams. Clin. Infect. Dis., 27: 10-

22.

Valverde JL and Pisani E (2016). The

Globalisation of the Pharmaceutical

Industry. IOS Press, Amsterdam,

Netherlands.

Vega JA, Ochoa PS and Holder P (2015).

Introduction to parenteral preparations. In:

Page 15: BACTERICIDAL ACTIVITY OF DIFFERENT BRANDS OF CEFEPIME ... · Bano and Arsalan, 2018). The resistance of antibioticis one of the most critical problems encountered by health-associated

Adeel Arsalan et al 67

Ochoa PS and Vega JA (eds.). Concepts in

Sterile Preparations and Aseptic Technique.

Jones and Bartlett Learning. New York,

USA. Chapter 1.

Veiga RP and Paiva JA (2018). Pharmaco-

kinetics-pharmacodynamics issues relevant

for the clinical use of beta-lactam

antibiotics in critically ill patients. Crit.

Care, 22(1): 233

Venkatesh M, Bairavi VG and Sasikumar KC

(2011). Generic antibiotic industries:

Challenges and implied strategies with

regulatory perspectives. J. Pharm. Bioalli.

Sci., 3(1): 101-108.

Ventola CL (2015). The antibiotic resistance

crisis part 2: Management strategies and

new agents. Pharm. Therapeut., 40(5):

344-352.

Vlad JL (2005). Microbiologic analysis of a

cefepime: Producing isolates 1-year period.

Annal. Fundeni Hosp., 10: 14-19.

Wang R, Cosgrove SE, Tschudin-Sutter S,

Jennifer H and Han JH (2016). Cefepime

therapy for cefepime-susceptible Extended-

Spectrum β- Lactamase- producing

Enterobacteriaceae bacteremia. Open

Forum Infect. Dis., 3(3): ofw132.

Wiegand I, Hilpert K and Hancock RE (2008).

Agar and broth dilution methods to

determine the minimal inhibitory

concentration (MIC) of antimicrobial

substances. Nat. Protocols, 3(2): 163-175.

World Health Organization (WHO) (1999).

Communicable Disease Surveillance and

Response Containing. Antimicrobial

resistance: Review of the literature and

report of a WHO workshop on the

development of a global strategy for the

containment of antimicrobial resistance.

Geneva, Switzerland.

World Health Organization (WHO) (1998).

Marketing authorization of pharmaceutical

products with special reference to

multisource (generic) products: A manual

for drug regulatory authorities. WHO

Division of Drug Management and Policies,

Geneva from 7 to 8 April and 6 to 8 July

1998.

Xu B, Shi XY, Wu ZS, Zhang YL, Wang Y

and Qiao YJ (2017). Quality by design

approaches for pharmaceutical development

and manufacturing of Chinese medicine.

China J. Chine. Mater., 42(6):1015-1024.

Xu Z, Shah HN, Misra R, Chen J, Zhang W,

Liu Y, Cutler RR and Mkrtchyan HV

(2018). The prevalence, antibiotic resistance

and mecA characterization of coagulase

negative staphylococci recovered from non-

healthcare settings in London, UK.

Antimicrob. Res. Infect. Cont., 7:73

Zuluaga AF, Agudelo M, Rodriguez CA and

Vesga O (2009). Application of

microbiological assay to determine

pharmaceutical equivalence of generic

intravenous antibiotics. BMC Clin.

Pharmacol., 9: 1.