MAJOR ARTICLE

Efcacy and Quality of Antibacterial Generic

Products Approved for Human Use: A
Systematic Review
Pierre Tattevin,1,2 Anne-Claude Crmieux,3,4 Christian Rabaud,5 and Rmy Gauzit6
1

Pontchaillou University Hospital, and 2INSERM U835, Universit Rennes 1, IFR140, Rennes; 3EA 3647, Versailles Saint-Quentin University, Versailles;
Raymond Poincar University Hospital, Garches; 5Brabois University Hospital, Nancy; and 6Htel- Dieu University Hospital, Assistance PubliqueHpitaux de Paris, Paris, France

Background. Concerns have recently emerged about the efcacy and the quality of antibacterial generic products approved for use in humans.
Methods. We searched Medline and Embase for original research articles on antibacterial generic products published in English or French before July 2013.
Results. We selected 37 original research articles: 15 on -lactams, 10 on glycopeptides, and 12 on other antibacterial agents. The majority of articles (73.0%) were published during 20082012. Study designs included analytical chemistry (n = 9), in vitro susceptibility studies (n = 14), animal experiments (n = 6, including 5 using the
neutropenic mouse thigh infection model), and clinical studies in humans (n = 15). Of the 37 studies, 14 (37.8%)
suggested that some generic products may be inferior to the innovator in terms of purity (n = 2), in vitro activity
(n = 3), in vivo efcacy in experimental models (n = 4), clinical efcacy (n = 2), taste (n = 2), or compliance and acceptability in children (n = 1). The majority of in vitro studies (78.6%) found no signicant difference between
generic products and the innovator. Most (5/6) in vivo studies suggesting a difference between generic products and
the innovator were performed in an animal model that is not validated for the evaluation of the efcacy of antibacterial agents. The level of evidence was constantly low in clinical studies.
Conclusions. Published data on antibacterial generic products are limited and heterogeneous, thus precluding
any attempt to generalize the study results. This systematic review suggests that additional evidence would be
needed before considering a revision of the marketing authorization process for antibacterial generic products.
Keywords. antibacterial agents; generics; pharmacokinetic; bactericidal activity; drug regulatory agency.

Generic medicinal products are copies of patented

drugs and can be marketed at low cost following patent
expiration of the brand leader product. As with all pharmaceutical products, generic products must comply
with standards of quality, efcacy, and reliability. The

Received 2 October 2013; accepted 14 November 2013; electronically published

21 November 2013.
Correspondence: Pierre Tattevin, Service des Maladies Infectieuses et de Ranimation Mdicale, CHU Pontchaillou, 2 rue Henri Le Guilloux, 35033 Rennes Cedex,
France (pierre.tattevin@chu-rennes.fr).
Clinical Infectious Diseases 2014;58(4):45869
The Author 2013. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
journals.permissions@oup.com.
DOI: 10.1093/cid/cit769

458

CID 2014:58 (15 February)

Tattevin et al

regulatory authorities of several countries, including

the US Food and Drug Administration (FDA) and the
European Medicines Agency (EMA), and the World
Health Organization (WHO) have issued guidelines
presenting the terms and conditions under which
generic medicinal products can be recognized as therapeutically equivalent to their brand name counterpart
(reviewed in [1]). Bioequivalence principles have been
dened (ie, 20% acceptance range [80%125%] for the
90% condence interval of the ratio between test and
reference least square means after log-transformation
of the pharmacokinetic parameters of interest, maximum concentration (Cmax) and area under the curve
(AUC). The objectives of drug policies supporting the
use of generic medicinal products are essentially

economic: (1) to decrease the cost of medicines as part of

healthcare spending, in particular in developed countries (eg,
in France, it is estimated that 1.3 billion was saved by introducing such policy in 2008 [2]), and (2) to facilitate access to care in
developing countries (eg, expanded access to effective antiretroviral combinations for human immunodeciency virusinfected patients). However, these economic considerations should
not occur at the price of lower quality of patient care.
The therapeutic equivalence of generic medicinal products
approved for use in humans has been challenged in various
therapeutic areas, including neurology [3], endocrinology, and
cardiovascular diseases [4]. The question was also raised for antibacterial agents, especially following publication of a study
performed with vancomycin generic products suggesting that,
despite similar pharmacokinetic parameters and in vitro antibacterial activities, some vancomycin generic products were
less bactericidal than the innovator in vivo in a neutropenic
mouse thigh infection model [5], and could induce more resistant subpopulations [6]. Following publication of these results,
a debate started worldwide, involving the scientic communities, drug regulatory agencies, and the general public [7]. Questions were raised about the current assumptions from the
WHO, FDA, and EMA, that 2 products of parenteral use are
considered therapeutically equivalent if they are pharmaceutically equivalent. This issue is of concern, as (1) it would imply
that patients may currently receive suboptimal antibacterial
therapy depending on the product that they receive; and (2)
deep changes would be required in the approval process of antibacterial generic products, including the need for more studies
on efcacy, which would, in turn, translate into increased costs
for approval. This systematic review of the literature was designed to objectively analyze published data regarding the efcacy and quality of antibacterial generic products.
METHODS
Search Strategy and Selection Criteria

We searched Medline and Embase for articles in English or

French published any time before July 2013, using the following keywords in various combinations: generics, generic products, antibacterial, antibacterial agent, antibiotic, -lactam
agent, penicillin, cephalosporin, penem, uoroquinolone, aminoglycoside, macrolide, cycline, glycopeptide, and vancomycin.
Data Extraction

Two independent researchers (P.T. and R.G.) reviewed all abstracts to identify articles that required full-text review, with a
nal decision reached through consensus. All articles were discussed with a third reviewer (A.-C.C.). For each reviewed
article, we extracted data on the study setting, objectives,
methods, and results, including details on the evaluated generic

products. We systematically searched for additional articles in

the reference lists of all articles reviewed. The heterogeneity of
study designs and the limited number of articles available precluded any meta-analysis.
RESULTS
We identied 37 studies that met inclusion criteria: 15 focused
on -lactam agents (Table 1), 10 on glycopeptides (Table 2),
and 12 on other antibacterial agents (Table 3). The majority of
articles (73.0%) were published during the last 5 years (2008
2012). Study designs included analytical chemistry (measurement of active pharmaceutical ingredients and/or impurities,
n = 9), in vitro susceptibility studies (eg, determination of
minimal inhibitory concentrations [MICs], minimal bactericidal concentrations [MBCs], time-kill curves, population analysis, n = 14), in vivo animal experiments (n = 6, including 5
studies using the neutropenic mouse thigh infection model),
and clinical studies in humans (ie, pharmacokinetic studies,
retrospective cohorts, studies on compliance and/or taste,
quasi-experimental study, case report, n = 15). Studies originated from Asia (n = 9), South America (n = 8), Europe (n = 7),
and North America (n = 6), or covered >1 continent (n = 7). Of
the 37 studies, 14 (37.8%) suggested that some generic products
may be inferior to the innovator in terms of purity (n = 2), in
vitro activity (n = 3), in vivo efcacy in experimental models
(n = 4), clinical efcacy (n = 2), taste (n = 2), or compliance and
acceptability in children (n = 1).
Of the 15 studies on -lactam generic products, 7 suggested
that some approved generic products may be inferior to the innovator. Rodriguez et al found that, despite similar MICs and
MBCs, the 9 generic products of oxacillin that they evaluated in
the neutropenic mouse thigh Staphylococcus aureus infection
model had lower Emax (maximum effect in log10 colonyforming units/g) than the innovator [8]. Jones et al evaluated
46 lots of piperacillin-tazobactam generic products manufactured in 17 countries and found that their in vitro activity, evaluated by incremental MIC antimicrobial assay, was on average
10% lower than that of the innovator [11, 12]. Lambert et al
studied the pharmaceutical qualities of 34 generic products of
ceftriaxone approved for use, and found that quality standards
were violated on 18 occasions [15]. Subsequently, in a mathematical model based on Monte Carlo simulations, Schito et al
suggested that most ceftriaxone generic products may not reach
the required pharmacokinetic/pharmacodynamic parameters [16].
In a quasi-experimental study, Mastoraki et al found that the
incidence of postcardiac surgery infections was signicantly
increased in patients who received prophylaxis with a generic
product of cefuroxime, as compared to the innovator [17]. Last,
Cohen et al found that the acceptability and the compliance of
amoxicillin-clavulanic acid generic products approved for oral

Antibacterial Generics: Systematic Review

CID 2014:58 (15 February)

459

460

Table 1.

-Lactam Generic Products: Description of Included Studies

CID 2014:58 (15 February)

Reference

Evaluated Generic Products

Study Design

Main Findings

Comments

Potential Conflicts of
Interest

9 oxacillin generic products

approved for intravenous use,
manufactured in Colombia

- In vitro: determination of API,

MIC, MBC
- In vivo neutropenic mouse
thigh infection model
- Comparison with the innovator
(Bristol-Myers Squibb)

- 4/9 generic products had lower

potency in vitro (API measured
by microbiological assay)
- 9/9 generic products were
equivalent to the innovator in
terms of MIC, MBC
- 9/9 generic products had lower
potency in vivo (Emax)

The neutropenic mouse

thigh infection model is
not the gold standard for
the evaluation of the
potency of antibacterial
agents

AstraZeneca, Wyeth,
Pfizer, Allergan, Roche,
GlaxoSmithKline,
Bristol-Myers Squibb,
Merck Sharp & Dohme

Del Tacca et al [9],

2009

2 amoxicillin generic products

approved for oral use (tablet
formulations), available on the
Italian market

- Single-dose, randomized, 3treatment, crossover, singleblind bioequivalence study in

healthy adult volunteers
(n = 24)
- Comparison with the innovator

Bioequivalence not
demonstrated for
generic product A
(inferior margin 0.7921,
ie, slightly below 0.80)

None declared

Wu et al [10], 2010

1 ampicillin/probenecid generic
product developed in China

Jones et al [11], 2008

26 samples of piperacillintazobactam generic products

from Philippines (n = 10 lots),
India (n = 5), Greece (n = 3),
China (n = 2), Spain (n = 2),
Taiwan (n = 2), Portugal (n = 1),
and Jordan (n = 1)
46 lots of piperacillin-tazobactam
generic products (29
manufacturers, 17 countries)

- Pharmacological and clinical

study in healthy volunteers
- Comparison of the generic
product and the innovator in
terms of PK properties,
bioavailability,
bioequivalence, and adverse
events
In vitro study (incremental MIC
antimicrobial assay)

As compared with the innovator:

- 90% CIs of AUC ratio were
[.82381.0502] for generic
product A, and [.81161.1007]
for generic product B
- 90% CIs of Cmax ratio were
[.79211.0134] for generic
product A, and [.82461.1199]
for generic product B
No significant differences

Compared to the innovator, all but

1 lot of generic product
demonstrated significantly
decreased activity, at 5 to
35% (average, 16%)

Data from this study were

included in the study by
Moet et al [12] (same
team)

Wyeth

In vitro study (incremental MIC

antimicrobial assay)

(1) Compared to the innovator, the

range of activity of the generic
products was 42% to 10%
(average, 16%);
(2) the range of activity between
lots of the innovator was 19%
to 7% (average, 6%)

Overall, the lots of the

innovator (Zosyn)
averaged 9%10%
greater activity per vial,
as compared with the
lots of generic products

Wyeth

In vitro susceptibility tests

Compared to the innovator, no

significant differences with
respect to potency, MICs,
critical concentrations, or
mutant selection

Rodriguez et al [8],
2010

Tattevin et al

Moet et al [12], 2009

Silva et al [13], 2010

Multiple samples of piperacillintazobactam, and meropenem

generic products purchased in
different pharmacies in
Colombia

Bioequivalence
demonstrated

Vitalis

Table 1 continued.

Reference

Evaluated Generic Products

Study Design

Main Findings

Comments

Potential Conflicts of
Interest

Antibacterial Generics: Systematic Review

CID 2014:58 (15 February)

461

Tschudin-Sutter et al
[14], 2011

1 piperacillin-tazobactam generic
product (Sandoz, Switzerland)

In vitro susceptibility tests

No significant differences in mean

and median MIC between the
generic product and the
innovator for all tested strains

None declared

Lambert & Conway

[15], 2003

34 ceftriaxone generic products

Pharmaceutical qualities of the

generic products compared
with the innovator

Roche

Schito & Keenan [16],

2005

34 ceftriaxone generic products

Mathematical modeling of PK/

PD parameters based on fluid
concentrations of nonprotein-bound ceftriaxone
and Monte-Carlo simulations
(pleural fluid, and plasma)

Quality standards specified in the

European and US
Pharmacopoeias were violated
for 18 generic products,
including those for sterility (4
generic products) and impurities
(5 generic products)
The innovator exceeded the
required PK/PD parameters,
whereas most generic products
did not

Mastoraki et al [17],
2008

1 intravenous cefuroxime generic

product purchased in Greece
(Normafenac)

Quasi-experimental
monocentric clinical study,
comparing the generic
product with the innovator in
the prophylaxis of post
cardiac surgery infection

Incidence of postoperative
infections higher in patients
who received the generic
product compared to the
innovator (12.8% vs 2.5%,
P < .001)

National drug organization

identified gaps in the
chain of the
manufacturer

None declared

Cohen et al [18],
2009

Amoxicillin, and amoxicillinclavulanic acid generic

products approved for oral use
in France

Observational study of
acceptability and compliance
of the generic products in
children, based on a
questionnaire completed by
parents

Compared to the innovator, the

generic products were:
- less likely to be rated
satisfactory (77.9% vs 65%,
P = .01)
- more likely to be spat out (28.7%
vs 19%, P = .05)
- treatment course less likely to be
completed (91.7% vs 82.3%,
P = .02)

For amoxicillin, no
significant difference
between the innovator
and the generic product

None declared

Wollner et al [19],
2011

Amoxicillin-clavulanic acid,
cefpodoxime, and cefuroxime
generic products approved for
oral use in France

Observational study of
acceptability and compliance
of the generic products in
children, based on a
questionnaire completed by
parents and physicians

Disparities in terms of
acceptability among different
generic products of the same
drug

Tansuphasawadikul
et al [20], 2011

Meropenem generic products

available in Thailand

Retrospective multicentric
cohort study of hospitalized
patients with serious
infections treated with either
the generic product or the
innovator

No significant differences
between the generic products
and the innovator in terms of
clinical outcome at days 3, 7,
and 14
- Less than 2% of patients in both
groups discontinued
meropenem due to drug-related
adverse events

None declared

397 patients enrolled

CID 2014:58 (15 February)

Tattevin et al

Abbreviations: API, active pharmaceutical ingredient; AUC, area under the curve; CI, confidence interval; Cmax, maximal plasma concentration; Emax, bactericidal maximal effect; MBC, minimal bactericidal
concentration; MIC, minimal inhibitory concentration; PK/PD, pharmacokinetic/pharmacodynamic.

600 patients enrolled

No significant differences
between the generic products
and the innovator in terms of
cure rates, superinfection rates,
and mortality (due to infection,
and overall), but a trend favoring
the innovator for all
comparisons
Imipenem/cilastatin generic
product available in Thailand
Piyasirisilp et al [22],
2010

Retrospective monocentric
cohort study of hospitalized
patients treated for >48 h
with either the generic
product or the innovator

Meropenem generic product

available in Thailand
Angkasekwinai et al
[21], 2011

Retrospective monocentric
cohort study of hospitalized
patients treated for >48 h
with either the generic
product or the innovator

No significant differences
between the generic products
and the innovator in terms of
clinical outcome (favorable vs
death)

600 patients enrolled

Potential Conflicts of
Interest
Comments
Main Findings
Study Design
Evaluated Generic Products

Reference

Table 1 continued.
462

use in France were lower than that of the innovator in children,

based on a questionnaire completed by their parents [18].
Of the 10 studies on glycopeptide generic products, 3 suggested that some approved generic products may be inferior to
the innovator. Rodriguez et al published a case report where a
liver transplant recipient with persistent bacteremia after 10
days of intravenous vancomycin generic product had sterile blood
cultures 24 hours after a switch to vancomycin innovator [25].
Vesga et al found that, despite similar MICs and MBCs, 3
generic products of vancomycin imported from France, Argentina, and the United States had lower Emax than the innovator
in the neutropenic mouse thigh S. aureus infection model [5].
The same team subsequently found, using the same model, that
serial exposure to generic vancomycin enriches resistant subpopulations, whereas exposure to the innovator reduces resistant subpopulations [6].
Of the 12 studies published to date on generic products of
other antibacterial agent classes, 4 suggested that some approved generic products may be inferior to the innovator.
Zuluaga et al found that, despite similar MICs and MBCs, 10 of
20 generic products of gentamicin had lower Emax than the innovator in the neutropenic mouse thigh Escherichia coli infection model [31]. Nightingale et al evaluated 65 generic products
of clarithromycin from 18 countries and found that 9% did not
contain between 95% and 105% of the clarithromycin content
claimed in the label, and 19% exceeded the 3% limit for total
impurities [33]. Two double-blind studies found that the taste
of trimethoprim-sulfamethoxazole generic products was rated
lower than that of the innovator [40, 42].
Regarding study design, almost half of the studies (n = 17) in
this systematic review were performed in humans and studied
pharmacokinetic parameters (n = 7, mostly bioequivalence
studies), clinical efcacy (n = 6), and tolerability or compliance
in children (n = 4). Nine studies focused on in vitro efcacy,
comparing generic products with the innovator. Six studies
were performed in animals, using the neutropenic mouse thigh
infection model (n = 5) or the rabbit endocarditis model
(n = 1). Five studies investigated the pharmaceutical qualities
(purity, content, and potency) of antibacterial generic products.
This heterogeneity in the outcomes measured further precluded
any meta-analysis, as pooling the studies focusing on major
issues (effectiveness in humans), relatively major issues
( potency in vitro or in animal models), and relatively less
importantalthough still signicantissues (taste), would make
little sense, and would be of limited clinical relevance.
DISCUSSION
This systematic review of studies that evaluated antibacterial
generic products reveals that the data available to date in the literature are limited and heterogeneous. This precludes any

Table 2.

Glycopeptide Generic Products: Description of Included Studies

Antibacterial Generics: Systematic Review

CID 2014:58 (15 February)

Reference

Evaluated Generic Products

Study Design

Main Findings

Comments

Potential Conflicts of Interest

Fujimura
et al [23],
2008

5 vancomycin generic
products approved in
Japan, imported from
Slovenia, France, Hungary,
and Taipei

- Measurement of the active

component of vancomycin
per vial
- In vitro susceptibility tests
(MICs)
- Potency equivalent per vial

- Content per vial within the stipulated

range for all drugs (ie, 10 to 15%)
- No significant differences with the
innovator

None declared

Fujimura
et al [24],
2011

7 teicoplanin generic
products purchased in
Japan

In vitro susceptibility tests

For 147 clinical isolates of MRSA,

MIC90 was similar (4 mg/L) for the
innovator and 5 generic products,
whereas it was 8 mg/L for the 2
remaining generic products

None declared

Rodriguez
et al [6],
2012

3 vancomycin generic
products purchased in
Colombia

- In vitro: no difference between the

generic products and the innovator
- In vivo: serial exposure to the generic
product enriches resistant
subpopulations, whereas exposure
to the innovator reduces resistant
subpopulations

The neutropenic mouse

thigh infection model is
not the gold standard for
the evaluation of the
efficacy of antibacterial
agents

None declared

Vesga et al
[5], 2010

3 vancomycin generic
products imported from
the US, France, and
Argentina

- In vitro: determination of MIC,

MBC, and population
analysis profile
- In vivo: serial passages of 1
clinical MRSA strain in the
neutropenic mouse thigh
infection model (12 cycles)
- Comparison with the
innovator (Eli Lilly)
- In vitro: determination of API,
MIC, MBC, and time-kill
curves
- In vivo: neutropenic mouse
thigh infection model
- Comparison with the
innovator (Eli Lilly)

- In vitro studies: generic products

undistinguishable from the innovator
- In vivo studies: all generic products
significantly inferior to the innovator
in terms of bactericidal effect (Emax)

The neutropenic mouse

thigh infection model is
not the gold standard for
the evaluation of the
efficacy of antibacterial
agents

AstraZeneca, Wyeth, Pfizer,

Allergan, Roche,
GlaxoSmithKline, Bristol-Myers
Squibb, Merck Sharp & Dohme

Rodriguez
et al [25],
2009

1 vancomycin generic
product purchased in the
US (approved by the FDA)

Case report

- In a liver transplant recipient,

persistent bacteremia after 10 d of
intravenous vancomycin generic
product
- Blood cultures became sterile 24 h
after switch to the innovator

None declared

Diaz et al
[26], 2011

20 samples of vancomycin
generic products
purchased from the
pharmacies in different
hospitals in Colombia

In vitro: determination of MIC,

MBC, critical concentrations,
and the production of
spontaneous mutants

No significant differences observed

between the generic products and
the innovator

Vitalis

Conte [27],
1987

The first vancomycin generic

product commercialized in
the US

In vitro: determination of MIC

and MBC

No significant differences observed

between the generic product and the
innovator

Lymphomed

Nambiar
et al [28],
2012

6 vancomycin generic
products approved for
parenteral use in the US

Samples tested for purities,

content, and potency

The quality parameters of all generic

products tested were above the US
Pharmacopeia acceptance criteria

Study performed by the FDA

463

No significant differences observed

between the generic products in
terms of in vitro bactericidal activity
(time-kill curves), and in vivo efficacy
(rabbit endocarditis model)
- In vitro: determination of timekill curves
- In vivo: MRSA rabbit
endocarditis model
6 vancomycin generic
products imported from
the US, France, Spain, and
Switzerland
Tattevin
et al [30],
2012

The quality parameters of all generic

products tested were above the US
Pharmacopeia acceptance criteria
Measurement of the active
component of vancomycin,
and the impurities, by 2
independent laboratories
(HPLC and ultra-HPLC)
Samples of vancomycin
generic products approved
for parenteral use in the US
Hadwiger
et al [29],
2012

CID 2014:58 (15 February)

Tattevin et al

Abbreviations: API, active pharmaceutical ingredient; Emax, bactericidal maximal effect; FDA, US Food and Drug Administration; HPLC, high-performance liquid chromatography; MBC, minimal bactericidal
concentration; MIC, minimal inhibitory concentration; MIC90, MIC required to inhibit the growth of 90% of organisms; MRSA, methicillin-resistant Staphylococcus aureus.

AstraZeneca, Astellas, Galderma,

Pfizer, Roche, Novartis, SanofiAventis, Merck Sharp &
Dohme, GlaxoSmithKline,
Bristol-Myers Squibb
- Rabbit endocarditis model
is the gold standard
animal model for the
evaluation of the efficacy
of antibacterial agents
- No comparison with the
innovator

Study performed by the FDA

Potential Conflicts of Interest

Comments
Main Findings
Evaluated Generic Products

Study Design

Reference

Table 2 continued.
464

attempt to generalize their ndings. Indeed, even for the classes

of antibacterial agents that received the most attention (ie, lactams and glycopeptides), published studies have not consistently demonstrated that some generic products approved for
use in humans were inferior to the innovator. The level of evidence from the 6 clinical studies that evaluated the efcacy of
antibacterial generic products was low. One case report and 1
quasi-experimental study suggested that generic products of,
respectively, vancomycin and cefuroxime, were less potent than
the innovator, whereas 3 retrospective cohort studies that enrolled a total of 1597 patients treated with meropenem or imipenem/cilastatin found no signicant difference between the
generic products and the innovator in terms of clinical
outcome. One randomized, open-label, clinical trial found that
a generic product of clarithromycin did not signicantly differ
from the innovator in terms of clinical or bacteriological efcacy or in terms of tolerability. In summary, none of the clinical
studies that compared the efcacy of generics and innovators in
humans is sufcient to raise signicant concern on the efcacy
of generics, as only 1 isolated case report and 1 quasi-experimental study suggested that generics may be suboptimal.
Of note, the 4 studies that are often cited to document the
suboptimal efcacy of generic products as compared to the innovator [5, 6, 8, 31] were all performed in an animal model that
has not been validated for the evaluation of the efcacy of antibacterial agents, that is, the neutropenic mouse thigh infection
model. Only 1 study evaluated the efcacy of generic products
in an animal model with long track records for the evaluation
of the bactericidal effect of antibacterial agents, that is, the
rabbit endocarditis model [30]. The latter study evaluated 6
vancomycin generic products approved for use in the United
States and Europe, and did not conrm the results observed in
the neutropenic mouse thigh infection model [5]. Discrepancies
between animal models are not rare, and may be responsible
for erroneous assumptions, as was the case with initial studies
on the role of Panton-Valentine leukocidin in the pathogenesis
of community-associated methicillin-resistant S. aureus
(MRSA) [43]. Hence, further studies with the appropriate
animal model(s) would be required to judge the comparative in
vivo efcacy of generic products and the innovator. Given that
most in vitro studies (11/14 [78.6%]) found no signicant difference between the generic products and the innovator in terms
of MICs and MBCs, we would expect similar in vivo efcacy in
an animal model with impaired immunity, such as the neutropenic mouse. Some authors suggested that discrepancies
between in vitro and in vivo efcacy could be related to excess
impurities, a signicant issue with antibacterial agents such as
vancomycin [5]. However, this hypothesis has not been conrmed by 2 recent studies where the quality parameters of all
parenteral vancomycin products tested surpassed the US Pharmacopeia acceptance criteria, including for generic products

Table 3.

Other Antibacterial Generic Products: Description of Included Studies

Reference

Evaluated Generic Products

Study Design

Potential Conflicts of
Interest

Main Findings

Comments

- In vitro study: 1 generic product

significantly inferior (MIC and
MBC, respectively, 45.3 and 64
vs 0.71 and 0.79 mg/L, P < .05)
- In vivo study: 10 generic products
displayed significantly lower
efficacy against Escherichia coli
Following authorization of generic
ciprofloxacin, the number of
marketed ciprofloxacin products
increased from 3 to 10, the
average price for 1 day of
treatment decreased by 53%,
ciprofloxacin use increased by
154%, and resistance to
ciprofloxacin increased by 200%

The neutropenic mouse

thigh infection model is
not the gold standard for
the evaluation of the
potency of antibacterial
agents

AstraZeneca, Wyeth, Pfizer,

Allergan, Roche, SanofiAventis, GlaxoSmithKline,
Bristol-Myers Squibb,
Merck Sharp & Dohme

Observational study

None declared

Antibacterial Generics: Systematic Review

20 gentamicin generic products

approved for intravenous use,
purchased in Colombia or imported
from Germany, Austria, and the US

- In vitro study: MIC, MBC

- In vivo study: neutropenic
mouse thigh infection
model

Jensen et al
[32], 2010

10 ciprofloxacin generic products

approved in Denmark

Retrospective ecological
study in a community
setting (7 Danish counties)

Nightingale
[33], 2005

65 clarithromycin generic products

manufactured in 18 countries

Generic products were

examined visually, assayed
by HPLC for clarithromycin
content and impurities, and
tested for dissolution
properties

- 9% of generic products did not

contain between 95% and 105%
of the amount of clarithromycin
claimed in the label (Latin
America, 17%; Asia-AfricaPacific, 8%, and Europe, 10%)
- 1 generic product failed to meet
the dissolution specification
(80% of the drug must dissolve
in 30 min)
- 19% (12/65) of generic products
exceeded Abbott Laboratories
3% limit for total impurities

Snyman et al
[34], 2009

1 clarithromycin extended-release
generic product (Klarithram MR)

Randomized, open-label,
clinical trial in patients
presenting with
pharyngitis, sinusitis, or
pneumonia

In comparison to the innovator

(Klacid XL), generic products
showed no significant
differences in terms of
tolerability, clinical, and
bacteriological cure rates

95% clinical cure rate

Boonleang
et al [35],
2007

1 azithromycin generic product approved

in Thailand

Randomized, double-blind,
crossover, pharmacokinetic
study in healthy volunteers

Cmax and AUC not statistically

different between the generic
product and the innovator

Bioequivalence
demonstrated

Najib et al
[36], 2001

1 azithromycin generic product approved

in Jordan (2 formulations, capsule and
suspension)

Open-label pharmacokinetic
study in healthy volunteers

Cmax, Tmax, and AUC not

statistically different between the
generic product and the
innovator

Bioequivalence
demonstrated

Gulati et al
[37], 2000

1 azithromycin generic product approved

in India

Open-label pharmacokinetic
study in healthy volunteers

Cmax, Tmax, and AUC not

statistically different between the
generic product and the
innovator

Bioequivalence
demonstrated

Zuluaga et al
[31], 2010

Abbott

CID 2014:58 (15 February)

Unison (Bangkok)

465

466

Table 3 continued.

CID 2014:58 (15 February)

Reference

Study Design

PieyroLpez et al
[38], 2005

1 azithromycin generic product approved

in Mexico

Agudelo &
Vesga [39],
2012

1 metronidazole generic product

approved for intravenous use in
Colombia

- Pharmacological and clinical

study in healthy volunteers
- Comparison to the innovator
in terms of PK property,
bioavailability,
bioequivalence, and
adverse events
- In vitro study: API, MIC,
spectrographic and
chromatographic profiles
- In vivo study: neutropenic
mouse thigh infection
model

El-Chaar et al
[40], 1996

Generic products of cephalexin,

erythromycin-sulfisoxazole and
trimethoprim-sulfamethoxazole
approved in the US

Randomized, double blind,

crossover, clinical study of
taste and compliance in
children, based on
questionnaire completed
by parents

- For cephalexin, and for

erythromycin-sulfisoxazole: no
significant differences between
generic products and the
innovator in terms of taste and
compliance
- For trimethoprimsulfamethoxazole, the innovator
tasted better than the generic
product, but there was no
difference in compliance

Liu et al [41],
2012

1 sulfadoxine + pyrimethamine generic

product developed in China

- Pharmacological and clinical

study in healthy volunteers
- Comparison of the generic
product with the innovator
in terms of PK properties,
bioavailability,
bioequivalence, and
adverse events

No significant differences

Samulak et al
[42], 1996

Generic products of cephalexin,

erythromycin ethylsuccinatesulfisoxazole, penicillin V, and
trimethoprim-sulfamethoxazole
approved in the US

Randomized, double-blind,
comparative evaluation of
the taste of the generic
product and the innovator
for each drug

- For cephalexin, penicillin V, and

erythromycin ethylsuccinate/
sulfisoxazole, the taste of
generic products was rated equal
to that of the innovators
- For trimethoprimsulfamethoxazole and
erythromycin estolate, the taste
of the innovators was rated
higher than that of the generic
products

Evaluated Generic Products

Main Findings

Comments

Tattevin et al

No significant differences

Bioequivalence
demonstrated

No significant differences observed

between the generic product and
the innovator

Therapeutic equivalence
demonstrated

Potential Conflicts of
Interest

None declared

None declared

Bioequivalence
demonstrated

Abbreviations: API, active pharmaceutical ingredient; AUC, area under the curve; Cmax, maximal plasma concentration; HPLC, high-performance liquid chromatography; MBC, minimal bactericidal concentration; MIC,
minimal inhibitory concentration; PK, pharmacokinetic; Tmax, time to peak concentration.

that were suboptimal in the neutropenic mouse model [28, 29].

Last, the nding by Rodriguez et al that serial exposure to
generic vancomycin enriches resistant subpopulations, whereas
exposure to the innovator reduces resistant subpopulations,
remains unexplained [6]. It must be outlined that this intriguing phenomenon was observed in the neutropenic mouse thigh
infection model after 12 sets of experiments in the model (ie,
isolates recovered from an experiment were reinoculated to new
groups of animals, and this process was repeated 12 times).
Given the complexity of this study design, the results may not
be relevant to the clinical use of vancomycin in humans. In addition, these ndings have not been conrmed in the rabbit
model of MRSA endocarditis [44].
The current controversy on the equivalence of generic medicinal products is of paramount importance, as their volume
surpasses that of branded medicinal products, and is continuously increasing, accounting for two-thirds of the worldwide
consumption of antimicrobial agents in 2010 (source: IMS
Health [2]). Promotion of the use of generic products has the
objective to decrease healthcare costs without compromising
quality of care and patient safety. Hence, to be approved for use
in humans, antibacterial generic products must comply with
standards of quality, efcacy, and reliability, as dictated by regulatory authorities and international organizations (eg, FDA,
EMA, and WHO). Although in some countries the quality of
available medicinal products may be inadequate in terms of
content of active ingredient, this issue also applies to branded
drugs, as most of these substandard drugs are counterfeit products [45]. These sobering facts are out of the scope of this systematic review on antibacterial generic products that received
regulatory approval. Among other concerns raised by the expanded access to generic products, Jensen et al found a relationship between community consumption and the number of
trade names of oral ciprooxacin. In their study, the introduction of generic ciprooxacin in Denmark was followed by a
sharp increase in the total consumption of ciprooxacin (from
0.13 to 0.33 dened daily doses/1000 inhabitant-days), while the
frequency of ciprooxacin resistance increased by 200% [32].
This study and others are reminders that drug policies supporting the use of antibacterial generic products must ensure that
the reduced price of antibacterial treatments does not translate
to increased use [46, 47]. Otherwise, excess use of antibiotics
and its ecological impact on bacterial resistance would invariably reduce the economical benet brought by the use of
generics.
This systematic review on the efcacy and quality of antibacterial generic products approved for use in humans has limitations. First, as in most literature reviews, our ndings are
sensitive to publication bias, implying that the studies analyzed may not be representative of all the studies performed on
this topic. Indeed, positive studies (ie, studies that found a

signicant difference between generic products and the innovator), are probably more likely to be submitted for publication
and more likely to be accepted by editors. In this regard, our
nding that 37.8% of studies reported signicant differences
between generic products and the innovator is probably an
overestimate. Second, the economical consequences of drug
policies for increased use of generic products may also carry a
risk of bias, in 2 opposite directions. Whereas pharmaceutical
companies who own an innovator product would probably encourage the publication of studies suggesting that generic products are suboptimal, regulatory authorities and international
organizations would try their best to demonstrate that this is
not the case. Last, most of these studies were not adequately
powered to demonstrate noninferiority. Hence, the absence of
any signicant difference in the parameters evaluated cannot
be interpreted as evidence that the generics are equivalent to
the innovators. Despite these limitations, our systematic review
provides a global picture of all studies published to date. Their
limited number and their heterogeneity did not allow for a
meta-analysis. Indeed, studies comparing the effectiveness of
generics and innovators in humans could obviously not be
pooled with studies comparing taste and acceptability of oral
solutions in children, or with studies comparing potencies in
vitro and in animal models. However, we found no convincing
data that antibacterial generic products approved by regulatory
authorities would be suboptimal compared with the innovator.
This suggests that additional evidence would be needed before
considering a revision of the marketing authorization process
for injectable and oral antibacterial generic products.
Notes
Acknowledgments. We are indebted to Dominique Monnet for his insightful comments, and for critical reading of the manuscript.
Potential conicts of interest. P. T. has received grants from Astellas,
AstraZeneca, Aventis, Bristol-Myers Squibb, Galderma, Gilead Sciences,
Janssen-Cilag, MSD, Novartis, Pzer, and ViiV Healthcare for consultancies, workshops, or travel to meetings and accommodation. A.-C. C. has received grants from Janssen-Cilag, Novartis, AstraZeneca, Aventis, and
Heraeus for consultancies, workshops, and travel to meetings and
accommodation. C. R. has received grants from Gilead Sciences, Tibotec,
Bristol-Myers Squibb, MSD, Sano, AbbVie, Janssen-Cilag, Thermo Scientic Biomarkers, ViiV Healthcare, and GSK Vaccines for consultancies,
workshops, or travel to meetings and accommodation. R. G. has received
grants from bioMrieux, MSD, Bayer, Janssen-Cilag, Novartis, Sano, AstraZeneca, and Astellas for consultancies, workshops, or travel to meeting and
accommodation.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conicts of Interest. Conicts that the editors consider relevant to the
content of the manuscript have been disclosed.

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