The generic medication contains the same components and specifications as the brand-name medication. In Colombia, generic medications are available for purchase 10 years after the commercial patent of the original brand-name medication expires. Generic medications must comply with a variety of conditions to be approved for commercial use. Broadly speaking, generic medications must contain the same quantitative and qualitative composition of active ingredients compared to their brand-name counterpart. Furthermore, the pharmaceutical presentation must be similar to their respective brand-name counterpart with regards to formulations (e.g., parenteral, enteral, etc.), safety profile, and pharmacokinetics.1 The prescription of generic medications is considered one of the most effective approaches for reducing cost and increasing global access to first-line medication for the treatment of diverse infections.2,3

Many countries have progressively opened their markets to generic medications. In 2010, generic antibiotics (GA) represented more than two-thirds of the global consumption of medications.3 In the United States, generic medications made up to 63% of total prescriptions in 2007,4 while in England that number was 83% in 2008.5 The generic medication market has likewise expanded in other developed countries such as Japan.2

Recently, the use of generic medications has caused controversy, particularly in the case of GA. It has traditionally been considered that GAs, principally in parental form, have the same efficacy as brand-name antibiotics (BNA).2,3,6–9 However, several studies have questioned the clinical effectiveness of GAs, reporting issues like clinical failure or emergence of bacterial resistance associated with the sustained use of Gas.3,5,7,8

Antibiotic resistance has also been related to a significant use of GAs following their release into the drug market. This collateral damage has been demonstrated in Germany and Denmark where use of generic quinolones generated a disproportionate increase in its use, followed by an increase in resistance levels from 7.7% to 25% and 0.8% to 4%, respectively.10,11 This phenomenon has also been reported in Colombia where the use of β-lactams has surpassed the 90th percentile of the defined daily dose, considerably more than has been reported in other countries.12–14 On a national level, some antibiotics are consumed more than others, as is the case with meropenem given the ready availability of its generic version. Meropenem provides adequate coverage against Pseudomonas aeruginosa and is considered first-line treatment for a number of complicated infections including intra-abdominal infections, bacterial meningitis, blood stream infections, nosocomial pneumonia, septicemia, and febrile neutropenia.15

On the other hand, the characteristics of GAs can be affected by a variety of elements, such as active ingredient, bioequivalence, impurities, additives, and excipients. Many of these elements depend on the manufacturing process, which can vary among GAs and BNAs. In a country where GAs represent a large portion of medications consumed due to limited resources, the therapeutic efficacy of GAs needs to be evaluated. This will contribute to greater confidence in the prescription of GAs, as well as provide a better understanding of possible deleterious effects related with their use.

Keeping in mind the current uncertainties regarding possible differences between GAs and BNAs, this study was designed to determine the clinical impact associated with the use of generic versus brand-name meropenem for the treatment of infections caused by Gram-negative bacteria susceptible to carbapenems. This study evaluated patients who were hospitalized in the intensive care unit (ICU) of a tertiary care hospital in Colombia.

In this study, we compared critically ill patients treated with generic versus brand-name meropenem. Results demonstrated greater mortality in the generic group and comparable total costs for both groups. History of cardiovascular disease was also found to be an independent risk factor for mortality. In contrast, the brand-name had a higher prevalence of comorbidities and history of hospitalization in the three months prior to hospital admission.

Meropenem is one of the most commonly-used antibiotics in critically ill patients due to its broad-spectrum bactericidal activity and its pharmacokinetic characteristics. The present study suggests clinical superiority of brand-name meropenem with similar costs in care. There are few clinical studies that compared clinical outcomes with treatment of generic versus brand-name antibiotics. Most studies have been conducted in vitro and animal models.23,24 Also, systematic reviews on the efficacy and quality of GAs have not been able to conclude their inferiority in relation to BNAs, maybe in part due to the heterogenous nature and different end points of the studies included, which precluded a definitive conclusion.25 Furthermore, it is difficult to have the possibility of evaluating brand versus generic meropenem in the same hospital, under the same conditions, like we were able to do in our study. For example in Thailand, a study comparing generic versus brand-name meropenem in hospitalized patients, of which 60% had documented microbiological data and some were infected with meropenem-resistant bacteria, did not find inferiority of either molecule.24 However, in our study the inclusion criteria was meropenem susceptible Gram-negative bacteria, eliminating the possibility that resistance could interfere with outcome ascertainment in the two groups. Another Colombian prospective cohort study that included 1015 patients with nosocomial infections showed in multivariate analysis a risk of death almost two-fold higher in patients treated with GAs compared to patients treated with BNAs (HR = 1.91; 95%CI = 1.43–2.55).21

Several studies led by Vesga et al. have compared GAs and BNAs using in vivo models. One of these studies using three different brands of generic vancomycin showed lower in vivo effectiveness compared to brand-name vancomycin despite similarities of chemical equivalence and potency. This difference was statistically significant and independent of route of administration or doses.7 Furthermore, Vesga et al. have shown difference in efficacy with other antibiotics, including meropenem, in which a pharmacologic equivalence did not translate into therapeutic equivalence in animal infection models.9 In this study, the authors proposed that differences in meropenem efficacy might be secondary to trisodium compounds that increase susceptibility in the face of hydrolysis within the organism. Finally, Vesga et al. also evaluated the impact of GA use on bacterial susceptibility profiles.8 An animal model was used to evaluate the resistance profile of Staphylococcus aureus in the face of successive cycles of GA and BNA. It was observed that generic vancomycin progressively selected subpopulations of resistant bacteria, confirming the effect of suboptimal bactericidal action of GA on microorganism susceptibility. In contrast to the Vesga et al. findings, some authors like Louie et al. and Hadwiger et al. have not been able to replicate these results.26,27 Irrespective of the contradictory findings with animal models, our study results show a statistically significant difference in the clinical outcomes.

Another key point is the therapeutic indications for GA. In the U.S., the Food and Drug Administration therapeutic indications for generic and brand-name meropenem are identical. However, the Colombian National Institute of Food and Drug Surveillance Agency (INVIMA in Spanish) has recommended only brand-name meropenem for the treatment of febrile neutropenia rather generic meropenem. Likewise, INVIMA recommends only brand-name vancomycin for the treatment of pneumonia, sepsis, or meningitis caused by penicillin-resistant Streptococcus pneumoniae; difference in the therapeutic indications between the GA versus the BNAs raises concerns whether GAs can be prescribed in all kinds of patients, especially when critically ill.

This study is different from other studies regarding the clinical outcomes between generic versus brand-name antibiotics. First, the selected study population was limited to critically ill patients. This population was selected because their conditions demand that antibiotics used have good effectiveness and safety due to severity of illness. Critical patients usually have alterations in the volume of distribution, tissue perfusion and renal functions among others, which may lead to significant challenges in achieving recommended pharmacokinetic and pharmacodynamic parameters for optimal treatment against bacterial infections.28 Second, only patients with documented Gram-negative infections susceptible to meropenem were included to maximize the likelihood of successful treatment with the selected antibiotics. To reduce confounding factors in the mortality analysis, patients with invasive fungal infections were excluded. Third, the economic analysis allowed the comparison of cost of hospitalization as well as the calculation of incremental cost of survival for each treatment used. Fourth, the groups of patients treated with generic and brand-name meropenem were comparable in terms of age and severity of infections. Furthermore, the group of patients treated with the brand-name molecule had a higher prevalence of cardiovascular disease, which was a significant risk factor for mortality.

Pharmacoeconomic analyses are important for an evaluation of costs and benefits of health interventions. In the present study, a cost-effectiveness model was created to compare costs when using each molecule. The net healthcare-associated costs were included in the assessment of each molecule, as well as the secondary costs of complications resulting from therapeutic failure and adverse reactions associated with the antibiotic. On the other hand, the cost-of-stay in the ICU was higher in the generic group due to the development of more complications and unfavorable clinical progression. At the end, there were no significant differences in the costs of treatment for each episode of infection between cohorts, which is the most cogent argument for using generics.

When the incremental cost effectiveness ratio (ICER) was calculated for the brand-name and generic molecules in our study, the ICER analysis showed that treatment with brand-name meropenem confers greater patient survival at a lower cost and is therefore is a better treatment option than its generic counterpart.

A limitation of this study is that only 67% of the anticipated sample size of 252 was achieved. This occurred primarily due to the inclusion and clinical follow-up criteria, which was strict and therefore led to the exclusion of many patients. Also, secondary to the smaller sample size achieved, some variables like SOFA or other non-cardiovascular comorbidities where not found to be associated with mortality in the multivariate analysis. While a smaller sample may alter the precision of the study, our results demonstrate a strong statistical association that is unlikely to be by chance. Even though the GA had a higher incidence of ventilator associated pneumoniae which may contribute in part to the higher mortality, the multivariate analysis did not show any difference associated with this type of infection. Also, as we explained before, we did not find any other factors that could explain the higher mortality with GA like changes in the antibiotic prescription or infection control practices.

In conclusion, the use of brand-name meropenem for the treatment of Gram-negative infections susceptible to carbapenems in the ICU is a more cost-effective option than generic meropenem. Institutions should follow clinical and microbiologic outcomes of patients treated with antibiotics, which in turn may allow for early detection of therapeutic failure. Ultimately, this approach can provide data that will help drug producers improve the development of antibiotics.

This study was funded by the International Center for Medical Training and Research (CIDEIM in Spanish). This study did not receive any funding from drug manufacturers or any other sources.

The authors declare no conflicts of interest.

We are grateful for the assistance we received from Obed David Suárez Anaya, Carmen Elisa Llanos Uribe, Luz Stella Salazar, and Camila Marin Peralta.

Karen Ordóñez designed the study, collected and interpreted data, revised the manuscript, and approves of the final version. Conceptualization, Data curation, Investigation, Methodology, Supervision, Validation, Visualization, Writing original draft, writing review and editing. Address: Carrera 18#12-75 Torre 1 Consultorio 1205, Postal Code 660003, Pereira, Colombia.

Max M. Feinstein collected and interpreted data, drafted the manuscript, and approves of the final version. Address: 2058 E. 115th St., Cleveland, Ohio, Postal Code 44106, USA. Data curation, formal analysis, writing original draft, writing review and editing.

Sergio Reyes collected and interpreted data, revised the manuscript, and approves of the final version. Data curation, formal analysis, investigation, supervision, validation, writing original draft. Address: Av. La Maria #19-225, Postal Code 760031, Cali, Valle del Cauca, Colombia.

Cristhian Hernández-Gómez designed the study, interpreted the data, revised the manuscript, and approves of the final version. Conceptualization, Formal analysis, investigation, methodology, software, supervision, validation, writing original draft, project administration writing review and editing. Address: Cra 9 # 131 A- 02, Lab de Investigacion 2 Piso, Postal Code 110121, Bogotá, Colombia.

Christian Pallares designed the study, interpreted the data, revised the manuscript, and approves of the final version. Conceptualization, formal analysis, methodology, software, validation, writing original draft, project administration, writing review and editing. Address: Av. La Maria #19-225, Postal Code 760031, Cali, Valle del Cauca, Colombia.

María V. Villegas designed the study, revised the manuscript, and approves of the final version. Conceptualization, funding acquisition, project administration, resources, supervision, validation, visualization, writing-review and editing. Address: Cra 9 # 131 A- 02, Lab de Investigacion 2 Piso, Postal Code 110121, Bogotá, Colombia.

All authors agree to be accountable for all aspects of the work and ensure the accuracy and integrity of the study.