antibiotics Review Gram-Positive Pneumonia: Possibilities Offered by Phage Therapy Lucía Fernández 1,2, María Dolores Cima-Cabal 3 , Ana Catarina Duarte 1,2 , Ana Rodríguez 1,2, María del Mar García-Suárez 3,* and Pilar García 1,2,* 1 Instituto de Productos Lácteos de Asturias (IPLA-CSIC), Paseo Río Linares s/n, 33300 Villaviciosa, Asturias, Spain; [email protected] (L.F.); [email protected] (A.C.D.); [email protected] (A.R.) 2 DairySafe Group, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Asturias, Spain 3 Escuela Superior de Ingeniería y Tecnología (ESIT), Universidad Internacional de la Rioja (UNIR), Av. de la Paz, 137, 26006 Logroño, La Rioja, Spain; [email protected] * Correspondence: [email protected] (M.d.M.G.-S.); [email protected] (P.G.) Abstract: Pneumonia is an acute pulmonary infection whose high hospitalization and mortality rates can, on occasion, bring healthcare systems to the brink of collapse. Both viral and bacterial pneumonia are uncovering many gaps in our understanding of host–pathogen interactions, and are testing the effectiveness of the currently available antimicrobial strategies. In the case of bacterial pneumonia, the main challenge is antibiotic resistance, which is only expected to increase during the current pandemic due to the widespread use of antibiotics to prevent secondary infections in COVID-19 patients. As a result, alternative therapeutics will be necessary to keep this disease under Citation: Fernández, L.; Cima-Cabal, control. This review evaluates the advantages of phage therapy to treat lung bacterial infections, in M.D.; Duarte, A.C.; Rodríguez, A.; particular those caused by the Gram-positive bacteria Streptococcus pneumoniae and Staphylococcus García-Suárez, M.d.M.; García, P. aureus, while also highlighting the regulatory impediments that hamper its clinical use and the Gram-Positive Pneumonia: difficulties associated with phage research. Possibilities Offered by Phage Therapy. Antibiotics 2021, 10, 1000. Keywords: pneumonia; antibiotic resistance; Streptococcus pneumoniae; Staphylococcus aureus; new https://doi.org/10.3390/ antibiotics10081000 therapies; phage therapy; endolysins Academic Editors: Marco Maria D’Andrea and Luís Melo 1. Introduction Received: 12 July 2021 Pneumonia is a disease that arises when a pathogen reaches the lower respiratory Accepted: 12 August 2021 tract, overcomes the host defense system and damages the pulmonary parenchyma. Al- Published: 18 August 2021 though non-infectious forms of this pathology do exist, the so-called idiopathic interstitial pneumonia, they are out of the scope of this review. Infectious pneumonia can be mild, Publisher’s Note: MDPI stays neutral but it may also progress to a severe, life-threatening condition, depending on the host with regard to jurisdictional claims in characteristics and the virulence of the pathogen. In adults, the risk of acquiring bacterial published maps and institutional affil- pneumonia increases with age, stays in long-term care facilities, and comorbidities, such iations. as stroke or neurological deterioration [1]. In young children, especially in low-income countries, childhood wasting and household air pollution are the underlying risk factors for morbidity and mortality due to this illness. It must be noted that after the introduction of Hib and pneumococcal conjugate vaccines (against Haemophilus influenzae type b and Copyright: © 2021 by the authors. Streptococcus pneumoniae, respectively), pneumonia mortality rates have significantly de- Licensee MDPI, Basel, Switzerland. creased [2]. However, this disease remains, to this day, a major cause of death in children, This article is an open access article the elderly and the immunocompromised. distributed under the terms and Pneumonia can be caused by a wide variety of germs, including bacteria, viruses and conditions of the Creative Commons fungi. Moreover, the recent advances in molecular detection techniques have revealed Attribution (CC BY) license (https:// that, in some cases, different microorganisms (e.g., a virus and a bacterium) can co-exist to creativecommons.org/licenses/by/ produce the disease. Depending on the environment where the pathogen is acquired, this 4.0/). Antibiotics 2021, 10, 1000. https://doi.org/10.3390/antibiotics10081000 https://www.mdpi.com/journal/antibiotics Antibiotics 2021, 10, x FOR PEER REVIEW 2 of 16 Antibiotics 2021, 10, 1000 2 of 15 to produce the disease. Depending on the environment where the pathogen is acquired, this illness is often broadly classified into community-acquired pneumonia (CAP) and illnesshospital-acquired is often broadly pneumonia classified (HAP). into community-acquired The latter is also referred pneumonia to as nosocomial (CAP) and pneumo- hospital- acquired pneumonia (HAP). The latter is also referred to as nosocomial pneumonia, and nia, and includes ventilator-associated pneumonia (VAP), which is defined as pneumonia includes ventilator-associated pneumonia (VAP), which is defined as pneumonia occurring occurring >48 h after endotracheal intubation. >48 h after endotracheal intubation. So far, at least 26 viruses have been associated with CAP in both children and adults. So far, at least 26 viruses have been associated with CAP in both children and adults. In adults, influenza viruses, rhinoviruses and coronaviruses are responsible for a third of In adults, influenza viruses, rhinoviruses and coronaviruses are responsible for a third of pneumonia cases, while respiratory syncytial virus, rhinovirus, human metapneu- pneumonia cases, while respiratory syncytial virus, rhinovirus, human metapneumovirus, movirus, human bocavirus and parainfluenza viruses are the main agents identified in human bocavirus and parainfluenza viruses are the main agents identified in children. children. HAP may also be caused by viral pathogens, resulting in a similar death rate to HAP may also be caused by viral pathogens, resulting in a similar death rate to that that observed for bacterial infections [3]. observed for bacterial infections [3]. Regarding fungi, there are several yeasts and molds (Pneumocystis jiroveci, Cryptococ- Regarding fungi, there are several yeasts and molds (Pneumocystis jiroveci, Cryptococcus neoformanscus neoformans, Aspergillus, Aspergillusand Fusariumand Fusarium) that) canthat also can colonizealso colonize the respiratory the respiratory tract and tract cause and diseasecause disease [4] (Figure [4] (Figure1). Over 1). the Over last the decades, last dec theades, incidence the incidence of fungal of fungal pneumonia pneumonia has risen has inrisen highly in highly immunosuppressed immunosuppressed patients, patients, such assu thosech as affectedthose affected by HIV/AIDS, by HIV/AIDS, cancer, cancer, solid organsolid organ transplants transplants and other and other chronic chronic pulmonary pulmonary diseases, diseases, such assuch cystic as cystic fibrosis. fibrosis. Figure 1. Main pathogens causing pneumoniapneumonia and their incidence. The major etiological etiological agents agents of of bacterial bacterial CAP CAP are are S. pneumoniaeS. pneumoniae andand H. influenzaeH. influenzae, alt-, althoughhough atypical atypical bacteria, bacteria, such such as as MycoplasmaMycoplasma pneumoniae pneumoniae, ,ChlamydiaChlamydia pneumoniae pneumoniae andand Le- gionella pneumoniae,, areare alsoalso responsibleresponsible forfor anan importantimportant numbernumber ofof casescases [[5].5]. In that sense, it mustmust bebe notednoted thatthat thethe termterm atypicalatypical pneumoniapneumonia isis somewhatsomewhat inaccurateinaccurate becausebecause thesethese microbes are not anan uncommonuncommon causecause ofof CAPCAP inin adults.adults. OnOn thethe otherother hand,hand, nosocomialnosocomial pneumonia isis mainly mainly caused caused by by Gram-negative Gram-negative bacteria, bacteria, including includingPseudomonas Pseudomonas aeruginosa aeru-, extended-spectrumginosa, extended-spectrumβ-lactamase-positive β-lactamase-positive (ESBL+) (ESBL+) Enterobacteriaceae, Enterobacteriaceae, multidrug multidrug resistant (MDR)resistantAcinetobacter (MDR) Acinetobacter baumannii baumannii, Stenotrophomonas, Stenotrophomonas maltophilia maltophiliaas well as as the well Gram-positive as the Gram- methicillin-resistantpositive methicillin-resistantStaphylococcus Staphylococcus aureus (MRSA) aureus [(MRSA)6]. [6]. Since February 2020, antibiotic use has risenrisen dramatically worldwide due to SARS- CoV-2 infections.infections. Indeed, it is estimated that 70–97% of hospitalized patients with COVID- 19 receivereceive antibiotic antibiotic therapy therapy [7 ].[7]. For For instance, instance, patients patients presenting presenting symptoms symptoms associated associated with awith respiratory a respiratory infection infection are often are treatedoften treated with antibioticswith antibiotics before before infection infection with SARS-CoV-2 with SARS- isCoV-2 confirmed. is confirmed. Additionally, Additionally, antibiotics antibiotic are sometimess are sometimes prescribed prescribed as a preventive as a preventive measure against secondary bacterial infections in severe COVID-19 patients, in which hospitalization and/or intubation increased the risk of such infections. The main bacteria associated with SARS-CoV-2 secondary infections and co-infections are S. pneumoniae and S. aureus, which Antibiotics 2021, 10, 1000 3 of 15 also happen to be the most prevalent Gram-positive microbes causing pneumonia [8]. These two