Immunomodulatory Effects of Antimicrobial Agents. Part I

Antibacterial and Antiviral Agents

Marie-Thérèse Labro

Disclosures

Expert Rev Anti Infect Ther. 2012;10(3):319-340. 

In This Article

Antibacterial Agents

Bacteria & Antibacterial Agents, Past, Present & Future

The first observation of bacteria dates back to 1676 when Anton Van Leeuwenhoek, 'the father of microbiology' used his handcrafted microscopes, to examine the tartar from his own teeth and described selenomonads, but the names 'Bacterium' and 'Bacillus' were coined much later by Ehrenberg in 1828 and Cohn in 1853.[4–7] For two centuries, a considerable amount of observation and microbiological discoveries[8] has prepared the burst of microbiology of the XIXth century with Louis Pasteur, Ferdinand Cohn, Jean-Joseph Toussaint, Robert Koch, among others, to support the germ theory of diseases.[4–7]

It should be recognized that mixtures with antimicrobial properties were described over 2000 years ago.[9] Antagonism between fungi and bacteria were first observed by John Tyndall in 1875, and antibiosis was further described in 1877 by Pasteur and Koch.[4–7] Antibacterial chemotherapy began in Germany with Paul Ehrlich and his team who, through systematic chemical modifications of the toxic drug atoxyl, succeeded in the first organic antisyphilitic compound, salvarsan in 1910. In 1928, the history of penicillin began and in 1939 Rene Dubos isolated thyrotricin from Bacillus brevis, a substance composed of gramicidin and tyrocidin, the first naturally derived antibiotics to reach the market. From 1935 to 1945, sulfonamides and penicillin, opened the era of 'the miracle drugs'.[7] At the same time, antibacterial vaccines have been responsible for a drastic reduction in global bacterial diseases. After the first laboratory-developed vaccine, the vaccine for chicken cholera, the first vaccine to immunize humans against a bacterial disease, the cholera vaccine, was launched in 1885, followed by vaccines against Salmonella typhi, Corynebacteria diphtheriae exotoxin, the BCG vaccine and many others. Research is still ongoing to improve accuracy and safety of existing vaccines and identify novel vaccines.[10,202]

Today, several classes of antibacterial agents are available (Table 1).[10] There is major concern over the emergence of resistant, and multidrug-resistant, pathogens and a significant decline in the production of new antibacterial agents. The major threat, defined as the 'ESKAPE' microbes, refers to Enterobacter, Staphylococcus aureus, Klebsiella, Acinetobacter, Pseudomonas aeruginosa, and Enterococcus.[11] The Infectious Diseases Society of America supports the '10 × '20' initiative, which has been created to develop ten new, safe and effective antibiotics by 2020.[12] An update on antibiotics undergoing clinical development or under regulatory evaluation has been provided recently.[13] The most recent class of antibiotics is that of pleuromutilins, discovered in 1950, approved for veterinary use in 1979, then for topical use in humans in 2007.[14]

To combat the increasing rates of antibiotic resistance, new approaches are also needed.[15] The use of compounds that overcome resistance to common antibacterials or of immunomodulators to stimulate host defense mechanisms, phage therapy,[16,17] bacteriocins, chelation of micronutrients that are essential for bacterial growth, biotherapy with protozoa,[18] and/or maggot therapy have also been proposed.[19]

Immune Adverse Events Generated by Antibacterial Agents

Allergic reactions to antibacterial agents are commonly reported. Various reviews have addressed the literature on the diagnosis of drug-hypersensitivity reactions, which can be classified as immediate or nonimmediate according to the time interval between the onset and the last drug administration. Skin reactions are among the most frequent adverse events with a frequency in general practice approximately 1% specifically for the combination of trimethoprim with sulfonamides (2.1%), penicillins(1.1%), and fluoroquinolones (1.6%).[20] The most common cutaneous manifestations of drug-induced allergic reactions are a generalized exanthema, urticaria and angioedema. The most severe forms are Stevens–Johnson syndrome and toxic epidermal necrolysis. The drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is another cutaneous, drug-induced, multiorgan inflammatory response that can be life threatening.

Idiosyncratic drug-induced agranulocytosis or acute neutropenia is an adverse event resulting in life-threatening and sometimes fatal infections.[21] In a single-center cohort, the annual incidence of symptomatic idiosyncratic drug-induced agranulocytosis was approximately six cases per million of the population: the most frequent causative drugs were antibiotics (25%), particularly β-lactams and cotrimoxazole.[21] Diverse ('toxic' or 'immune') mechanisms are involved, and genetic/epigenetic susceptibility have also been proposed to explain idiosyncratic drug-induced reactions.[22] A Drug Allergy and Hypersensitivity Database is already available online.[23]

The main immune adverse events are reviewed according to antibacterial classes and summarized in Table 2.

β-lactams Allergic reactions to penicillins have been reported since their early uses and the first idiosyncratic drug reaction whose mechanism was studied in detail was that of penicillin-induced allergic reactions. The β-lactam ring of penicillin reacts irreversibly with the free amino and sulfhydryl groups on proteins, which may lead to an immune response against the penicillin–protein adduct and thus caused a severe IgE-mediated allergic reaction. Hypersensitivity reactions to β-lactams may cover the four types of classification by Gell and Coombs:[24] immediate IgE-mediated reactions (type I; from Quincke edema, rashes up to anaphylactic reactions); IgG-dependent (type II) reactions may lead to hemolytic anemia, neutropenia, eosinophilia; immune complex-mediated (type III) reactions include localized (skin eruption) and systemic (arthritis, fever) events; delayed cell-mediated (type IV) reactions are characterized by skin eruptions from mild exanthema to life-threatening, severe reactions, such as Stevens–Johnson syndrome, toxic epidermal necrolysis, acute exanthematic pustulosis or cytopenias. Nonimmediate reactions are mainly mediated by T cells but the precise underlying mechanisms are not well elucidated.[25] IgE-specific antibodies may recognize the benzylpenicilloyl structure or another part of the molecule, such as the side chain, as antigenic determinants. Allergic reactions, can be produced by all classes of β-lactams which share a common β-lactam ring structure,[26] but the extent of allergic cross-reactivity between penicillin and cephems/carbapenems is uncertain.[27] Various diagnostic tests exist for IgE-mediated reactions and for nonimmediate reactions, and there are also in vitro and in vivo tests, with variable degrees of sensitivity and specificity.[28] Recently, β-lactam antibiotic hypersensitivity has been reported to be associated with IL-4 and IL-13 receptors in Italian, Chinese and French populations.[29,30]

Phenicols Chloramphenicol commonly causes bone marrow suppression during treatment. This effect first manifests as a fall in hemoglobin levels. The anemia is fully reversible once the drug is stopped and does not predict future development of aplastic anemia, the most serious side effect of chloramphenicol. This effect is rare (~one out of 50,000) and generally fatal: there is no treatment and no way of predicting its occurrence. Aplastic anemia usually occurs weeks or months after chloramphenicol treatment has been stopped, and there may be a genetic predisposition. This unwanted effect is believed to be related to the p-NO2 group which has been replaced by SO2-CH3 in thiamphenicol. Thiamphenicol has never been associated with aplastic anemia; it is now available in the US and Europe as a veterinary antibiotic. An increased risk of childhood leukemia with chloramphenicol, has been reported in a Chinese case-controlled study.[31]

Sulfone & Sulfonamides Dapsone-hypersensitivity syndrome is a potentially life-threatening adverse drug reaction consisting of fever, hepatitis, exfoliative dermatitis, lymphadenopathy and hemolytic anemia. The incidence is estimated to be 2% in leprosy patients. Because the incidence of this drug eruption may be different in different ethnicities and diseases, the incidence of hypersensitivity has been investigated in nonleprosy patients. The incidence among nonleprosy patients is 1.66% and the reaction is relatively benign as compared with leprosy patients.[32] Circulating autoantibodies against antigens of 190 and 230 kDa have been found by immunoblotting analysis using epidermal extracts.

Sulfonamides (particularly trimethoprim/sulfamethoxazole) may cause delayed cutaneous maculopapular/morbilliform eruptions and they are by far the most common cause of Stevens–Johnson syndrome and toxic epidermal necrolysis.[33] DRESS syndrome may occur in 1–6% of patients.[34] Thrombocytopenia and hemolytic anemia have also been observed with these antibacterials. The N4 aromatic amine is critical for the development of delayed reactions to sulfonamide antibiotics (through oxidation to hydroxylamines and nitroso compounds), and it has been suggested that the N1 substituted ring is important for IgE-mediated reactions.[35]

Ansamycins Many of the adverse events induced by rifampin have been considered allergic in origin. The flu-like syndrome and other hypersensitivity reactions seem to be caused by immune complexes, although their pathogenetic mechanisms are not fully elucidated. Many cases have been reported of the flu-like syndrome, thrombocytopenia, hemolytic anemia, and renal failure caused by rifampin. In almost all of the patients, antirifampin antibodies were detected.[36]

Cyclines Minocycline is able to elicit a drug hypersensitivity syndrome that can resemble infectious mononucleosis. The underlying mechanism is unknown: minocycline may generate an iminoquinone derivative and it has been proposed that this reactive metabolite binds to tissue macromolecules and causes cell damage, or can act as a hapten, eliciting an immune response. Neither tetracycline nor doxycycline contains the amino acid side-chain that has the potential to form a reactive intermediate. Anaphylaxis to tetracycline is less common: several reports have described anaphylactoid reactions to tetracycline, doxycycline and oral minocycline.[37]

Aminoglycosides Allergic reactions to gentamicin are well recognised; few cases of anaphylaxis have been reported. Contact allergy to neomycin is reported in approximately 1.6–7.7% of patients.[38] In a recent retrospective analysis of allergy test data concerning 47,559 patients, 2.5% had positive reactions to neomycin sulfate and allergic contact dermatitis was diagnosed in approximately 1.1% of patients.[39]

Macrolides Allergy to macrolides is extremely rare (0.4–3%). An immediate IgE-dependent hypersensitivity has been shown with erythromycin but the mechanism remains unknown and skin tests are quite often negative.[40]

Quinolones Hypersensitivity reactions to quinolones, especially anaphylactic reactions, have become more common, possibly owing to their increased consumption. Nonimmediate hypersensitivity reactions also exist, especially maculopapular exanthema and fixed drug eruptions, and a T-cell mechanism has been demonstrated.[41] The prevalence of a cutaneous reaction to individual fluoroquinolones varies between 0.04 and 0.37%; most cutaneous reactions involve ciprofloxacin and the most frequent adverse cutaneous reaction is maculopapular rash (39.7%).[42]

Glycopeptides There are few reports of DRESS syndrome involving vancomycin.[34,43] A few cases of vancomycin-induced linear IgA bullous dermatosis (a rare autoimmune vesiculobullous disorder that clinically resembles toxic epidermal necrolysis) have been reported.

Other antibacterials Dermatologic complications secondary to clindamycin are rare. A case of Sweet syndrome, an inflammatory neutrophilic dermatoses, and of DRESS syndrome have been reported. Whereas thrombocytopenia and anemia are common side effects with linezolid, rare cases of reversible myelosuppression have been reported;[44–46] in a hemodialysis patients undergoing treatment for methicillin-resistant S. aureus infection, myelosuppression was associated with high linezolid blood concentration.[46] The underlying mechanism has not been elucidated.

Immunomodulatory Properties of Antibacterial Agents

The direct interference of antibacterial agents with immune effectors is widely investigated. In vitro effects and animal models are the subject of an extensive literature search; the main data are summarized in Table 3 .[47–51]

The therapeutic relevance of these immunomodulatory properties remains controversial: the clinical benefit of the immunostimulating/restoring effects of antibacterial agents is considered minimal compared with their direct antibacterial activity; however 'immunosuppressive' antibacterials have shown promise in inflammatory diseases. The nonantibiotic therapeutic prospects of antibacterial agents are summarized in Table 4 .

Anti-inflammatory Antibacterial Agents

The anti-inflammatory activity of various antibacterials has been observed from their early approval. For instance, dapsone and clofazimine have been used in various inflammatory and autoimmune dermatoses.[52,53] Recently, dapsone has also been proposed for refractory immune thrombocytopenia, acne and polyarteritis nodosa.[54–57] Clofazimine has been reported to be effective in treating chronic discoid lupus erythematosus and other autoimmune diseases such as psoriasis, Crohn's disease and ulcerative colitis. The identification of novel targets/mechanisms of the immunosuppressive property of clofazimine, has extended its anti-inflammatory spectrum to broader therapeutic promises, such as multiple sclerosis and Type I diabetes mellitus.[58] T lymphocytes, in particular, are sensitive to the immunomodulatory actions of clofazimine: a mechanistic study of clofazimine has shown that this drug is a Kv1.3 (KCNA3) potassium channel blocker[58] suggesting that it could potentially be used for treatment of multiple sclerosis, rheumatoid arthritis and Type 1 diabetes because the Kv1.3-high effector memory T cells are actively involved in the development of these diseases.[59] Sulfonamide antibacterials also display anti-inflammatory activity: in particular, sulfasalazine has been used in spondyloarthritis[60] and Crohn's disease.[61] The sulfonamide chemical moiety is present in other medications such as celecoxib, a selective inhibitor of cyclo-oxygenase-2, used in the treatment of osteoarthritis and rheumatoid arthritis.

Three classes have stimulated widespread interest in the context of inflammation: macrolides, cyclines and ansamycins.

The potential of rifampin as an antirheumatic drug has not been confirmed in various studies involving large groups.[62,63] Intra-articular rifamycin is effective against active synovitis and has also been evaluated in children with juvenile oligopolyarthritis. Crohn's disease is another target for ansamycins particularly rifaximin, a nonabsorbable broad-spectrum antibiotic. The ansamycin class has been extensively studied by cancer researchers and various geldanamycin derivatives have entered clinical evaluation.[64]

Many reviews have focused on the pleiotropic immunomodulatory properties of macrolides and their beneficial effects to patients with respiratory diseases associated with chronic inflammation.[47] Diffuse panbronchiolitis and cystic fibrosis (CF) are the two main clinical indications for macrolide action. It must be noted that only erythromycin A-derived macrolides, including azithromycin, are endowed with anti-inflammatory properties.[65] Some studies have reported small improvements in lung function with macrolide treatment of stable asthma. Randomized, controlled clinical trials involving larger patient samples are needed to confirm the clinical benefit in asthma.[66] Other beneficial effects of erythromycin A-derived macrolides have been noted in bronchiolitis obliterans syndrome, a form of chronic allograft dysfunction in lung transplant recipients, chronic obstructive pulmonary disease and bronchopulmonary dysplasia, a pulmonary disorder which causes significant morbidity and mortality in premature infants.[47,67,68] The use of macrolides in inflammatory skin diseases is also increasing. By contrast, the early promise that the anti-inflammatory action of macrolides may be of benefit to patients who had experienced an acute coronary event, has not been fulfilled by prospective trials. Similar deception has come for the treatment of Crohn's disease with clarithromycin.[69] The potential benefit of clarithromycin in cancer has been proposed.[47,70,71]

The nonantibiotic properties of tetracycline and its analogues, and their potential for clinical application have been reviewed.[72] Therapeutic target of cyclines include periodontal diseases, skin diseases – in particular acne and immunobullous disorders, rheumatoid arthritis and early diffuse scleroderma for minocycline. The possible benefits of doxycycline in diabetic nephropathy have been reported recently.[73] Tetracycline and related compounds have been proposed for the treatment of several chronic inflammatory airway diseases including asthma, bronchiectasis, acute respiratory distress syndrome, chemical induced lung damage and CF.[74] Minocycline is reported to be the only cycline with neuroprotective activity[75] and it seems also of interest as an adjunct to antipsychotic medication in patients with schizophrenia.[76] Tetracyclines are also developed as anti-allergy drugs to prevent IgE production, by targeting T-cell pathways.[77] Removal of the dimethylamine group at C4 of the tetracycline molecule reduces its antibiotic properties, enhancing its nonantimicrobial actions. Nonantibiotic chemically modified tetracyclines, are developed to inhibit tumor growth and metastases and a representative agent of this class, COL-3, is currently undergoing Phase I clinical trials.[78] In addition, tetracyclines, semisynthetic tetracyclines and chemically modified nonantibiotic tetracyclines have been proposed to play a role in the treatment of various ophthalmologic diseases such as diabetic retinopathy, age-related macular degeneration and cataract, among others.[79] Hypertension and cardiovascular diseases are possible therapeutic targets.

Other avenues for the therapeutic immunomodulatory potential of antibacterials concern CF, cancer and motor neuron degeneration.

CF transmembrane conductance regulator (CFTR) is a chloride ion channel whose mutations lead to CF. More than 1500 mutations have been described since the discovery of the gene, including premature stop mutations, in approximately 10% of all patients. In vitro aminoglycoside antibiotics (e.g., gentamicin) suppress nonsense mutations located in CFTR, permitting translation to continue to the natural termination codon. A pilot study has been conducted to determine whether intravenous gentamicin suppresses stop codons in CF patients presenting various stop mutations and whether it has clinical benefits.[80] After in vitro gentamicin incubation, the readthrough efficiency for CFTR increased, and in six of the nine patients with the Y122X mutation, CFTR protein was detected at the membrane of the nasal epithelial cells, sweat chloride value decreased and the respiratory status also improved. No change was observed in the Y122X patients with no protein expression and in patients without this stop mutation. A novel aminoglycoside NB54 has been developed that exhibits reduced toxicity and enhanced suppression of premature termination codons in vitro and in a CF animal model.[81]

Quinolones administered for prophylaxis of infections among cancer patients have been reported to reduce all-cause mortality. The results of a meta-analysis of trials comparing quinolones to placebo or no treatment, suggested an anticancer effect of quinolone antibiotics.[82] New derivatives, possessing both anticancer and antibacterial activity, have a promising therapeutic potential due to their selective cytoxicity coupled with the ability to reduce bacterial infections in immunocompromised cancer patients.[83]

Glutamate toxicity is considered a downstream event in motor neuron degeneration in amyotrophic lateral sclerosis and lower motor neuron disease.[84] Interestingly, β-lactam antibiotics have been identified as potent inducers of a glutamate transporter-1 expression. Subsequent in vivo analysis in a mouse model of amyotrophic lateral sclerosis showed that ceftriaxone could delay the loss of motor neurons and muscle strength, and extend the life span.[85] This effect was attributed to the ability of ceftriaxone to transcriptionally increase the expression of the glutamate transporter-1. The therapeutic effect of ceftriaxone has been confirmed in a murine model of spinal muscular atrophies.[86] The neuroprotective effect seems to be mediated by multiple mechanisms that encompass the increase of the glutamate transporter Glt1 and the transcription factor Nrf2. There is currently an ongoing clinical trial in which the safety and efficacy of ceftriaxone in amyotrophic lateral sclerosis patients is being tested.[204]

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