Severe Staphylococcal Infections Research Articles

Ceftaroline in CNS and ocular infections: a case series.

There are limited data describing outcomes of patients treated with ceftaroline for infections with CNS or ocular involvement. To describe outcomes of patients treated with ceftaroline for methicillin-resistant staphylococcal infections involving the CNS or eye. This was a retrospective review of 10 patients at an academic medical centre who received ceftaroline for CNS or ocular infections. All patients were treated with ceftaroline as part of a combination for salvage therapy. Four patients died, whereas six patients experienced clinical cure. Only one experienced microbiological recurrence. These preliminary data suggest that ceftaroline may be an option for salvage therapy of severe staphylococcal infections when used in combination.

Population Pharmacokinetic and Pharmacodynamic Analysis for Maximizing the Effectiveness of Ceftobiprole in the Treatment of Severe Methicillin-Resistant Staphylococcal Infections.

Ceftobiprole is a fifth-generation cephalosporin used for different Gram-positive bacterial infections. A population pharmacokinetic analysis was conducted in real-life clinical patients to assess the adequacy of current dosages. Population pharmacokinetics was conducted using non-linear mixed effect modeling. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) of free trough or steady-state concentration over MIC (fCtrough/MIC or fCss/MIC) ≥ 1 or ≥4 associated with both the standard and intensified dosing regimens adjusted for renal function. Cumulative fraction of response (CFR) against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) were also calculated. A total of 132 patients with 503 concentrations were included. Most of them (107/132, 81.1%) had hospital- or community-acquired pneumonia, endocarditis, and bacteremia. A three-compartment model adequately fitted ceftobiprole concentration-time data. Estimated glomerular filtration rate significantly affected drug clearance. Monte Carlo simulations showed that the optimal target of fCtrough/MIC or fCss/MIC ≥ 4 is achieved only with the use of the standard dosages administered by continuous infusion (CI) against MRSA infections in patients with preserved renal function. Intensified dosages administered by CI are needed in patients with impaired renal function and/or augmented renal clearance against MRSA and in patients with preserved renal functions against MRSE.

Community-acquired and healthcare-associated Staphylococcus aureus infections in a pediatric hospital in southern Brazil over 8 years: how common is MRSA?

Both healthcare-associated and community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections are relevant in children. The objective of our study was to evaluate their impact in a pediatric hospital in southern Brazil. Data from patients under 18 years of age with S. aureus infections between January 2013 and December 2020 were retrospectively analyzed. Data were collected regarding infection site, infection type (community-acquired or healthcare-associated), susceptibility to oxacillin [methicillin-susceptible S. aureus (MSSA) or MRSA] and other antimicrobials. We analyzed the evolution of the susceptibility rates for the isolates over this period. A total of 563 patients were included, among whom the prevalences of community- and hospital-acquired MRSA infections were 46.1% and 8.1%, respectively. No significant change occurred in these prevalences over the study period. In community-acquired infections, MSSA was significantly more associated with osteoarticular infections and MRSA was more associated with respiratory and intra-abdominal infections. In healthcare-associated infections, there was an association between MSSA and primary bloodstream infections and between MRSA, skin/soft tissue infections, and respiratory infections. Community-acquired MRSA were highly susceptible to trimethoprim-sulfamethoxazole (96.1%), clindamycin (88.4%), and doxycycline (99.0%). Our study draws attention to the high rates of MRSA in community-acquired staphylococcal infections in this population, indicating a need to review initial protocols for severe staphylococcal infections according to local epidemiology.

Targeting multidrug resistant Staphylococcus aureus with cationic chlorpromazine-peptide conjugates.

Antimicrobial resistance is a serious public health risk. Its severity is fueled on an unprecedented scale, necessitating the demand for novel antimicrobial scaffolds aimed at novel targets. Herein, we present cationic chlorpromazine peptide conjugates that are rationally intended to targetmultidrug-resistant (MDR) bacteria. The most potent compound, CPWL, of all the conjugates evaluated, showed promising antibacterial activity against clinical, MDR S. aureus, with no cytotoxicity. The molecular docking experiments confirmed that CPWL possessed a very high affinity for S. aureus enoyl reductase (saFabI). Furthermore, CPWL antibacterial action against saFabI was further corroborated by MD simulation studies. Thus, our findings highlight cationic chlorpromazine as a promising scaffold for the development of saFabI inhibitors to target severe staphylococcal infections.

TIGAR Protects Cochlear Hair Cells against Teicoplanin-Induced Damage

Teicoplanin is a glycopeptide antibiotic used to treat severe staphylococcal infections. It has been claimed that teicoplanin possesses ototoxic potential, although its toxic effects on cochlear hair cells (HCs) remain unknown. The TP53-induced glycolysis and apoptosis regulator (TIGAR) plays a crucial role in promoting cell survival. Prior research has demonstrated that TIGAR protects spiral ganglion neurons against cisplatin damage. However, the significance of TIGAR in damage to mammalian HCs has not yet been investigated. In this study, firstly, we discovered that teicoplanin caused dose-dependent cell death in vitro in both HEI-OC1 cells and cochlear HCs. Next, we discovered that HCs and HEI-OC1 cells treated with teicoplanin exhibited a dramatically decrease in TIGAR expression. To investigate the involvement of TIGAR in inner ear injury caused by teicoplanin, the expression of TIGAR was either upregulated via recombinant adenovirus or downregulated by shRNA in HEI-OC1 cells. Overexpression of TIGAR increased cell viability, decreased apoptosis, and decreased intracellular reactive oxygen species (ROS) level, whereas downregulation of TIGAR decreased cell viability, exacerbated apoptosis, and elevated ROS level following teicoplanin injury. Finally, antioxidant therapy with N-acetyl-L-cysteine decreased ROS level, prevented cell death, and restored p38/phosphorylation-p38 expression levels in HEI-OC1 cells injured by teicoplanin. This study demonstrates that TIGAR may be a promising novel target for the prevention of teicoplanin-induced ototoxicity.

MRSA and Skin Infections in Psoriatic Patients: Therapeutic Options and New Perspectives.

Psoriatic patients present various infectious risk factors, but there are few studies in the literature evaluating the actual impact of psoriasis in severe staphylococcal skin infections. Our narrative review of the literature suggests that psoriatic patients are at increased risk of both colonization and severe infection, during hospitalization, by S. aureus. The latter also appears to play a role in the pathogenesis of psoriasis through the production of exotoxins. Hospitalized psoriatic patients are also at increased risk of MRSA skin infections. For this reason, new molecules are needed that could both overcome bacterial resistance and inhibit exotoxin production. In our opinion, in the near future, topical quorum sensing inhibitors in combination with current anti-MRSA therapies will be able to overcome the increasing resistance and block exotoxin production. Supplementation with Vitamin E (VE) or derivatives could also enhance the effect of anti-MRSA antibiotics, considering that psoriatic patients with metabolic comorbidities show a low intake of VE and low serum levels, making VE supplementation an interesting new perspective.

Clinical experience with the use of newer antibiotics in internal medicine.

The alarming rise in antibiotic resistance between Gram-positive and Gram-negative bacteria makes maximum use of known and available antibiotics necessary. The aim of this work is to highlight some advantages and disadvantages of antibiotics that have appeared on the market in recent years, and share clinical experience with their use in internal medicine. Flucloxacillin is an antibiotic with a significant antistaphylococcal effect, the most significant indications of the oral form are infections of the skin and soft tissues with the causative agent of Staphylococcus aureus and streptococci. The intravenous variant of flucloxacillin is an noninferior alternative to oxacillin and can be used in severe staphylococcal infections including infective endocarditis. Contributing to the treatment of uncomplicated urinary infections are the oral antibiotics mecilinam and fosfomycin. Their advantages are wide spectrum, good tolerability and possibility to use them in pregnant woman. Other antibiotics expand the treatment options for intravenous treatment of serious infections caused by multidrug-resistant bacteria. Ceftazidime/avibactam is effective for infections caused by Pseudomonas aeruginosa and enterobacteria including producers of broad-spectrum beta-lactamase ESBL, AmpC, KPC and OXA-48. The most important advantage of ceftolozane/ tazobactam is their antipseudomonal effect, is characterized by excellent clinical efficacy even against serious infections caused by Pseudomonas aeruginosa, including some multi-resistant strains.

Identification of major sequence types among aminoglycoside resistant Staphylococcus aureus and Staphylococcus epidermidis strains isolated from clinical samples.

Aminoglycosides have been widely used for treating severe staphylococcal infections. Production aminoglycoside modifying enzymes (AMEs) is the main mechanism of resistance to this antibiotic. The aim of this study was to determine the prevalence of AME genes and molecular characterization of aminoglycoside-resistant Staphylococcus aureus and Staphylococcus epidermidis strains isolated from clinical specimens in Iran. A total of 42 clinical isolates of Gram-positive cocci (20 S. aureus and 22 S. epidermidis) with resistance to gentamicin were tested for antimicrobial resistance and differentiated by multilocus sequence typing (MLST). All 42 isolates were resistant to methicillin, kanamycin, and most of them were also resistant to amikacin (98%), tobramycin (98%) and netilmycin (78.5%). Overall, aac(6')-Ie-aph(2")-Ia was the dominant AME gene found in 100% of isolates, followed by aph(3')IIIa found in 90% of isolates. MLST classified S. aureus and S. epidermidis into 5 and 9 distinct sequence types (ST), respectively. The majority of the strains belonged to ST239 (50%) for S. aureus and ST2 (36%) for S. epidermidis. The resistance to aminoglycosides was mainly due to the presence of the aac(6')-Ie-aph(2")-Ia and aph(3') IIIa genes as well as the ST239 for S. aureus and ST2 for S. epidermidis have become the predominant clones in the selected university hospital of Tehran, Iran. Thus, it is critical that clinicians and healthcare workers are aware of the population of S. aureus and S. epidermidis present in order to make decisions for appropriate treatment and infection control practices.

Poly (ε-caprolactone)/Poly (lactic acid) fibers produced by rotary jet spinning for skin dressing with antimicrobial activity.

The rotary jet spinning technique permits the production of biomaterials that can be used as devices that come into contact with biological systems (including biological fluids) for diagnostic or surgical applications. These materials are composed of synthetic or natural compounds and allow the incorporation of drugs for therapeutic purposes. Two solutions containing 50% poly(lactic acid) (PLA) and 50% poly(ε-caprolactone) (PCL) diluted in three different solvents were prepared for rotary jet spinning (RJS) process. Vancomycin, an antibiotic indicated for the treatment of severe staphylococcal infections in patients with penicillin allergy, was added in the polymer solutions, to obtain drug-loaded fibrous mats. Morphological surface characterization by scanning electron microscopy revealed heterogeneous pores in the microfibers. Vancomycin loading interfered with the morphology of all samples in terms of fiber size, leading to smaller diameter fibers. Attenuated total reflectance/Fourier transform infrared spectroscopy was used for identification of the samples. The vibrational characteristics of PCL/PLA and vancomycin were consistent with expectations. Vero cell culture assays by the extract dilution and direct contact methods revealed the absence of cytotoxicity, except for the sample prepared with 50% of PCL and of a 9/2 (V/V) vancomycin content, with the growth of confluent and evenly spread cells on the fibrous mats surface. Microbiological analysis, performed on Staphylococcus aureus by the halo inhibition test and by the broth dilution method, showed that the antibacterial activity of vancomycin was maintained by the loading process in the polymer fibers. The results showed that rotary jet spinning produces satisfactory amounts of Vancomycin-loaded fibers, as potential web dressing for wound repair.

Population Pharmacokinetics of Vancomycin in Adult Patients with Long Bones’ Fractures

Abstract Vancomycin is a tricyclic glycopeptide antibiotic, mostly used in the treatment of severe staphylococcal and enterococcal infections, especially in orthopedic surgery. The purpose of this analysis was to develop a population pharmacokinetic (PPK) model of vancomycine in hospitalized patients with bone fractures and identify important factors which influence its clearance (CL). A total of ninety-nine measurements of vancomycin serum concentrations were used in our population modeling. A two-compartment model was applied to describe the pharmacokinetics of vancomycin using subroutines ADVAN3 and TRANS4. The study population included patients of both sexes, with the mean age of 62.12±14.69 years and body weight of 80.32±12.44kg. Vancomycin was administered as intravenous infusion with average daily dose of 1772.73±521.34mg. Out of twenty different factors evaluated in the study (including demographic, clinical and laboratory data), only daily dose of vancomycin (DD) and co-medication with piperacillin/tazobactam (PT) showed significant effect on clearance of vancomycin. The final model was described by the following equation: CL (l/h) = 0.03 + 0.000468 x DD + 0.675 x PT. Bootstrapping was used for validation of the final model. In conclusion, the main causes of variability in the clearance of vancomycin among adult patients with bone fractures are daily dose of vancomycin and co-medication with piperacillin/tazobactam.

Development of Vancomycin Delivery Systems Based on Autologous 3D Platelet-Rich Fibrin Matrices for Bone Tissue Engineering.

Autologous platelet-rich fibrin (PRF) is derived from the blood and its use in the bone tissue engineering has emerged as an effective strategy for novel drug and growth factor delivery systems. Studies have approved that combined therapy with PRF ensures higher biological outcomes, but patients still undergo additional treatment with antibiotic drugs before, during, and even after the implantation of biomaterials with PRF. These systematically used drugs spread throughout the blood and lead not only to positive effects but may also induce adverse side effects on healthy tissues. Vancomycin hydrochloride (VANKA) is used to treat severe Staphylococcal infections but its absorption in the target tissue after oral administration is low; therefore, in this study, we have developed and analyzed two kinds of VANKA carriers—liposomes and microparticles in 3D PRF matrices. The adjustment, characterization, and analysis of VANKA carriers in 3D PRF scaffolds is carried out in terms of encapsulation efficiency, drug release kinetics and antibacterial activity; furthermore, we have studied the micro- and macrostructure of the scaffolds with microtomography.

Staphylococcal Panton-Valentine Leucocidin and Gamma Haemolysin Target and Lyse Mature Bone Marrow Leucocytes.

Staphylococcus aureus is a major human pathogen, inducing several infections ranging from the benign to the life-threatening, such as necrotising pneumonia. S. aureus is capable of producing a great variety of virulence factors, such as bicomponent pore-forming leucocidin, which take part in the physiopathology of staphylococcal infection. In necrotising pneumonia, Panton–Valentine leucocidin (PVL) induces not only lung injury and necrosis, but also leukopenia, regarded as a major factor of a poor prognosis. The aim of the present study was to evaluate the effect of bicomponent pore-forming leucocidin, PVL and gamma haemolysin on bone marrow leucocytes, to better understand the origin of leukopenia. Using multi-parameter cytometry, the expression of leucocidin receptors (C5aR, CXCR1, CXCR2, and CCR2) was assessed and toxin-induced lysis was measured for each bone marrow leucocyte population. We observed that PVL resulted in myeloid-derived cells lysis according to their maturation and their C5aR expression; it also induced monocytes lysis according to host susceptibility. Haemolysin gamma A, B, and C (HlgABC) displayed cytotoxicity to monocytes and natural killer cells, hypothetically through CXCR2 and CXCR1 receptors, respectively. Taken together, the data suggest that PVL and HlgABC can lyse bone marrow leucocytes. Nevertheless, the origin of leukopenia in severe staphylococcal infection is predominantly peripheral, since immature cells stay insensitive to leucocidins.

Innate Immune Response against Staphylococcus aureus Preincubated with Subinhibitory Concentration of trans-Anethole.

The study aimed to analyze morphological and functional changes of Staphylococcus aureus cells due to trans-anethole (a terpenoid and the major constituent of fennel, anise, or star anise essential oils) exposition, and their consequences for human neutrophils phagocytic activity as well as IL-8 production (recognized as the major chemoattractant). The investigation included the evaluation of changes occurring in S. aureus cultures, i.e., staphyloxanthin production, antioxidant activities, cell size distribution, and cells composition as a result of incubation with trans-anethole. It was found that the presence of trans-anethole in the culture medium reduced the level of staphyloxanthin production, as well as decreased antioxidant activities. Furthermore, trans-anethole-treated cells were characterized by larger size and a tendency to diffuse in comparison to the non-treated cells. Several cell components, such as phospholipids and peptidoglycan, were found remarkably elevated in the cultures treated with trans-anethole. As a result of the aforementioned cellular changes, the bacteria were phagocytized by neutrophils more efficiently (ingestion and parameters associated with killing activity were at a higher level as compared to the control system). Additionally, IL-8 production was at a higher level for trans-anethole modified bacteria. Our results suggest that trans-anethole represents a promising measure in combating severe staphylococcal infections, which has an important translational potential for clinical applications.

The treatment of resistant staphylococcal infections.

Staphylococcus aureus of the many staphylococcal species is the most common cause of both skin and soft tissue infection and severe staphylococcal infections including Staphylococcus aureus bacteremia (SAB). Many antibiotics are active against the staphylococci, yet over the last 40 years antibiotic resistance, particularly resistance to beta-lactam antibiotics, has plagued antimicrobial therapy. The term “methicillin resistance” is a historic term and now refers to the ability of staphylococci, in particular methicillin-resistant Staphylococcus aureus (MRSA), to resist the action of beta-lactam antibiotics. This resistance is encoded by the mecA gene carried in a complex genetic cassette, SCC mec. Vancomycin and old antibiotics remain the keystone of treatment for resistant staphylococci. Other newer agents, and some older agents, show good activity against resistant staphylococci which are the focus of this review: trimethoprim-sulfamethoxazole, ceftaroline, daptomycin, fosfomycin, linezolid, dalbavancin, televancin, and omadacycline. Other agents with novel mechanisms of action are under development, for use as single anti-staphylococcal agents or for combination use to augment the action of the primary anti-staphylococcal agent. Vancomycin therapy carries specific risks, particularly renal dysfunction, but despite its foibles, vancomycin remains the standard of care for the treatment of resistant staphylococcal infections. Some clinicians implement an early switch from vancomycin at the earliest signs of renal dysfunction. The near horizon holds promise also of augmentation of both cellular and humoral responses to staphylococcal infection. Pending newer clinical trials that show clear superiority of one anti-staphylococcal agent over another or over vancomycin, it will remain to expert clinical judgment in determining antibiotic choice and duration of anti-staphylococcal therapy.

Performance of the Revised Version of an Immunochromatographic Assay for Detection of mecA - and mecC -Mediated Methicillin Resistance in Staphylococci

Detection of methicillin resistance in staphylococcal isolates is crucial to quickly optimize the treatment in case of severe staphylococcal infections.….

Infective Endocarditis in the Intravenous Drug Use Population at a Tertiary Hospital in Melbourne, Australia

Infective endocarditis has been associated with underlying cardiac pathology and streptococci infections. Intravenous drug use (IVDU) is increasingly implicated as a contributing factor, resulting in a shift to a younger patient demographic, tricuspid valve involvement, severe staphylococcal infection, and unique management challenges. The objective of this study was to describe the clinical features, management and outcomes of patients with IVDU-associated infective endocarditis in the Australian context. A retrospective review of all episodes of IVDU-associated infective endocarditis at a tertiary hospital in Melbourne, Australia, from 2008 to 2015, was conducted. Included cases met Duke Criteria for 'definite' or 'possible' infective endocarditis, and had a history of IVDU within 3 months of presentation. Demographic data, substance use history, clinical features, surgical intervention, follow-up, and mortality data was collected. We explored factors associated with surgical intervention, recurrence and mortality. Fifty-five (55) episodes of IVDU-associated infective endocarditis were identified in 46 patients; the median age was 40 years and 58% were male. The tricuspid valve was most commonly affected (38%), and left heart pathology was documented in 53% of cases. Methicillin-sensitive Staphylococcus aureus was the most common pathogen (67%). Thirty-six (36%) per cent of patients underwent surgical intervention, and all patients received antibiotics as a component of treatment, with a median duration of 42 days (IQR 21, 42 days). Heart failure and a vegetation larger than 1 cm were significantly associated with surgical intervention. Total mortality was 14.5%; surgical mortality was 10%. Opioid replacement therapy and the absence of psychiatric co-morbidities were protective factors for surgical intervention and disease recurrence. In contrast to common perception, left-sided endocarditis was more common than tricuspid valve endocarditis. Left heart pathology is typically a more severe clinical entity, however, our study determined mortality rates remained similar when compared to right heart pathology. Further research is required to assess rates of left sided disease in the IVDU population, and elucidate the relationship between IVDU and left heart pathology.

The effects of iclaprim on exotoxin production in methicillin-resistant and vancomycin-intermediate Staphylococcus aureus.

Extracellular protein toxins contribute to the pathogenesis of Staphylococcus aureus infections. The present study compared the effects of iclaprim and trimethoprim - two folic acid synthesis inhibitors - with nafcillin and vancomycin on production of Panton-Valentine leukocidin (PVL), alpha haemolysin (AH) and toxic-shock syndrome toxin I (TSST-1) in methicillin-resistant and vancomycin-intermediate S. aureus (MRSA and VISA, respectively). Northern blotting and RT-PCR were used to assess gene transcription; toxin-specific bioassays were used to measure protein toxin production. As shown previously, sub-inhibitory concentrations (sub-MIC) of nafcillin increased and prolonged MRSA toxin gene transcription and enhanced PVL, TSST-1 and AH production. Sub-inhibitory doses of iclaprim and trimethoprim delayed maximal AH gene (hla) transcription and suppressed AH production; both drugs delayed, but neither reduced, maximal TSST-1 production. Trimethoprim significantly increased lukF-PV expression and PVL production compared to both untreated and iclaprim-treated cultures. Higher concentrations of iclaprim and trimethoprim markedly suppressed MRSA growth, mRNA synthesis and toxin production. In VISA, iclaprim, vancomycin and nafcillin variably increased tst and hla expression, but only nafcillin increased toxin production. Despite its ability to increase hla expression, iclaprim was the most potent inhibitor of AH production. We conclude that, due to its ability to suppress toxin production, iclaprim should be effective against severe staphylococcal infections caused by toxin-producing MRSA and VISA strains, especially given its ability to concentrate at sites of infection such as skin and skin structures and the lung.

Lack of Receptor for Advanced Glycation End Products Leads to Less Severe Staphylococcal Skin Infection but More Skin Abscesses and Prolonged Wound Healing.

Lack of receptor for advanced glycation end products (RAGE) ameliorates several infections including Staphylococcus aureus pneumonia. We sought to investigate the role of RAGE in staphylococcal skin infection in mice. Wild-type (WT) and RAGE deficient (RAGE-/-) mice were subcutaneously inoculated with S. aureus SH1000 strain in abscess-forming dose or necrotic dose. Clinical signs of dermatitis, along with histopathological changes, were compared between the groups. The skin lesion size was smaller in RAGE-/- mice. Infected RAGE-/- mice expressed lower proinflammatory cytokines in local skins compared to control mice. Low dose of bacteria caused more abscess formation in RAGE-/- mice compared to skin necrosis that was more often observed in WT mice. As a result of more abscess formation, the wound healing was prolonged in RAGE-/- mice. Importantly, RAGE-/- mice had lower bacterial loads in the skin than controls, which is correlated with higher local levels of myeloperoxidase before skin infection. In vitro, enhanced phagocytic capacity of neutrophils and macrophages obtained from RAGE-/- mice compared to control mice was observed. RAGE deficiency up-regulates phagocytic capacity of phagocytes, resulting in lower bacterial burden in local skin and milder skin lesions in mice with staphylococcal skin infection.

Staphylococcal scalded skin syndrome: An uncommon symptomatology revealing an immune deficiency

Primary immune deficiencies associated with hyper-IgE syndrome are rare diseases with clinical features dominated by recurring cutaneous and visceral bacterial infections, particularly infections due to Staphylococcus species. Most of these infections are associated with milder inflammation compared to normal. We report a primary immune deficiency associated with a hyper-IgE syndrome revealed by a staphylococcal scalded skin syndrome in a 5-year-old girl. The patient presented with a severe staphylococcal infection with extensive skin lesions and disseminated intravascular coagulation. She received intravenous fluids to compensate for fluid losses and anti-staphylococcal antibiotics. Coagulopathy was also corrected. However, the progression was rapidly fatal.

Clinical manifestations of somatic pathology in patients with temporomandibular joint disorders

Clinical examination results of 248 patients with temporomandibular joint disorders (mean age – 26.0±7.4 years) are shown. Clinical manifestations of cardiovascular diseases, tonsils condition (in particular, nasopharynx microbial flora), indicators of the acute phase reactions are studied. In a number of patients moderate, diffuse, myocardial metabolic alterations, rhythm disturbances (sinus arrhythmia, tachycardia, bradycardia, extrasystoles, His bundle branch block), mitral valve disease were revealed, which are the signs of connective tissue dysplasia and also severe tonsils hypertrophy, chronic tonsillitis, nasopharyngeal streptococcal and staphylococcal infection.