# Lecture 7: Other Gram-Negative Bacteria ## Unit 2.8: Microbiology --- ## Learning Objectives By the end of this lecture, students will be able to: 1. Describe Pseudomonas aeruginosa and its clinical significance 2. Explain Haemophilus influenzae and related organisms 3. Describe Vibrio, Campylobacter, and Helicobacter 4. Explain Bordetella pertussis and whooping cough 5. Describe Legionella and Legionnaires' disease 6. Explain Brucella, Francisella, and Pasteurella --- ## Lecture Outline ### I. Pseudomonas aeruginosa Pseudomonas aeruginosa is one of the most important opportunistic pathogens in medicine, causing severe infections in hospitalized patients, immunocompromised individuals, and patients with cystic fibrosis. This gram-negative bacterium is remarkable for its metabolic versatility, intrinsic resistance to many antibiotics, and ability to cause rapidly progressive infections with high mortality. Understanding the unique characteristics and clinical presentations of P. aeruginosa is essential for recognizing and treating these potentially devastating infections. Pseudomonas aeruginosa possesses several distinctive microbiological features that aid in laboratory identification. It is a gram-negative rod that is motile via a single polar flagellum. Unlike the Enterobacteriaceae, P. aeruginosa is an obligate aerobe that does not ferment glucose; instead, it derives energy through oxidative metabolism, which is reflected in a positive oxidase test. This characteristic distinguishes it from oxidase-negative enteric bacteria. On culture media, P. aeruginosa produces distinctive water-soluble pigments: pyocyanin (blue-green) and pyoverdine (yellow-green fluorescent), which combine to give colonies and the surrounding medium a characteristic blue-green appearance. Colonies often have a grape-like or tortilla-like fruity odor, which experienced clinicians and laboratorians recognize immediately. P. aeruginosa is ubiquitous in the environment, particularly in moist settings including soil, water, sinks, and respiratory therapy equipment. It forms robust biofilms on surfaces, contributing to persistent environmental contamination in healthcare settings and chronic colonization in patients with cystic fibrosis. The virulence of P. aeruginosa derives from an extensive array of virulence factors. Exotoxin A is the most potent toxin produced, functioning similarly to diphtheria toxin by ADP-ribosylating elongation factor 2 (EF-2) to inhibit protein synthesis. Type III secretion systems inject effector proteins (ExoS, ExoT, ExoU, ExoY) directly into host cells, causing cytotoxicity and tissue damage. Elastase (LasB) and alkaline protease degrade host tissue proteins including elastin, collagen, and immunoglobulins, facilitating tissue invasion and destruction. Phospholipase C (hemolytic) and rhamnolipid destroy lung surfactant and cell membranes. Pyocyanin, beyond its role in identification, generates reactive oxygen species that damage host tissues and impair ciliary function. The lipopolysaccharide (LPS) of P. aeruginosa triggers inflammation and can cause septic shock. In patients with cystic fibrosis, P. aeruginosa undergoes phenotypic changes including production of alginate, a mucoid exopolysaccharide that forms protective biofilms within the airways. These mucoid strains are extremely difficult to eradicate and cause progressive lung damage. Pseudomonas aeruginosa causes a diverse spectrum of infections, predominantly in patients with compromised host defenses. Ventilator-associated pneumonia is a leading hospital-acquired infection, occurring in patients who are mechanically ventilated and have impaired airway defenses. In cystic fibrosis patients, chronic P. aeruginosa respiratory infection is nearly universal by adulthood and is the primary driver of lung function decline and mortality. Catheter-associated urinary tract infections occur in patients with indwelling urinary catheters. Wound infections are common in burn patients, surgical wounds, and chronic wounds including diabetic foot ulcers. Malignant (necrotizing) otitis externa is a life-threatening infection occurring predominantly in elderly diabetic patients, beginning as otitis externa but progressing to involve the skull base, causing osteomyelitis, cranial nerve palsies, and potentially meningitis or brain abscess. External otitis ("swimmer's ear") is a more benign infection of the ear canal associated with water exposure. In neutropenic patients with cancer or receiving chemotherapy, P. aeruginosa bacteremia causes rapidly fatal sepsis if not treated promptly with appropriate antibiotics. Ecthyma gangrenosum is a characteristic skin manifestation of P. aeruginosa bacteremia, presenting as necrotic skin lesions with a black eschar surrounded by erythema, typically in neutropenic patients. Panel A: Pseudomonas aeruginosa characteristics showing the gram-negative rod with single polar flagellum, colonial appearance with blue-green pigmentation (pyocyanin plus pyoverdine) on agar plate, oxidase-positive reaction, and environmental reservoirs (sink drains, respiratory equipment, water systems). Panel B: Major virulence factors illustrated on a bacterial cell: exotoxin A ADP-ribosylating EF-2, type III secretion system injecting effector proteins into host cells, elastase and proteases degrading tissue, phospholipase C and rhamnolipid damaging membranes, pyocyanin generating reactive oxygen species, and alginate forming mucoid biofilm in cystic fibrosis airways. Panel C: Clinical infections spectrum showing ventilator-associated pneumonia (intubated patient with pneumonia infiltrates), malignant otitis externa (elderly diabetic with ear canal infection progressing to skull base involvement and cranial nerve palsies), burn wound infection (colonized burn surface), and ecthyma gangrenosum (necrotic skin lesion with black center and erythematous border in neutropenic patient). Panel D: Cystic fibrosis lung disease progression showing initial P. aeruginosa acquisition in childhood, transition from non-mucoid to mucoid alginate-producing phenotype, biofilm formation in airways, chronic infection with progressive bronchiectasis, and eventual respiratory failure, emphasizing the challenge of eradicating mucoid strains. --- ### II. Other Non-Fermenters Beyond Pseudomonas aeruginosa, several other non-fermenting gram-negative bacteria cause clinically significant infections, particularly in healthcare settings. These organisms share certain features including environmental reservoirs, ability to survive in hospital environments, and often significant antimicrobial resistance. Recognition of these pathogens is important because their resistance patterns and treatment requirements differ substantially from typical Enterobacteriaceae. Acinetobacter baumannii has emerged as one of the most problematic hospital-acquired pathogens due to its remarkable ability to acquire antimicrobial resistance and survive on environmental surfaces. It is a gram-negative coccobacillus that can be distinguished from Pseudomonas by its negative oxidase test. A. baumannii causes ventilator-associated pneumonia, wound infections (particularly in military personnel with combat injuries), catheter-associated urinary tract infections, and bloodstream infections. The organism can survive for weeks on dry hospital surfaces and equipment, facilitating patient-to-patient transmission in intensive care units. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains are increasingly common, with some strains resistant to all available antibiotics except colistin. Treatment options for susceptible strains include carbapenems, but carbapenem resistance is widespread. Ampicillin-sulbactam has unique activity against Acinetobacter due to sulbactam's intrinsic antibacterial activity against this organism. For highly resistant strains, combinations including polymyxins (colistin), tigecycline, and newer agents may be required. Stenotrophomonas maltophilia is an important cause of hospital-acquired infections, particularly in patients with cystic fibrosis, malignancy, or prolonged hospitalization with prior antibiotic exposure. Unlike other gram-negative organisms, S. maltophilia is intrinsically resistant to carbapenems due to a chromosomally encoded metallo-beta-lactamase, making empiric carbapenem therapy ineffective. This unexpected resistance pattern can lead to treatment failure if the organism is not identified and appropriate therapy initiated. Trimethoprim-sulfamethoxazole is the drug of choice for S. maltophilia infections and should be used empirically when this organism is suspected. The Burkholderia cepacia complex comprises several species that are significant pathogens in cystic fibrosis patients. These organisms are intrinsically resistant to multiple antibiotics and can be transmitted from patient to patient, leading to strict infection control measures in CF centers to prevent cross-infection. In some CF patients, B. cepacia complex causes a rapidly fatal necrotizing pneumonia with bacteremia called "cepacia syndrome." Treatment is extremely difficult given intrinsic resistance; options include trimethoprim-sulfamethoxazole, minocycline, and certain cephalosporins, but susceptibility testing is essential. Burkholderia pseudomallei causes melioidosis, a disease endemic to Southeast Asia and Northern Australia. Infection is acquired through environmental exposure (soil, water) through skin inoculation or inhalation. Clinical presentations range from localized skin infection to severe pneumonia and disseminated septicemia with abscess formation in multiple organs. Diabetes mellitus is a major risk factor. Treatment requires prolonged therapy with ceftazidime or meropenem for the intensive phase, followed by trimethoprim-sulfamethoxazole for eradication, typically totaling several months of therapy to prevent relapse. Panel A: Acinetobacter baumannii characteristics and clinical significance showing gram-negative coccobacilli morphology, oxidase-negative reaction distinguishing it from Pseudomonas, hospital environment survival on surfaces, military wound infection association, and increasing resistance patterns (MDR, XDR), with treatment options including ampicillin-sulbactam (unique activity due to sulbactam) and polymyxins for resistant strains. Panel B: Stenotrophomonas maltophilia showing intrinsic carbapenem resistance mechanism (chromosomal metallo-beta-lactamase), clinical settings (CF patients, ICU, malignancy), and treatment with trimethoprim-sulfamethoxazole as drug of choice, with warning that empiric carbapenems will fail against this organism. Panel C: Burkholderia cepacia complex in cystic fibrosis showing patient-to-patient transmission concern requiring strict infection control, severe respiratory decline, cepacia syndrome (rapidly fatal necrotizing pneumonia with septicemia), and treatment challenges with multidrug intrinsic resistance. Panel D: Melioidosis caused by B. pseudomallei showing endemic regions (Southeast Asia, Northern Australia highlighted on map), environmental exposure through soil and water, clinical presentations (pneumonia, skin lesions, abscesses in liver, spleen, and other organs), risk factor of diabetes, and treatment requiring prolonged intensive then eradication phases. --- ### III. Haemophilus influenzae Haemophilus influenzae is a small gram-negative coccobacillus that was historically one of the most important pediatric pathogens, causing meningitis, epiglottitis, and other serious invasive infections in young children. The development and widespread use of the Haemophilus influenzae type b (Hib) conjugate vaccine has dramatically reduced invasive Hib disease, representing one of the great success stories of modern vaccinology. However, non-typeable H. influenzae (NTHi) strains remain important causes of respiratory infections in children and adults. The microbiological characteristics of H. influenzae include its requirement for specific growth factors. The organism requires factor X (hemin, derived from hemoglobin) and factor V (NAD, nicotinamide adenine dinucleotide) for growth. These factors are released by red blood cell lysis, explaining why H. influenzae grows on chocolate agar (heated blood agar that releases these factors) but not on standard blood agar. The organism can also grow on blood agar near colonies of Staphylococcus aureus, which releases NAD, in a phenomenon called satellitism. H. influenzae strains are classified as encapsulated (typeable, serotypes a through f based on capsular polysaccharide) or non-encapsulated (non-typeable, NTHi). Type b (Hib) possesses a capsule composed of polyribosylribitol phosphate (PRP), which is the target of the conjugate vaccine. The virulence of H. influenzae type b is primarily attributable to its polysaccharide capsule, which inhibits phagocytosis and complement-mediated killing, allowing the organism to survive in the bloodstream and cause invasive disease. In the pre-vaccine era, Hib was the leading cause of bacterial meningitis in children under five years of age, with approximately 20,000 cases annually in the United States. It also caused epiglottitis, a life-threatening infection of the epiglottis causing airway obstruction; pneumonia, particularly in young children; septic arthritis and osteomyelitis; and cellulitis, characteristically buccal cellulitis with a violaceous hue. IgA protease cleaves secretory IgA at mucosal surfaces, facilitating colonization. Adhesins including pili and outer membrane proteins mediate attachment to respiratory epithelium. The Hib conjugate vaccine links the PRP capsular polysaccharide to a protein carrier (tetanus toxoid in PRP-T, or outer membrane protein complex in PRP-OMP), converting the T-independent polysaccharide antigen into a T-dependent antigen that induces immunological memory and is effective in infants. Since vaccine introduction in the late 1980s, invasive Hib disease has declined by over 99 percent in countries with high vaccine coverage. This dramatic impact makes Hib disease rare in vaccinated populations, and many current practitioners have never seen a case of Hib meningitis or epiglottitis. Non-typeable H. influenzae, which lacks a capsule and thus is not covered by the Hib vaccine, remains an important cause of respiratory tract infections including acute otitis media (the second most common cause after Streptococcus pneumoniae), acute sinusitis, bronchitis, and acute exacerbations of chronic obstructive pulmonary disease. NTHi also causes conjunctivitis, including the Brazil purpuric fever associated with H. influenzae biogroup aegyptius. Treatment of H. influenzae infections is complicated by beta-lactamase production, present in 30 to 40 percent of isolates. Beta-lactamase-producing strains are resistant to ampicillin and require treatment with ampicillin-sulbactam, amoxicillin-clavulanate, or cephalosporins. For invasive infections including meningitis, third-generation cephalosporins (ceftriaxone, cefotaxime) are the drugs of choice. Panel A: Haemophilus influenzae microbiological characteristics showing small gram-negative coccobacilli, growth factor requirements (X factor = hemin, V factor = NAD), growth on chocolate agar but not blood agar, satellitism around S. aureus colonies on blood agar, and classification into encapsulated (typeable a-f) versus non-encapsulated (NTHi). Panel B: Pre-vaccine Hib disease spectrum showing meningitis in young child (CSF findings), epiglottitis with classic thumbprint sign on lateral neck X-ray and cherry-red swollen epiglottis, buccal cellulitis with violaceous hue, and other invasive infections (septic arthritis, pneumonia, bacteremia), with note about devastating impact before vaccine. Panel C: Hib vaccine mechanism and impact showing PRP capsular polysaccharide conjugated to protein carrier converting T-independent to T-dependent antigen, inducing memory B cells, dramatic graph showing over 99% reduction in invasive Hib disease since vaccine introduction in late 1980s, and current routine childhood immunization schedule. Panel D: Non-typeable H. influenzae (NTHi) disease burden showing otitis media (bulging tympanic membrane), sinusitis, bronchitis and COPD exacerbations, conjunctivitis, noting that NTHi is not covered by Hib vaccine and remains common, with treatment considerations including beta-lactamase testing and appropriate antibiotic selection. --- ### IV. Other Haemophilus and Related Organisms Beyond H. influenzae, several related organisms cause distinctive clinical syndromes. These include H. ducreyi, the cause of chancroid, and the HACEK group of fastidious gram-negative organisms that cause culture-negative endocarditis. Understanding these organisms and their clinical associations enables recognition of specific syndromes and guides appropriate diagnostic testing and treatment. Haemophilus ducreyi causes chancroid, a sexually transmitted infection characterized by painful genital ulcers with tender suppurative inguinal lymphadenopathy (buboes). Unlike the chancre of primary syphilis, which is typically painless, the ulcers of chancroid are painful and have irregular, ragged, undermined edges with a necrotic base. Chancroid is uncommon in the United States but remains endemic in parts of Africa, Asia, and the Caribbean. Transmission occurs through sexual contact with direct inoculation through breaks in the genital epithelium. Buboes may become fluctuant and rupture spontaneously if untreated. Diagnosis is typically clinical, as culture of H. ducreyi is difficult and not routinely available. Treatment with azithromycin as a single dose or ceftriaxone is effective. The HACEK organisms are a group of fastidious gram-negative bacteria that share a propensity to cause infective endocarditis, particularly in individuals with underlying valvular abnormalities. The acronym encompasses Haemophilus species (now reclassified, including Aggregatibacter aphrophilus), Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella species. These organisms are normal inhabitants of the oropharyngeal cavity and may enter the bloodstream following dental procedures or periodontal disease. Because they grow slowly and may require prolonged incubation, they are a classic cause of "culture-negative" endocarditis when blood cultures are held for the standard five days. Extended incubation (two to three weeks) or notification to the laboratory of suspected endocarditis allows for their recovery. HACEK endocarditis typically follows a subacute course similar to viridans streptococcal endocarditis. Treatment with ceftriaxone for four weeks is effective for HACEK endocarditis. Kingella kingae has emerged as an important pathogen in young children, particularly those under five years of age. It is a leading cause of septic arthritis and osteomyelitis in this age group, though its true prevalence was underrecognized before the routine use of molecular diagnostic methods. Infection often follows upper respiratory infection, with the organism colonizing the oropharynx and then disseminating hematogenously. Children typically present with joint pain, limp, or refusal to bear weight. Culture of K. kingae is challenging because the organism is fastidious; inoculation of synovial fluid or bone specimens directly into blood culture bottles improves yield. PCR has significantly improved detection. Treatment with beta-lactam antibiotics is usually effective. Eikenella corrodens is another HACEK organism notable for its association with human bite wounds and clenched-fist injuries (fight bites). It is part of normal oral flora and is introduced into deep tissues when teeth penetrate skin during bites or punches. The organism characteristically pits the agar surface when cultured. Infections often involve mixed flora and may include abscess formation. Eikenella is susceptible to ampicillin and amoxicillin-clavulanate but resistant to clindamycin and first-generation cephalosporins. Panel A: Chancroid caused by H. ducreyi showing painful genital ulcer with irregular undermined edges and necrotic base, contrasted with the painless chancre of syphilis, tender inguinal lymphadenopathy that may become fluctuant (bubo), geographic distribution (endemic in Africa, Asia, Caribbean), and treatment with single-dose azithromycin or ceftriaxone. Panel B: HACEK organisms and endocarditis showing list of organisms (Haemophilus/Aggregatibacter, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella), their origin in oropharyngeal flora, subacute endocarditis presentation, need for prolonged blood culture incubation, and treatment with ceftriaxone for four weeks. Panel C: Kingella kingae in pediatric bone and joint infections showing typical age (less than 5 years), preceding URI with oropharyngeal colonization, hematogenous spread to bones and joints, clinical presentation (limp, joint pain, refusal to bear weight), diagnostic challenges (inoculate into blood culture bottles, use PCR), and treatment with beta-lactam antibiotics. Panel D: Eikenella corrodens and human bite wounds showing oral flora origin, clenched-fist injury mechanism (punch to mouth causing tooth penetration), characteristic pitting of agar on culture, susceptibility pattern (susceptible to amoxicillin-clavulanate, resistant to clindamycin), and wound management approach including surgical debridement and appropriate antibiotics. --- ### V. Vibrio The genus Vibrio comprises curved gram-negative rods associated with aquatic environments and seafood. Several species cause human disease, including Vibrio cholerae (the cause of cholera), Vibrio parahaemolyticus (gastroenteritis from seafood), and Vibrio vulnificus (severe wound infections and septicemia). These organisms share a requirement for salt (halophilic) and association with marine environments. Vibrio cholerae causes cholera, a severe diarrheal disease that has caused seven pandemics throughout history and remains a major cause of morbidity and mortality in regions with inadequate sanitation. V. cholerae is a curved gram-negative rod with a single polar flagellum that provides rapid darting motility. The two serogroups that cause epidemic cholera are O1 (which has two biotypes, classical and El Tor) and O139. Transmission occurs through ingestion of fecally contaminated water or food, particularly shellfish harvested from contaminated waters. The infectious dose is high (10 to the sixth to 10 to the eighth organisms) because stomach acid kills most ingested bacteria, though the dose is reduced in individuals with hypochlorhydria or who consume food that buffers stomach acid. Cholera toxin is the principal virulence factor of V. cholerae and produces the characteristic watery diarrhea. It is an A-B toxin with a pentameric B subunit that binds to GM1 ganglioside on intestinal epithelial cells and an A subunit that ADP-ribosylates the stimulatory G protein Gsα, locking it in the active state. This permanently activates adenylyl cyclase, causing sustained elevation of intracellular cyclic AMP. Elevated cAMP activates the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, causing massive secretion of chloride ions into the intestinal lumen. Sodium and water follow osmotically, producing the profuse watery diarrhea characteristic of cholera. The toxin mechanism is essentially identical to that of the heat-labile toxin (LT) of enterotoxigenic E. coli (ETEC). The clinical presentation of cholera is dramatic and life-threatening. After an incubation period of one to three days, patients develop sudden-onset painless watery diarrhea that rapidly becomes massive, with fluid losses exceeding 20 liters per day in severe cases. The stool has a characteristic "rice water" appearance, consisting of clear fluid with flecks of mucus but no blood or inflammatory cells, reflecting the non-inflammatory, secretory nature of the disease. Without treatment, severe dehydration develops rapidly, causing hypovolemic shock, metabolic acidosis (from bicarbonate loss), hypokalemia (from potassium loss), and death within hours. Treatment centers on aggressive fluid and electrolyte replacement; oral rehydration solution (ORS) is remarkably effective and can be lifesaving even in resource-limited settings. Antibiotics (doxycycline or azithromycin) shorten the duration and volume of diarrhea but are secondary to rehydration. Oral cholera vaccines are available and provide moderate protection. Vibrio parahaemolyticus is a leading cause of seafood-associated gastroenteritis worldwide, particularly from raw or undercooked shellfish (especially oysters). It is halophilic, requiring salt for growth. The illness presents as watery diarrhea with abdominal cramps, sometimes with nausea and vomiting, beginning 12 to 24 hours after consumption. Most cases are self-limited. Vibrio vulnificus causes two distinct clinical syndromes. Primary septicemia occurs in individuals who consume raw oysters contaminated with V. vulnificus, particularly those with underlying liver disease, iron overload (hemochromatosis), or immunocompromise. Patients develop septicemia with characteristic bullous skin lesions and hemorrhagic necrosis; mortality is extremely high (over 50 percent) even with treatment. Wound infections occur when cuts or abrasions are exposed to seawater containing V. vulnificus; these can progress rapidly to necrotizing fasciitis. Treatment requires aggressive surgical debridement and combination antibiotic therapy, typically doxycycline plus a third-generation cephalosporin. Panel A: Vibrio cholerae morphology and transmission showing curved gram-negative rod with single polar flagellum, fecal contamination of water source, shellfish as vehicle, and conditions favoring transmission (inadequate sanitation, natural disasters, overcrowding), with global distribution map showing endemic and outbreak areas. Panel B: Cholera toxin mechanism showing the A-B toxin binding to GM1 ganglioside via the pentameric B subunit, A subunit ADP-ribosylating Gsα, locking adenylyl cyclase in active state, elevated cAMP activating CFTR chloride channel, massive chloride and water secretion into intestinal lumen, resulting in profuse watery diarrhea with rice-water stool appearance. Panel C: Cholera clinical presentation and treatment showing rice-water stool (clear with mucus flecks), severe dehydration signs (sunken eyes, poor skin turgor, weak pulse), metabolic consequences (acidosis, hypokalemia), treatment with oral rehydration solution as cornerstone (composition shown), IV fluids for severe cases, and antibiotics as adjunct (doxycycline, azithromycin). Panel D: V. vulnificus disease showing primary septicemia pathway (raw oyster ingestion, liver disease risk factor) and wound infection pathway (seawater exposure through cut), characteristic bullous hemorrhagic skin lesions, rapid progression to necrotizing fasciitis, high mortality, and treatment requiring surgical debridement plus doxycycline and ceftriaxone combination therapy. --- ### VI. Campylobacter and Helicobacter Campylobacter and Helicobacter are curved or spiral gram-negative bacteria that cause important gastrointestinal diseases. Campylobacter jejuni is the most common cause of bacterial gastroenteritis in developed countries, while Helicobacter pylori causes chronic gastritis, peptic ulcer disease, and is associated with gastric malignancy. Despite sharing curved morphology, these organisms occupy different ecological niches and cause distinct clinical syndromes. Campylobacter jejuni is a slender, curved or S-shaped gram-negative rod with a characteristic gull-wing appearance on Gram stain. It is microaerophilic, requiring reduced oxygen concentration (approximately 5 percent O2 and 10 percent CO2) for growth, and thermophilic, growing optimally at 42 degrees Celsius (which is exploited for selective culture). The primary reservoir is poultry, with undercooked chicken being the most common source of human infection. Contaminated unpasteurized milk, water, and contact with infected animals are additional sources. The infectious dose is relatively low (fewer than 1000 organisms), and person-to-person transmission can occur, particularly in settings of poor hygiene. Campylobacter enteritis presents two to five days after exposure with diarrhea (often bloody), fever, and abdominal cramping. Symptoms may be severe enough to mimic acute appendicitis or inflammatory bowel disease. The illness is typically self-limited, resolving in about one week without treatment. Antibiotic treatment with azithromycin is reserved for severe cases or immunocompromised patients; fluoroquinolone resistance has increased substantially, limiting their usefulness. The most important complication of Campylobacter infection is Guillain-Barre syndrome (GBS), an acute demyelinating polyneuropathy that develops one to three weeks after infection. Molecular mimicry between Campylobacter lipooligosaccharide and gangliosides in peripheral nerve myelin is thought to trigger an autoimmune response. Approximately one in 1000 Campylobacter infections is followed by GBS, and Campylobacter is the most commonly identified antecedent infection in GBS cases. Reactive arthritis is another post-infectious complication. Helicobacter pylori is a spiral gram-negative bacterium that colonizes the gastric mucosa and is the most common chronic bacterial infection in humans, affecting approximately half of the world's population. The organism produces abundant urease, which hydrolyzes urea to ammonia and carbon dioxide, neutralizing stomach acid to create a local alkaline microenvironment that allows survival in the acidic stomach. This urease activity is exploited in diagnostic testing. H. pylori infection causes chronic gastritis, which in most individuals remains asymptomatic but carries long-term consequences. Peptic ulcer disease (both duodenal and gastric ulcers) is strongly associated with H. pylori infection; virtually all duodenal ulcers and most gastric ulcers not attributable to NSAIDs are H. pylori-associated. Eradication of H. pylori dramatically reduces ulcer recurrence. H. pylori is classified as a class I carcinogen due to its association with gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Low-grade MALT lymphoma may regress completely with H. pylori eradication. Diagnosis of H. pylori can be accomplished through invasive tests requiring endoscopy (histology, rapid urease test on biopsy, culture) or non-invasive tests including urea breath test (patient ingests labeled urea; if H. pylori urease is present, labeled CO2 is exhaled and detected), stool antigen testing, and serology. Serology indicates exposure but cannot distinguish active from past infection and should not be used to confirm eradication. Treatment of H. pylori requires combination therapy, as no single antibiotic is effective. Standard regimens include a proton pump inhibitor plus two or three antibiotics (such as clarithromycin, amoxicillin, and/or metronidazole) for 10 to 14 days. Bismuth-containing quadruple therapy is an alternative. Increasing antibiotic resistance, particularly to clarithromycin and metronidazole, has reduced treatment success rates, and local resistance patterns should guide regimen selection. Panel A: Campylobacter jejuni characteristics and epidemiology showing curved or S-shaped gram-negative rods with gull-wing appearance, microaerophilic and thermophilic growth requirements (5% O2, 42 degrees Celsius), poultry as primary reservoir (chicken handling and consumption), and other sources (unpasteurized milk, contaminated water, animal contact). Panel B: Campylobacter enteritis and complications showing clinical presentation (bloody diarrhea, fever, cramping, 2-5 day incubation), self-limited course in most cases, treatment with azithromycin for severe disease, and post-infectious complications with Guillain-Barre syndrome mechanism (molecular mimicry between Campylobacter LOS and nerve gangliosides triggering autoimmune demyelination) and reactive arthritis. Panel C: Helicobacter pylori colonization and pathogenesis showing spiral morphology, urease activity creating alkaline microenvironment for survival in stomach, colonization of gastric mucosa beneath mucus layer, chronic gastritis progression, and associated diseases (peptic ulcer disease, gastric adenocarcinoma, MALT lymphoma), with class I carcinogen designation. Panel D: H. pylori diagnosis and treatment showing non-invasive tests (urea breath test with labeled urea ingestion and CO2 detection, stool antigen) and invasive tests (histology, CLO rapid urease test on biopsy), treatment with triple or quadruple therapy (PPI plus antibiotics such as clarithromycin, amoxicillin, metronidazole), and importance of confirming eradication in ulcer disease. --- ### VII. Bordetella pertussis Bordetella pertussis is the causative agent of pertussis (whooping cough), a highly contagious respiratory infection characterized by severe paroxysmal coughing. Despite the availability of effective vaccines, pertussis remains a significant public health problem due to waning vaccine immunity and suboptimal vaccine coverage. Understanding the unique pathogenesis and clinical phases of pertussis enables recognition of this potentially life-threatening infection, particularly in infants. Bordetella pertussis is a small gram-negative coccobacillus that requires specialized media (Bordet-Gengou or Regan-Lowe agar) for isolation. The organism produces multiple virulence factors that contribute to disease pathogenesis. Pertussis toxin is the signature virulence factor, an A-B toxin that ADP-ribosylates the inhibitory G protein Giα. This modification prevents Gi from inhibiting adenylyl cyclase, resulting in increased intracellular cyclic AMP. The systemic effects of pertussis toxin include lymphocytosis (one of the most striking laboratory findings in pertussis) and sensitization to histamine. Adenylate cyclase toxin (ACT) is a bifunctional toxin that directly enters host cells and produces supraphysiological levels of cAMP, impairing phagocyte function. Tracheal cytotoxin is a peptidoglycan fragment that specifically destroys ciliated epithelial cells, impairing mucociliary clearance and contributing to the prolonged cough. Filamentous hemagglutinin (FHA) and pertactin are surface adhesins that mediate attachment to respiratory epithelium. Pertussis progresses through three clinical phases. The catarrhal phase lasts one to two weeks and presents as a nonspecific upper respiratory infection with rhinorrhea, sneezing, low-grade fever, and mild cough. This phase is highly contagious, but the nonspecific symptoms typically do not prompt consideration of pertussis. The paroxysmal phase lasts two to four weeks (sometimes longer) and is characterized by the distinctive paroxysms of coughing. Paroxysms consist of multiple forceful coughs during a single expiration, followed by a forceful inspiratory effort that produces the characteristic "whoop" as air rushes past a partially closed glottis. Post-tussive vomiting is common. Infants may not whoop but instead may present with coughing episodes followed by apnea or cyanosis. The convalescent phase lasts weeks to months, during which cough gradually subsides but may be triggered by other respiratory infections. Diagnosis of pertussis is optimally made during the catarrhal or early paroxysmal phase when bacterial burden is highest. Nasopharyngeal culture on specialized media can isolate B. pertussis but has low sensitivity, particularly later in illness or after antibiotic initiation. PCR testing of nasopharyngeal specimens is more sensitive and has become the preferred diagnostic method. Direct fluorescent antibody (DFA) testing is rapid but less sensitive and specific. Serologic testing can support the diagnosis retrospectively but is not useful for acute diagnosis. Treatment with macrolide antibiotics (azithromycin, clarithromycin, or erythromycin) is recommended, though antibiotics have limited effect on disease duration if started during the paroxysmal phase; their primary value is reducing transmission. Prophylaxis of close contacts with macrolides is recommended regardless of vaccination status. Prevention relies on vaccination with acellular pertussis vaccines given as DTaP (diphtheria, tetanus, acellular pertussis) in childhood (five doses by age six) and Tdap (tetanus, diphtheria, acellular pertussis) booster for adolescents, adults, and during each pregnancy. Vaccination during pregnancy (ideally between 27 and 36 weeks gestation) allows transfer of maternal antibodies that protect infants during the vulnerable period before they can be vaccinated. Despite vaccination, pertussis continues to circulate because vaccine-induced immunity wanes over time and acellular vaccines may be less effective at preventing transmission than the older whole-cell vaccines. Panel A: Bordetella pertussis characteristics showing small gram-negative coccobacillus, specialized culture media (Bordet-Gengou with pearly colonies), and major virulence factors: pertussis toxin (ADP-ribosylates Giα causing increased cAMP, lymphocytosis), adenylate cyclase toxin (enters cells and generates cAMP, impairs phagocytes), tracheal cytotoxin (destroys ciliated epithelium), and adhesins (FHA, pertactin) for attachment. Panel B: Three phases of pertussis illustrated as timeline: catarrhal phase (1-2 weeks, nonspecific URI symptoms, most contagious), paroxysmal phase (2-4+ weeks, characteristic paroxysms with multiple coughs followed by inspiratory whoop, post-tussive vomiting, infants may have apnea instead of whoop), and convalescent phase (weeks to months, gradually decreasing cough that may be retriggered), with cough frequency graph overlaid. Panel C: Diagnosis and treatment showing nasopharyngeal specimen collection, PCR as preferred diagnostic method (more sensitive than culture), characteristic lymphocytosis on CBC, treatment with macrolides (azithromycin 5 days), noting limited effect on symptoms if started late but reduces transmission, and post-exposure prophylaxis for close contacts. Panel D: Pertussis vaccination strategy showing DTaP schedule in childhood (5 doses by age 6), Tdap booster in adolescence and adulthood, importance of Tdap during pregnancy (27-36 weeks) to provide maternal antibodies protecting infants, concept of cocooning (vaccinating household contacts of newborns), and explanation of ongoing circulation despite vaccination (waning immunity, imperfect prevention of transmission). --- ### VIII. Legionella Legionella pneumophila and related species cause Legionnaires' disease, a severe form of pneumonia, and Pontiac fever, a self-limited febrile illness. Legionella was first recognized following an outbreak of pneumonia at an American Legion convention in Philadelphia in 1976, which gave the organism and disease their names. The unique ecology of Legionella, its intracellular lifestyle, and specific diagnostic and treatment considerations distinguish it from other causes of community-acquired pneumonia. Legionella species are gram-negative rods that stain poorly with the Gram stain due to their lipid-rich cell wall; silver staining or direct fluorescent antibody (DFA) testing provides better visualization. Legionella will not grow on standard microbiological media and requires buffered charcoal yeast extract (BCYE) agar supplemented with L-cysteine and iron for growth. This fastidious growth requirement reflects the organism's intracellular lifestyle and dependence on host cells for specific nutrients. In the environment, Legionella inhabits freshwater sources including cooling towers, air conditioning systems, water heaters, hot tubs, decorative fountains, and hospital water distribution systems. The organism survives within free-living amoebae, which serve as environmental hosts and may enhance virulence. Human infection occurs through inhalation of contaminated aerosols; person-to-person transmission does not occur. Legionella enters the respiratory tract through inhalation of contaminated water droplets and is engulfed by alveolar macrophages. Unlike most bacteria, which are killed within phagolysosomes, Legionella manipulates the host cell to prevent phagosome-lysosome fusion, instead forming a specialized replication vacuole derived from the endoplasmic reticulum. Within this protected niche, Legionella replicates until the cell lyses, releasing bacteria to infect additional macrophages. This intracellular lifestyle has important therapeutic implications: antibiotics that do not penetrate cells, including beta-lactams and aminoglycosides, are ineffective despite in vitro activity. Legionnaires' disease presents as severe community-acquired pneumonia with several characteristic features. Patients are typically older adults with underlying conditions such as smoking, chronic lung disease, or immunocompromise. Clinical features include high fever, cough (initially non-productive, later may produce purulent sputum), dyspnea, and frequently gastrointestinal symptoms (diarrhea, nausea, vomiting) and neurological manifestations (confusion, altered mental status) that distinguish Legionella from other pneumonia causes. Laboratory findings include hyponatremia, which is particularly characteristic and may suggest Legionella when present in a patient with severe pneumonia. Chest radiography shows rapidly progressive infiltrates that may involve multiple lobes. Mortality ranges from 5 to 30 percent depending on patient factors and treatment timeliness. Diagnosis of Legionnaires' disease employs several methods. The urinary antigen test is rapid and highly specific but detects only Legionella pneumophila serogroup 1, which accounts for approximately 80 percent of cases. A positive test is diagnostic, but a negative test does not exclude Legionnaires' disease caused by other serogroups or species. Culture on BCYE agar provides definitive diagnosis and detects all species and serogroups but requires specialized media and extended incubation. PCR testing of respiratory specimens is increasingly available and can detect multiple species. Treatment requires antibiotics that achieve intracellular concentrations, primarily fluoroquinolones (levofloxacin, moxifloxacin) or macrolides (azithromycin); beta-lactams are not effective. Pontiac fever is a milder, self-limited influenza-like illness caused by Legionella that presents with fever, myalgias, and headache but not pneumonia; it resolves spontaneously without specific treatment. Panel A: Legionella characteristics showing gram-negative rods that stain poorly on Gram stain (silver stain demonstration showing organisms better), growth on BCYE agar requiring L-cysteine and iron (comparison with standard blood agar showing no growth), and environmental reservoirs (cooling towers, hospital water systems, hot tubs, decorative fountains) with amoebae serving as hosts. Panel B: Legionella intracellular life cycle showing inhalation of contaminated aerosol, uptake by alveolar macrophage, manipulation of phagosome to prevent lysosomal fusion, formation of replication vacuole derived from ER, bacterial multiplication, cell lysis, and infection of additional macrophages, with note that this intracellular lifestyle makes beta-lactams ineffective. Panel C: Legionnaires' disease clinical presentation and diagnosis showing typical patient (older, smoker, chronic lung disease), clinical features (high fever, pneumonia, GI symptoms, confusion), characteristic hyponatremia on labs, rapidly progressive infiltrates on chest X-ray, diagnostic tests (urinary antigen rapid but only detects serogroup 1, culture on BCYE definitive, PCR increasing), and mortality range. Panel D: Treatment and prevention showing effective antibiotics (fluoroquinolones, macrolides) that achieve intracellular concentrations and ineffective antibiotics (beta-lactams) that cannot reach intracellular bacteria, contrast with Pontiac fever (mild self-limited flu-like illness without pneumonia), and prevention strategies (water system maintenance, temperature control, disinfection in healthcare facilities). --- ### IX. Brucella, Francisella, and Pasteurella Several gram-negative bacteria cause zoonotic infections transmitted from animals to humans. Brucella species cause brucellosis (undulant fever), Francisella tularensis causes tularemia, and Pasteurella multocida causes rapidly progressive soft tissue infections following animal bites. These organisms are acquired through different exposures but share the characteristic of animal reservoirs. Brucella species are small gram-negative coccobacilli that cause brucellosis, one of the most common zoonotic diseases worldwide. Different species have different animal reservoirs: B. melitensis (goats and sheep, most virulent), B. abortus (cattle), B. suis (pigs), and B. canis (dogs). Transmission to humans occurs through consumption of unpasteurized dairy products (particularly cheese and milk), direct contact with infected animals or their secretions (occupational risk for farmers, veterinarians, slaughterhouse workers), or rarely through inhalation of aerosolized organisms. Brucella is a facultative intracellular pathogen that survives within macrophages, leading to granuloma formation in affected organs. Brucellosis, also called undulant fever or Malta fever, presents as a systemic febrile illness with protean manifestations. The incubation period ranges from weeks to months. Patients develop fever that classically has an undulating pattern (rising and falling over days), though this is not consistently observed. Constitutional symptoms include malaise, fatigue, sweating, and weight loss. Arthralgias and frank arthritis (particularly affecting the sacroiliac joint) are common. Hepatosplenomegaly reflects reticuloendothelial system involvement. Complications include endocarditis, neurobrucellosis, and osteomyelitis. Diagnosis is made by blood culture (which may require prolonged incubation) or serologic testing. Because Brucella is highly infectious in the laboratory setting (a CDC select agent), the laboratory should be notified when brucellosis is suspected. Treatment requires combination antibiotic therapy for a prolonged course, typically doxycycline plus streptomycin (or gentamicin) for six weeks. Francisella tularensis causes tularemia, a disease transmitted through tick bites, contact with infected rabbits or other animals, ingestion of contaminated water, or inhalation of aerosolized bacteria. Tularemia presents in several clinical forms depending on the route of inoculation. Ulceroglandular tularemia, the most common form, presents with an ulcer at the site of inoculation (tick bite or animal contact) with regional lymphadenopathy. Glandular tularemia presents with lymphadenopathy without an ulcer. Oculoglandular tularemia results from conjunctival inoculation. Pneumonic tularemia, the most severe form, results from inhalation or hematogenous spread and can be fatal. Due to its high infectivity, potential for aerosol transmission, and severity of pneumonic disease, F. tularensis is classified as a Category A bioterrorism agent. Treatment requires aminoglycosides (streptomycin or gentamicin). Pasteurella multocida is part of the normal oral flora of cats and dogs and causes rapidly progressive cellulitis following animal bites. Within 24 hours of a cat or dog bite (cat bites are more likely to become infected due to their puncture nature), patients develop erythema, swelling, and pain at the bite site, often with purulent drainage. Infection can progress to abscess formation, tenosynovitis, septic arthritis, or osteomyelitis, particularly with deep puncture wounds from cat bites. Bacteremia may develop in immunocompromised patients. Treatment with amoxicillin-clavulanate is effective; prophylaxis following animal bites is controversial but often given for high-risk wounds. Panel A: Brucella and brucellosis showing four species with animal reservoirs (B. melitensis from goats, B. abortus from cattle, B. suis from pigs, B. canis from dogs), transmission routes (unpasteurized dairy products, direct animal contact, inhalation), intracellular survival in macrophages, clinical features (undulant fever, sweats, hepatosplenomegaly, sacroiliitis), and treatment (doxycycline plus aminoglycoside for 6 weeks). Panel B: Tularemia caused by F. tularensis showing transmission (tick bite, rabbit contact, contaminated water, inhalation), clinical forms (ulceroglandular with ulcer at inoculation site plus lymphadenopathy, oculoglandular from eye inoculation, pneumonic from inhalation being most severe), Category A bioterrorism agent designation, and treatment with aminoglycosides. Panel C: Pasteurella multocida and animal bite infections showing the organism as normal oral flora of cats and dogs, rapid onset cellulitis within 24 hours of bite, cat bites more infection-prone due to puncture nature, complications (abscess, tenosynovitis, osteomyelitis), and treatment with amoxicillin-clavulanate. Panel D: Comparison of zoonotic bacteria in summary format: Brucella (dairy and animal contact, systemic illness with undulating fever), Francisella (ticks and rabbits, ulceroglandular most common, pneumonic most dangerous), Pasteurella (cat and dog bites, rapid cellulitis), with key distinguishing features and treatment for each. --- ### X. Other Important Gram-Negative Bacteria Several additional gram-negative bacteria cause distinctive clinical syndromes and warrant recognition. These include Capnocytophaga canimorsus (dog bite sepsis), Bartonella species (cat scratch disease and bacillary angiomatosis), and Gardnerella vaginalis (bacterial vaginosis). Though diverse in their clinical presentations, awareness of these organisms enables appropriate diagnosis and management. Capnocytophaga canimorsus is a gram-negative rod found in the oral flora of dogs and cats that causes severe infection following dog bites or even dog licks on non-intact skin. While most dog bites cause infection with Pasteurella or mixed flora that remains localized, C. canimorsus can cause rapidly fatal septicemia, particularly in patients with asplenia, alcoholism, or immunocompromise. The clinical presentation is dramatic, with high fever, septic shock, disseminated intravascular coagulation (DIC), and gangrene of extremities developing within days of exposure. Mortality exceeds 30 percent even with treatment. The organism is fastidious and may not grow on routine culture media, potentially delaying diagnosis. Treatment is with penicillin or amoxicillin-clavulanate. Patients with asplenia should be counseled about the risk of dog bites and the importance of seeking immediate medical attention if bitten. Bartonella species cause several clinical syndromes depending on the species and host immune status. Bartonella henselae causes cat scratch disease, the most common Bartonella infection, characterized by regional lymphadenopathy developing one to three weeks after a cat scratch or bite. The affected lymph nodes become enlarged and tender, and may suppurate; systemic symptoms including low-grade fever and malaise are common. The infection is self-limited in immunocompetent patients, typically resolving over weeks to months without treatment, though azithromycin may accelerate resolution. In immunocompromised patients, particularly those with AIDS, B. henselae and B. quintana cause bacillary angiomatosis, a vascular proliferative disease producing red papular skin lesions that may resemble Kaposi sarcoma, as well as peliosis hepatis (blood-filled hepatic cysts). Treatment with doxycycline or erythromycin for prolonged courses is required. Bartonella quintana, transmitted by body lice, causes trench fever (recurring fever named for its occurrence among soldiers in World War I). Gardnerella vaginalis is a gram-variable rod (or coccobacillus) associated with bacterial vaginosis (BV), a polymicrobial condition characterized by replacement of normal lactobacilli-dominant vaginal flora with a mixed flora including Gardnerella, anaerobes (Bacteroides, Prevotella, Mobiluncus), and Mycoplasma. The clinical features of BV include thin, grayish vaginal discharge with a characteristic fishy odor that intensifies when alkali (such as KOH) is added (positive whiff test). Examination shows the discharge coating the vaginal walls but without significant inflammation (distinguishing BV from vaginitis). Microscopy reveals clue cells, which are vaginal epithelial cells studded with adherent bacteria that obscure the cell borders. The Amsel criteria (three of four: homogeneous discharge, pH greater than 4.5, positive whiff test, clue cells) or Nugent scoring system on Gram stain can establish the diagnosis. BV is associated with increased risk of preterm labor, pelvic inflammatory disease, and acquisition of sexually transmitted infections including HIV. Treatment is with metronidazole or clindamycin (oral or intravaginal). Panel A: Capnocytophaga canimorsus infection showing dog bite or lick exposure, risk factors (asplenia prominently featured, alcoholism, immunocompromise), fulminant sepsis presentation (high fever, DIC, shock, gangrene of extremities), high mortality rate, fastidious culture growth, and treatment with penicillin or amoxicillin-clavulanate, with warning for asplenic patients about dog bite risks. Panel B: Bartonella species and associated diseases showing B. henselae causing cat scratch disease (cat scratch or bite, regional lymphadenopathy developing over 1-3 weeks, self-limited in immunocompetent, treatment with azithromycin), and bacillary angiomatosis in immunocompromised (vascular proliferative skin lesions, peliosis hepatis, requires prolonged doxycycline treatment), with B. quintana causing trench fever transmitted by body lice. Panel C: Bacterial vaginosis showing polymicrobial etiology (Gardnerella plus anaerobes replacing normal Lactobacillus flora), clinical features (thin grayish discharge, fishy odor, positive whiff test with KOH, no significant inflammation), clue cells on microscopy (epithelial cells with adherent bacteria obscuring borders), Amsel diagnostic criteria, and treatment with metronidazole or clindamycin. Panel D: Comparison of these diverse gram-negative infections summarized: Capnocytophaga (dog bites, fulminant sepsis in asplenic), Bartonella (cat scratch, lymphadenopathy, bacillary angiomatosis in AIDS), Gardnerella (bacterial vaginosis, fishy odor, clue cells), with key clinical pearls for recognition and treatment of each. --- ## Summary - Pseudomonas aeruginosa is an oxidase-positive non-fermenter producing blue-green pigment; causes HAP, CF lung infections, UTI, burns, malignant otitis externa, and ecthyma gangrenosum; requires antipseudomonal antibiotics - Acinetobacter baumannii is oxidase-negative, highly resistant (MDR/XDR common); Stenotrophomonas maltophilia is intrinsically carbapenem-resistant (treat with TMP-SMX); Burkholderia cepacia complex causes severe infection in CF patients - H. influenzae type b caused invasive disease (meningitis, epiglottitis) in children before Hib conjugate vaccine reduced cases by greater than 99%; NTHi causes otitis media, sinusitis, bronchitis - Vibrio cholerae causes profuse watery diarrhea (rice-water stools) through cholera toxin activating cAMP; treatment is rehydration; V. vulnificus causes septicemia and wound infections in liver disease patients - Campylobacter jejuni causes bloody diarrhea from poultry; associated with Guillain-Barre syndrome - H. pylori causes peptic ulcer disease and gastric cancer; diagnosed by urea breath test or stool antigen; treated with triple/quadruple therapy - Bordetella pertussis causes whooping cough in three phases (catarrhal, paroxysmal, convalescent); prevented by DTaP/Tdap vaccines - Legionella causes severe pneumonia from contaminated water sources; diagnosed by urinary antigen; treated with fluoroquinolones or macrolides (not beta-lactams) - Brucella causes undulant fever from dairy/animal contact; Francisella causes tularemia; Pasteurella causes rapid cellulitis from cat/dog bites --- ## Key Terms | Term | Definition | |------|------------| | Non-fermenter | Bacteria that oxidize rather than ferment glucose; typically oxidase-positive (e.g., Pseudomonas, Acinetobacter) | | Pyocyanin | Blue-green pigment produced by P. aeruginosa; generates reactive oxygen species and aids identification | | BCYE agar | Buffered charcoal yeast extract agar; specialized medium required for Legionella culture (needs L-cysteine and iron) | | Cholera toxin | A-B toxin of V. cholerae that ADP-ribosylates Gs, activating adenylyl cyclase and causing secretory diarrhea | | Rice-water stool | Characteristic appearance of cholera stool; clear fluid with mucus flecks, no blood or inflammatory cells | | Whooping cough | Pertussis; characterized by paroxysmal cough with inspiratory whoop and post-tussive vomiting | | Guillain-Barre syndrome | Acute demyelinating polyneuropathy; most commonly associated with preceding Campylobacter infection | | Undulant fever | Brucellosis; named for the classically fluctuating fever pattern; systemic zoonotic illness | | Ulceroglandular | Most common form of tularemia; skin ulcer at inoculation site with regional lymphadenopathy | | Cat scratch disease | Lymphadenitis caused by Bartonella henselae following cat scratch or bite; usually self-limited | | Clue cells | Vaginal epithelial cells coated with bacteria obscuring cell borders; diagnostic of bacterial vaginosis | | Bacillary angiomatosis | Vascular proliferative disease caused by Bartonella in immunocompromised patients; resembles Kaposi sarcoma | --- *This content is subject to the [MIT License](https://opensource.org/licenses/MIT). © 2024–2026 Hibbert School of Medicine.*